Osteoporosis

Mary Beth O’Connell, Jill S. Borchert, Erin M. Slazak, and

Joseph P. Fava

KEY CONCEPTS
1 Osteoporosis is a public health epidemic that affects all
ages, genders, races, and ethnicities. Lifestyle behaviors,
Chapter 112
(T-score between −1.0 and −2.5) and a FRAX 10-year
probability of major osteoporotic fracture of 20% or more or
diseases, and medications should be reviewed to hip fracture of 3% or more. Patients with secondary causes
identify the risk factors for developing osteoporosis and might receive therapy at younger ages or higher T-scores.
osteoporotic fractures. Healthcare professionals should 7 The recommended dietary calcium intake for American
identify and resolve reversible risks. Secondary causes of adults is 1,000 to 1,200 mg of elemental calcium daily with
bone loss should be explored, especially for patients with diet as the preferred source. Supplements are added when
early-onset or severe osteoporosis. diet is insufficient.
2 Bone physiology and pathophysiology are complex 8 The recommended daily dietary vitamin D intake for
involving coupled bone resorption and formation in bone American adults is 600 units and for older adults 800
remodeling processes. These processes result from many units. Some organizations and guidelines recommend
different cell lines, transmitters, pathways, and biofeedback higher doses of at least 800 to 1,000 units daily. Vitamin D
systems. As these processes become more delineated, intake is achieved through sun exposure, fortified foods,
additional targets are identified for medications. and supplements. Vitamin D insufficiency and deficiency,
3 All patients taking medications known to increase bone defined as 25-hydroxyvitamin D (25[OH] vitamin D)
loss, falls, and fractures should practice a bone-healthy concentrations of less than 30 ng/mL (mcg/L; 75 nmol/L)
lifestyle, be evaluated for a switch to a safer alternative and less than 20 ng/mL (mcg/L; 50 nmol/L) respectively, are
medication, and/or be considered for osteoporosis common in Americans. Higher vitamin D daily intakes and/
therapy. The most common causes of medication-induced or replenishment doses are then required.
osteoporosis are long-term oral glucocorticoids and certain 9 Alendronate, risedronate, zoledronic acid, and denosumab
chemotherapeutic agents. decrease vertebral, hip, and nonvertebral fractures and
4 Ten-year probabilities for a major osteoporotic and hip are first-line osteoporosis treatments for those with high
fracture can be estimated for women (postmenopausal to fracture risk. Therapy continues for about 5 years in mild
90 years old) and men (50-90 years old) with the fracture osteoporosis and 5 to 10 years in moderate-to-severe
risk assessment tool (FRAX) tool. This tool is a questionnaire osteoporosis. Other antiresorptive (ibandronate, raloxifene),
that can be used in any setting, including pharmacies, anabolic (abaloparatide, teriparatide), and combination
health fairs, and clinics. Central bone mass densitometry can anabolic and antiresorptive (romosozumab) medications
determine bone mass, predict fracture risk, and influence are alternatives. These medications decrease osteoporotic
patient and provider treatment decisions. fracture risk but not hip fractures. In patients with very
5 Throughout life, everyone should practice a bone-healthy high fracture risk, sequential therapy with abaloparatide,
lifestyle, which emphasizes regular exercise, nutritious diet, romosozumab, or teriparatide followed by an antiresorptive
tobacco avoidance, minimal alcohol use, and fall prevention agent is recommended.
to prevent and treat osteoporosis. Adherence to osteoporosis medications is suboptimal.
6 Treatment should be considered for postmenopausal Poor adherence is associated with less fracture prevention.
women and men older than 50 years who have a low- Healthcare professionals should assess medication
trauma hip or vertebral fracture, T-score of −2.5 or less administration technique and adherence at each visit, provide
at the femoral neck, total hip, or spine, or low bone mass education, and resolve medication-related problems.

BEYOND THE BOOK

Create a team of three classmates. Each team member selects one of the below patients to workup. This activity is useful to enhance
your understanding of the COLLECT, ASSESS, and PLAN steps in the patient care process, the osteoporosis treatment algorithm, and
individualization of patient care.
In your patient workup:

• Identify osteoporosis risks and secondary causes.

• Calculate a FRAX score (https://www.sheffield.ac.uk/FRAX/).

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• Estimate calcium intake (https://www.osteoporosis.foundation/educational-hub/topic/calcium-calculator).

• Determine the calcium and vitamin D Institute of Medicine recommended daily intakes and deficits.
• Develop a prevention or treatment plan.
• Present your patient’s risk factors, assessments, and treatment plan to each other.
• Compare and contrast these three women’s cases and treatment plans.
SECTION     Rheumatologic Disorders

Patient 1: A 57-year-old White, nonsmoking woman living in the United States. Patient’s weight is 77 kg and height is 5 ft 6 in
(168 cm). She has had no previous fractures and has no family history of fracture. Her T-scores are femoral neck -2.2 and spine -2.0.
She has hypertension, hyperlipidemia, and GERD. The patient’s current medications are omeprazole (Prilosec), atorvastatin (Lipitor),
and amlodipine (Norvasc). The patient reports no vitamins or supplements. The patient drinks 1 glass of milk daily and eats 1 serving
of yogurt daily. She does not drink alcohol.
14 Patient 2: A 67-year-old Hispanic woman living in the United States. Patient’s weight is 77 kg and height is 5 ft 6 in (168 cm).
She has had no previous fractures but her mother had a hip fracture. Her T-scores are femoral neck -2.4 and spine -2.0. She has
hypertension, diabetes type 2, and hyperlipidemia. The patient’s current medications are canagliflozin (Invokana), atorvastatin
(Lipitor), and enalapril (Vasotec). The patient reports taking Centrum(R) Silver(R) Women’s 50+ every day. Social history: the patient
drinks 1 glass of milk daily and eats 1 serving of yogurt daily. She smokes tobacco products but does not drink alcohol.
Patient 3: A 77-year-old Asian woman living in the United States. Patient’s weight is 77 kg and height is 5 ft 6 in (168 cm). She
has had no previous fractures and no family history of fracture. Her T-scores are femoral neck -2.6 and spine -2.9. She has diabetes
type 2, rheumatoid arthritis, hypertension, and lactose intolerance. The patient’s current medications are metformin (Glucophage),
lisinopril (Prinivil), adalimumab (Humira), and celecoxib (Celebrex) as needed. Prior to adalimumab, she had used prednisone 5 to
10 mg daily for over 5 years. The patient uses no vitamins or supplements. The patient drinks 1 glass of fortified soy milk daily and eats
1 serving of tofu daily. She does not drink alcohol or smoke.

disparities.3,4 The prevalence of osteoporosis in women is 16.5%.4

INTRODUCTION Low bone density was estimated to occur in 45% of non-Hispanic
1 Osteoporosis is a bone disorder characterized by low bone den- White, 43% of Mexican American, and 30% of non-Hispanic Black
sity, impaired bone architecture, and compromised bone strength women aged 50 years and older.3,5 Osteoporosis affects 13.4% of
that predisposes a person to increased fracture risk. Osteoporosis is Mexican American, 10.2% of non-Hispanic White, and 4.9% of non-
a major public health threat, with about 50% of people 50 years of Hispanic Black women aged 50 years and older. Disease prevalence
age and older expected to develop this disease.1 In the United States, greatly increases with age; from 7% in women aged 50 to 59 years to
10.2 million Americans are estimated to have osteoporosis.2 An 35% in women aged 80 years and older.4 White American (17%) and
additional 43.4 million Americans are estimated to have low bone Hispanic American (14%) women have the highest fragility fracture
density and are at risk for osteoporosis. Attention to bone health is rate followed by Black American (6%) women.
required throughout life. Osteoporosis and osteoporotic fractures are Although more prevalent in women, men can also have low
multifactorial conditions, beginning at birth with genetics and con- bone density and osteoporosis. Based on FRAX estimates, approxi-
tinuing throughout life due to health behaviors that influence bone mately 16% of men aged 50 years and older have low bone density
growth and maintenance, skeletal factors that lead to compromised rising to 46% in men aged 80 years and older.6 Osteoporosis rises
bone strength, and nonskeletal factors that lead to falls (Fig. 112-1). from 3% in men aged 50 to 59 years to 11% in men aged 80 years
Healthcare professionals should educate people about bone-healthy and older.5 Osteoporosis prevalence also varies by race and ethnic-
lifestyles and empower them to practice these health behaviors. ity in men: 6% in Mexican American, 4% in non-Hispanic White
Osteoporosis is underdiagnosed and undertreated. Bone health American, and 1% in non-Hispanic Black American men.3,5
screenings, osteoporosis prevention programs, accurate diagnoses, Fragility wrist and vertebral fractures are common through-
and optimal medication management are needed to prevent and out adulthood, with hip fractures more common in older adults.
treat osteoporosis and prevent fractures. Although osteoporosis is common in adults with fractures, 12% of
Editors’ note: In this and other chapters in Pharmacotherapy, fracture patients have normal BMD and 52% have low bone density,
references to biologic sex (as assigned at birth) are used based on supporting fractures can occur in all.7
prior literature being discussed or anatomical or physiologic dif- Gender differences in osteoporotic fractures exist with 70%
ferences. We recognize that not all individuals later identify with occurring in women and 30% in men.2 As a woman ages, her
their sex at birth, and to the degree possible when discussing thera- risk of any fracture increases from 10% at age 50 years to 22% at
peutics, we avoid use of references to gender. In this chapter on 80 years old; with hip fractures increasing from 0.3% to 9% over the
Osteoporosis, “men” and “women” are used in discussing prior stud- same time frame.8 For men over the same time frame, fracture risk
ies, published guidelines, and other recommendations for diagnosis increases from 7% to 8% and hip fracture increases from 0.2% to 3%.
and treatment based on biological sex and do not necessarily reflect Fracture outcomes are worse for people of color.3
an individual’s gender identity. Osteoporosis creates an economic health burden. In 2011,
1.7 million hospitalizations occurred for fragility fractures with 3 mil-
lion osteoporotic fractures expected in 2025.9 By 2025, osteoporosis
EPIDEMIOLOGY treatment costs are estimated to be about $25 billion.2 Because of asso-
1 Low bone density, osteoporosis, and osteoporotic fractures are ciated morbidity, hip fracture is the most costly complication of osteo-
common in all people, with race and ethnic differences in osteo- porosis, accounting for almost 72% of fracture costs. Osteoporosis
porosis detection, treatment and outcomes likely due to health costs exceed costs for breast cancer, heart attack, or stroke.

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• Bone mineral density (BMD): Categorize lowest T-score as

normal, low bone mass, or osteoporosis
• FRAX 10-year risk of major osteoporotic fractures and hip

CHAPTER        Osteoporosis
fracture
• Laboratory data and presence of secondary causes (see
Tables 112-2 and 112-3)
• Patient preferences including injectable medications and
concern about adverse effects
• Potential barriers to adherence (eg, administration route, 112
frequency, cost, health literacy)

Plan
• Medication regimen including specific agent, dose, route,
frequency, and duration (see Fig. 112-3, Tables 112-7
and 112-8), and calcium and vitamin D supplements as
necessary
Patient Care Process for Osteoporosis • Monitoring parameters including efficacy (eg, BMD, fracture,
25(OH)-vitamin D concentration) and safety (eg, common
The image shows the five fundamental steps included in and serious adverse effects, serum creatinine, calcium).
The Pharmacist’s Care Process endorsed by the Joint Include frequency and timing of follow-up
Commission for Pharmacy Practitioners (2014). The
tagline of this process reads collaborate, communicate,
and document. The five fundamental steps listed here are Implement*
collect, assess, plan, implement, and follow-up: monitor • Provide patient education regarding treatment plan (eg,
and evaluate. All these steps are listed in a circular block purpose of treatment, dietary calcium sources, medication-
diagram. specific administration/injection technique in patient’s
primary language, adverse effects) (see Tables 112-7 and
Collect 112-8)
• Patient characteristics (eg, age, sex, race, ethnicity, • Consider risk communication tool to explain medication
postmenopausal status) benefit and rare adverse effects
• Medical history (personal and family; eg, maximum • Schedule laboratory tests as needed and DXA (generally
height, falls, fractures, dental issues, gastroesophageal 2-5 years after initiation)
reflux/heartburn, and for women age at menarche and • Schedule referrals when appropriate (eg, physical therapist
menopause) for fall prevention, dietitian)
• Social history (eg, tobacco and alcohol use, physical activity, • For zoledronic acid, coordinate with infusion center for
and dietary habits, including calcium-containing food and administration
beverage intake) • For nongeneric therapies, coordinate prior authorization
• Current medications including calcium and vitamin D, process as necessary
dietary supplements, multivitamins, and herbal
product use
• Past medications (eg, hormone therapy and medications Follow-up: Monitor and Evaluate*
causing osteoporosis; see Table 112-3) • Patient adherence to treatment plan and administration
• Objective data instructions
oo Height, weight • Presence of adverse effects (see Table 112-8)
oo Laboratory results (see Table 112-4) and secondary • BMD, fractures, falls, and laboratory parameters
causes • Changes in habits (eg, dietary calcium, exercise, alcohol, and
oo Central dual-energy x-ray absorptiometry (DXA) at the tobacco use)
spine and hip • Re-evaluate duration of therapy after 1 year (romosozumab),
oo Fracture evidence (eg, vertebral fracture assessment 2 years (abaloparatide, teriparatide), 3 years (intravenous
[VFA], radiographs) bisphosphonate), 5 years (oral bisphosphonate),
or as suggested by response to therapy and adverse
Assess effects
• Adequacy of dietary calcium and calcium/vitamin D
supplement intakes *Collaborate with patient, caregivers, and other healthcare professionals.

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• Genetics
• Diet
• Lifestyle
• Hormonal status
• Diseases
SECTION     Rheumatologic Disorders

• Medications

14 Aging Bone loss Suboptimal

peak bone mass

Skeletal factors— Skeletal factors—

impaired bone quality decreased bone density

Non-skeletal factors
(↑ fall risk) Reduced bone strength

Low trauma fractures

FIGURE 112-1 Etiology of osteoporosis and osteoporotic fractures.

BMD.9 Changes in bone mass do not fully reflect changes in bone

ETIOLOGY thinning and decreased connectivity, both related to strength.
1 Figure 112-1 depicts a model describing osteoporosis and frac- BMD explains only 70% of femur and 44% of spine bone strength.
ture etiology. The major risk factors (see Table 112-1) influencing Even women with normal bone mass (3.4%) and low bone mass
bone loss are hormonal status, genetics, exercise, aging, nutrition, (5.3%) fracture, rates slightly lower than women with osteopo-
lifestyle, concomitant diseases, and medications. Nonhormonal risk rotic bone mass (6.8%). Accelerated bone turnover can increase
factors are similar between women and men. the amount of immature bone that is not adequately mineral-
ized. Sex differences exist with thinning of trabeculae, with aging
in men causing less bone quality damage and impaired bone
Low Bone Density strength than in women.12 With aging, fracture risk increases for
BMD is a major predictor of fracture risk. Every standard deviation a given T-score, partly related to bone quality changes; for exam-
decrease in BMD in women represents a 10% decrease in bone mass ple, at a T-score of −2.5, a 50-year-old postmenopausal woman
and a 1.6- to 2.6-fold increase in fracture risk.2 In contrast, increasing has about a 4% probability of a hip fracture, whereas a 70-year-
peak bone mass in younger years by 10% was estimated to create 13 old woman has about a 9% probability.23
more years without a fracture in older women.16 Low BMD can occur
as a result of failure to reach a normal peak bone mass, bone loss, or Falls
both. Genetics accounts for 50% to 85% of peak bone mass variability.4,14 Each year, 15% to 45% of community-dwelling older adults and up
Bone loss occurs when bone resorption exceeds bone formation, which to 60% of nursing home residents fall, with more women falling than
also can result from high bone turnover when the number or depth of men.4,24 Hip fractures only occurred in 1% to 2% of falls; however,
bone resorption sites greatly exceeds the rate and ability of osteoblasts to 90% of hip fractures resulted from a fall.8,25 Falls lead to accidental
form new bone. Women and men begin to lose a small amount of bone death in about 70% of older adults.24 Inpatient and outpatient fall
mass starting in the third to fourth decade of life, about 0.5% to 1% per care is expensive.24 The risk factors for falls overlap with the risk fac-
year.12,14 During perimenopause and menopause, bone loss occurs pre- tors for osteoporosis and osteoporotic fractures.2,24 Environmental
dominantly due to increases in bone resorption. By age 80 years, 30% of factors also contribute to falls (eg, electric cords, throw rugs, and
a woman’s bone mass is lost.4 Older adults steadily lose bone mass as a poor lighting).
consequence of an accelerated rate of bone remodeling combined with
reduced bone formation.
PATHOPHYSIOLOGY
Impaired Bone Quality Normal Bone Physiology
Bone strength is highly affected by the quality of the bone’s com- 2 The skeleton has two types of bone. Cortical bone makes up the
position and its structure and is a better predictor of fracture than majority of the skeleton (80%) and is found mostly in the long bones

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TABLE 112-1  Risk Factors for Osteoporosis and TABLE 112-2  Select Medical Conditions Associated
Osteoporotic Fractures with Osteoporosis in Children and Adults
Low bone mineral density (BMD)a Endocrine/Hormonal
Female sexa Primary or secondary ovarian failure
Advanced agea Testosterone deficiency

CHAPTER        Osteoporosis
Race/ethnicitya Hyperthyroidism
History of a previous fragility (low-trauma) fracture including radiographic Cushing’s syndrome (hypercortisolism)
vertebral fracture as an adulta (especially clinical vertebral fracture or Growth hormone deficiency (in children)
hip fracture)
Hyperparathyroidism
Osteoporotic fracture in a first-degree relative (especially parental hip
fracturea) Diabetes, type 1 and type 2
Gastrointestinal
Low body weight or body mass indexa
112
Premature menopauseb Nutritional disorders (eg, anorexia nervosa)
Secondary osteoporosisa,b Malabsorptive states (eg, Crohn’s disease, celiac disease, cystic fibrosis,
gastrectomy, and bariatric surgery)
Rheumatoid arthritis a

Chronic liver disease (eg, primary biliary cirrhosis)

Past or present systemic oral glucocorticoid therapy (prednisolone 5 mg
daily or more for >3 months)a,c Disorders of Calcium Balance
Current smokinga,c Hypercalciuria
Alcohol intake of 2 or more drinks/day a,c Calcium and or vitamin D deficiency
Low calcium intake Inflammatory Disorders
Low physical activity or immobilization Rheumatoid arthritis
Vitamin D insufficiency and deficiency Chronic Illness
Recent falls Chronic kidney disease
Cognitive impairment Malignancies (eg, multiple myeloma, lymphoma, and leukemia)
Impaired vision Human immunodeficiency virus infection/acquired immunodeficiency
syndrome
a
Factors included in World Health Organization fracture risk assessment tool (FRAX).
Organ transplant
b
Secondary causes included in the FRAX tool are type 1 diabetes, osteogenesis
imperfecta as an adult, long-standing untreated hyperthyroidism, hypogonadism, Disuse/Immobility
premature menopause, chronic malnutrition, malabsorption, and chronic liver Immobilization
disease.
Muscular dystrophy
Risk is higher with greater exposure.
c

Data from References 2, 4, and 10-13. Multiple sclerosis

Stroke/cerebrovascular accident
Genetic
Osteogenesis imperfecta
(eg, forearm and hip).14 Trabecular bone is found mostly in the ver- Cystic fibrosis
tebrae and ends of long bones. This bone type is metabolically more
Hemochromatosis
active compared with cortical bone due to a much higher bone turn-
over rate because of its large surface area and honeycomb-like shape. Hypophosphatasia
Bone is made of collagen and mineral components.9,14 The col- Data from References 2, 4, and 10-16.
lagen component gives bone its flexibility and energy-absorbing
capability. The mineral component (mostly calcium and phospho-
rus), which accounts for 50% to 70% of bone mass, gives bone its
stiffness and strength. The correct balance of these substances is Within these sections, the bone remodeling activities of bone resorp-
needed for bone to adequately accommodate stress and strain and tion and bone formation are coupled and balanced. Bone remodel-
resist fractures. Imbalances can impair bone quality and lead to ing is triggered to repair microdamage to the skeleton and serves
reduced bone strength. to support calcium homeostasis by maintaining a normal serum
Bone strength reflects the integration of bone mass, bone calcium, releasing calcium from the bone into the blood stream as
strength and quality (composition and microarchitecture).9,16 Bone needed. Within an active bone remodeling unit, osteoclasts (bone
mass increases rapidly throughout childhood and adolescence. Peak resorbing cells) work to resorb bone during the resorptive phase,
bone mass is attained by age 18 to 25 years. Peak bone mass is highly then this process reverses and osteoblasts (bone-forming cells) work
dependent on genetic factors, which accounts for 60% to 80% of the to form bone during the formation phase. Osteoblasts then become
variability. The remaining 20% to 40% is influenced by modifiable incorporated into the bone matrix as osteocytes or cover the surface
factors such as nutritional intake (eg, calcium, vitamin D, and pro- as lining cells, both with bone-communication activities. The unit
tein), exercise, adverse lifestyle practices (eg, smoking), hormonal then becomes inactive and enters a quiescent phase. If remodeling
status, and certain diseases and medications (see Tables 112-2 becomes unbalanced and bone resorption surpasses bone forma-
and 112-3). Optimizing peak bone mass is important for prevent- tion or if the phases become uncoupled and bone resorption occurs
ing osteoporosis. The higher the peak bone mass, the more bone a without adequate formation, a decrease in BMD results. Osteocytes
person can lose before being at an increased fracture risk. As the and lining cells play key roles in the process and can trigger a new
microarchitecture of bone deteriorates, the bone strength greatly remodeling cycle.
decreases. Three schemas show the overview and molecu-
Bone remodeling is a dynamic process that occurs continuously lar level details of the bone remodeling cycle. Schema (A)
throughout life (see Fig. 112-2A-C).14,17 One to two million tiny sec- on the top gives the overview of remodeling process with the six
tions of bone are in the process of remodeling at any given time. steps involved in bone remodeling: Step 1 = initiation, Step 2 and

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TABLE 112-3  Select Medications Associated with β ligand (RANKL), interleukins 1 and 6 (IL-1, IL-6), macrophage
Increased Bone Loss and/or Fracture Risk colony stimulating factor (m-CSF), parathyroid hormone (PTH),
parathyroid-releasing protein (PTHrP), 1,25(OH) vitamin D, tis-
Medications Comments
sue growth factor-β (TGF-β), prostaglandin E2 (PGE2), insulin-like
Antiseizure therapy ↓ BMD and ↑ fracture risk; increased
growth factor (IGF), sclerostin, integrins, platelet-derived growth
(phenytoin, carbamazepine, vitamin D metabolism leading
phenobarbital, and valproic to low 25(OH) vitamin D factor, bone morphometric proteins (BMP), fibroblast growth factor
acid) concentrations (FGF), and tumor necrosis factor-α (TNF-α).
SECTION     Rheumatologic Disorders

Aromatase inhibitors (eg, ↓ BMD and ↑ fracture risk; reduced The signaling of the bone remodeling cycle through the steps
letrozole and anastrozole) estrogen concentrations from resorption through quiescence is highly complex.14,17 Many
Calcineurin inhibitors (eg, ↓ BMD and ↑ fracture risk; increase cytokines, growth factors, and hormones influence each step. The
cyclosporine and tacrolimus) osteoclast activity complete physiology of bone remodeling is not fully known but
Glucocorticoids (long-term oral ↓ BMD and ↑ fracture risk; appears to begin with signals from lining cells or osteocytes that are
14 therapy) increased bone resorption and
decreased bone formation, and
triggered by stress, microfractures, biofeedback systems responsive
to cytokines and growth factors and potentially certain diseases and
decreased calcium absorption
and reabsorption; dose and
medications (see Fig. 112-2B, step 1). A major stimulus for hema-
duration dependent; see “Special topoietic stem cell differentiation to become mature osteoclasts is
Populations” section the receptor activator of nuclear factor kappa β ligand (RANKL),
Gonadotropin-releasing ↓ BMD and ↑ fracture risk; decreased which is a cytokine emitted from osteoblasts or osteocytes in step 2.
hormone agonists (eg, sex hormone production IL-1, IL-6, m-CSF, PTH through RUNX2/cbfa1, PTHrP, 1,25(OH)
leuprolide and goserelin) or vitamin D, TGF-β, PGE2 IGF, sclerostin, and TNF-α stimulate
analogs (ganirelix)
RANKL release, whereas estrogen and calcitonin inhibit RANKL
Heparin (unfractionated, UFH) or ↓ BMD and ↑ fracture risk (UFH >>> release. RUNX2/cbfa1 also inhibit osteoprotegerin. The RANKL
low molecular weight heparin LMWH) with long-term use (eg,
then binds to the receptor activator of nuclear factor kappa β
(LMWH) >6 months); decreased osteoblast
replication and increased (RANK) on the surface of osteoclast precursors initiating differen-
osteoclast function tiation. The RANKL also stimulates mature osteoclast activation and
Loop diuretics (eg, furosemide) ↑ fracture risk; increased calcium bone adherence via αvβ3 integrins to resorb bone (step 3). This step
renal elimination is influenced by TGF-β, IGF 1 and 2, platelet-derived growth fac-
Medroxyprogesterone acetate ↓ BMD, fracture risk unknown; tor, BMP, and FGF. After bone attachment, the osteoclasts secrete
depot administration possible BMD recovery with hydrogen and chloride ions and proteinases, such as cathepsin K,
discontinuation; decreased collagenase, gelatinase, tartrate-resistant acid phosphate isoenzyme
estrogen concentrations
5 (TRACP5b), and matrix metalloproteases (MMP) to dissolve the
Nucleoside/nucleotide reverse ↓ BMD, fracture risk unknown; mineralized bone. Hydrogen ion production is under nonrecep-
transcriptase inhibitors (NRTIs) greater risk when combined with
(tenofovir disoproxil fumarate pharmacological boosters
tor tyrosine kinase (Src) control, which needs to be bound to other
> other NRTIs) compounds such as E3 ubiquitin ligase (Cbl), focal adhesion kinase
Proton pump inhibitor therapy ↓ BMD and ↑ fracture risk; possible
(FAK), and phosphatidylinositol 3-kinase (Pl3K).
(long-term therapy) calcium malabsorption secondary After bone is resorbed and a cavity is created, osteoclasts
to acid suppression for calcium produce cytokines and growth factors to elicit osteoblast differen-
carbonate salts tiation from mesenchymal stem cells, maturation, and activity (step
Selective serotonin reuptake ↓ BMD and ↑ fracture risk; decreased 4).14,17 Osteoblast differentiation can be inhibited by PPARγ, which
inhibitors osteoblast activity directs mesenchymal cell maturation to adipocytes instead of osteo-
Sodium glucose cotransporter ↓ BMD and ↑ fracture risk; alteration blasts. However, leptin produced by adipocytes can stimulate bone
2 (SGLT2) inhibitors in calcium and phosphate formation. Mature osteoblasts and osteocytes produce osteopro-
(canagliflozin; class effect homeostasis; increased bone
uncertain) resorption
tegerin (OPG) that binds to RANKL, thereby stopping bone resorp-
tion. Leucine-rich repeat-containing G protein (LGR4) also binds
Thiazolidinediones (pioglitazone ↓ BMD and ↑ fracture risk; decreased
and rosiglitazone) osteoblast function
RANKL and stops resorption.
The process of bone formation is complicated (see
Thyroid—excessive ↓ BMD and ↑ fracture risk associated
supplementation with suppressed serum TSH; Fig. 112-2C).14,17 First, wingless tail ligands (Wnt) bind to low-
possible increase in bone density lipoprotein receptor–related protein 5 or 6 (LRP5/6) and a
resorption frizzled coreceptor. Wnt binding is influenced by PTH and PTHrP,
Vitamin A—excessive chronic ↓ BMD and ↑ fracture risk; decreased which fit into the same receptor PTH1R, IGF-1, and irisin, which is
intake (>10,000 units of osteoblast activity and increased increased during exercise. Next, LRP5/6 binds to disheveled cyto-
retinol form) osteoclast activity plasmic protein (DSH), which then binds to axin. Axin now cannot
BMD, bone mineral density; TSH, thyroid-stimulating hormone. bind to glycogen synthase kinase-3β (GSK-3β), thereby preventing
Data from References 2, 14, and 17-22. degradation of β-catenin by casein kinase 1α (Csk1α) (step 5). Irisin
also increases β-catenin. Accumulated β-catenin then enters the
nucleus and binds to T-cell-specific transcription factor 4/lymphoid
enhancer factor 1 (TCF/LEF). This complex signals target genes to
create proteins to fill the resorption cavity with osteoid. Growth
3 = resorption, Step 4 =reversal, Step 5 = formation, and Step 6 = hormone and IGF-1 also increase bone collagen production. Next
quiescence. The schema (B) in the middle gives the molecular mineralization of bone with calcium, magnesium, and phosphorus
level detail of major pathways during bone resorption (mainly steps follows to give the new matrix strength.
2 and 3). The schema (C) at the bottom gives the molecular level Once the cavity is mineralized, bone formation can be
detail of major pathways during bone formation (mainly steps 4 stopped through multiple signaling processes.14,17 Secreted friz-
and 5). Hence, steps 2 to 5 are also points of osteoporosis medica- zled-related proteins (sFRP) or Wnt inhibitory factor 1 (WIF1)
tion targets. A mature osteoclast is formed from hematopoietic stem can bind to Wnt, preventing it from binding to LRP 5/6. Both
cell under the action of receptor activator of nuclear factor kappa sclerostin and Dickkopf-1 (Dkk-1 or Kremen) are secreted from

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Hematopoietic
stem cell
Mesenchymal
stem cell

CHAPTER        Osteoporosis
Osteoblast 2 Osteoclast
precursor precursor
cell cell
3
112
4

1 5

6
Osteoclast
Osteoclast
Lining cells

Osteoblasts

Osteocytes
Resorption Reversal Formation Quiescence

Initiation

Bone resorption
Hematopoietic
m-CSF stem cell

Sclerostin IGF-1
RANKL

RANK
PTH
fal
Cb

Osteoblast Mature
osteoclast
LGRY
OPG TRAF – 6
CbI
NF – κβ
Src
PI3K
Osteocyte
FAK
αvβ3 MMP
OPG integrins
H+
H H+ CI– TRACP5b
+ Cathepsin K
NCP, collagen,
H+ H+ CI– other
Ca++, Mg++, Phos
CI– enzymes
B

FIGURE 112-2 (Continued)

osteocytes and bind to LRP5/6, which also prevents Wnt from Quiescence is the phase when bone is at rest until another
binding with LRP 5/6. Axin can then bind to adenomatous pol- remodeling cycle is initiated.14,17 Later, osteocytes can trigger ini-
yposis coli (APC), Csk1α, and GSK-3β, which then can cause tiation of a new remodeling cycle through secretion of sclerostin
β-catenin degradation, osteoblast apoptosis, and the end of or RANKL to stimulate osteoclasts and bone resorption.
osteoblastic activity (step 6). The mature osteoblasts can become Hormones can influence the remodeling steps. Estrogen has
lining cells or osteocytes. many positive effects on the bone remodeling process in people of

CH112.indd 1529 06-12-2022 14:51:42

 1530
Parathyroid
gland
Mesenchymal IGF-1 PTH Bone formation
cell inhibition
PTH or PTHrP
PPARγ Wnt PTHIR
Osteocyte
BMP H
PT
RunX2
SECTION     Rheumatologic Disorders

Adipocyte Cbfa1 Irisin

L e p ti WISE

n
Bone Wnt
formation Osteoblast
differentiation Sclerostin
Wnt WIFI
DKK-1
Irisin
14
LRP k LRP
PTH 5/6
5/6 r
e
m
FZD DSH
PTHrP e
Axin n
DSH

Axin APC
Irisin
GSK-3β β-catenin
F GSK-3β CSK1α
/LE

β-catenin
TCF

degradation
Nucleus Target
Cytoplasm genes
No target
Osteoblast genes
C

FIGURE 112-2 Bone remodeling cycle. (A) Overview of remodeling process, Step 1 = initiation, Steps 2 and 3 = resorption, Step 4 =
reversal, Step 5 = formation, and Step 6 = quiescence. (B) Molecular level detail of major pathways during bone resorption steps 2 and
3, which also showcase osteoporosis medication targets. (C) Molecular level detail of major pathways during bone formation steps 4
and 5, which also showcase osteoporosis medication targets.14,17 (APC, adenomatous polyposis coli; BMP, bone morphogenetic protein;
Ca++, elemental calcium; cbfa1, core-binding factor alpha 1; Cbl, E3 ubiquitin ligase; Cl−, chloride ion; Csk1α, casein kinase 1α Dkk-1,
Dickkoff1; DSH, disheveled cytoplasmic protein; FAK, focal adhesion kinase; GSK-3β, glycogen synthase kinase-3β; H+, hydrogen ion;
IGF-1, insulin-like growth factor 1; LGR4, leucine-rich repeat-containing G protein; LRP5/6, lipoprotein-receptor–related protein 5 or 6;
m-CSF, macrophage-colony-stimulating factors; Mg++, magnesium; MMP, matrix metalloproteinases; NF-kβ, nuclear factor kappa beta;
NCP, noncollagenous proteins; OPG, osteoprotegerin; Phos, phosphorous; Pl3K, phosphatidylinositol 3-kinase; PPARγ, peroxisome
proliferator-activated receptor; PTH, parathyroid hormone; PTH1R, PTH and PTHrP receptor; PTHrP, parathyroid hormone-related
protein; RANK, receptor activator of nuclear factor-kβ; RANKL, receptor activator of nuclear factor-kβ ligand; RunX2, runt-related
transcription factor; Scr, nonreceptor tyrosine kinase; sFRP, secreted frizzled-related proteins; TCF/LEF, T cell specific transcription
factor 4/lymphoid enhancer factor 1; TRACP 5b, tartrate-resistant acid phosphate isoenzyme 5; TRAF-6, tumor necrosis factor receptor
associated factor 6; WIFI, Wnt inhibitory factor 1; WISE, Wnt modulator insurface ectoderm; Wnt, wingless tail ligands.)

both genders. Most of estrogen’s actions help to maintain a nor- is also secreted that increases vitamin D metabolism to 25(OH)
mal bone resorption rate.26 Estrogen suppresses the proliferation vitamin D.
and differentiation of osteoclasts and increases osteoclast apopto- Bone physiology has many genomic and genetic influences.
sis. Estrogen decreases the production of several cytokines that are Isolating one or a few genes for correction will unlikely resolve the
potent stimulators of osteoclasts, including IL-6, IL-7, IL-17, TNF-α, problems in an aging population for whom osteoporosis is a com-
and m-CSF, and increases IL-4, IL-10, TGF-β, and TGF-α, which mon problem.16 Genetic mutations do result in bone disorders such
increases osteoclast apoptosis. Estrogen also decreases RANKL and as osteoporosis, osteogenesis imperfecta, and juvenile idiopathic
increases OPG to reduce osteoclastogenesis. osteoporosis. Heredity is important since family history, especially
Most of testosterone’s bone effects relate to its metabolism to of a hip fracture in a parent, is a strong risk factor for osteoporosis
estradiol and the above estrogen bone effects; however, testoster- development and fracture.
one does have some direct and indirect effects on osteoblasts.13,27 At least 56 loci have been identified that influence BMD and
Testosterone increases osteoblast proliferation and differentia- 14 loci for fracture risk, ranging from impacts on bone resorp-
tion directly via the androgen receptor, and indirectly by increas- tion (RANKL, OPG) to formation (Wnt, LRP5, and sclerostin).28,29
ing TGF-β, IGF-2, and decreasing IL-6 stimulation of osteoclasts. Calcium, vitamin D, and estrogen receptors are also under genetic
Testosterone also increases muscle strength, which can decrease falls influence. Studies are conflicting as to whether an association exists
leading to fractures. Leydig cells secrete insulin-like factor 3 (INSL3) between response to currently available antifracture medications
that stimulates relaxin family peptide receptor 2 (RXFP2) thereby and genetic profiles. Genetic modulation is in its infancy for osteo-
increasing osteoblast and osteocyte functions.13 A 25-hydroxylase porosis prevention and treatment, but epigenomics and gene editing

CH112.indd 1530 06-12-2022 14:51:42

 1531
might lead to the creation of new medications and/or the ability to RANKL and less OPG. Loss of estrogen also increases calcium excre-
tailor medication choices to an individual’s genetic profile.29 tion and decreases calcium gut absorption through decreases in
TRPV6 activity and 1,25(OH) vitamin D binding proteins. Estrogen
Calcium Homeostasis, Vitamin D, and deficiency can also be seen in other settings such as anorexia ner-
Parathyroid Hormone vosa and lactation, and from medications, such as prolonged depot
medroxyprogesterone acetate implants, aromatase inhibitors, and
2 Calcium homeostasis is maintained by vitamin D and PTH,

CHAPTER        Osteoporosis
gonadotropin releasing hormone agonists.
which influence calcium gastrointestinal (GI) absorption and renal Accelerated bone loss of both mass and strength begins during
reabsorption. Calcium absorption under normal conditions is perimenopause (1-5 years premenopause) and continues up to 10
approximately 30% and is improved with vitamin D sufficiency.30,31 years after menopause due to increased bone resorption that exceeds
Calcium absorption is lower in the winter due to decreased expo- bone formation.2 During this time, increased bone loss can be as
sure to required ultraviolet light that converts cholesterol in the high as 2% per year, with total BMD loss due to menopause about
skin to vitamin D. Absorption is reported to be higher in obesity,
which is associated with greater vitamin D storage. Calcium absorp-
10% to 12%.4 About 30% of peak bone mass is lost by the age of 80 112
years. Bone strength decreases by about 2.5% per year.9 The num-
tion is predominantly an active rate-limited process in the duode- ber of remodeling sites increases, and resorption pits are deeper and
num and jejunum, which is controlled by many hormones, such inadequately filled by normal osteoblastic function. During meno-
as 1,25-dihydroxyvitamin D (1,25[OH] vitamin D), estrogen, and pause, trabecular bone is most susceptible, leading predominantly to
transient receptor potential cation channel subfamily V member vertebral and wrist fractures. Initially, women with early menopause
6 (TRPV6). A calcium transporter (calmodulin or calbindin) is (ie, before the age of 40 years) due to natural or induced causes have
required to bring calcium from the gut into the tissue wall and then lower BMD than matched premenopausal women. After the age of
across the enterocyte. Calcium is extruded into the circulation via 70 years, risk for fractures and low bone density becomes the same
calcium (Ca++) adenosine triphosphatase (ATPase) and the sodium- between the groups.
calcium exchanger. Throughout the intestine, paracellular passive
calcium diffusion occurs. This diffusion accounts for less than 15%
of absorbed calcium, is not rate limited, and possibility is sensitive Male Osteoporosis
to 1,25(OH) vitamin D. Solvent drag plays a minor role in calcium 2 Men lose about 0.8% of bone mass per year after the age of 60
absorption. years and 20% experience hypogonadism in their older adult years.12
When the calcium-sensing receptor on parathyroid cells detects Men are at a lower risk for developing osteoporosis and osteopo-
low serum calcium, PTH production increases. PTH then directly rotic fractures because of larger bone size, greater peak bone mass
(minimal effect) and indirectly (predominant effect via increasing and connectivity, increase in bone width with aging, fewer falls, and
calcitriol production) causes calcium reabsorption by the kidney.30,32 shorter life expectancy. With aging, sex hormone binding globulin
Calcium reabsorption increases as 25(OH) vitamin D concentra- increases, which results in less free testosterone and thereby less
tions increase, plateauing around 10 to 15 ng/mL (mcg/L; 25-37 testosterone available for conversion to estrogen. Estrogen inhibits
nmol/L). Loop diuretics decrease, and thiazide diuretics increase bone resorption in men; however, androgen deficiency increases
calcium resorption in the kidney. RANKL release and bone resorption. Mortality rate after a fracture
Sometimes, the increased fractional calcium absorption is is greater for men (19.5%) than women (12.5%).
insufficient to maintain normal serum calcium, requiring bone Male osteoporosis results from aging or secondary causes (see
resorption for correction.30,31 Consistent and high concentrations of Tables 112-2 and 112-3).12,13,27 The most common risk factors for
PTH and calcitriol increase RANKL and decrease OPG, resulting in men are smoking, alcohol abuse, low body weight, weight loss, age,
increased osteoclast activity, which releases calcium from bone to long-term glucocorticoid use, androgen deprivation therapy, and
restore calcium homeostasis. Of note, low PTH concentrations for a low testosterone concentrations. Medical conditions and medica-
short time (eg, teriparatide) increase bone formation. tions that cause hypogonadism can increase bone loss. Although
Active 1,25(OH) vitamin D concentrations depend on skin many causes and serious fracture outcomes, osteoporosis is under-
conversion, dietary and supplemental intake, and PTH control.30,32 diagnosed in men.
The sun’s ultraviolet B rays convert 7-dehydrocholesterol in the
skin to cholecalciferol (vitamin D3), which is the most abundant Age-Related Osteoporosis
vitamin D source. A few foods contain ergocalciferol (vitamin D2). 2 Age-related bone mass and strength loss begin after peak bone
Supplements and multivitamins contain cholecalciferol or ergocal- mass is reached.16 About 0.5%-1% of BMD is loss each year after
ciferol. Subsequent conversion of cholecalciferol and ergocalciferol the age of 30 years in men and until menopause for women.4 Bone
to 25-hydroxyvitamin D (25[OH] vitamin D; calcidiol) occurs in loss accelerates to 2% for 1 to 3 years before and 5 to 10 years post
the liver, and then, PTH stimulates conversion of 25(OH) vitamin D menopause before returning to normal aging bone loss.4 After the
via 25(OH) vitamin D-1α-hydroxylase (CYP27B1) to its final active age of 60 years, bone loss for both sexes is 1% to 1.5% per year.8
form, 1,25-dihydroxyvitamin D (calcitriol; 1,25[OH] vitamin D), Age-related osteoporosis occurs in older adults because of acceler-
in the kidney. Calcitriol binds to the intestinal vitamin D receptor ated bone turnover rate and reduced osteoblast bone formation.23,90
(VDR) and then increases the action of calcium-binding proteins These bone changes occur from hormone deficiencies; calcium and
calmodulin and calbindin. As a result, the intestinal absorption of vitamin D deficiencies due to changes in intake, absorption, and
calcium and phosphorus is increased. The feedback system is com- metabolism; decreased production or function of cytokines or other
pleted with CYP27B1 activity inhibited by adequate calcium and bone biochemicals; decreased molecular signaling; increase in redox
phosphorus, and FGF23 inhibiting PTH synthesis. status and free radical formation; increase in adipocytes; decreased
body water; telomere shortening; and less exercise. Fracture risk for
Postmenopausal Osteoporosis a given BMD value increases with aging.8 For example, at a T-score
2 Estrogen deficiency causes significant bone density loss and of -2.5, a 50-year-old postmenopausal woman has about a 4% prob-
compromises bone architecture.4,26,66 Estrogen deficiency increases ability of a hip fracture, whereas a 70-year-old woman has about a
proliferation, differentiation, and activation of new osteoclasts and 9% probability.23 Hip fracture risk rises dramatically in older adults
prolongs survival of mature osteoclasts. Interleukins 7 and 17, TNF- because of the cumulative loss of cortical and trabecular bone and an
α, and interferon γ increase and TGF-β decreases resulting in more increased risk for falls.

CH112.indd 1531 06-12-2022 14:51:42

 1532
Sarcopenia increases with aging with risk factors similar to TABLE 112-4 Clinical Presentation of Osteoporosis
osteoporosis.14 The decrease in muscle strength and function results
General
in weakness and balance instability leading to a greater likelihood • Many patients are unaware they have osteoporosis until testing or
of falls and fractures. Falls accounted for 87% of fractures in older fracture.
adults. • Fractures can occur after bending, lifting, or falling, or independent of
any activity.
Illness-Induced Secondary Causes of Symptoms
SECTION     Rheumatologic Disorders

• Frequently asymptomatic
Osteoporosis • Pain
1 2 A secondary medical cause of osteoporosis is common (see • Immobility
• Depression, fear, and low self-esteem from physical limitations and
Table 112-2). Symptoms, laboratory test results, certain diseases and
deformities
medications, and/or a decreased Z-score from a DXA can suggest a
Signs
secondary cause, warranting a more comprehensive workup.
14 • Shortened stature (>1.5 in. [4 cm] loss from maximum height; >0.8 in.
[2 cm] loss in 1 year), kyphosis, or lordosis
Medication-Induced Secondary Causes of • Fragility (low-trauma) vertebral, hip, wrist, or forearm fracture
Osteoporosis Laboratory tests
• Routine tests: comprehensive metabolic profile (creatinine, calcium,
1 3 Medication-related reductions in BMD and associated frac- phosphorous, electrolytes, alkaline phosphatase, and albumin), 25(OH)
tures are a common secondary cause of osteoporosis. Table 112-3 vitamin D, thyroid-stimulating hormone, complete blood count, total
lists select medications associated with bone loss and/or fracture testosterone (for men), and 24-hour urine calcium and creatinine
risk as well as the proposed mechanisms of bone loss.18-22 Alternative concentrations
• Bone turnover markers (eg, serum NTX, serum CTX, and serum PINP) are
medications should be used when possible, with consideration given sometimes used, especially to determine if high bone turnover exists
to patients’ individual risk and baseline BMD status. When these • Additional testing if the patient’s history, physical examination, or initial
medications cannot be avoided, periodic re-assessment of benefits laboratory and or diagnostic tests suggest a specific secondary cause
and risks should be performed, as reversal of bone loss might be (eg, intact parathyroid hormone, free testosterone, serum parathyroid,
possible upon discontinuation of some of these medications. Two of and celiac panel)
the most common causes of medication-induced osteoporosis, glu- Other diagnostic tests
• Spine and hip bone density measurement using central dual-energy
cocorticoids, and certain cancer chemotherapies are discussed later
x-ray absorptiometry (DXA)
in this chapter. • Vertebral fracture assessment (VFA) with DXA technology
• Radiograph ordered for other reasons that shows low bone density
CLINICAL PRESENTATION • Radiograph to confirm fracture
• Balance and mobility tests
Table 112-4 outlines the clinical presentation of osteoporosis. CTX, C-terminal crosslinking telopeptide of type 1 collagen; NTX, N-terminal
Osteoporosis is a silent disease, frequently not detected until a frac- crosslinking telopeptide of type 1 collagen; PINP, procollagen type 1 N-terminal
ture is experienced or noticed on x-ray. Many vertebral fractures are propeptide.
asymptomatic, with patients sometimes attributing mild back pain to Data from References 2, 4, 6, 10, 21, 33, and 34.
other factors, such as advanced age or work. Some new vertebral frac-
tures present with moderate-to-severe back pain that can radiate down
the leg. The pain usually subsides after 2 to 4 weeks; however, residual Wrist fractures occur more commonly in younger postmeno-
chronic back pain can persist. Multiple vertebral fractures decrease pausal women and are frequently a result of a fall on an outstretched
height and sometimes curve the spine (kyphosis or lordosis). Patients hand. Although they cause less disability than other fracture sites,
with a nonvertebral fracture frequently present with severe pain, swell- negative outcomes include prolonged pain and weakness, and dif-
ing, and reduced function and mobility at the fracture site. ficulty with activities such as meal preparation, using a keyboard,
and lifting at work.
Consequences of Osteoporosis Once a low-trauma fracture has occurred, the risk for subse-
Osteoporosis can lead to fragility/low-trauma fractures defined as quent fractures goes up exponentially.8 Vertebral fractures, even if
fracture that occurs as a result of a fall from standing height or less or asymptomatic, are a major predictor of a future fracture with up to
with minimal to no trauma.2 Fractures of the vertebrae, hip, forearm, a five- to seven-fold increase in future vertebral fractures and an
and humerus are considered major osteoporotic fractures, whereas increased risk at other sites.4 Patients with a hip fracture have a 2%
other fractures are generally not considered osteoporosis-related. to 10% chance of a second hip fracture.4
Osteoporotic fractures can lead to increased morbidity and mortality
and decreased quality of life. Pain and physical deformity are com- Patient Assessment
mon, and these changes can lead to other health consequences.4 For Laboratory tests and other assessments are described in Table 112-4.
example, severe kyphosis can lead to respiratory problems as a result Height should be measured annually using a wall-mounted stadiom-
of compression of the thoracic region and GI complications such eter. Low bone density (sometimes called osteopenia) reported on
as poor nutrition from intra-abdominal compression. Depression is routine radiographs is a sign of significant bone loss and requires fur-
common because of fear of falling/fracture, pain, loss of self-esteem ther evaluation for osteoporosis. Additional tests will be required that
from physical deformity, and loss of independence and mobility are specific to potential secondary causes (Tables 112-2 and 112-3).
after fracture. In addition to physical examination and laboratory tests, patients
Hip fractures are associated with the greatest increase in mor- can be assessed with risk factor assessment tools, osteoporosis qual-
bidity and mortality. After a hip fracture, 40% of patients have ity of life questionnaires, peripheral and central DXA, ultrasonogra-
mobility limitations, 50% no longer can live independently or phy, and bone turnover markers (BTM).
require long-term care (25%), and about 12% to 20% die within the
year from complications of the hip fracture or other comorbid dis- Risk Factor Assessment
ease processes.2,8 Men have a higher 1-year mortality rate after hip The aim of an initial osteoporosis risk assessment screening is to
fracture than women.12 People of color have greater morbidity and identify those patients who are at risk for osteoporosis and osteopo-
mortality after a fracture than non-Hispanic White people.3 rotic fractures (see Table 112-1) and/or would benefit from further

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 1533
evaluation or pharmacologic intervention. The most commonly include DXA, quantitative computed tomography (QCT), digital
used assessment is the fracture risk assessment (FRAX) tool2; the x-ray radiogrammetry, and radiographic absorptiometry. Central
Garvan tool35 is another option. DXA is the most widely used technique and preferred for making
4 The FRAX tool was created to be used for screening and therapeutic decisions.37 It has high precision, short scan times, low-
diagnosis.2 It can be used without DXA results; however, estimates radiation dose (comparable to the average daily dose from natural
improve when T-scores are available. This tool uses 11 risk factors: background), and stable calibration. Measurements of lumbar spine,

CHAPTER        Osteoporosis
age, race/ethnicity, sex, previous fracture, parent history of hip femoral neck, and total hip BMD are recommended with the low-
fracture, body mass index, glucocorticoid use (current use or past est BMD value used for diagnosis. The forearm (distal third of the
use for three or more months of the equivalent of at least 5 mg of radius) can be used as an alternative if the preferred areas cannot
prednisolone daily), current smoking, alcohol use of three or more be scanned.2,4,34,37 Trabecular bone score (TBS) is a newer technol-
drinks per day, rheumatoid arthritis, and select secondary causes of ogy available on some densitometers that can provide measurements
osteoporosis (see Table 112-1); with optional entry for femoral neck of bone quality and microarchitecture. Low TBS is independently
BMD (g/cm2 or T-score). The FRAX tool calculates an individual’s associated with increased fractures and can be used in combination 112
percent probability of any major osteoporotic fracture and hip frac- with BMD and FRAX scores to better identify those at increased
ture in the next 10 years. Each country establishes cut-off points fracture risk.
for fracture risk treatment decisions. For the United States, they are Several consensus guidelines and position statements are con-
20% or higher for major osteoporotic fracture and 3% or higher for sistent in recommending central BMD testing for all women aged 65
hip fracture. Most guidelines use these universal cutoffs, but oth- years or older, men aged 70 years or older, postmenopausal women
ers are beginning to recommend age-adjusted FRAX cutoffs to pre- younger than 65 years and men 50 to 69 years old with risk factors
vent undertreatment of younger people and overtreatment of older for fracture, and patients with an identified secondary cause for bone
people or create a middle zone in which BMD would be needed to loss.2,4,12,37 The US Preventive Services Task Force (USPSTF) provides
determine treatment.34 For example, for a 55-year-old person, a 10% similar recommendations for screening in women 65 years or older
10-year risk of major osteoporotic fracture would be used, and for and in women under the age of 65 years with additional risk factors
an 80-year-old person, 30% would be used. For postmenopausal as determined by a clinical risk assessment tool, such as FRAX.36 This
women younger than 65 years, a 10-year major osteoporotic frac- group, however, has concluded that current data are insufficient to
ture risk of greater than 8.4% would result in a referral for a cen- make recommendations for screening in men. Patients with a fragil-
tral DXA.2,36 Some important risk factors for fracture, for example, ity fracture do not need a DXA for an osteoporosis diagnosis, but the
falls, multiple fractures, recent fracture, or other common secondary results are helpful for determining the severity of osteoporosis and as
causes, are not accommodated in the FRAX model. a baseline for monitoring response to therapy.2 The DXA results can
The Garvan calculator uses four risk factors (age, sex, low- also help patients make decisions about the need for lifestyle changes
trauma fracture, and falls) with the option to also use BMD.2,6,35 It and prescription osteoporosis medications. In the absence of a sus-
calculates 5- and 10-year risk estimates of any osteoporotic/fragility pected or known secondary cause for osteoporosis or a history of a
fracture and hip fracture. This tool corrects some disadvantages of low-trauma fracture, central BMD testing is not recommended for
the FRAX tool since it includes falls and number of previous frac- children,15 women,38 or men younger than 50 years.13
tures, but it does not use as many other risk factors. A central DXA BMD report provides the actual bone density
value (in g/cm2), T-score, and Z-score.37 The T-score is used for diag-
Screening Using Peripheral Bone Mineral Density nosis and is a comparison of the patient’s BMD to the mean BMD of
Devices a healthy, young (20-29 year olds), and sex-matched White reference
Peripheral bone density devices that use DXA (pDXA) or quantita- population. It is not adjusted for age, race, or ethnicity. The T-score
tive ultrasonography (QUS) are helpful as screening tools to deter- is the number of standard deviations from the mean of the reference
mine which patients require further evaluation with central DXA population.37 The Z-score is similar but compares the patient’s BMD
or for decision making if central DXA testing is not available.2,36,37 to the mean BMD for a healthy sex- and age-matched population.
Peripheral DXA of the forearm, heel, or finger uses a low amount of The patient’s race and ethnicity should be used for the Z-score if
radiation and requires personnel with special training. Quantitative available. The Z-score is sometimes helpful in determining whether
ultrasonography at the heel and other peripheral sites uses sound a secondary cause for osteoporosis is present and is used for diag-
waves without radiation, and specially trained personnel are not nosis (value ≤ −2.0) in children, premenopausal women, and men
needed. The heel is the only skeletal site at which QUS has been vali- younger than 50 years. The actual bone density value is most useful
dated.37 The QUS has better fracture predictive value than pDXA and for serial monitoring of therapy response. Follow-up BMD is rec-
has demonstrated the ability to predict fractures in postmenopausal ommended every 1 to 3 years by some guidelines,2,4 although other
women and in men 65 years of age or older. The specific peripheral guidelines recommend every 5 years in postmenopausal women.1,34
T-score threshold for referral is not universally defined and varies by The DXA results after medication initiation need to be above the
device. These tests should not be used for diagnosis or for monitor- machine’s least significant change to be clinically relevant. For
ing response to therapy.37 patients with normal bone density or those in the upper range of low
Peripheral devices are considerably less expensive than central bone mass, time between follow-up scans can be lengthened. Most
DXA, easy to use, portable, fast (less than 5 minutes), and can pre- insurance carriers, including Medicare, cover BMD testing every
dict general fracture risk. They are popular for screening patients at 2 years.
health fairs and community pharmacies. Patients already identified Using the spine DXA image, a VFA can be performed to assess for
as being at high risk for osteoporosis based on risk factors, fragility vertebral fractures that might otherwise go undetected.2,4,37 Each verte-
fracture, or secondary causes for osteoporosis should be referred for bra is visually evaluated for fracture and fractures are assessed for sever-
central DXA testing. ity. This result becomes important for treatment decisions in patients
with low bone mass. Because many vertebral fractures are asymptom-
Central Dual-Energy X-Ray Absorptiometry atic, VFA is recommended for those at high risk of an undiagnosed
4 BMD measurements at the hip or spine can be used to assess vertebral fracture. This includes patients with a T-score less than −1.0
fracture risk, establish the diagnosis and severity of osteoporo- when one or more of the following criteria are also present: women aged
sis, and confirm osteoporosis following a low-trauma fracture.2,34 at least 70 years or men aged at least 80 years; a historical height loss
Multiple techniques are available for measurement of BMD and of more than 1.5 in. (4 cm); a self-reported but undocumented prior

CH112.indd 1533 06-12-2022 14:51:42

 1534
vertebral fracture; or patients on glucocorticoid therapy (≥5 mg pred- treatment is a bone-healthy lifestyle. Supplements and medica-
nisone or equivalent daily for 3 months or more). tions are used when lifestyle habits are insufficient or suboptimal,
osteoporosis has developed, and/or a low-trauma fracture occurs.
Laboratory Tests Guidelines and position statements recommend considering pre-
Routine laboratory testing (see Table 112-4) is used for initial bone scription therapy in any postmenopausal woman or man aged 50
health assessment.2,4,10,12,15 To evaluate secondary causes, additional years and older presenting with one of the following scenarios: a hip
testing is conducted, which will be specific to the suspected second- or vertebral fracture; T-score of −2.5 or lower at the femoral neck,
SECTION     Rheumatologic Disorders

ary cause. total hip, or spine; or low bone mass (T-score between −1.0 and
−2.5 at the femoral neck, total hip, or spine) with a FRAX 10-year
Bone Turnover Markers probability of hip fracture of 3% or more or any major osteoporosis-
BTM are commonly used in clinical trials and sometimes in clinical related fracture of 20% or more. Figure 112-3 provides an osteopo-
practice.2,4 They can be used to assess bone pathophysiology, predict rosis management algorithm for postmenopausal women and men
14 fracture risk, monitor response to osteoporosis medications, evalu- aged 50 years and older that incorporates both nonpharmacologic
ate medication adherence, and determine the need for restarting and pharmacologic approaches.
bisphosphonates after a drug holiday. Although many BTMs exist,
serum carboxyterminal propeptide of type-I collagen (PINP) and Nonpharmacologic Therapy
bone-specific alkaline phosphatase (BSAP) are the preferred bone 5 Nonpharmacologic therapy, referred to as a bone-healthy life-
formation markers, and serum C-terminal telopeptide type-1 col- style, includes proper nutrition, moderation of alcohol intake, smok-
lagen (CTX) is the preferred bone resorption marker. Response to ing cessation, exercise, and fall prevention. A bone-healthy lifestyle
osteoporosis therapy can be measured with BTMs as early as 2 to that is employed early in life will help to optimize peak bone mass,
3 months; however, monitoring is usually done 3 to 6 months after and if continued throughout life, it will minimize bone loss over
osteoporosis medication initiation. Goal values would be at or below time. A bone-healthy lifestyle not only maintains or increases BMD
median premenopausal concentrations for antiresorptive medica- but it also helps decrease falls and fragility fractures.
tions and significant increase for formation medications.2 Circadian
variability, seasonal variations, food intake, recent exercise, some Diet
diseases and conditions, and assay variability can affect results and 5 Overall, a diet well balanced in nutrients and minerals with lim-
decrease utility in clinical practice. Fasting morning samples should ited salt, alcohol, and caffeine use are important for bone health.
be obtained with repeat tests done at the same facility with the same Adequate amounts of calcium and vitamin D have documented
assay to decrease interassay variability. Of note, fractures increase impacts on bone health. Protein is required for bone, thus the rec-
BTMs for a short time frame. These tests can be expensive with ommended dietary allowances (RDAs) of 0.8 g/kg body weight per
coverage varying by health insurance plan. As an alternative, bone- day is recommended for adults increasing to 1 to 1.2 g/kg body
specific alkaline phosphatase can be used, which is usually covered. weight in older adults and to 1.5 g/kg body weight for some chronic
illnesses.8 Magnesium, boron, and vitamin K have a physiologic role
Diagnosis of Osteoporosis in bone development and maintenance but either no or insufficient
6 The diagnosis of osteoporosis is based on a low-trauma fracture data exist to establish them independently as supplemental agents
or femoral neck, total hip and/or spine DXA using World Health for prevention and treatment of osteoporosis. Some of these agents
Organization (WHO) T-score thresholds.2 Low bone mass (preferred are included in calcium combination products and are found in mul-
term) or osteopenia is a T-score between –1 and –2.5, and osteoporosis tivitamins. Strontium ranelate has documented positive bone effects
is a T-score at or below –2.5. Although these definitions are based on and is marketed in Europe for prevention of osteoporosis.
data from postmenopausal white women, they are also applied to peri- Eating disorders are associated with increased bone loss and
menopausal women, men aged 50 years and older, and adults from dif- fractures.11,15 Being thin or having anorexia nervosa are well known
ferent races and ethnicities. The diagnosis of osteoporosis in children,15 to decrease bone mass. In the past, obesity was thought protec-
premenopausal women,11 and men under 50 years of age13 should be tive due to increased estrogen production and stimulation of bone
based on a Z-score at or less than –2.0 in combination with other risk remodeling due to weight bearing; however, emerging literature sug-
factors or fracture. Without a history of clinically significant fracture, gests adipocytes have negative impacts on bone health.
children, premenopausal women, and men are given a diagnosis of
bone mass below the expected range for age. Calcium
5 7 Adequate calcium intake is necessary for calcium homeo-
stasis throughout life, bone development during growth, and
PREVENTION AND TREATMENT bone maintenance thereafter. The Institute of Medicine (IOM)
Desired Outcomes recommended calcium intakes are based on age and gender
(Table 112-5).2,34,39 These values represent the average daily amount
The primary goal of osteoporosis care should be prevention.
needed to meet requirements for 97% to 98% of healthy people.
Optimizing skeletal development and peak bone mass accrual in
Higher intakes might be needed when concomitant diseases and
childhood, adolescence, and early adulthood will ultimately reduce
medications known to negatively affect calcium and vitamin D
the future incidence of osteoporosis. Once low bone mass or osteo-
homeostasis exist. Ingesting calcium-containing and/or calcium-
porosis develops, the objective is to improve or stabilize bone mass
fortified foods and beverages is the preferred method to achieve daily
and strength, and prevent fractures. In patients who have already
calcium requirements. Dairy products generally have the highest
suffered osteoporotic fractures, reducing pain and deformity,
amount of calcium per serving and are available in low-fat options.
improving functional capacity, improving quality of life, and reduc-
Some food sources result in good calcium absorption but have low
ing future falls and fractures are the main goals.
elemental calcium content (eg, broccoli). Carbohydrates increase
General Approach to Prevention and calcium absorption, whereas phylates (eg, beans, seeds, wheat bran)
and oxalates (eg, spinach and rhubarb) decrease absorption.6,35
Treatment People should be encouraged to evaluate their food and bever-
5 6 A bone-healthy lifestyle should begin at birth and continue age intake to determine if they are receiving adequate amounts of
throughout life. The foundation of osteoporosis prevention and calcium. To calculate the amount of calcium in a serving of food,

CH112.indd 1534 06-12-2022 14:51:42

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CHAPTER        Osteoporosis
112

FIG. 112-3 aaMajor clinical risk factors for fracture: advanced age, current smoker, low body weight or body mass index, personal
history of fracture as an adult (after age 50 years), history of osteoporosis/low trauma fracture in a first-degree relative, excessive
alcohol intake.
b
Some providers use age adjusted FRAX thresholds versus set thresholds for all age groups.
c
Fragility fracture is high risk for ES guidelines, and very high risk for AACE/ACE guideline.
d
Bone-healthy lifestyle includes well-balanced diet with adequate calcium, vitamin D, and protein intakes; smoking cessation; limited
alcohol intake; weight-bearing/resistance exercises; and fall prevention.
e
Dietary calcium preferred. If diet is inadequate, supplement as necessary.
f
Higher vitamin D doses might be needed to achieve 25(OH) vitamin D concentrations >30 ng/mL.
g
Some increased BMD effects will be seen for women using menopausal hormonal therapy and for men using testosterone for
hypogonadism. For women and men on hormonal therapy and at high risk or very high risk for osteoporotic fractures, an osteoporosis
medication will also be prescribed, creating a case for combination therapy.
h
Raloxifene option for postmenopausal women < 60 years old with low hip fracture, stroke, and venous thromboembolic risk and high
breast cancer risk.
i
Restart therapy when BMD goes below T-score ≤-2.5 or a fracture; alternative is to use raloxifene or denosumab, or in some cases a
bone formation medication during the drug holiday.
jDo not use romosozumab in patients with at high risk for or past myocardial infarction and/or stroke.
(BMD, bone mineral density; CEE, conjugated equine estrogens, DXA, dual-energy x-ray absorptiometry, FRAX = World Health
Organization fracture risk assessment tool)
Data from references 1,3,7,42, and 43

consumers can add a zero to the percent of the daily value listed on Native Americans (79%), African Americans (75%), and Hispanic
food labels. For example, a serving of milk (8 oz. [~240 mL]) has Americans (51%) are higher than in White Americans (21%).41
30% of the daily value of calcium. This translates to 300-mg calcium Patients with lactose-intolerance have several options to increase
per serving. Websites can be used to identify foods and beverages dietary calcium intake, including products containing lactase
high in calcium.31 (Lactaid®), lactose-reduced milk, lactose-free milk, calcium-fortified
Although many foods and beverages are high in calcium, the milk alternatives (eg, soy and almond milk), certain aged cheeses,
average daily dietary calcium intake is insufficient in many chil- or yogurt with active cultures along with other nondairy calcium-
dren and adults.31 In addition, lactose intolerance limits dietary fortified products (eg, orange juice, breakfast cereals, and energy
calcium intake. The incidence in Asian Americans (15%-100%), bars). Vegan diets sometimes have insufficient calcium intake, but

CH112.indd 1535 06-12-2022 14:51:43

 1536
TABLE 112-5  Calcium and Vitamin D Recommended antagonist effects throughout the body. Isoflavones are found in soy
Dietary Allowances (RDAs) and Tolerable products, lignans in seeds, berries, and grains, and coumestans in
Upper Intake Levels (ULs) peas, beans, broccoli, and alfalfa sprouts. Genistein and daidzein
are biologically active isoflavones found in soybeans. Isoflavones,
Calcium Vitamin D
Tolerable Tolerable genistein, and daidzein are also available as single-agent or com-
Elemental Upper Vitamin D Upper bination supplements. Isoflavones produce estrogenic activity and
Group and Calcium Intake Level RDA Intake Level increase IGF-1. The evidence supporting a positive bone benefit
SECTION     Rheumatologic Disorders

Ages RDA (mg) (mg) (units)a (units) from phytoestrogen intake is conflicting with most studies showing
Infants little or no effect. The effect is greater on trabecular bone. Doses
Birth to 6 200b 1,000 400b 1,000 and products studied are quite varied with potentially more BMD
months activity with higher doses. Spine but not hip BMD is increased
7-12 months 260b 1,500 400b 1,500 in some studies when compared to placebo. Isoflavones from soy
14 Children foods appear safe; however, more information is needed, especially
1-3 years 700 2,500 600 2,500 in women with breast cancer and for isoflavone supplements versus
4-8 years 1,000 2,500 600 3,000
food sources.44
9-18 years 1,300 3,000 600 4,000 Alcohol
Adults 3 Chronic and excessive but not moderate alcohol consump-
19-50 years 1,000 2,500 600b,c 4,000 tion is associated with an increased risk for osteoporosis and frac-
51-70 years 1,000 2,000 600b,c 4,000 tures.2,45 Alcohol increases bone resorption by increasing RANKL
(men) and decreases bone formation by inhibiting Wnt signaling pathway
51-70 years 1,200 2,000 600b,c 4,000 and increasing oxidative stress that results in osteoblast apoptosis.
(women) Patients with alcohol-use disorder might also have poor nutrition,
>70 years 1,200 2,000 800b,c 4,000 decreased calcium absorption, altered vitamin D metabolism, estro-
a
Some guidelines recommend intake to achieve a 25(OH) vitamin D concentration
gen inhibition, decreased testosterone production, chronic liver dis-
of >30 ng/mL (mcg/L; 75 nmol/L),1,3,8 which is higher than the Institute of Medicine ease, and balance impairments resulting in more falls and fractures.
goal of >20 ng/mL (mcg/L; 50 nmol/L).40 Typical recommendations for alcohol consumption should be sug-
Adequate intake (evidence insufficient to determine an RDA). gested, which are not to exceed 2 drinks per day for women and 3
b

Guidelines recommend 800-1,000 units1 or 1,000-2,000 units3,8 for adults with drinks per day for men.
c

osteoporosis.
Data from References 2, 34, and 39. Caffeine and Tea
5 Although results are conflicting, excessive caffeine consumption
products such as tofu, calcium-fortified milk alternatives, and juices is associated with increased calcium excretion, increased rates of
can be used. When diet cannot be enhanced to achieve adequate bone loss, and a modestly increased risk for fracture.45 Greater nega-
intakes, calcium supplements will be required.
tive effects are seen in women. Ideally, caffeine consumption should
Vitamin D be limited to two servings or less per day. For those with greater
5 8 Table 112-5 also lists the IOM recommended adequate intakes, the increased calcium excretion might be compensated by
intakes for Vitamin D.2,34,39 The three main sources of vitamin D additional calcium intake. Chronic tea drinking might have a posi-
are sunlight (conversion of 7-dehydrocholesterol to vitamin D3), tive benefit on bone mass, but no fracture outcomes exist.
diet, and supplements. Vitamin D3 comes from oily fish, eggs, and
fortified dairy products. Vitamin D2 comes from fungi and eggs
Smoking
(chickens given vitamin D2 in their diet). Websites can be used to 5 Cigarette smoking is an independent risk factor for osteoporosis and
identify the few foods high in vitamin D.42 To calculate the amount of is associated with increased relative risk for fracture at all sites.46 The
vitamin D in a serving of food, consumers can multiply the percent effect is dose- and duration-dependent, but even passive smoking shows
daily value of vitamin D listed on the food label by 4 (eg, 20% adverse effects on BMD. The negative bone effects are associated with
vitamin D = 80 units). reduced intestinal calcium absorption, lower 25(OH) vitamin D con-
The overall prevalence of hypovitaminosis D (<20 ng/mL [mcg/L; centrations possibly due to increased hepatic metabolism, an increase in
50 nmol/L]) in American adults has been estimated at 29%; with higher bone resorption from a decrease in production and increase in metabo-
prevalence ratios observed in those who are older than 60 years, from lism of estradiol leading to an increase in RANKL and decrease in OPG,
a minority, have lower education levels, obese, physically inactive, and/ decrease in osteoblasts and bone formation secondary to increase in
or current smokers.43 Low vitamin D concentrations can result from cortisol and dehydroepiandrosterone sulfate, and impairment of osteoid
insufficient intake, dietary fat malabsorption, decreased sun exposure, production and mineralization.16,46 The detrimental effects of smoking
decreased skin production, and/or decreased liver and renal metabo- on physical function and balance can contribute to an increased risk of
lism. Endogenous synthesis of vitamin D can be decreased by factors that falls. Per guidelines, counseling patients of all ages on smoking cessa-
affect exposure to or decrease skin penetration of ultraviolet B light rays. tion can help to optimize peak bone mass, minimize bone loss, and ulti-
Sunscreen use, full body coverage with clothing (eg, women wearing mately reduce fracture risk2; however, few studies have explored these
veils and full-length dresses), and darkly pigmented skin can all decrease outcomes.46
vitamin D production. Seasonal variations in vitamin D concentra-
tions are also seen with nadirs in late winter and peaks in late summer.
Exercise
Because few foods are naturally high or fortified with vitamin D, most 5 Physical activity or exercise is an important nonpharmacologic
people, especially older adults, require supplementation to achieve IOM approach to preventing osteoporotic fractures. Exercise increases
recommended adequate intakes. bone mechanical strain, especially in weaker bone, thus stimulat-
ing osteocytes leading to bone resorption and then new stron-
Isoflavones ger bone formation.9 Weight-bearing exercise inhibits myostatin,
5 Phytoestrogens (isoflavones, lignans, and coumestans) are which increases muscle and bone mass and decreases fat mass, and
plant-derived compounds that possess weak estrogenic agonist and sclerostin and Dickoff-1, which prevents them from stopping bone

CH112.indd 1536 06-12-2022 14:51:44

 1537
formation.17 Irisin is increased by exercise leading to increased bone compression fractures. Although used to stabilize damaged ver-
formation by stimulating runX2, LRP 5/6, and β–catenin. Exercise tebrae, reduce pain, and decrease opioid intake, this therapy is
can decrease the risk of falls and fractures by stabilizing bone density decreasing based on results showing effects that are similar to sham
and improving muscle strength, coordination, balance, and mobil- interventions, being short-term, and having no major pain benefit,
ity.2,14,16,47 Physical activity is especially important early in life since and or are associated with vertebral fracturing around the cement,
peak bone mass is gained at that time and lack of exercise during cement leakage into the spinal column, and nerve damage (rare).52

CHAPTER        Osteoporosis
growth can lead to suboptimal loading/straining, decreased stimula- The AACE/ACE guideline lists vertebral augmentation as an uncer-
tion of bone deposition, and reduced peak bone mass.9 Although bone tain therapy due to limited data, potential for adverse treatment out-
mass might not increase, bone strength will increase in older adults. comes, and lack of long-term effects.2
All people of any age who are medically fit should be encouraged to
perform a moderate-intensity weight-bearing activity (eg, running), Pharmacologic Therapy
plyometric (eg, jumping, hopping, bounding), and resistance activity 9 Because nonpharmacologic interventions alone are frequently
(eg, weight machines, free weights, or elastic bands). Walking, swim- insufficient to prevent or treat osteoporosis, medication therapy is 112
ming, cycling, and yoga have less impact on osteogenics but are still often necessary. Osteoporosis medication effects on fracture risk
important. People at risk of osteoporosis should participate in exer- and BMD (Table 112-6), dosing (Table 112-7), and adverse effects
cise, including weight-bearing activities, at least three to four times and monitoring (Table 112-8) are described. Medication use should
weekly for 30 to 40 minutes per session. Adult recommendations be combined with a bone-healthy lifestyle. People of color were less
for exercise from the American Heart Association can be suggested, likely to receive osteoporosis prescription medications3; thus, health
which are 150 minutes of moderate-intensity aerobic exercise weekly disparities need to be resolved to provide osteoporosis prevention to
or 75 minutes of vigorous-intensity exercise per week, and moderate- all women and men.
to high-intensity muscle strengthening at least twice a week.48 The North American Menopause Society guidelines for post-
Fall Prevention menopausal women, Endocrine Society guideline for postmenopausal
women, the American Association of Clinical Endocrinologists and
5 Risk of falling increases with advanced age predominantly as a
American College of Endocrinology guideline for postmenopausal
result of balance, gait, and mobility problems, poor vision, reduced
women, the American College of Physicians guideline for women
muscle strength, impaired cognition, multiple medical conditions
and men, and the Bone Health and Osteoporosis Foundation guide-
(eg, arrhythmias, postural hypotension, Alzheimer’s disease, and
line for women and men provide guidance on osteoporosis preven-
Parkinson disease), and polypharmacy (especially psychoactive, car-
tion and treatment strategies.1,2,4,39
diovascular, diabetes, seizure, and pain medications).2,24 The ability
to adapt to falls also decreases with aging. Older adults are more Medication Treatments of First Choice
likely to sustain a hip or pelvic fracture because they tend to fall
9 Alendronate, risedronate, zoledronic acid, and denosumab
backward or sideways instead of forward.
reduce both hip and vertebral fracture risks.2 Abaloparatide, calcito-
Because of the link between falls and fractures, all older adults
nin, ibandronate, raloxifene, romosozumab, and teriparatide reduce
should be asked at least annually if they have fallen. The US Centers
vertebral but not hip fracture risks. Estrogen and testosterone thera-
for Disease Control and Prevention have created an assessment
pies are not used for osteoporosis treatment, but when prescribed for
tool.49 If an older adult scores 4 or more, a comprehensive falls
other conditions will have a positive bone effect.27 In theory, sequen-
assessment should be conducted. Many other assessment tools exist
tial therapy starting with bone formation medications and fol-
to evaluate falls.
lowed by antiresorption medications is recommended, especially in
Generally, intervention programs that are multifactorial
patients with osteoporosis and very high risk for fracture. Formation
have greater effects on decreasing falls, fractures, other injuries,
medication cost and injectable dosage forms limit sequential therapy
and nursing home and hospital admissions than single interven-
as initial therapy. The algorithm (see Fig. 112-3) helps determine for
tions.2,24,40,47,50 Medication profiles should be reviewed for any
whom medication therapy should be used. In general, prescription
unnecessary medications that can affect cognition and balance,
therapy combined with adequate intakes of calcium and vitamin D
and potentially increase fall risk. Consideration should be given
should be considered for any postmenopausal woman or man aged
to deprescribing or substitution with safer medications. Although
50 years and older presenting with a fragility fracture, osteoporosis,
Vitamin D supplementation has been advocated to reduce falls and
or low bone mass combined with a FRAX 10-year probability of hip
fractures in some guidelines, the most recent USPSTF recommen-
fracture of 3% or more or any major osteoporosis-related fracture
dation states the evidence is inadequate to prescribe this therapy
of 20% or more. Type of fracture risk (spine, hip, or both) will also
for fall and fracture prevention. Maintenance of a regular individ-
determine medication of choice. Calcitonin is a last-line therapy.
ualized exercise program, such as tai chi, resistance training, and
The use of osteoporosis prescription medications in children,10,15,57,58
strengthening, should be recommended to improve body strength,
premenopausal women,11 and men younger than 50 years12,13 occurs
balance, and agility. Other recommendations include resolving
in special cases and is generally related to secondary medical and
heart rate/rhythm irregularities, low blood pressure, and vision and
medication causes or genetic disorders.
foot problems, and using proper footwear. A home environment
safety assessment is helpful to identify environmental solutions to
decrease falls.24,40,51 External hip protectors are specialized under-
Antiresorptive Therapies
garments designed to pad the area surrounding the hip, decreasing Antiresorptive therapies include calcium, vitamin D, bisphospho-
the force of impact from a sideways fall.8 Conflicting results and nates, denosumab, estrogen agonists/antagonists (EAA), tissue
poor adherence limit their use. Many patient education materi- selective estrogen complexes (TSEC), calcitonin, estrogen, and
als exist with the US Centers for Disease Control and Prevention testosterone.
older adult falls prevention program being an excellent resource for Calcium Supplementation 7 Calcium imbalance can result
patients and providers.40 from inadequate dietary intake, decreased fractional calcium
absorption, enhanced calcium excretion, and diseases and medi-
Vertebroplasty and Kyphoplasty cations altering these processes. Adequate calcium intake (see
During vertebroplasty and kyphoplasty cement is injected into frac- Table 112-5) is considered a foundation for osteoporosis preven-
tured vertebra(e) for patients with debilitating pain from vertebral tion and treatment in the guidelines and should be combined with

CH112.indd 1537 06-12-2022 14:51:44

 1538
TABLE 112-6  Fracture and Bone Mineral Density Effects of Osteoporosis Medications from Pivotal Fracture Trialsa in
Postmenopausal Women
% Change in Spine % Change in Hip
Medication Vertebral Fracture Nonvertebral Fracture Hip Fracture BMDb BMDb,c
Abaloparatide 86%↓ 43%↓ ↔ 10.4%↑ 4.3%↑
Bazedoxifene 35%-42%↓ ↔d ↔ 2.1-3.0%↑ 0.5%↑
SECTION     Rheumatologic Disorders

Bazedoxifene with conjugated ND ND ND 0.24%-1.6%↑ 0.2%-1.5%↑

equine estrogens
Bisphosphonates 41%-70%↓ 20%-38%↓e 28%-50%↓f 3.1%-6.0%↑ 1.8%-4.0%↑
Calcitonin 33%↓ ↔ ↔ 3%↑ ↔
Denosumab 68%↓ 20%↓ 40%↓ 9.2%↑ 6.0%↑
14 Estrogen with or without a 33%-40%↓ 13%-27%↓ 30%-50%↓ 3.5%-7%↑f 1.7%-5%↑g
progestogen
Raloxifene 30%-68%↓h ↔ ↔ 2.6%↑ 2.1%↑
Romosozumab 73%↓ ND/19%↓i ND/38%↓i 11.3%-13.7%↑g 4.1%-6.9%↑
Teriparatide 65%↓ 53%↓ ↔ 8.6%-9.7%↑ 3.5%↑
a
Fracture reductions are relative risk reductions, no head to head fracture studies except for raloxifene and bazedoxifene. Data should only be used for relative between
class comparisons. Clinical trials have different patient samples and study designs. Most pivotal fracture trials were of 3-year duration except for abaloparatide (2 years),
romosozumab (1 year) and teriparatide (18 months) studies.
b
Relative to placebo; may vary based on duration of therapy and timing relative to menopause.
c
Total hip (alendronate, ibandronate, zoledronic acid, bazedoxifene, denosumab, estrogen, abaloparatide, teriparatide, romosozumab) or femoral neck (calcitonin, estrogen,
risedronate, and raloxifene).
d
50% decreases in nonvertebral fractures in subgroup of high-risk postmenopausal women (very low BMD and/or previous fractures).
e
Risedronate and zoledronic acid only; nonvertebral fracture reductions with ibandronate were not significant.
f
Alendronate, risedronate, and zoledronic acid only; hip fracture data not reported with ibandronate.
g
Data obtained from nonpivotal fracture trials.
h
Includes data from a pivotal bazedoxifene trial with raloxifene as one of the comparators.
i
Second year results after 1 year of romosozumab followed by alendronate or denosumab for 1 year.
Includes data from teriparatide versus romosozumab study.
j

%, percent; BMD, bone mineral density; ↓, decrease; ↑, increase; ↔, no significant change; ND, no data.
Data from References 1, 2, 4, 39, and 53-56.

TABLE 112-7 Dosing of Medications for Osteoporosis

Medication Brand Name Dose Comments
Antiresorptive Medications—Nutritional Supplements
Calcium Various Adequate daily intake: IOM: 200-1,200 mg/ Recommend food sources first to achieve
day, varies per age; see Table 112-5); goal intake.
supplement dose is the difference Available in different salts including
between required adequate intake and carbonate and citrate, absorption of
dietary intake. other salts not fully quantified.
Immediate-release doses should be Different formulations including
<500-600 mg. chewable, liquid, gummy, softgel,
drink, and wafer; different combination
products.
Review package to determine number
of units per serving size and desired
amount of elemental calcium.
Give calcium carbonate with meals to
improve absorption.
Vitamin D Over the counter Adequate daily intake: IOM: 400-800 units/ Vegetarians and vegans need to read
D3 (cholecalciferol) • Tablets, 400, 1,000, and 2,000 units day to achieve adequate intake (see label to determine if the vitamin D
D2 (ergocalciferol) • Capsules, 400, 1,000, 2,000, 5,000, Table 112-5); guidelines: 800-2,000 units source is plant-based.
and 10,000 units orally daily; if low 25(OH) vitamin D Slight advantage of D3 over D2 for
• Gummies, 300, 500, and 1,000 units concentrations, malabsorption, or altered increasing serum 25(OH) vitamin D
• Drops, 300, 400, 1,000, and 2,000 metabolism higher doses (>2,000 units concentrations.
units/mL or drop daily) might be required. For drops, make sure measurement is
• Solution, 400 and 5,000 units/mL Vitamin D deficiency: 5,000 units or higher correct for desired dose.
• Spray, 1,000 and 5,000 units/spray daily preferred over 50,000 units orally Ability of sprays, lotions, and creams
• Creams and lotions, 500 and 1,000 once to twice weekly for 8-12 weeks; to resolve deficiencies or maintain
units per ¼ teaspoonful repeat as needed. Higher doses until adequate intakes is unknown.
Prescription therapeutic concentrations reached.
• Capsule, 50,000 units
• Solution, 8,000 units/mL

(Continued)

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 1539
TABLE 112-7 Dosing of Medications for Osteoporosis(Continued)
Medication Brand Name Dose Comments
Antiresorptive Prescription Medications
Bisphosphonates
Alendronate Fosamax Treatment: 10 mg orally daily or 70 mg orally Generic available, effervescent tablet is

CHAPTER        Osteoporosis
Fosamax Plus D weekly brand only.
Binosto (effervescent tablet) Prevention: 5 mg orally daily or 35 mg orally 70-mg dose is available as a tablet,
weekly effervescent tablet, solution, or
combination tablet with 2,800 or 5,600
units of vitamin D3.
Administered in the morning on an empty
stomach with 6-8 ounces (180-240
mL) of plain water. Do not eat and
remain upright for at least 30 minutes 112
following administration.
Do not coadminister with any other
medications or supplements, including
calcium and vitamin D.
Caution if CrCl <35 mL/min (0.58 mL/s).
Ibandronate Boniva Treatment: 150 mg orally monthly, 3-mg Generics available.
intravenous quarterly Administration instructions same as
Prevention: 150 mg orally monthly alendronate, except must delay eating
and remain upright for at least
60 minutes.
Caution if CrCl <30 mL/min (0.50 mL/s).
Risedronate Actonel Treatment and prevention: 5 mg orally Generics available.
daily, 35 mg orally weekly, 150 mg orally 35-mg dose is also available as a delayed-
Atelvia (delayed-release) monthly release product.
Administration instructions same as for
alendronate, except delayed-release
product is taken immediately following
breakfast with at least 120 mL (ounces)
of plain water.
Caution if CrCl <30 mL/min (0.50 mL/s).
Zoledronic acid Reclast Treatment: 5-mg intravenous infusion yearly Generic available.
Prevention: 5-mg intravenous infusion every Can premedicate with acetaminophen to
2 years decrease infusion reactions.
Contraindicated if CrCl <35 mL/min
(0.58 mL/s).
Also marketed under the brand name
Zometa (4 mg) with different dosing for
oncology-related indications.
RANK Ligand Inhibitor
Denosumab Prolia Treatment: 60-mg subcutaneously every Administered by a healthcare practitioner.
6 months Correct hypocalcemia before
administration.
Also marketed under the brand name
Xgeva (70 mg/mL) with different
dosing for treatment of hypercalcemia
of malignancy, multiple myeloma, bone
metastases from solid tumors, and
giant cell tumor of bone.
Estrogen Agonist/Antagonist and Tissue Selective Estrogen Complex
Raloxifene Evista 60 mg daily Generic available.
Bazedoxifene with Duavee 20 mg plus 0.45 mg CEE daily For postmenopausal women with a
conjugated equine uterus; no progestogen needed.
estrogens (CEE) Bazedoxifene monotherapy available in
some countries.
Calcitonin
Calcitonin (salmon) Fortical 200 units (1 spray) intranasally daily, Nasal formulation only available as a generic.
alternating nares every other day. Refrigerate nasal spray until opened for
daily use, then room temperature.
Prime with first use.
Also available as a subcutaneous injection.
Formation Medications
Recombinant Human Parathyroid Hormone (PTH 1-34 units)
Teriparatide Forteo 20-mcg subcutaneously daily First dose sitting or lying.
Bonsity Refrigerate before and after each use.
Use new needle with each dose. Inject in
thigh or abdomen.
Discard after 28 days or if cloudy.
Forteo and Bonsity not interchangeable.

(Continued)

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 1540
TABLE 112-7 Dosing of Medications for Osteoporosis (Continued)
Medication Brand Name Dose Comments
Human Parathyroid Hormone–Related Peptide (PTHrP [1-34]) Analog
Abaloparatide Tymlos 80-mcg subcutaneously daily for up to First dose sitting or lying.
2 years Refrigerate before use then keep at room
temperature.
SECTION     Rheumatologic Disorders

Use new needle with each dose. Inject in

abdomen.
Discard after 30 days.
Formation and Antiresorptive Medication
Sclerostin Inhibitor
Romosozumab Evenity 210-mg subcutaneously monthly for Correct hypocalcemia before
14 1 year; administered as two single use administration.
105-mg/1.17-mL prefilled syringes Refrigerate. Leave at room temperature for
at least 30 minutes before use.
Provider administration, exploring patient
self-administration.
Inject in abdomen, thigh, or upper arm;
preferably each injection at a different site.

IOM, Institute of Medicine; NSAID, nonsteroidal anti-inflammatory drug.

TABLE 112-8 Medication Adverse Reactions and Monitoring

Medication Adverse Reactions Monitoring Parameters Comments
Antiresorptive Medications—Nutritional Supplements
Calcium Constipation, gas, upset stomach, kidney Dietary calcium intake, Education about a bowel healthy lifestyle
stones constipation (eg, adequate water, fiber, and exercise).
Vitamin D Hypercalcemia, hypercalciuria, weakness, Serum 25(OH) vitamin D Adverse effects usually not experienced until
headache, somnolence, nausea concentration, symptoms 25(OH) vitamin D concentration more
Rare: cardiac rhythm disturbance than 100-150 ng/mL (mcg/L; 250-375
nmol/L), which are generally not achieved
with recommended therapeutic doses.
Antiresorptive Prescription Medications
Bisphosphonates
Bisphosphonates Dyspepsia (oral), transient or chronic Bone density, fractures, GI Adherence is suboptimal, thus it should be
musculoskeletal pain, nausea, transient flu- symptoms, muscle aches assessed frequently.
like illness (injectable) Serum calcium for zoledronic Assess correct use of product with refills.
Rare: GI perforation, ulceration, and/or acid Risk outweighs benefit in pregnancy, use
bleeding (oral); osteonecrosis of the jaw; prior to or during pregnancy might cause
atypical femoral shaft fracture, severe fetal medication exposure.
musculoskeletal pain
RANK Ligand Inhibitor
Denosumab Back pain, arthralgia, eczema, dermatitis, and Bone density, fractures, serum REMS: Medication guide and monitoring
infection calcium plan due to risks of hypocalcemia,
Rare: osteonecrosis of the jaw, atypical femoral osteonecrosis of the jaw, atypical femoral
shaft fracture shaft fractures, serious infections, and
dermatologic adverse reactions.
Contraindicated in pregnancy.
Estrogen Agonist/Antagonist and Tissue Selective Estrogen Complex
Raloxifene Hot flushes, leg pain, spasms, or Bone density, fractures, hot Contraindicated in pregnancy.
cramps, peripheral edema, venous flushes, leg cramps, and Warning for fatal stroke; rare events
thromboembolism (warm swollen leg, chest blood clots predominantly seen in women at high-risk
pain, shortness of breath, coughing up for stroke.
blood, and change in vision)
Bazedoxifene with Similar to raloxifene and estrogens Bone density, fractures, leg Contraindicated in pregnancy.
conjugated equine cramps, blood clots
estrogens
Calcitonin
Calcitonin (salmon) Rhinitis, epistaxis Bone density, fractures, nasal Limited information regarding use in
irritation pregnancy.
Formation Prescription Medications
Recombinant Human Parathyroid Hormone (PTH 1-34 units) Analog
Teriparatide Orthostasis with first few injections, pain at Bone density, fractures, If serum calcium is high (>10.6 mg/dL
injection site, nausea, headache, dizziness, trough serum calcium [2.65 mmol/L]), calcium intake should be
leg cramps, increase in uric acid, transient concentration 1 month decreased.
hypercalcemia, hypercalciuria after therapy initiation, Warning about osteosarcoma in rats and
urinary calcium if prior therefore contraindicated in patients at
hypercalciuria or active high risk for this adverse event.
urolithiasis In pregnancy, adverse events noted in animal
studies. Not for use in pregnancy.

(Continued)

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 1541
TABLE 112-8 Medication Adverse Reactions and Monitoring (Continued)
Medication Adverse Reactions Monitoring Parameters Comments
Human Parathyroid Hormone–Related Peptide [PTHrP (1-34)] Analog
Abaloparatide Orthostasis with first few injections, pain Bone density, fractures, serum Warning about osteosarcoma in rats and
at injection site, headache, dizziness, leg calcium concentration, therefore contraindicated in patients at
cramps, increase in uric acid, hypercalcemia, urinary calcium if prior high risk for this adverse event.

CHAPTER        Osteoporosis
hypercalciuria hypercalciuria or active Not for use in pregnancy.
urolithiasis
Formation and Antiresorptive Prescription Medication
Sclerostin Inhibitor
Romosozumab Arthralgias, headache, muscle spasms, Bone density, fractures, joint Box warning about myocardial infarction,
hypocalcemia, mild injection site pain, pain, injection site, serum stroke, and cardiovascular death.
myocardial infarction, stroke, cardiovascular calcium prior to and during 112
death. Antibody production with some therapy Not for use in pregnancy.
neutralizing, an effect on efficacy or toxicity
not reported. Rare: osteonecrosis of the jaw,
atypical femoral fractures

REMS, risk evaluation and mitigation strategies.

Data from Reference 1; product prescribing labeling.

vitamin D, especially when osteoporosis medications are taken.2,34,39 the highest amount of elemental calcium (40%) and is typically the
If dietary intake cannot be increased to achieve adequate intake, cal- least expensive. Calcium carbonate should be taken with meals,
cium supplements can be used. which increases gastric acidity resulting in product disintegra-
tion and dissolution. Calcium citrate (21% elemental calcium) has
Efficacy Calcium generally maintains BMD, although small BMD acid-independent absorption and does not need to be administered
increases (0.6%-1.8%) have been documented.2,59 These BMD effects
with meals. Although tricalcium phosphate contains 38% elemental
are less than those observed with other osteoporosis medications. A
calcium, calcium-phosphate complexes could limit overall calcium
USPSTF report states insufficient data exist to support using calcium
absorption. This product might be helpful in patients with hypo-
and vitamin D supplementation to reduce fracture incidence.
phosphatemia that cannot be resolved with increased dietary intake.
Adverse Events Calcium’s most common adverse reaction, consti- Disintegration and dissolution rates vary significantly between
pation, can first be treated with increased water intake, dietary fiber, products and lots. Products labeled United States Pharmacopeia
and exercise. If still unresolved, smaller and more frequent calcium “USP Verified” should be recommended. This indicates that the
administration or a lower total daily dose can be tried. Calcium car- products have undergone the voluntary USP verification program,
bonate can create gas and cause upset stomach. Calcium citrate, a which ensures that the product contains the ingredients shown on
formulation with fewer GI side effects, is often recommended if cal- the label at the stated strength/potency, and has been produced
cium carbonate is not tolerated. using safe, clean, and controlled manufacturing processes as speci-
Calcium supplementation when combined with vitamin D fied by the USP and the US Food and Drug Administration (FDA).
can increase the risk of kidney stone formation. However, in some Products from unrefined oyster shell or coral calcium should not be
cases, calcium binds to oxalate in the gut, which decreases urinary recommended because of concerns for high concentrations of lead
oxalate excretion thereby decreasing kidney stones. Increased fluid and other heavy metals. Some calcium products come in alternative
intake and decreased salt intake might be warranted to prevent kid- dosage forms (eg, chewable tablets, dissolvable tablets, and liquid),
ney stones. Calcium supplements resulting in total calcium intakes which can be beneficial for select patients with issues such as swal-
above the upper limit of intake can slightly increase coronary artery lowing large tablets. For all products, encourage patients to read
calcification and cardiovascular disease events.1,31,60 the labeling carefully as the serving size is often more than just one
tablet. In addition, product labeling sometimes recommends taking
Interactions Since calcium carbonate requires acid for disintegra- doses providing 1,000 to 1,200 mg/day, which often provides more
tion, medications such as proton pump inhibitors and histamine calcium than needed to meet IOM requirements and could exceed
type-2 receptor antagonists can decrease absorption from the car- tolerable upper limits when dietary calcium intake is adequate.
bonate product.31 Fiber laxatives can also decrease the absorption Some commercial calcium supplements contain other nutri-
of calcium if given concomitantly. Calcium can decrease the oral ents associated with bone physiology such as magnesium, vitamin
absorption of some medications including iron, tetracyclines, qui- K, “natural estrogens,” or isoflavones. Minimal BMD and no fracture
nolones, bisphosphonates, and thyroid supplements. data exist for these combination products. These products are also
Dosing and Administration Many patients, especially those aged typically more expensive. Additionally, combining too many vita-
60 years or older, do not ingest sufficient dietary calcium and there- mins and supplements might exceed upper-tolerable nutrient limits
fore require supplements. To ensure adequate calcium absorption, and increase toxicities.
25(OH) vitamin D concentrations should be at least 10 to 15 ng/
mL (mcg/L; 25-37 nmol/L). Because fractional calcium absorption Vitamin D Supplementation 8 The IOM recommends ade-
is dose-limited, maximum single doses of 500 to 600 mg or less of quate intakes of vitamin D from diet and/or supplementation for
elemental calcium are recommended.2 Despite this, slow-release all ages (see Table 112-5). Current osteoporosis guidelines recom-
and/or absorbable calcium formulations (eg, Citracal Slow Release mend slightly higher vitamin D maintenance doses (800-2,000 units
1,200) are available in doses of 1,200 mg and advertised to be taken daily).2,34,38
once daily. These high-dose products are sometimes two 600-mg The desired therapeutic range for vitamin D is controversial. The
tablets that can be taken at different times. Supplemental doses this IOM defines 20 ng/mL (50 nmol/L; 1 ng/mL = 2.5 nmol/L) as the cut
high are usually not needed unless a severe dietary deficiency of cal- point for normal 25(OH) vitamin D, below which a patient would be
cium exists. Calcium carbonate is the salt of choice as it contains considered deficient. Current guidelines recommend treating patients

CH112.indd 1541 06-12-2022 14:51:44

 1542
with osteoporosis to a concentration of at least 20 ng/mL (mcg/L; 50 1 month, approximately 3 months of therapy are required before a
nmol/L) or 30 to 50 ng/mL (mcg/L; 75-125 nmol/L) 25(OH) vitamin D. new steady state is achieved and a repeat 25(OH)-vitamin D concen-
Concentrations higher than 50 to 60 ng/mL (mcg/L; 125-150 nmol/L) tration should be obtained to assess efficacy of therapy.
can be associated with adverse effects.2,38 Individuals with deficient concentrations of vitamin D are at
The major effects of vitamin D are achieved with 25(OH) risk for osteomalacia, a condition that can be mistaken for osteo-
vitamin D concentrations between 6 and 20 ng/mL (mcg/L; 15-50 porosis, which is characterized by decreased mineralization or
nmol/L), including increasing calcium absorption (16 ng/mL “softening” of bone matrix. In patients who are pregnant, obese, or
SECTION     Rheumatologic Disorders

[mcg/L; 40 nmol/L]) and decreasing BMD loss (up to 20 ng/mL with disorders (eg, celiac disease, cystic fibrosis, Crohn’s disease,
[mcg/L; 50 nmol/L]).61 Daily vitamin D doses of 500 to 700 units chronic kidney disease) or medications (eg, anticonvulsants, gluco-
generally are sufficient to achieve vitamin D concentrations more corticoids, antifungals, and antiretroviral medications used in treat-
than 20 ng/mL (mcg/L; 50 nmol/L), leading some experts to sug- ment of acquired immunodeficiency syndrome) affecting vitamin
gest the higher daily doses recommended in guidelines are not war- D absorption and/or metabolism, higher doses and more frequent
14 ranted. Other experts state not everyone achieves a 25(OH) vitamin monitoring might be required.
D concentration greater than 30 ng/mL (mcg/L; 75 nmol/L), and
Bisphosphonates 9 Alendronate, risedronate, and intravenous
therefore recommend 800 to 2,000 units daily, especially in adults at
zoledronic acid are approved by the FDA for postmenopausal, male,
high risk or with osteoporosis. Furthermore, since most products are
and glucocorticoid-induced osteoporosis. Intravenous and oral iban-
inexpensive and safe, the higher recommended doses are appropri-
dronate and some specialized oral formulations of other bisphos-
ate.2,34,39 These higher recommendations are within the upper limit
phonates are indicated only for postmenopausal osteoporosis.
for vitamin D in adults, which is 4,000 units daily.
Serum 25(OH) vitamin D is the best indicator of total body Pharmacology Bisphosphonates mimic pyrophosphate, an
vitamin D status.42 Interassay variability exists; thus, the same labo- endogenous bone resorption inhibitor.2,64 Bisphosphonate anti-
ratory should be used for repeat testing. Measurement of 25(OH) resorptive activity results from binding to hydroxyapatite in bone
vitamin D concentration can be considered in anyone with high risk with preference for areas with active bone remodeling. This leads to
for low vitamin D, low bone density, history of a low-trauma frac- decreased osteoclast maturation, number, recruitment, bone adhe-
ture, frequent falls, unexplained muscle weakness, and/or bone pain. sion, and life span.
Efficacy Supplemental vitamin D given at doses of 700 to 800 units
per day significantly reduces the incidence of both hip and nonver- Pharmacokinetics
tebral fractures.2 Small increases in BMD, improvement in muscle Oral bisphosphonate bioavailability is less than 1% and is greatly
strength, and improvement in balance have also been observed. Sev- decreased with concomitant food and beverages.64,65 Within 24
eral studies have analyzed the effect of supplemental vitamin D on hours of administration, bisphosphonates undergo rapid skeletal
falls; however, the USPSTF recommends against the use of supple- uptake and any medication not incorporated into bone is renally
mental vitamin D specifically for fall prevention.24 excreted. Elimination decreases linearly with declining renal func-
tion. Incorporation into bone gives bisphosphonates long biologic
Interactions Some medications can induce vitamin D metabolism half-lives of up to 10 years. Bisphosphonates differ in the strength
including rifampin, phenytoin, barbiturates, valproic acid, and car- of binding to bone (zoledronic acid greater than alendronate which
bamazepine. Vitamin D absorption can be decreased by cholestyr- is greater than ibandronate which is greater than risedronate) with
amine, colestipol, orlistat, and mineral oil. Vitamin D can enhance zoledronic acid having the greatest bone absorption and longest
the absorption of aluminum; therefore aluminum-containing prod- bone retention.
ucts should be avoided to prevent aluminum toxicity.
Efficacy Bisphosphonates consistently provide fracture risk reduc-
Dosing and Administration Dosing of supplemental vitamin D tion and BMD increases (see Table 112-6) with noted difference in
should be based on IOM adequate intakes (see Table 112-5) or to sites of fracture reduction between agents.53 Fracture clinical trial
achieve a 25(OH) vitamin D concentration of ≥30 ng/mL (mcg/L; data are from daily oral bisphosphonate or annual intravenous ther-
75 nmol/L), especially in those with osteoporosis.2 Almost 30% apy, not weekly, monthly, or quarterly regimens.65 Bisphosphonate
of older adults have hypovitaminosis D (≤20 ng/mL [mcg/L; 50 comparative fracture prevention trials do not exist. Hip-fracture
nmol/L]), with higher prevalence in Black (72%) and Hispanic reduction has not been demonstrated with daily oral ibandronate;
(43%) patients.43,62 Replenishment doses will first be required in however, the study might have been underpowered.2 Because of
these patients before recommended maintenance doses. the lack of hip-fracture reduction data, ibandronate is not a first-
Vitamin D can be taken as a single-agent or combination prod- line therapy (see Fig. 112-3). Annual intravenous zoledronic acid
uct. Supplements and multivitamins contain vitamin D3 or D2. has documented secondary fracture prevention and a decrease in
Synthesized vitamin D3 can be made from irradiated sheep’s wool mortality when given after a first hip fracture.53 Administration of
and vitamin D2 from irradiated mushrooms. Guidelines suggest intravenous zoledronic acid at an extended 18-month interval in
either product for prevention and treatment of vitamin D deficiency. women 65 years of age or older with osteopenia also decreased both
Current guidelines recommend dosing with 5,000 units once daily vertebral and nonvertebral fractures over 6 years.
for 8-12 weeks to achieve a target 25(OH) vitamin D concentration Bone turnover reaches an equilibrium with a lower rate of bone
of ≥30 ng/mL (mcg/L; 75 nmol/L), followed by a maintenance dose turnover evident within 3 to 6 months of bisphosphonate starting
of 1,000 to 2,000 units daily.2,63 The preferred dosage form is vitamin therapy, which results in BMD increases and a reduced fracture risk
D3 (cholecalciferol).2 Higher-dose prescription vitamin D regimens seen within the first 6 to 12 months.53,65 For all bisphosphonates,
have less support8 but are sometimes used,63 especially when adher- increases in BMD are typically greater at the spine than at the hip.53
ence and cost are concerns. An example regimen is 50,000 units Small increases in BMD continue for 4 to 5 years before plateauing.
given once weekly for 8 to 12 weeks, or until the 25(OH) vitamin After discontinuation, the increased BMD is sustained for a pro-
D concentration reaches 30 ng/mL (mcg/L; 75 nmol/L), followed longed period of time that varies based on different binding affinities
by 1,000 to 2,000 units daily to maintain this concentration. More of the individual bisphosphonates.2 Because of the sustained effects,
than one multivitamin or large doses of cod liver oil daily are no drug holidays can be considered for bisphosphonates.
longer advocated because of the risk of hypervitaminosis A, which The BMD increases with alendronate, risedronate, zoledronic acid,
can increase bone loss. Because the half-life of vitamin D is about and oral ibandronate in men are similar to those in postmenopausal

CH112.indd 1542 06-12-2022 14:51:44

 1543
women.6 Because of a lack of fracture data from pivotal trials in men, has lapsed, that dose is skipped. If a patient misses a monthly dose, it
bisphosphonates are only FDA indicated to increase BMD, not to can be taken up to 7 days before the next administration.
reduce fracture risk in men. However, no evidence suggests that efficacy Before intravenous bisphosphonates are used, the patient’s serum
profiles are expected to be different in men. calcium concentration must be normal. Serum creatinine should be
monitored before each dose of zoledronic acid. The intravenous prod-
Adverse Effects Oral bisphosphonates are well tolerated if
ucts need to be administered by a healthcare provider. The quarterly
patients are selected for therapy appropriately and the patient takes

CHAPTER        Osteoporosis
ibandronate injection is given intravenously over 15 to 30 seconds
them correctly (see Table 112-8). Patients with creatinine clearances
or can be diluted and given with a syringe pump. Zoledronic acid
(CrCl) less than 30 to 35 mL/min (0.50-0.58 mL/s), who have seri-
should be infused once yearly over at least 15 minutes with a pump.
ous GI conditions (abnormalities of the esophagus that delay empty-
Acetaminophen can be given to decrease acute phase reactions.
ing, such as stricture or achalasia), or who are pregnant should not
Although these medications are effective, adherence is poor
take bisphosphonates. Some evidence suggest bisphosphonates can
and results in decreased effectiveness.2,66 Adherence is improved
be used in select patients with age-related decline in renal function
without added adverse effects.
with once-weekly bisphosphonate administration over daily therapy; 112
however, it is unclear if once-monthly therapy improves adherence
GI complaints, including heartburn and dyspepsia, are one of
more. While dosing frequency is a common barrier to adherence,
the most common reasons cited by patients for discontinuing ther-
adverse effects and concerns about adverse effects remain impor-
apy.2,65 While these mild GI effects are common, bisphosphonates
tant predictors of adherence and persistence. Using decision aids in
are also associated with rare severe GI events, such as esophageal
discussions about medication therapy choices and periodic follow-
erosion, ulcer, or GI bleeding. If GI adverse events occur, switch-
up with a healthcare professional could improve adherence and
ing to a different bisphosphonate or less frequent administration
persistence to therapy. These decision aids visually display the pros
schedule might resolve the problem. Patients should be encouraged
of bisphosphonate therapy (ie, fracture avoidance) to the cons (ie,
to discuss GI complaints with a healthcare provider. Intravenous
adverse effects) based on an individualized fracture risk.67 To help
zoledronic acid or ibandronate can be used for patients with GI
overcome barriers associated with oral dosing frequency, intrave-
contraindications or intolerances to oral bisphosphonates. Other
nous ibandronate and zoledronic acid could be used as alternatives.
common bisphosphonate adverse effects include injection reactions
and musculoskeletal pain. If severe musculoskeletal pain occurs, the Duration The ideal duration of bisphosphonate therapy is not
medication can be discontinued temporarily or permanently. Acute known.2 Bisphosphonates are deposited into the bone and continue
phase reactions (eg, fever, flu-like symptoms, myalgias, and arthral- to suppress bone turnover after discontinuation. Some adverse
gias) are typically associated with intravenous administration, but effects, such as atypical fracture, are associated with duration of
rarely reported with oral bisphosphonates. This reaction usually therapy. To balance risk and benefit, some clinicians recommend
diminishes with subsequent administration. a “bisphosphonate/drug holiday,” defined as disruption of therapy
Rare adverse effects include osteonecrosis of the jaw (ONJ) during which medication effects exist with a plan for medication
and subtrochanteric femoral (atypical) fractures.2 ONJ occurs more reinstitution. Two randomized, double-blind studies with a bisphos-
commonly in patients with cancer, receiving higher-dose intra- phonate/drug holiday after therapy with alendronate for 5 years
venous bisphosphonate therapy. In osteoporosis, the incidence of or zoledronic acid for 3 years showed a continued fracture benefit
ONJ is 0.001% to 0.01%. Maxillary or mandibular bone surgery and after discontinuation of therapy. Because a beneficial response was
poor oral hygiene are dental-specific risk factors for development of predicted by hip T-score, experts recommend that a bisphospho-
ONJ. When possible, major dental work should be completed before nate holiday could be considered in postmenopausal women after
bisphosphonate initiation. For patients already on therapy, some 5 years of oral bisphosphonates or 3 years of intravenous bisphos-
practitioners withhold bisphosphonate therapy during and after phonates if no significant fracture history, hip BMD T-score is above
major dental procedures, but no data exist to support any benefit of –2.5, and fracture risk is not high. In women initially with very high
such practice. Atypical femoral shaft fractures are rare but can occur fracture-risk who remain high-risk, continuing oral bisphospho-
without trauma. Some evidence suggests the risk could increase with nates for 10 years or intravenous bisphosphonates for 6 years should
longer duration of bisphosphonate use (greater than 5 years). Since be considered. These recommendations are based on limited data
some patients with atypical fracture experience prodromal thigh or and questions remain regarding what therapy to reinitiate and
hip pain, any such pain should be evaluated. the applicability of this approach for men and patients with
­glucocorticoid-induced osteoporosis. Patients should be monitored
Interactions Because of poor bioavailability, oral bisphosphonates during the drug holiday and restarting therapy considered if frac-
should not be administered at the same time as other medications. tures occur or if there are significant BMD losses.
The administration instructions described below should be followed.
Denosumab 9 Denosumab is approved by FDA for the treat-
Dosing and Administration Because bioavailability is poor for ment of osteoporosis in postmenopausal women and men at high
bisphosphonates and to minimize GI side effects, each oral tablet risk for fracture. It is also approved for glucocorticoid-induced
should be taken with at least 6 ounces (~180 mL) of plain water (not osteoporosis and to increase bone mass in men receiving andro-
coffee, juice, mineral water, or milk) at least 30 minutes (60 minutes gen deprivation therapy for nonmetastatic prostate cancer and in
for ibandronate) before consuming any food, supplements (includ- women receiving adjuvant aromatase inhibitor therapy for breast
ing calcium and vitamin D), or medications (see Table 112-7). The cancer who are at high risk for fracture.
patient should also remain upright (ie, either sitting or standing)
Pharmacology Denosumab is a fully human monoclonal anti-
for at least 30 minutes after alendronate and risedronate and 1 hour
body that binds to RANKL, blocking its ability to bind to its RANK
after ibandronate administration. For patients with swallowing dif-
receptor on the surface of osteoclast precursor cells and mature
ficulties (eg, stroke and tube feeding), an effervescent tablet form of
osteoclasts.68 Denosumab inhibits osteoclastogenesis and increases
alendronate, which is dissolved in 4 ounces (∼120 mL) of room tem-
osteoclast apoptosis.
perature water, could be used. This formulation has the same food
restrictions as traditional oral tablets. In contrast, delayed-release Pharmacokinetics Following subcutaneous injection, rapid sup-
risedronate is available, and it is administered immediately following pression of bone turnover occurs within 12 hours.68,69 Denosumab
breakfast with at least 4 ounces (∼120 mL) of plain water. A patient achieves peak concentration in approximately 10 days. The half-life
who misses a weekly dose can take it the next day. If more than 1 day is approximately 25 days, and the concentration slowly declines over

CH112.indd 1543 06-12-2022 14:51:44

 1544
a period of 4 to 5 months. The medication does not accumulate with effects at different tissue sites.55,56 Raloxifene is an agonist at bone
repeated dosing at 6-month intervals. No dosage adjustment is nec- receptors and antagonist at breast receptors and has minimal effect
essary in renal impairment; however, hypocalcemia is more com- on the uterus. Bazedoxifene is an agonist at bone, and antagonist at
mon in severe renal impairment. No studies have been conducted in the uterus and breast; however, reduction in breast cancer risk has
hepatic impairment. not yet been demonstrated in large-scale clinical trials.
Efficacy Over 3 years, denosumab significantly decreased vertebral Pharmacokinetics Food has a nonsignificant effect on absorp-
SECTION     Rheumatologic Disorders

fractures, nonvertebral fractures, and hip fractures in postmenopausal tion, which is about 2% for raloxifene and 6% for bazedoxifene due
women with low bone density (see Table 112-6).53 Continued increases to extensive presystemic glucuronidation.56,70,71 Raloxifene is 95%
in BMD are demonstrated with long-term treatment over 10 years. For protein bound. The half-life of both raloxifene and bazedoxifene is
postmenopausal women previously treated with oral bisphosphonates, 28 hours. EAAs are predominantly metabolized via glucuronidation
switching to denosumab for 1 year provided greater increases in BMD and eliminated in the feces.
at the spine and hip over switching to zoledronic acid; however, fracture
14 outcomes are unknown.2 Denosumab is not incorporated into bone
Efficacy Raloxifene and bazedoxifene decrease vertebral but not
hip fractures. In a post hoc analysis of the Multiple Outcomes with
and drug holidays are not recommended. Upon medication discontinu-
Raloxifene Evaluation trial, raloxifene decreased nonvertebral frac-
ation, a rapid increase in bone turnover above baseline is noted with
tures in postmenopausal women with the most severe vertebral frac-
a corresponding loss of protection against vertebral fractures and case
tures at baseline. Bazedoxifene also decreased nonvertebral fractures
reports of multiple vertebral fracture. Therefore, for those with high
in a subgroup of women with a higher fracture risk at baseline.55,56
fracture risk, denosumab therapy should be continued or alternative
The fracture prevention effects of bazedoxifene combined with CEE
antiresorptive therapy (ie, bisphosphonate) should be initiated if deno-
are not known. EAAs increase spine and hip BMD, but to a lesser
sumab is discontinued.
extent than bisphosphonates (see Table 112-6). Raloxifene’s vertebral
Adverse Events In trials up to 10 years in duration, denosumab fracture prevention is greater in women without previous fracture.4
was generally well tolerated (see Table 112-8).2 Dermatologic reac- Upon discontinuation, the medication effect of EAAs is lost, with
tions not specific to the injection site and serious infections were bone loss returning to age- or disease-related bone loss rates. EAAs
noted in initial clinical trials, although an increased incidence has have a positive impact on the lipid profile but have not demonstrated
not been noted in long-term, follow-up trials nor with denosumab a benefit on cardiovascular disease.4,55
used in higher doses (Xgeva) for oncologic indications.2
Adverse Events Hot flushes are common with raloxifene but
As with bisphosphonates, rare, serious adverse effects from
decreased with bazedoxifene with CEE (see Table 112-8).55,56,70,71 Raloxi-
bone turnover suppression have been reported with denosumab
fene rarely causes endometrial thickening and bleeding; bazedoxifene
including ONJ and atypical femoral fracture.68 Major dental work
decreases these adverse events making progestogen therapy unneces-
should be completed before use when possible. Hypocalcemia can
sary when it is combined with CEE. Leg cramps and muscle spasms
occur and any existing hypocalcemia should be corrected prior
are also common with both medications. Thromboembolic events are
to use. Severe hypocalcemia is more common in patients with
uncommon (less than 1.5%), but can be fatal. In large trials, no change
underlying kidney dysfunction. The manufacturer recommends
in overall death, cardiovascular death, or overall stroke incidence was
monitoring of serum calcium, magnesium, and phosphorus within
seen with raloxifene; however, a slight increase in fatal stroke (0.7/1,000
14 days of administration in those with a CrCl less than 30 mL/min
women – year difference) was documented, which resulted in a boxed
(0.50 mL/s).
warning for raloxifene.55 Fatal stroke with raloxifene occurred most fre-
Interactions No interactions have been identified with denosumab. quently in women with an increased risk of stroke at baseline. Baze-
doxifene with CEE also has all the adverse effects listed for estrogens as
Dosing and Administration Denosumab is administered subcu- a class including increased thromboembolic events.
taneously in the upper arm, upper thigh, or abdomen by a healthcare
professional including pharmacists in some states. The product is Interactions Because of raloxifene’s highly protein bound nature
available as a refrigerated prefilled syringe that can be stored at room (95%), when given concomitantly with other highly protein bound
temperature up to 14 days before administration (see Table 112-7). medications, like warfarin, a potential for binding interactions exists
and, therefore, monitoring of both medications is suggested. Cho-
Duration After 5 to 10 years of therapy, patients should be reevalu- lestyramine can decrease raloxifene absorption. Rifampin, pheny­
ated for medication continuation, discontinuation, or switching to a
toin, carbamazepine, and phenobarbital can decrease bazedoxifene
different medication.
concentrations by inducing intestinal and liver uridine diphosphate
Mixed Estrogen Agonists/Antagonists and Tissue Selec- glucuronosyltransferase (UGT) metabolism. Estrogen metabolism
tive Estrogen Complexes 9 Raloxifene is a second-generation is altered with CYP3A4 and CYP1A2 inducers and inhibitors.
mixed estrogen agonist/antagonist (EAA; previously known as a Dosing and Administration EAAs/TSECs are administered
selective estrogen receptor modulator, or SERM) approved by the orally once daily (see Table 112-7).70,71 They are contraindicated for
FDA for prevention and treatment of postmenopausal osteoporo- women with an active or past history of venous thromboembolic
sis and for reducing the risk of invasive breast cancer in postmeno- disease, pregnancy, or childbearing potential. Therapy should be
pausal women with and without osteoporosis. Raloxifene might be stopped if a patient anticipates extended immobility. Women at high
considered as a treatment option for women with no to minimal risk for a stroke or coronary events and those with known coronary
postmenopausal symptoms at low risk for hip fracture and with an artery disease, peripheral vascular disease, atrial fibrillation, or a
increased breast cancer risk. Bazedoxifene is a third-generation EAA prior history of cerebrovascular events might not be good candidates
combined with conjugated equine estrogens (CEE) making it a TSEC for EAAs/TSECs. These medications should be used with caution in
that is approved by FDA for prevention of postmenopausal osteopo- patients with severe liver impairment or moderate-to-severe renal
rosis and vasomotor menopausal symptoms.55,56 Bazedoxifene with impairment due to a lack of data. Bazedoxifene with CEE has all the
CEE can be considered for younger postmenopausal women with contraindications and precautions for estrogens as a class.
a uterus, menopausal symptoms, and at risk for osteoporosis.2,4,55,56
Calcitonin 9 Calcitonin is FDA-indicated for osteoporosis treat-
Pharmacology EAAs bind with α- and β-estrogen receptors and ment for women who are at least 5 years past menopause.72 Intrana-
coactivators or corepressors to cause varying agonist or antagonist sal calcitonin therapy (200 units daily) decreases vertebral fractures

CH112.indd 1544 06-12-2022 14:51:44

 1545
alone with no fracture reduction demonstrated with higher and with differing amino acids at positions 23 to 34. While both agents
lower doses (see Table 112-6).2 Once calcitonin is discontinued, the bind to the PTH type I receptor, abaloparatide binds with higher
benefits are lost over the next 1 to 2 years. A meta-analysis revealed affinity to the RG confirmation, which results in an increased ana-
a higher incidence of cancer in patients taking calcitonin. While the bolic effect. Further, abaloparatide demonstrates less of an effect on
FDA found that evidence was insufficient for a causal relationship, activating bone resorption and remodeling than teriparatide. With
calcitonin is considered a last-line therapy since there are more effec- both medications bone mass is improved.

CHAPTER        Osteoporosis
tive treatment options. Intranasal calcitonin might provide some
Pharmacokinetics Bioavailability for teriparatide and abalopara-
short-term pain relief to some patients with acute vertebral fractures.
tide are 95% and 36%, respectively. The peptides are cleared through
Dosing and Administration Some patients do not like to admin- hepatic and extrahepatic pathways, with a half-life of 1 hour and 1.7
ister medications intranasally (see Table 112-7). In clinical trials of hours, respectively. Increases in the area under the curve are noted
calcitonin, a high dropout rate exists. If the nasal product is used for with decreasing renal function but there are no dosage adjustments
vertebral fracture pain, calcitonin should be prescribed for short- noted in renal insufficiency. No studies have been performed in
term (4 weeks) treatment and should not be used in place of other hepatic impairment. Alternative delivery formulations are being 112
more effective and less-expensive analgesics nor should it preclude investigated.54
the use of more appropriate osteoporosis therapy.
Efficacy Two years of teriparatide or abaloparatide reduce verte-
Hormone Therapies bral and nonvertebral fracture risk in postmenopausal women (see
Table 112-6).53 Compared with alendronate, teriparatide has dem-
Estrogen In women, estrogens with or without a progestogen sig- onstrated reductions in vertebral fracture rates in patients taking
nificantly decrease fracture risk and bone loss (see Table 112-6).2,4,34,36
glucocorticoids; however, no reductions in nonverterbral fractures
Estrogen therapy is approved by FDA for prevention of postmeno-
were evident.54 Lumbar spine BMD increases are greater than with
pausal osteoporosis but not for treatment. For women going through
antiresorptive agents. Observational data for teriparatide suggest a
early menopause, estrogen therapy can be considered when protection
similar fracture benefit in men; no data are available regarding aba-
against bone loss is needed in addition to reduction of vasomotor symp-
loparatide use in men. Discontinuation of parathyroid hormone
toms.4,73 Other anti-osteoporosis therapies are reserved for treatment
analog therapy results in a decrease in BMD, which can be alleviated
closer to the average age of natural menopause. Estrogens should not
with subsequent antiresorptive therapy.2
be prescribed solely for the prevention or treatment of osteoporosis if
other anti-osteoporosis therapies can be used.1,2,38 Oral and transdermal Adverse Events Transient hypercalcemia can occur and is less
estrogens at equivalent doses and continuous or cyclic hormone therapy common with abaloparatide than with teriparatide (3.4% vs 6.4%,
regimens have similar BMD effects. Effect on BMD is dose-dependent, respectively) (see Table 112-8).54 Because of an increased incidence
with some benefit seen with lower estrogen doses. Fracture risk reduc- of osteosarcoma in rats, both medications contain a box warning
tion has not been demonstrated with the lower doses. When estrogen against use in patients at increased baseline risk for osteosarcoma
therapy is discontinued, bone loss accelerates and fracture protection (eg, Paget’s bone disease, unexplained elevations of alkaline phos-
is lost. A complete discussion of adverse events, drug interactions, phatase, pediatric patients, young adults with open epiphyses, or
dosing, and administration for estrogen can be found in Chapter 102, patients with prior radiation therapy involving the skeleton). This
“Hormone Therapy in Women.” adverse effect has not been seen in humans.
Testosterone No fracture data are available, but some data dem- Interactions An increased calcium concentration could be a con-
onstrate BMD improvements with testosterone use.74 Testosterone cern in patients on digoxin therapy.
is used to treat hypogonadism in men, but an osteoporosis medica-
Dosing and Administration Teriparatide and abalopara-
tion should be added when risk for osteoporotic fracture is high.12,74
tide are commercially available as a prefilled pen delivery device
A complete discussion of adverse events, drug interactions, dosing,
(see Table 112-7). A daily subcutaneous injection is delivered to the
and administration for testosterone products for men can be found
abdominal area with site rotation. Teriparatide can also be given in
in Chapter 103, “Erectile Dysfunction.”
the thigh. The administration of the first dose should take place with
the patient either sitting or lying down in case orthostatic hypotension
Formation Medications occurs. Both medications should be stored in the refrigerator before
first use. After first use, abaloparatide can be kept at room tempera-
Parathyroid Hormone Analogs ture for up to 30 days. In contrast, teriparatide must be returned for
9 Abaloparatide is an analog of PTHrP and teriparatide is an analog of storage in the refrigerator after each use and special precautions must
PTH.2,54 These agents are FDA-indicated for the treatment of postmeno- be taken for travel. The teriparatide pen should be discarded after 28
pausal women with osteoporosis at high risk for fracture defined as mul- days. Due to the theoretical risk for osteosarcoma, these medications
tiple risk factors for fracture, a history of osteoporotic fracture, or failed are generally limited to 2 years of use cumulatively in a patient’s life-
or intolerant to other therapies. Teriparatide is additionally approved by time with additional use of teriparatide considered on a risk-benefit
FDA for osteoporosis in men who are at high risk for fracture or intol- basis. In select patients, a second trial with teriparatide can be tried.
erant to other osteoporosis medications and glucocorticoid-induced Suboptimal adherence is documented to decrease efficacy.
osteoporosis. Patients who have a very high fracture risk, history of Besides the conditions listed above, parathyroid hormone ana-
osteoporotic fracture, low bone density (eg, T-score less than –3.5), or logs should not be used in patients with hypercalcemia, metabolic
have failed or are intolerant of previous bisphosphonate therapy could bone diseases other than osteoporosis, metastatic or skeletal cancers,
be candidates for PTH analog therapy. previous radiation therapy, or premenopausal women of childbear-
Pharmacology Teriparatide is a recombinant human product ing potential.
representing the first 34 amino acids in human PTH.54 Unlike con-
tinuous PTH effects from primary hyperparathyroidism that can
Formation and Antiresorptive Medication
decrease BMD, when administered intermittently (ie, subcutane- Romosozumab
ously once daily) teriparatide increases bone formation with a minor 9 Romosozumab is approved by FDA for postmenopausal women
increase in bone resorption for a net anabolic effect. Abaloparatide at high risk for fracture defined as multiple risk factors for fracture,
is a synthetic analog of PTHrP sharing the first 22 amino acids but a history of osteoporotic fracture, or failed or intolerant to other

CH112.indd 1545 06-12-2022 14:51:44

 1546
therapies. This medication might be the anabolic osteoporosis medi- healthcare provider. Each syringe is injected into two different sites
cation of choice for patients with previous radiation therapy,2 and during the same visit (see Table 112-7). Patient self-administration
those at risk for osteosarcoma and hypercalcemia.75 is being explored.
Pharmacology Romosozumab is a humanized monoclonal anti-
body that binds to sclerostin to prevent inhibition of bone formation
Sequential and Combination Therapy
and decrease bone resorption, an activity that separates this medica- 9 In sequential therapy, an anabolic agent is given first to increase
bone remodeling units and bone mass, followed by an antiresorp-
SECTION     Rheumatologic Disorders

tion from other anabolic medications.54,75 By binding sclerostin, Wnt

signaling can continue to increase gene transcription, which results tive agent to continue with bone formation. Although this sequential
in increased osteoblast synthesis, differentiation, and bone matrix therapy is recommended in the guidelines, in practice this regimen is
building. This medication inhibits bone resorption by decreasing generally reserved for patients with severe osteoporosis because of the
RANKL and m-CSF, and increasing OPG. cost of anabolic agents. Starting with an antiresorptive first and then
switching to teriparatide results in lower BMD compared to starting
14 Pharmacokinetics About 50% to 70% of a dose is absorbed. with the bone formation medication first. Thus starting teriparatide
Peak serum concentrations after subcutaneous administration are after antiresorption therapy is not preferred.2 However, this therapy will
reached within 3 to 4.5 days, with no accumulation with subsequent be used, especially for patients who have fractured or continue to lose
doses. Romosozumab has a half-life of 6 to 7 days. bone mass while on antiresorptive therapy. Romosozumab can be used
Efficacy After 1 year of romosozumab, vertebral fractures are after previous treatment with parathyroid hormone analogs.2 Small
statistically decreased by 73%, with a nonsignificant decrease in increases in BMD can be seen when switching from an oral bisphospho-
nonvertebral fractures by 25% in postmenopausal women (see nate to denosumab. Switching to denosumab thus can be used during a
Table 112-6).2,39,54,75 Fracture prevention was higher if the study partici- bisphosphonate drug holiday or for bisphosphonate treatment failures
pants in Latin America were removed from the multi-country study (ie, BMD decreases or fracture).
analysis because this cohort had lower fracture rates even in the placebo Because of no documented fracture benefit, increased cost,
arm. Fracture risk was also decreased by 48% for vertebral fractures, concern for dual suppression of bone turnover, and potential for
19% for nonvertebral fractures, and 38% for hip fractures after 1 year more adverse effects, combination therapy is rarely used.2,53,54
of romosozumab followed by 1 year of alendronate. Lumbar spine and Combination therapy of two antiresorptive agents or two anabolic
hip BMD statistically increased after 1 year of romosozumab treatment. agents did not increase bone mass compared to monotherapy even
To prevent BMD loss after discontinuation, therapy with denosumab or though they have different pharmacologic properties. Combination
alendronate for 1 year after romosozumab resulted in BMD continuing of teriparatide with oral bisphosphonates generally resulted in less
to increase at hip and bone sites. Vertebral, femoral neck, and hip BMD BMD gains than monotherapy, and thus is not used. Combination
and hip bone strength increased after romosozumab therapy in post- teriparatide and denosumab resulted in greater hip BMD effects,
menopausal women who had received at least 3 years of prior bisphos- but long-term results were generally similar to sequential therapy.
phonate therapy.73 These BMD increases were not as large as reported in Estrogen therapy combined with a bisphosphonate did not increase
bisphosphonate naïve women but were greater than teriparatide therapy bone mass more than monotherapy. Antiresorptive therapy can be
BMD effects after bisphosphonate therapy. Comparing published results initiated after estrogen discontinuation to help negate the acceler-
in postmenopausal women, romosozumab might be better to prevent ated bone loss that occurs once estrogen is stopped. For postmeno-
hip fractures compared to abaloparatide and teriparatide while these pausal women with menopause symptoms and an osteoporosis
last agents might be better for vertebral fracture prevention.75 Romoso- diagnosis, an osteoporosis medication should be prescribed along
zumab increased BMD in men by 12.1% at the lumbar spine, 2.5% total with menopausal hormone therapy. When raloxifene is used for
hip, and 2.2% femoral neck, all significantly different than placebo after breast cancer prevention, sometimes another antiresorptive agent
1 year of therapy.54 Fracture data were not captured in men. will be prescribed, especially if hip fracture risk is high.

Adverse Effects Headache and arthralgia were the most

common adverse effects, followed by hypercalcemia (<1%) (see Table
SPECIAL POPULATIONS
112-8).2,39,54 Mild injection site irritation occurred in 6% to 8% of Osteoporosis is a particular threat in some subgroups because of age,
patients. Romosozumab antibodies developed in 10% to 20% patients, genetic abnormalities, diseases, and medications.
sometimes being transient. The antibodies generally are not neutraliz-
ing antibodies nor did they alter efficacy. Serious cardiovascular events Children and Adolescents
have been reported in a few trials, but the incidence is low (<2.5%) 6 Osteoporosis in children and adolescents is uncommon but can
and not much higher nor significantly different from the alendronate lead to significant pain, deformity, and chronic disability. Pediatric
treatment arm (1.9%) in postmenopausal women at 1 year. The seri- osteoporosis is due to genetic disorders such as osteogenesis imper-
ous cardiovascular events increased to 6.5% and 6.1%, respectively, after fecta and idiopathic juvenile osteoporosis, or secondary causes
both arms were switched to alendronate for year 2. In men, the cardio- including chronic inflammatory diseases, growth hormone defi-
vascular event rates were 4.9% in men receiving romosozumab versus ciency, celiac disease, diabetes, anorexia nervosa, and glucocorticoid
2.5% receiving placebo. Myocardial infarction, stroke, and cardiovascu- use (see Tables 112-2 and 112-3 for other causes). Female athlete
lar death are listed as a boxed warning. Romosozumab should not be triad and anorexia nervosa, which are common in this age group,
used within 1 year of a myocardial infarction or stroke and benefit risk can lead to osteoporosis and fractures.
evaluation should be conducted in patients at risk for these conditions The diagnosis and treatment of osteoporosis in children and
or with these conditions in their past medical history. Rare cases of ONJ adolescents are challenging. Low bone mass is defined as a Z-score
and atypical femoral fractures have been reported. Because Wnt signal- of −2.0 or less (adjusted for gender, age, and race/ethnicity) or
ing is also related to malignancies, the medication-induced increased T-score <−2.5 when adult height has been achieved using central
activity could be a concern. However, this adverse effect was not seen in DXA of the spine or total body minus head.10,15 Ability to lie still dur-
the premarketing clinical trials. ing the DXA and radiation doses of some tests create concerns for
this age group. Routine DXA monitoring is not required10; however,
Interactions None
some criteria for this test have been suggested.15 An osteoporosis
Dosing and Administration The medication comes as two diagnosis requires a DXA Z-score of −2.0 or less and 2 long-bone
prefilled syringes requiring refrigeration until administered by a fractures by age of 10 or 3 long-bone fractures by the age of 19.10

CH112.indd 1546 06-12-2022 14:51:45

 1547
DXA monitoring is done every 1 to 2 years for bone health and cause for osteoporosis and no history of fracture should be treated
annually for children on bisphosphonate therapy.10 Spine x-rays can with a bone-healthy lifestyle and watchful waiting.
also be monitored every 6 months to 2 years. Genetic testing might Osteoporosis medication safety during pregnancy and breast-
be required to identify an underlying cause.15 feeding have not been adequately studied. While some data suggest
The first step in management is correcting any underlying pri- that use prior to conception and during the first trimester of preg-
mary or secondary causes and instituting a bone-healthy lifestyle nancy is safe, bisphosphonates are generally not used in women of

CHAPTER        Osteoporosis
especially adequate calcium, vitamin D, and exercise.10,15,58 This step childbearing age due to concern for fetal harm resulting from the
includes weight gain for anorexia nervosa and decreased exercise long half-lives of these agents.73,76 Bisphosphonate use should be
intensity for those with the female athlete triad. avoided within 12 months of conception and use of contraceptive
Pharmacologic treatment has been used for children and ado- agents should be encouraged to reduce the likelihood of becoming
lescents with low bone mass and fragility fractures. Unlike adults, pregnant during therapy. Human data on the safety of denosumab
many children can reshape vertebral fractures and reclaim more and bone-forming agents such as teriparatide in pregnancy are
BMD with treatment.58 Growth hormone can be helpful in children lacking; however, some animal data suggest congenital defects fol- 112
with a documented deficiency but has no effect if no underlying lowing exposure. Therefore, these agents should be avoided during
deficit.57 The optimal osteoporosis medication, dose, and duration of pregnancy.11
therapy are unknown and can vary by age and cause of osteoporosis.
More safety data are needed.15,58 Older Adults
Bisphosphonates can be used off-label in children/adolescents but Although osteoporosis, osteoporotic fractures, and postfracture
should be discontinued when the Z-score goes above -2.0.10 Children morbidity and mortality increase with age, osteoporosis is under-
and adolescents on glucocorticoids frequently need bisphosphonate diagnosed and undertreated in older adults. One-third of older
therapy for longer periods.10,15,58 For children less than 40 kg, the alen- adults older than 65 years old and about 50% of older adults older
dronate dose is 5 mg/day or 35 mg/week and risedronate is 15 mg/ than 80 years old fall annually; with 20% to 30% of these falls result-
week.10 Zoledronic acid is dosed 0.0125 to 0.05 mg/kg (maximum dose ing in moderate to severe injury.2 More than 50% of women older
4 mg) every 6 to 12 months. A major concern with bisphosphonates is than 75 years old have osteoporosis. Fewer than 25% of older adults
their effect on longitudinal bone growth and modeling. Fracture heal- had a DXA completed or received osteoporosis medications after a
ing, skeletal growth/maturation, and the appearance of growth plates fracture. After a hip fracture, more than 50% of older adult women
do not appear to be impaired by bisphosphonates. Because bisphos- will require assistance including long-term nursing home residence
phonates are released from bone for many years and cross the placenta, (25%).2,4 Only 33% of nursing home residents with an osteoporosis
teratogenic effects are also a concern. Bisphosphonates should not be diagnosis or past fracture received an osteoporosis medication, even
used if pregnancy is planned within the year. Pediatric experience with though 89% of them were considered at high risk for a fracture.77
denosumab is limited but positive.57 Hypogonadism is present in about 29% of older men.12 Sarcopenia
Teriparatide has a box warning to avoid use in children due to resulting in decreased muscle mass and function is prevalent in
a concern for osteosarcoma. Newer agents have not been evaluated older adults8 and is associated with increased falls and fractures.78
in pediatric patients. Guidelines recommend central DXA for adults aged 65 years
and older; however, all older adults are not evaluated for osteoporosis.
Premenopausal Women Reference standards for osteoporosis assessment tools are generally
6 Clinically significant bone loss and fractures in healthy pre- not available for the oldest older adults (eg, maximum age for FRAX
menopausal women are rare.73 Risk factors are similar between is 90 years). In clinical practice, estimates for a 90-year-old person
premenopausal and postmenopausal osteoporosis. While bone loss are applied to those adults older than 90 years. FRAX slightly overes-
occurs during pregnancy and lactation, it is usually gained back 6 to timates, whereas ultrasound underestimates osteoporosis in nursing
12 months after pregnancy or breastfeeding is complete. Secondary home residents. In an older adult with falls, the Garvan calculator
causes are involved in 50% to 90% of premenopausal women with might be preferred since it includes falls, whereas FRAX does not.2
osteoporosis (see Tables 112-2 and 112-3) for the bone loss.11 Older adults should practice a bone-healthy lifestyle, ingest ade-
Common secondary causes in this group are amenorrhea, anorexia quate calcium and vitamin D, and implement measures to prevent falls
nervosa, glucocorticoid use, and celiac disease. Premenopausal (see above sections).2,8,12,14,79 While some guidelines recommend ade-
women with prior fracture have a higher risk of postmenopausal quate amounts of calcium and vitamin D, the USPSTF feels evidence is
osteoporotic fractures.11,73,76 insufficient to support fall and fracture prevention with supplementa-
Routine bone density screening should not be performed in tion. Lactose intolerance and hypercholesterolemia increase with aging
healthy premenopausal women. Premenopausal women with known and can lead to lower calcium intake from dairy products, which can
osteoporosis risk factors and low-trauma fractures can undergo increase the need for calcium supplements. Limited sun exposure due
central DXA examinations.73 In this case, the Z-score is used, with to frailty and institutional residence can increase the need for vitamin D
Z-scores of −2.0 or less defined as bone mass below the expected supplementation for bone and muscle health. Protein intakes of 1 g/kg/
range for age.11,37,73,76 The categorization of osteopenia or osteopo- day (up to 1.5 g/kg/day for some chronic illnesses) are suggested, and
rosis based on T-score alone should be avoided in premenopausal these also help with decreasing sarcopenia. Exercise might be difficult
women unless there is a history of low-trauma fracture or a second- in older adults due to osteoarthritis or limited by underlying cardiac
ary cause of osteoporosis. and respiratory diseases. However, walking and lifting light weights
Pharmacologic therapy for osteoporosis should be used with can still stimulate bone remodeling. Encouraging older adults to do
caution in premenopausal women as antifracture efficacy and safety a home safety evaluation for falls can assist with fracture prevention.
have not been adequately demonstrated.11,73 All premenopausal Multidisciplinary fall prevention programs with multiple interventions
women should practice a bone-healthy lifestyle, including adequate generally have greater impact on fall prevention than single discipline or
calcium and vitamin D intake. Secondary causes of bone loss should single intervention.47 Exercise is a major component of these interven-
be resolved. For example, gaining weight and resumed menses are tions. Many fall prevention materials are available without cost on the
more effective in correcting bone loss secondary to anorexia ner- Internet.
vosa than oral contraceptives.73,76 If the contributing factor cannot be Some data exist to support osteoporosis medication ben-
eliminated, for example, chemotherapy or glucocorticoids, pharma- efits in older adults; however, data are limited for the oldest older
cological therapy can be considered. Women with an unidentified adults.8,14,75 In a Medicare study, antiosteoporotic medications after

CH112.indd 1547 06-12-2022 14:51:45

 1548
a fracture lowered subsequent fracture risk by 21%. When deciding Denosumab is not renally eliminated and thus can be used. When
whether to use prescription medications in older adults, the follow- denosumab is used in CKD-MBD or dialysis, serum calcium levels
ing factors need to be taken into consideration: remaining life span, need to be monitored since these patients can develop hypocalcemia,
ability to take and afford medications, cognitive function, swallow- especially if also receiving calcium-sensing receptor agonists. According
ing ability, GI disorders, polypharmacy, desire to avoid additional to product labeling, oral bisphosphonates are not recommended and
medications, and regimen complexity. Challenges with oral bisphos- zoledronic acid is contraindicated if CrCl is less than 30 or 35 mL/min
phonate administration requirements exist for older adults who are (0.50 or 0.58 mL/s). However, guidelines suggest bisphosphonates can
SECTION     Rheumatologic Disorders

bed bound, have difficulties swallowing, have fluid restrictions for be used, particularly when decreased renal function is the result of
cardiovascular or kidney diseases, forget to drink adequate amounts aging alone. Insufficient data exist to support lower doses for shorter
of fluid, or cannot stay upright for the given time. Diuretics, nephro- durations, which have been suggested to account for decreased renal
toxic medications, and dehydration can increase acute and chronic bisphosphonate elimination. Dialysis does eliminate bisphosphonates,
renal failure when zoledronic acid is administered too quickly.2 but if the dose is given after dialysis, a lower dose or longer interval is
14 The cost of antiosteoporosis medications can quickly cause an suggested.80 Bisphosphonates should not be given at the same time as
older adult with the Medicare Part D (medications) to enter the cov- phosphate binders or other medications. Patients with CKD should be
erage gap, or “donut hole,” which is the period when out-of-pocket reassessed in 3 years or after a fracture for bisphosphonate continua-
medication expenses can be higher. Having to pay for antiosteoporosis tion decisions. Raloxifene is not suggested for patients with severe renal
medications might create adherence problems. Sometimes not initiat- impairment. Teriparatide can help patients with adynamic bone and
ing or stopping osteoporosis medications might be warranted for older those with low PTH and BMD but not for patients with high bone turn-
adults with conditions such as severe Alzheimer disease or during pal- over. A role for abaloparatide and romosozumab could exist since these
liative or hospice care. Comprehensive medication reviews and depre- medications are not renally eliminated, do not accumulate in bone, and
scribing can decrease all-cause mortality and potentially inappropriate can overcome some CKD-MBDs; however, little evidence is available
medication use but does not increase nor decrease falls.50 to guide use. Since many patients with decreased renal function have
cardiovascular disease, use of romosozumab might be limited. Fracture
Chronic Kidney Disease risk increases with osteoporosis medication discontinuation, so a post-
Low BMD and fractures occur in patients with chronic kidney disease discontination plan is needed. Kidney and/or bone specialists usually
(CKD, glomerular filtration rate (GFR) less than 60 mL/min/1.73 m2 provide care to patients with significant kidney disease and osteoporosis.
[0.58 mL/s/m2]), using chronic dialysis, and/or after kidney trans-
plant.80 Some medications for CKD and transplant can further com- Drug-Induced Osteoporosis
promise bone health. Fractures occur earlier and have greater 1-year Glucocorticoid-Induced Osteoporosis 3 Glucocorticoid use
mortality rates (64%). Osteoporosis and decreased renal func- is the most common cause of medication-induced osteoporosis. Up
tion due to aging are different from other chronic kidney disease- to 40% of patients taking chronic oral glucocorticoids will experi-
mineral and bone disorders (CKD-MBD) such as renal osteodys- ence a clinical fracture or show evidence of vertebral fracture on
trophy (see Chapter 69 “Calcium and Phosphorus Homeostasis” x-ray.82,83 In patients who take 2.5 to 7.5 mg/day of prednisone or
and Chapter 62 “Chronic Kidney Disease”), which can be related to the equivalent, the relative risk of vertebral fracture doubles and the
high bone turnover, adynamic bone, or a combination of both. A relative risk of hip fracture increases by 50%.84 All glucocorticoid
DXA with VFA when appropriate can be used to assess bone loss doses and formulations have been associated with increased bone
and FRAX can be used to determine fracture risk; however, neither loss and fractures; however, risk is much greater with prednisone
assessment distinguishes between renal and nonrenal causes of bone doses of 5 mg or more daily or equivalent and with oral therapy ver-
loss.81 The DXA result can underestimate fracture risk since changes sus inhaler and intranasal therapy.84,85 Although a well-documented
in bone quality from CKD are not captured. Similarly, FRAX can risk, many patients receiving glucocorticoids are not evaluated or
underestimate risk since renal failure is not included as a risk factor. treated for glucocorticoid-induced osteoporosis (GIO); therefore,
When the diagnosis of the underlying bone disease pathophysiology greater vigilance by all healthcare professionals is needed.82,84
could influence treatment, a bone biopsy can be conducted but is Bone losses with glucocorticoids are rapid with up to 12% loss
no longer a Kidney Disease Improving Global Outcomes (KDIGO) over the first year. The greatest decrease occurs in the first 3 to 6
requirement.80 Laboratory tests such as serum calcium, 25(OH) vita- months of therapy. Afterward, bone loss is about 2% to 3% per year.84
min D, intact PTH, and serum phosphorus can help with identifying The risk of fracture increases within 3 months of initiating gluco-
underlying CKD-MBD. Non-kidney-retained BTM such as bone- corticoid therapy and peaks at 1 year. Trabecular bone is affected
specific alkaline phosphatase (BSAP), PINP and tartrate-resistant more than cortical bone; therefore, vertebral fractures are more
acid phosphatase 5b (TRAP 5b) can be used to monitor therapy and common. The pathophysiology of glucocorticoid-induced bone
guide reinstitution of therapy after a bisphosphonate drug holiday.81 loss is multifactorial.83 Glucocorticoids decrease bone formation
Other markers are being investigated.80 through decreased proliferation and differentiation and enhanced
The first treatment step is to manage underlying disease condi- apoptosis of osteoblasts. They can interfere with the bone’s natu-
tions, including calcium and vitamin D abnormalities, hyperphos- ral repair mechanism through increased apoptosis of osteocytes.
phatemia, and hyperparathyroidism (discussed in Renal Disorders Glucocorticoids increase RANKL and decrease OPG, leading to an
chapters of this textbook).80 Limited data exist on osteoporosis increase in the number of osteoclasts and increased bone resorption.
medications for patients with CKD, dialysis, and/or post kidney They can reduce estrogen and testosterone concentrations. A nega-
transplant.2,80,81 Calcium intake is preferred by diet with supplements tive calcium balance is created from decreased calcium absorption
used only to achieve RDAs when diet is insufficient. A 25(OH) and increased urinary calcium excretion via alterations in calcium
vitamin D level is obtained to assess bone health with vitamin D transporters. The underlying disease requiring glucocorticoids (see
treatment prescribed as needed to maintain therapeutic concentra- Table 112-2) also can negatively affect bone metabolism.
tions, which are the same as non-CKD patient recommendations. FRAX and central DXA are recommended by current guide-
Sometimes 1,25-(OH)2-vitamin D might also be used for underlying lines for evaluation, though neither adequately accounts for the
CKD-induced deficiencies, creating a need for adding prescription rapid increase in fracture risk following glucocorticoid initiation.82,83
calcitriol therapy to over-the-counter vitamin D therapy. Since FRAX does not account for specific dose, duration or accu-
Osteoporosis medication studies in patients with CKD are lacking mulation of glucocorticoids, scores must be adjusted based on pred-
and often with insufficient sample sizes or were post hoc analyses.2,80,81 nisone dose or equivalent.82 For those taking more than 7.5 mg or

CH112.indd 1548 06-12-2022 14:51:45

 1549
equivalent per day, FRAX risk of major osteoporotic fracture should therapy for those taking high-glucocorticoid doses (30 mg of pred-
be increased by 15% (ie, multiplied by 1.15) and FRAX risk of hip nisone or more per day or a cumulative dose greater than 5 g in the
fracture by 20% (ie, multiplied by 1.2). Based on glucocorticoid- past year), a fracture 18 months or more after starting osteoporosis
adjusted FRAX estimates of the 10-year risk of major osteoporotic therapy, medication adherence or absorption concerns, or other risk
fracture and hip fracture, the patients are risk stratified into low, factors for osteoporosis. VFA is also suggested for patients receiving
moderate, and high risk for fracture. Criteria for classification into a 5 mg or more prednisone or equivalent daily for 3 months or more.37

CHAPTER        Osteoporosis
risk category is detailed in Table 112-9. An initial BMD assessment All patients using glucocorticoids should practice a bone-
is recommended prior to or within 6 months of glucocorticoid ini- healthy lifestyle and minimize glucocorticoid exposure when pos-
tiation for adults 40 years of age or older and for adults under the age sible.82-84 All patients starting or receiving glucocorticoid therapy
of 40 with a history of fragility fracture or other risk factors. Repeat (any dose or duration) should consume 1,000 to 1,200 mg elemental
BMD testing is recommended every 2 to 3 years during osteoporosis calcium and 600 to 800 units of vitamin D daily or more to achieve
therapeutic 25(OH) vitamin D concentrations. Minimizing fall risk
is important. Osteoporosis prevention counseling should occur for 112
TABLE 112-9  Classification of Fracture Risk in Patients all patients using this medication for three months or more regard-
Treated with Glucocorticoids less of dose. Glucocorticoids should be used at the lowest dose and
Fracture for the shortest duration possible. Upon discontinuation of glu-
Risk Adults ≥40 Years Old Adults <40 Years Old cocorticoid therapy, fracture risk decreases and BMD increases,
Low FRAXa 10-year risk of major None of the risk factors though they might not increase to baseline levels.84
osteoporotic fracture <10% listed below for
Alendronate, risedronate, zoledronic acid, denosumab, and teripa-
FRAXa 10-year risk of hip moderate- or high-
fracture ≤1% fracture risk ratide are approved by FDA for GIO.84 The current guidelines from the
American College of Rheumatology divide recommendations for pre-
Moderate FRAXa 10-year risk of major Hip or spine BMD
osteoporotic fracture Z-score <−3.0, or scription osteoporosis medication use in GIO by fracture risk and age
10%-19% rapid bone loss (see Tables 112-9 and 112-10).82 Therapy recommendations are based
FRAXa 10-year risk of hip (≥10% at the hip or on comparative efficacy, potential for toxicity, and cost.
fracture >1% and <3% spine over 1 year) Oral bisphosphonates are recommended first-line, though intra-
and continuing
glucocorticoid venous bisphosphonates can be used in patients who are not adherent
therapy with or unable to take the oral preparations. Teriparatide is recommended
≥7.5 mg/day for for patients who cannot use a bisphosphonate, and denosumab is rec-
≥6 months ommended if neither a bisphosphonate nor teriparatide can be used.
High History of osteoporotic Prior osteoporotic Denosumab is not recommended first-line for GIO due to limited safety
fracture, or fracture data in this population. Consideration should be given to potential risk
hip or spine BMD T-score
≤−2.5 in men ≥50 years
of infection in patients taking immunosuppressive agents or biologic
old and postmenopausal therapies. Raloxifene does not have an FDA indication for GIO, but
women, or does have some clinical data documenting improved BMD at the lum-
FRAXa 10-year risk of major bar spine in patients taking glucocorticoids.84 It is recommended only
osteoporotic fracture
in postmenopausal women if no other osteoporosis medications can be
≥20%, or
FRAXa 10-year risk of hip used. Standard osteoporosis therapy doses are used. The recommenda-
fracture ≥3% tions are similar for women of childbearing potential who do not plan to
become pregnant and are using effective contraception or are not sexu-
a
If glucocorticoid treatment is >7.5-mg prednisone or equivalent per day, the FRAX
risk score should be multiplied by 1.15 for major osteoporotic fracture and by 1.2 ally active.82
for hip fracture and then used to determine overall fracture risk. Patients receiving glucocorticoids are considered high risk, and,
Date from Reference 82. therefore, a bisphosphonate drug holiday is generally not considered

TABLE 112-10  Therapy to Prevent or Treat Glucocorticoid-Induced Osteoporosis in Adults Beginning Long-Term
Glucocorticoid Treatment (≥2.5-mg Prednisone or Equivalent Per Day for ≥3 Months)
Patient Population Low-Fracture Risk Moderate-Fracture Risk High-Fracture Risk
All Optimize calcium and vitamin Optimize calcium and vitamin D intake; Optimize calcium and vitamin D intake;
D intake; bone-healthy bone-healthy lifestyle bone healthy lifestyle
lifestyle
Adults age ≥40 years No prescription osteoporosis Oral bisphosphonate Oral bisphosphonate
therapy alternatives: IV bisphosphonate, alternatives: IV bisphosphonate,
teriparatide, denosumab, or raloxifeneb teriparatide, denosumab, or raloxifeneb
Adults age <40 years No prescription osteoporosis Oral bisphosphonate Oral bisphosphonate
therapy alternatives: IV bisphosphonate, alternatives: IV bisphosphonate,
teriparatide, or denosumab teriparatide, or denosumab
Women of childbearing No prescription osteoporosis Oral bisphosphonate Oral bisphosphonate
potentialc,d therapy alternative: teriparatide alternatives: teriparatide,
IV bisphosphonate, or denosumab

IV, intravenous.
a
Listed in order of preference; abaloparatide and romosozumab were not yet approved during guideline development.
b
Recommended only for postmenopausal women when other alternative therapies cannot be used.
c
Women of childbearing potential who do not intend to become pregnant during the osteoporosis treatment period and are using effective birth control or are not sexually
active.
d
Fetal risks from osteoporosis medications during pregnancy.
Data from Reference 82.

CH112.indd 1549 06-12-2022 14:51:45

 1550
after 5 years. Bisphosphonate treatment for 7 to 10 years is recom- machine. A statistical change needs to be greater than the least sig-
mended if patients continue glucocorticoid use. Since glucocorti- nificant change for that specific piece of equipment based on local
coids can cause hypogonadism, sometimes hormone therapy will data with the team of technicians.
be prescribed. The hormonal therapy for correcting hypogonadism The AACE/ACE guidelines recommend central DXA every 1 to
symptoms most likely will have some positive bone effects as well. 2 years after medication initiation until BMD is stable at which time
the interval for reassessment could be lengthened.2 The Endocrine
Cancer Treatment–Induced Bone Loss Society guidelines recommend waiting 3 years for zoledronic acid,
SECTION     Rheumatologic Disorders

3 Cancers, some associated treatments and metastatic bone dis- 5 years for other bisphosphonates, and 5 to 10 years for deno-
ease can cause bone loss and osteoporosis.59,63 Medications used to sumab.39 Financial support for testing at intervals less than 2 years
treat hormone-responsive cancers—such as aromatase inhibitors might not be provided by insurance plans. In patients with condi-
and androgen deprivation therapy, and some cytotoxic chemo- tions associated with higher rates of bone loss (eg, glucocorticoid
therapies—are associated with a reduction in BMD. Chemotherapy- use and certain chemotherapy agents), more frequent monitoring
14 induced ovarian failure can enhance bone loss. Glucocorticoids used might be warranted.
as chemotherapy, chemotherapy premedication, and/or treatment Like central DXA, BTM can be used to identify nonadherence
for chemotherapy-induced nausea and vomiting also increase bone and lack of response to therapy.2 The markers are measured 3 to
loss in patients with cancer. 6 months after therapy initiation and compared to baseline values.2,88
Central DXA screening is advocated for patients at high risk Significant changes need to be greater than the least significant
for osteoporosis, which would include certain chemotherapies and change for that test.2 Because no consensus on result interpretation
cancers.59 Patients with at least 1 risk factor should be offered BMD and high-test variability exists, these tests are not routinely ordered.
testing with central DXA. In patients on medications that cause bone
loss or whose BMD is near the threshold of treatment with FRAX, Osteoporosis Services
BMD testing should be offered every 2 years or more frequently con- Despite the availability of effective therapies, many patients
sidering the results of the BMD and anticipated bone loss, but not (approximately 70%) are not being evaluated or do not receive
more than annually. FRAX can be used to estimate the risk for osteo- appropriate osteoporosis therapy.2 In fact, the proportion of patients
porotic fracture; however, it has not been validated in patients with receiving osteoporosis medication following a hip fracture has
cancer. When using FRAX, secondary osteoporosis can be checked decreased. People of color receive even fewer DXA screenings and
“yes” when premature menopause and/or hypogonadism caused by less medication therapy, and have poorer results after a fracture.3
chemotherapy and cancer are present, though fracture risk is likely To combat this trend, many institutions are implementing an Own
still underestimated in this group.86 the Bone program or a fracture liaison service, which is gener-
Certain osteoporosis medications are used to prevent bone loss ally an interprofessional, multifaceted program to increase treated
or treat osteoporosis due to chemotherapy, cancer, and metastases. patient numbers, enhance adherence, and improve osteoporosis
Bisphosphonates and denosumab decrease chemotherapy-induced treatment outcomes. All providers and programs should work to
bone loss and in some trials, reduce fractures.59 Most research has decrease health disparities in osteoporosis prevention and treat-
been conducted in women with breast cancer and men with pros- ment.3 Communicating risk is important for people to understand
tate cancer. Raloxifene decreases the risk of invasive breast cancer in their risk for and consequences of fractures, especially in relation
high-risk women.2,34 Due to risk of osteosarcoma, teriparatide and to other medical conditions.2 Community pharmacists and other
abaloparatide are specifically contraindicated in patients with bone healthcare professionals can provide osteoporosis screenings using
metastases or prior radiation to the skeleton. Zoledronic acid and the FRAX tool to estimate fracture risk in the community, especially
denosumab are used for cancer-related hypercalcemia and skeletal- at health fairs. Osteoporosis prevention and treatment services have
related events.63 They are marketed with different product names for been clinically successful in community pharmacies and in ambula-
these indications since dosages are much higher than for osteopo- tory care settings. At 1 year, only 26% to 56% of patients still use
rosis. For additional information see Chapter 150, “Supportive Care their osteoporosis medications. Thus, all healthcare professionals
in Cancer.” should identify and resolve barriers to optimal medication initiation
and adherence. The main reasons for nonadherence are medication
EVALUATION OF THERAPEUTIC cost, fear of adverse effects, resistance to medication use, and per-
ceived lack of medication need. Routine follow-up with healthcare
OUTCOMES professionals and enhanced risk-benefit communication tools could
improve treatment and adherence rates. Databases can be used to
Monitoring of Patient-Centered Care Plan identify patients after a low-trauma fracture who have not had a
Assessment of adherence and tolerability of medication should DXA screening or osteoporosis medication started. Patient medica-
be performed during each encounter patients have with the health- tion assistance programs can be used to decrease cost.
care system. Having patients repeat back instructions for medica- To improve patient care, the US Centers for Medicare and
tion administration will help identify administration problems and Medicaid Services have created this quality measure—the percent
enable timely correction. Assessment of fracture, back pain, and of women 50 to 85 years old with a recent fracture that is screened
height loss can help identify worsening osteoporosis. or treated within 6 months.1,44,89 Financial incentives tied to these
The role of routine monitoring of BMD via central DXA is measures could help bridge the gap in quality of care.
controversial and recommendations vary since change in BMD is
only one component of fracture risk.2,87 Nonetheless, decreases in
BMD while on treatment are associated with increases in fracture
CONCLUSION
risk compared to stable or increased BMD. Since BMD continues Osteoporosis prevention begins at birth and continues throughout
to decrease with aging, no change from baseline can be an accept- life by practicing a bone-healthy lifestyle (adequate calcium and
able response. However, BMD is considered a failure if BMD sig- vitamin D intake, exercise, no smoking, minimal alcohol use, and
nificantly decreases while on treatment. This treatment failure could fall prevention). Generally, osteoporosis occurs in postmenopausal
indicate nonadherence, a lack of response, or the presence of sec- women and older men; however, the disease can occur in all ages
ondary causes contributing to continued bone loss.2 To minimize because of secondary causes such as genetics, diseases, and medica-
test variability, BMD testing should be performed on the same DXA tions. FRAX tool can be used for screening and to assist in identifying

CH112.indd 1550 06-12-2022 14:51:45

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patients at high risk for fracture requiring treatment. Central DXA PTH parathyroid hormone
can be used for osteoporosis screening, diagnosis, and monitoring. PTHrP parathyroid hormone-related protein
Alendronate, risedronate, zoledronic acid, and denosumab QCT quantitative computed tomography
are first-line therapies for those with high fracture risk since these QUS quantitative ultrasound
medications decrease hip, nonvertebral, and vertebral fractures. RANK receptor activator of nuclear factor-kappa β
Abaloparatide, romosozumab, and teriparatide are the only medica- RANKL receptor activator of nuclear factor-kappa β ligand

CHAPTER        Osteoporosis
tions that can build bone; however, cost, subcutaneous administra- RDA recommended dietary allowances
tion, and lack of hip fracture prevention limit their use. Although runX2 runt-related transcription factor
medications decrease fracture risk, prescribing of osteoporosis med- Scr nonreceptor tyrosine kinase
ications and patient adherence to them is suboptimal. All healthcare sFRP secreted frizzled related proteins
professionals need to be actively involved with people of all ages to TBS trabecular bone score
provide osteoporosis education and counseling, prevent osteoporo- TCF/LEF T-cell-specific transcription factor 4/lymphoid
sis development across the lifespan, treat osteoporosis, and improve enhancer factor 1 112
medication adherence to prevent osteoporotic fractures. TGF-β tissue growth factor-β
TNF-α tumor necrosis factor-α
A­BB­RE­VI­AT­IONS TRACP5b
TRPV6
tartrate-resistant acid phosphatase isoenzyme 5
transient receptor potential cation channel
25(OH) 25-hydroxyvitamin D/calcidiol subfamily V member 6
vitamin D TSEC tissue selective estrogen complex
APC adenomatous polyposis coli UL upper limits
ATPase adenosine triphosphatase USP United States Pharmacopeia
BMD bone mineral density USPSTF United States Preventive Services Task Force
BMP bone morphometric proteins VDR vitamin D receptor
BSAP bone-specific alkaline phosphatase VFA vertebral fracture assessment
BTM bone turnover markers WIFI Wnt inhibitory factor 1
Ca++ Calcium WISE Wnt modulator insurface estoderm
Cbfa1 core-binding factor alpha 1 WHO World Health Organization
Cbl E3 ubiquitin ligase Wnt wingless tail ligands
CEE conjugated equine estrogens
Csk1α casein kinase 1α
CKD-MBD chronic kidney disease-mineral and bone disorder R­EF­ER­EN­CES
CrCl creatinine clearance
1. Qaseem A, Forciea MA, McLean RM, et al. Treatment of low bone
CTX c-terminal type 1 collagen telopeptide density or osteoporosis to prevent fractures in men and women:
Dkk-1 Dickkoff-1 A clinical practice guideline update from the American College of
DPD deoxypyridinoline Physicians. Ann Intern Med. 2017;11:818–839. 10.7326/M15-1361.
DSH disheveled cytoplasmic protein 2. Camacho PM, Petak SM, Binkley N, et al. American Association of
DXA dual-energy x-ray absorptiometry Clinical Endocrinologists/American College of Endocrinology clinical
practice guidelines for the diagnosis and treatment of postmenopausal
EAA estrogen agonist antagonist osteoporosis-2020 update. Endocr Pract. 2020;Suppl 1:1–46.
FAK focal adhesion kinase doi:10.4158/gl-2020-0524suppl
FDA US Food and Drug Administration 3. Noel SE, Santos MP, Wright NC. Racial and ethnic disparities in
FGF fibroblast growth factor bone health and outcomes in the United States. J Bone Miner Res.
FRAX World Health Organization fracture risk October2021;36(10):1881–1905. 10.1002/jbmr.4417.
4. Management of osteoporosis in postmenopausal women: The 2021
assessment tool position statement of the North American Menopause Society.
GFR glomerular filtration rate Menopause. 2021;9:973–997. doi:10.1097/gme.0000000000001831
GI gastrointestinal 5. Wright NC, Looker AC, Saag KG, et al. The recent prevalence of
GIO glucocorticoid-induced osteoporosis osteoporosis and low bone mass in the United States based on bone
GSK-3β glycogen synthase kinase-3β mineral density at the femoral neck or lumbar spine. J Bone Miner Res.
2014;11:2520–2526. doi:10.1002/jbmr.2269
ICTP c-terminal telopeptide 6. Adler RA. Update on osteoporosis in men. Best Pract Res Clin
IGF insulin-like growth factor Endocrinol Metab. 2018;5:759–772. doi:10.1016/j.beem.2018.05.007
IOM Institute of Medicine 7. Carlson BC, Robinson WA, Wanderman NR, et al. The American
LGR4 leucine-rich repeat-containing G protein Orthopaedic Association’s Own the Bone® database: A national
LRP5/6 lipoprotein-receptor related protein quality improvement project for the treatment of bone health in
fragility fracture patients. Osteoporos Int. 2018;9:2101–2109. 10.1007/
m-CSF macrophage-colony stimulating factor
s00198-018-4585-7.
MMP matrix metalloproteases 8. Bouvard B, Annweiler C, Legrand E. Osteoporosis in older adults. Joint
NF-Kβ nuclear factor kappa β Bone Spine. 2021;3:105135. doi:10.1016/j.jbspin.2021.105135
NHANES National Health and Nutrition Examination Survey 9. Troy KL, Mancuso ME, Butler TA, et al. Exercise early and often: Effects
NTX n-terminal type 1 collagen telopeptide of physical activity and exercise on women’s bone health. Int J Environ
Res Public Health. 2018;5. doi:10.3390/ijerph15050878
OCN osteocalcin
10. Galindo-Zavala R, Bou-Torrent R, Magallares-López B, et al. Expert
ONJ osteonecrosis of the jaw panel consensus recommendations for diagnosis and treatment of
OPG osteoprotegerin secondary osteoporosis in children. Pediatr Rheumatol Online J.
P13K phosphatidyl inositol 3-kinase 2020;1:20. doi:10.1186/s12969-020-0411-9
pDXA peripheral dual-energy x-ray absorptiometry 11. Pepe J, Body JJ, Hadji P, et al. Osteoporosis in premenopausal women:
A clinical narrative review by the ECTS and the IOF. J Clin Endocrinol
PICP procollagen type 1 carboxy(C)-terminal
Metab. 2020;105:dgaa306. doi:10.1210/clinem/dgaa306
propeptide 12. Rinonapoli G, Ruggiero C, Meccariello L, et al. Osteoporosis in men:
PINP procollagen type 1 amino(N)-terminal propeptide A review of an underestimated bone condition. Int J Mol Sci. 2021;4.
PPARγ peroxisome proliferator-activated receptor gamma doi:10.3390/ijms22042105

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 SECTION
16 DERMATOLOGIC DISORDERS

Acne Vulgaris
Debra Sibbald and Cathryn Sibbald

KEY CONCEPTS
1 Acne is a highly prevalent disorder affecting adolescents
and adults, with a large psychosocial impact.
6
Chapter 117
Nondrug measures are aimed at long-term prevention and
treatment. Patients should eliminate aggravating factors,
2 The etiology of this complex disease originates from maintain a balanced, low-glycemic load diet, and control
multiple causative and contributory factors, including stress. Cleanse twice daily with mild soap or soapless
genetics and environment. The diagnosis is based on the cleanser and use only oil-free cosmetics. Comedone
patient’s history and clinical presentation. extraction in approximately 10% of patients produces
immediate cosmetic improvement. Shave infrequently as
3 Acne is a disease of the pilosebaceous unit. Elements of
possible, using a sharp blade or electric razor.
pathogenesis involve defects in epidermal keratinization,
androgen secretion, sebaceous function, bacterial growth, 7 First-, second-, and third-line therapies should be
inflammation, and immunity. appropriate for the severity and staging of the clinical
presentation and directed toward control and prevention.
4 Acne vulgaris is a chronic disorder which cannot be
“cured.” Goals of treatment and prevention include 8 Treatment regimens should be tapered over time, adjusting
control and alleviation of symptoms by reducing the to response. Combine the smallest number of agents at
number and severity of lesions, slowing progression, the lowest possible dosages to ensure efficacy, safety,
limiting disease duration and recurrence, prevention avoidance of resistance, and patient adherence.
of long-term disfigurement associated with scarring 9 Once control is achieved, maintenance regimens should
and hyperpigmentation, and avoidance of psychologic be simplified to continue with some suppressive therapy.
suffering. Targeting goals may increase patient adherence Therapy must be continued beyond 8 weeks: efficacy is
to therapy. assessed through comedonal and inflammatory lesion
5 The most critical target for treatment is the count, control or progression of severity, and management
microcomedone. Minimizing or reversing follicular of associated anxiety or depression. Safety end points
occlusion will arrest the pathogenic acne cascade and include monitoring for treatment adverse effects.
involve combining treatment measures to target all Motivate the patient to continue long-term therapy through
pathogenic elements. empathic and informative counseling.

BEYOND THE BOOK pathophysiology of acne; relevant treatment with nondrug measures;
and comparisons of pharmacologic agents, including drugs of choice
Watch the video entitled “Acne” by Dr Sheilagh Maguiness, recommended in best-practice guidelines. Options include a variety of
pediatric dermatologist, available on the Society for alternatives such as retinoids, antimicrobial agents, hormones, and light
Pediatric Dermatology Website (https://tinyurl.com/saa9t4s). therapy. Formulation principles are discussed in relation to drug deliv-
This 5-minute video provides a brief overview regarding ery. Patient assessment, general approaches to individualized therapy
information patients need to know about acne vulgaris. The plans, and monitoring evaluation strategies are presented.
video is useful to enhance student understanding regarding
what information to provide to patients regarding causes of EPIDEMIOLOGY
acne, triggers, cleansing, over-the-counter and prescription 1 Acne vulgaris is a chronic disease and the most common one
options, directions for use, and precautions. It gives a brief treated by dermatologists. There is a high degree of variability in
summary of take-home points useful to direct counseling. prevalence, age of onset, distribution, severity, and age of resolution.
The lifetime prevalence of acne approaches 90%, with the high-
est incidence in adolescents; it affects 9.4% of the general population,
INTRODUCTION with trends reflecting higher rates in urban areas compared to rural
villages, although these rates are subject to selection and detection
In this chapter, we review the latest developments in understanding bias due to differential access to providers.1
acne vulgaris and its treatment. The contents provide an analysis of the The onset of acne vulgaris during puberty occurs at a younger
physiology of the pilosebaceous unit; the epidemiology, etiology, and chronologic age in girls than boys (12% age 25-58 vs 3% in males of
1611

CH117.indd 1611 13-12-2022 15:23:44

 1612
the same age) and periodic premenstrual flares may continue until such as intense anger and stress, can exacerbate acne, causing flares
menopause. It is triggered in children by the initiation of androgen or increasing mechanical manipulation: picking, excoriating, or
production by the adrenal glands and gonads, and it usually subsides pinching lesions sometimes subconsciously or in sleep. This is prob-
after the end of growth. However, to some degree, most patients con- ably the result of increased glucocorticoid secretion by the adrenal
tinue to have symptoms into their mid-twenties, and there is evi- glands, which appears to potentiate the effects of androgens.6
dence that the duration of acne may last into middle age for most Dietary influences Current investigations explore associations
women, recorded in 54% of women and 40% of men older than 25 between dietary influences and acne. Under study are dietary influ-
SECTION     Dermatologic Disorders

years of age.2 In puberty, acne is often more severe in boys in about ences as factors in acne development as well as potential treatment
15% of cases, which is 10-fold greater than in girls. Women often modalities. This follows the dismissal of overinterpreted 40-year-
have more severe forms during adulthood. When untreated, acne old, poorly designed studies that disavowed potential effects of
usually lasts for several years until it spontaneously remits. After the dietary ingestions on acne.7-9 Three primary influences on develop-
disease has ended, scars and dyspigmentation are not uncommon ment include dairy and growth factors in milk; whey protein in milk;
16 permanent negative outcomes. and hyperglycemic-load diets.
Genetic factors have been recognized; there is a high concor- A series of studies have linked consumption of dairy products
dance among identical twins, and there is also a tendency toward with acne.10,11 Acne has been positively associated with the reported
severe acne in patients with a positive family history of acne. quantity of milk ingested, particularly skim milk.12 The Nurses
There are believed to be no gender differences in acne preva- Health Retrospective Study examining diet during high school in
lence. A systematic review included five studies, with a pooled odds 47,355 women found an association between acne and milk intake,
ratio of 1.07 (95% CI 0.42-2.7, males with reference to females), sug- suggesting natural hormonal components of milk and/or other bio-
gesting only a slightly higher odds in males.3 active molecules in milk could exacerbate acne.13
An international group of epidemiologists, community medi- Lactoferrin is a whey milk protein with anti-inflammatory
cine specialists, and anthropologists have questioned whether acne activity. Lactoferrin-enriched fermented milk ameliorated acne
might be predominantly a disease of Western civilization.4 They vulgaris, selectively decreasing triacylglycerols in skin surface lip-
assert that since acne vulgaris is nearly universal in westernized ids.13 Lactoferrin administered as a dietary supplement twice daily
societies (afflicting 79%-95% of the adolescent population), one in mild-to-moderate acne vulgaris led to an overall improvement in
causative factor might be the Western glycemic diet. While this acne lesion counts in adolescents and young adults.14
hypothesis is based on the observation that primitive societies sub- A meta-analysis of observational studies examined association
sisting on traditional (low glycemic) diets have no acne, the theory of dairy intake and acne in children, adolescents, and young adults.
awaits validation and acceptance by the dermatologic community. Any dairy product—including milk, yogurt, and cheese—was asso-
ciated with an increased odds ratio for acne in individuals aged 7
to 30 years; however, studies were heterogeneous in design, making
ETIOLOGY comparisons difficult.15
2 Acne is a multifactorial disease. Genetic, racial, hormonal, Other studies suggest a role for insulin-like growth factor
dietary, and environmental factors have been implicated in its devel- (IGF), increased by ingestion of high glycemic loads.16,17 The stron-
opment. Its psychologic impact can be severe. gest evidence supports a high-glycemic-load (HGL) diet as a signifi-
Four major etiologic factors are involved in the development of cant factor in acne. In a randomized controlled trial, patients who
acne: increased sebum production, due to hormonal influences; alter- eliminated high glycemic index foods showed a significant reduction
ation in the keratinization process and hyperproliferation of ductal in acne. Those who consumed a low-glycemic-load diet compared
epidermis; bacterial colonization of the duct with Propionibacterium with a conventional HGL diet had improvements of facial acne
acnes; and production of inflammation with release of inflammatory after 12 weeks. Accompanying changes in physical and endocrino-
mediators in acne sites. These are reviewed in the “Pathophysiology” logic parameters suggest that decreases in total energy intake, body
section later in this chapter. weight, and indices of androgenicity and insulin resistance may also
The role of heredity in acne has not been clearly defined; how- be associated with observed improvements in acne.18 Another study
ever, there is a significant tendency toward more serious involve- reported an improvement in acne and insulin sensitivity in low-
ment if one or both parents had severe acne during their youth. glycemic-load diets compared with controls, suggesting nutrition-
Environmental factors play a major role in determining the related lifestyle factors play a role in acne etiology.19 Independent
severity and extent of acne and may influence the choice of topi- effects of weight loss versus dietary intervention need to be isolated.
cal treatments. Heat and humidity may induce comedones; pressure In an Australian study, participants who consumed low-glycemic-
or friction caused by protective devices such as helmets, shoulder load diets had no reported cases of acne.12
pads, or pillows, and excessive scrubbing or washing can exacerbate Other studies showed correlations between increases in the
existing acne by causing microcomedones to rupture. Pressure may ratio of saturated to monoun-saturated fatty acids, acne lesion
cause acne lesions to form in patients who do not have acne vulgaris: counts, and increased sebum outflow, suggesting a possible role of
this variant is called mechanical acne. Friction, wool, or other rough desaturase enzymes in sebaceous lipogenesis and the clinical mani-
textured fabrics and occlusive clothing may also be mechanical irri- festation of acne. These require further investigation.20
tants. Hair styles that are low on the forehead or neck may cause Univariate and multivariate analyses were used to examine results
excessive sweating and occlusion, exacerbating acne. In most cases of a 2015 French survey of individuals (age 15-24 years) reporting or
acne is worse in winter and improves during the summer, suggest- not reporting acne with associated epidemiologic variables. Daily con-
ing a salutary effect of sunlight. However, in some cases, exposure sumption of chocolate and sweets (odds ratio 2.38) and regular use of
to sunlight worsens the disease.5 Studies examining the relationship cannabis (odds ratio 2.88) was independently and highly associated
between tobacco smoking and acne show inconsistent results; how- with acne. Smoking tobacco (>10 cigarettes daily) was highly protec-
ever, dermatologists have begun to counsel people to quit tobacco tive. Respective roles of sugar, lipids, and milk were not investigated.21
smoking as a potential auxiliary treatment for acne. The role of dietary factors in the development or progression
The importance of psychologic factors in this prolonged and of acne vulgaris cannot be dismissed. The practical recommenda-
capricious condition has been repeatedly stressed. Two-thirds of tions would be to avoid excess sugar and skim milk. Further studies
affected teenagers wish that they could speak with their physician are ongoing, including reviewing antioxidants from nutritional and
and healthcare provider about acne, but only one-third do. Emotions, topical sources and probiotics as potential acne-fighting agents.12

CH117.indd 1612 13-12-2022 15:23:46

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PATHOPHYSIOLOGY glands increase their size and activity in response to circulating
androgens. Most patients with acne do not overproduce androgens
3 The pathogenesis of acne includes hyperseborrhea, abnormal (with some exceptions); instead, they have sebaceous glands that
follicular keratinization, and Propionibacterium acnes prolifera- are hyperresponsive to androgens.24 Patients with acne have a sig-
tion in the pilosebaceous unit. Recent research has shed some new nificantly greater number of lobules per gland compared with unaf-
light on the involvement of the sebaceous gland, as well as on the fected individuals.
pro-inflammatory activity of the cutaneous microbiome. Acne pro-

CHAPTER        Acne Vulgaris
Sebum production is induced by different receptors expressed
gresses through the following four major stages: by the sebaceous gland. Involved are the histamine receptor (acti-
1. Increased sebum production by the sebaceous gland vated by histamines); the hormonal DHT receptor (activated by
androgens); the neuromodulator receptor (mainly substance P);
2. P. acnes follicular colonization (and bacterial lipolysis of
and corticotrophin-releasing hormone (CRH) receptor (mainly
sebum triglycerides to free fatty acids)
activated by stress); molecular research has identified three other
3. Release of inflammatory mediators receptors that are expressed by the sebocyte and control sebum pro- 117
4. Increased follicular keratinization duction. Each of these newly identified receptors is activated by a
dietary substance.23
Improved understanding of acne development on a molecular level
The peroxisome proliferator-activated receptors are stimulated
suggests that acne is a disease that involves both innate and adaptive
by free fatty acids and cholesterol, which act in concert with retinoid
immune systems and inflammatory events. Receptors that regulate
X receptors to regulate epidermal growth and differentiation as well
sebaceous lipid metabolism work in concert with receptors regulat-
as lipid metabolism.
ing epidermal growth and differentiation. Acne can be considered
The insulin-like growth factor (IGF)-1 receptor is stimulated
as a model of immune-mediated chronic inflammatory skin disease:
by sugar to increase lipid formation, mediated by sterol response
an innate immune response that is not able to control P. acnes fol-
element binding proteins. The leptin receptor is stimulated by fat.
lowed by a Th1-mediated adaptive immune response that becomes
Leptin is responsible for creating lipid droplets within the sebocyte
self-maintaining independently from P. acnes itself.22
and induces pro-inflammatory enzyme and cytokine (interleukin
Acne usually begins in the prepubertal period, when the adre-
[IL]-6 and IL-8) secretion as well.23
nal glands mature, and progresses as androgen production and
The sebaceous gland also acts as an endocrine organ in
sebaceous gland activity increase with gonad development. During
response to changes in androgens and other hormones. Oxidized
puberty, alteration of the sebaceous lipid profile, called dyssebor-
squalene can stimulate hyperproliferative behavior of keratinocytes,
rhea, together with stress, irritation, cosmetics, and potential dietary
and lipoperoxides produce leukotriene B4, a powerful chemoat-
factors lead to inflammation and formation of different types of acne
tractant.24 The composition of sebum is changed, with a reduction
lesions.23
in linoleic acid. The growth of keratinocytes changes. The infrain-
As shown in Fig. 117-1, acne results from the development of
fundibulum increases its keratinization of cells with hypercornifi-
an obstructed sebaceous follicle, called a microcomedone. Sebaceous
cation and development of the microcomedone, the primary lesion
of both noninflammatory and inflammatory acne.22 Cells adhere to
each other in an expanding mass, which forms a dense keratinous
plug. Androgen hormones could be a stimulus to pilosebaceous duct
hypercornification. Sebum, produced in increasing amounts by the
active gland, becomes trapped behind the keratin plug and solidifies,
Abnormal Micro contributing to open or closed comedone formation.
Normal follicle
keratinization comedone Interleukin-1-α upregulation contributes to the development
of comedones independently of colonization with P. acnes. A relative
Increased
sebum
linoleic acid deficiency has also been described.24
production A prominent role is played by the follicular colonization by
Dilated pore P. acnes. P. acnes displays several activities which promote the
development of acne lesions, including the promotion of follicular
Open Closed hyperkeratinization; the induction of sebogenesis; and the stimula-
comedone comedone
tion of an inflammatory response by the secretion of proinflamma-
tory molecules and by the activation of innate immunity, followed
by a P. acnes–specific adaptive immune response. In addition,
P. acnes–independent inflammation mediated by androgens or by a
Dilated pore
neurogenic activation, followed by the secretion in the skin of proin-
flammatory neuropeptides, can occur in acne lesions.22
Pustule Papule The pooling of sebum in the follicle provides ideal substrate
conditions for proliferation of the anaerobic bacterium P. acnes, gen-
Foreign erating a T-cell response, which results in inflammation.25 P. acnes
body
produces a lipase that hydrolyzes sebum triglycerides into free fatty
response
Cascade of the acids. These free fatty acids may trigger the changes that lead to an
pathogenesis of acne increase in keratinization and microcomedone formation.26,27 This
Nodule or cyst closed comedone, or whitehead, is the first clinically visible lesion of
acne. It takes approximately 5 months to develop. The closed come-
© Debra Sibbald done is almost completely obstructed to drainage and has a tendency
to rupture.28-30
FIGURE 117-1 Cascade of the pathogenesis of acne. (Reprinted, As the plug extends to the upper canal and dilates its opening,
with permission, from Mills OH, Kligman AM. Comedogenicity of an open comedone, or blackhead, is formed. Its dark color is not due
sunscreens: Experimental observations in rabbits. Arch Dermatol. to dirt but to either oxidized lipid and melanin or to the impacted
1982;18(6):417-419.) mass of horny cells. The cylindrically shaped, open comedone is very

CH117.indd 1613 13-12-2022 15:23:46

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stable and may persist for a long time as soluble substances and liq- (WHOQOL), Skindex,37 the Dermatology QOL Index,38 and the
uid sebum escape more easily. Acne that is characterized by open Children’s Dermatology Life Quality Index (CDLQI). Examples of
and closed comedones is termed noninflammatory acne. acne-specific scales include the Acne-specific QOL questionnaire,39
Acne produces chemotactic factors and promotes the synthe- the Acne QOL Scale,40 the Acne Disability Index (ADI), and the
sis of tumor factor-α and interleukin-1β. Cytokine induction by Cardiff Acne Disability Index (CADI).35 The Acne QOL Scale was
P. acnes occurs. Both recruitment of polymorphs into the follicle developed to measure the impact of facial acne across four domains
during the inflammatory process and release of P. acnes–generated (acne symptoms, role-emotional, self-perception, and role-social)
SECTION     Dermatologic Disorders

chemokines lead to pus formation. The pus eventually bursts on of health-related QOL. Health-state utilities (such as time trade-off
the surface with resolution of the inflammation or into the dermis. [TTO]) are quantitative measures of patient preferences of health
P. acnes also produces enzymes that increase the permeability of the outcomes ranging from 0 (death) to 1 (perfect health) and can be
follicular wall, causing it to rupture, releasing keratin, hair, and lipids used in clinical trials as outcome measures of treatment effects. TTO
and irritating free fatty acids into the dermis. Several different types utilities for acne in the range of 0.94 to 0.96 can be compared with
16 of inflammatory lesions may form, including pustules, nodules, and those of other diseases (eg, 0.92 for epilepsy, 0.94 for myopia), and
cysts and may lead to scarring. help to identify the impact of acne on self-perception and psycho-
Postinflammatory hyperpigmentation (PIH) and scarring are logic functioning.41
two sequelae of acne. A time delay of up to 3 years between acne
onset and adequate treatment correlates to degree of scarring and Differential Diagnosis
emphasizes the need for early therapy.7,8 Acne vulgaris is rarely misdiagnosed. The conditions most com-
monly mistaken for acne vulgaris include rosacea, perioral dermati-
tis, gram-negative folliculitis, and drug-induced acne.42
CLINICAL PRESENTATION Acne rosacea (adult acne) is a chronic, progressive relaps-
ing condition occurring after age of 30 years in fair-complexioned
To correctly diagnose acne vulgaris, the clinician considers patient
persons. The diagnosis is clinical and based on history and physi-
assessment, which includes distinguishing all the presenting signs
cal findings. There are four subtypes: erythematotelangiectatic
and symptoms of the clinical presentation, reviewing diagnostic and
changes (erythema, flushing, telangiectasia [spider veins], stinging
assessment considerations (see Clinical Presentation box), as well as
and burning); progressing to papular-pustular changes (inflamma-
considering psychosocial issues, differential diagnosis, and the pos-
tory lesions, with edema, papules, and pustules on central facial
sibility of drug-induced acne.
areas such as nose, cheeks, chin, and forehead); phymatous changes
(thickened skin and prominent pores on nose, ears, chin, and eye-
Psychosocial Issues lids); and ocular changes (foreign body sensation, dryness, burning,
Acne causes profound negative psychological and social effects on the eyelid erythema).
quality of life (QOL) of patients. Assessment of acne’s impact on QOL Rosacea has key differences from acne vulgaris. Onset is not
is an important consideration in clinical decision-making. The nega- linked to androgens or endocrine changes; and comedones are not
tive impact of facial acne is one of the primary motivators for patients usually present. Aggravating factors include endogenous triggers:
to seek and to adhere to treatment.34 The European Dermatology ingestion of alcohol, spicy foods, or hot drinks (especially those con-
Forum S3-Guideline for the Treatment of Acne recommended adopt- taining caffeine), smoking; and exogenous triggers: overexposure to
ing a QOL measure as an integral part of acne management.35 Specific sunlight; exposure to temperature extremes, heat and humidity, fric-
QOL indicators represent patients’ perceptions of and reactions to tion, irritating cosmetics, and steroids. Treatment may include anti-
their health. Assessing QOL impairment in patients with acne may biotics, particularly doxycycline (low, anti-inflammatory dose) or
aid in management by evaluating psychologic impact, which may not erythromycin, topical metronidazole, pimecrolimus or azelaic acid
correlate with clinical severity; aid in detection of depression or need as well as agents to reduce erythema (alpha adrenergics).43
for psychologic care; and improve therapeutic outcomes. Perioral dermatitis occurs primarily in young women and ado-
Acne adversely affects all aspects of QOL. In addition to docu- lescents and is characterized by erythema, scaling, and papulopustu-
mentation regarding acne-specific QOL impairment, acne impact lar lesions commonly clustered around the nasolabial folds, mouth,
on general health and psychologic status has been assessed for rela- and chin. The cause is unknown.44
tionship between sociodemographic variables, disease severity, and Gram-negative folliculitis (Proteus, Pseudomonas, Klebsiella)
mental status on QOL of acne sufferers. In a report of 195 cases, may complicate acne, with a sudden change to pustules or large
acne impact on health status was worse compared to other chronic inflammatory cysts occurring after long-term treatment of acne with
diseases. Authors concluded acne is not a minor disease in com- oral antibiotics. Folliculitis may be caused by staphylococci. There
parison with other chronic conditions. Age of onset is capable to is a sudden onset of superficial pustules around the nose, chin, and
influence general health quality (GHQ status), which in turn affects cheeks. Patients with suspected folliculitis should be referred.45
QOL.36 Patients with acne experience functioning and emotional Several conditions include acne vulgaris as a characteristic
effects from their skin disease comparable with those experienced component, and understanding the mechanisms involved in these
by patients with psoriasis, and patients with severe acne reported syndromes provides insight into the pathogenesis of acne. These
levels of social, psychological, and emotional problems as great as include polycystic ovary syndrome (elevated androgen levels); PAPA
those reported by patients with chronic disabling asthma, epilepsy, syndrome (pyogenic arthritis, pyoderma gangrenosum, acne; early
diabetes, back pain, or arthritis.35 onset arthritis with increased inflammatory activity), and SAPHO
The European Academy of Dermatology and Venereology syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis syn-
Task Force on QOL and Patient Oriented Outcomes and the Task drome; sterile inflammatory arthro-osteitis, with P. acnes as a pos-
Force on Acne, Rosacea and Hidradenitis Suppurativa have docu- sible trigger).25
mented the QOL instruments that have been used in acne patients,
with information on validation, purposes of their usage, descrip- Drug-Induced Acne
tion of common limitations and mistakes in their usage, and overall In addition to the conditions induced by drugs that are presented
recommendations.35 in Chapter e121, “Drug-Induced Dermatologic Disorders,” acne-
There are many global scales that have been used to evaluate iform eruptions can also be caused by medications. Drug-induced
acne. Some include the World Health Organization Quality of Life acne is monomorphic, either comedonal with some inflammation

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CLINICAL PRESENTATION Acne Vulgaris

Lesion Type: Acne Vulgaris Can Be • One or more anatomic areas may be involved in
Noninflammatory or Inflammatory any given patient
• Noninflammatory acne is characterized by open and • The pattern of involvement, once present, tends to
remain constant

CHAPTER        Acne Vulgaris
closed comedones that develop from the subclinical
microcomedo • Comedones frequently have a midfacial
• The closed comedo is visible as a 1 to 2 mm distribution in childhood and, when evident early,
whitehead most easily seen when the skin is are indicative of a poor prognosis
stretched. It is often inconspicuous with no visible • Skin, scalp, and hair are frequently oily
follicular opening
• Is the first clinical sign of acne Severity Grading Taxonomies 117
• Has a tendency to rupture US Food and Drug Administration (FDA) Investigator
• The open comedo or blackhead is large, Global Assessment 200531
approximately 2 to 5 mm, and dark-topped with Type 1 Almost clear: rare noninflammatory lesions
contents extruding with no more than 1 small IL
• is relatively stable Type 2 Mild, some noninflammatory lesions, no
• Inflammatory acne is traditionally characterized more than a few inflammatory lesions
as having papulopustular and/or nodular lesions, (papules/pustules only, no nodules)
which may arise from the microcomedo or from Type 3 Moderate: many noninflammatory lesions,
noninflammatory clinically apparent lesions some inflammatory lesions, no more than
• A pustule is formed from a superficial aggregation of one nodule
neutrophils Type 4 Severe: up to many noninflammatory and
• Appears as a raised white lesion filled with pus, inflammatory lesions, but no more than a few
usually less than 5 mm in diameter nodular lesions
• Superficial pustules usually resolve within a few
days without scarring
• A nodule is produced through deeper, dermal, European Union Guidelines Clinical Classification32,33
inflammatory infiltration I Comedonal acne
• Is the most severe variant of acne II Mild-to-moderate papulopustular (MMPP) acne
• Appears as warm, tender, firm lesions, with a III Severe papulopustular acne, moderate nodular
diameter of 5 mm or greater acne (this level combines FDA types 3 and 4, above)
• May be suppurative or hemorrhagic within IV Severe nodular acne, conglobate acne (this is an
the dermis, may involve adjacent follicles and additional level beyond the FDA types above)
sometimes extend down to fat
• Cysts are suppurative nodules named because they Diagnostic and Assessment
resemble inflamed epidermal cysts
Considerations
• Cystic acne may show double comedones,
resulting from prior inflammation and fistulous Palliating factors Sunlight
links between neighboring sebaceous units Provoking factors Premenstrual flares, humid
• Progression of inflammatory lesions environments, excessive sweating;
• Pustules and cysts often rupture spontaneously exposure to chemicals; occlusive
and drain a purulent or bloody but odorless clothing; friction; oily cosmetics;
discharge31 manual manipulation; stress; diet
• Inflammatory lesions may itch as they erupt (high glycemic load, dairy)
and can be tender or painful. Nodules may Associated symptoms Itch, pain, fever
Medical conditions May contribute to or coexist with
develop exudative sinus tracts resulting in tissue
acne, including endocrine factors
destruction
(eg, irregular menses, hirsutism,
• Often resolution of these lesions leaves alopecia), pregnancy, atopy
erythematous or pigmented macules that can
Allergies May cause acne symptoms, or present
persist for months or longer, especially in dark-
a contraindication to therapy
skinned individuals Medication history Products may cause or interact with
• Nodules and deep lesions may result in scarring acne signs and symptoms
Social habits Diet or smoking
Regions of Involvement Family history Genetic predisposition to acne
• Acne lesions can occur anywhere on the body apart Psychosocial issues Assess global and disease-specific
from the palms and soles quality of life (QOL) indicators or
• Are usually located on the face, back, neck, health-state utilities
shoulders, and chest
• May extend to buttocks or extremities

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or papular–pustular. Drugs most commonly implicated in inducing may decrease side effects and minimize resistance or tolerance to
comedonal/inflammatory acne include those with hormonal effects individual treatments.
(steroids, OCP), halogens (iodide, bromide), vitamins (B2, B6, B12), The approach to acne management is largely determined by:
tuberculostatic drugs (isoniazid, ethambutol), lithium salts, antiepi-
1. Severity index
leptics (phenytoin), cyclosporine, and azathioprine. Drugs that most
commonly induce papular–pustular reactions include anti-inflam- 2. Lesion type: predominantly noninflammatory or
matory medications (NSAIDs), sulfamethoxazole–trimethoprim, inflammatory
SECTION     Dermatologic Disorders

cephalosporins, and diltiazem. 3. Treatment preferences including patient choices

Systemic corticosteroids can cause a pustular inflammatory 4. Cost implications
form of acne, especially on the trunk. Onset is abrupt at 2 to 6 weeks
after initiation of therapy. Acne has also been associated with most 5. Skin type and/or ethnic group
of the potent topical steroids, but not with hydrocortisone, which 6. Patient age
16 lacks the ability to inhibit protein synthesis. Discontinuation of the 7. Adherence
steroid results in an initial worsening of appearance due to removal
8. Response to previous therapy
of the anti-inflammatory action of the steroid itself. Caution patients
about this reaction, which can be subdued through judicious use of 9. Presence of scarring
topical hydrocortisone.44-47 10. Psychologic effects
Antiepileptics and tuberculostatics are the most commonly 11. Family history of persistent acne
implicated in drug-induced acne, followed by lithium. Other heavy
metals inducing acne include cobalt (in vitamin B12).48 Halogens, Topical therapy is the standard of care for mild-to-moderate acne.
especially an excess of iodide in seafood, salt, and health foods, can Those with moderate-to-severe acne will require systemic therapy.
exacerbate acne. In addition, halogens can provoke de novo acne Topical treatments work only where applied. To reduce new
lesions in individuals who have increased external exposure often lesion development, they must be applied to the entire affected area
due to occupational contact, or pool or hot tub disinfection; this rather than individual spots. Most cause initial skin irritation, which
variant is called chloracne. may result in nonadherence or discontinuation. Irritation can be
In addition, certain minor ingredients in cosmetics have been minimized by starting with lower strengths and gradually increas-
implicated in cosmetic acne, including isopropyl myristate, cocoa ing frequency or dose. Where irritation persists, changing formula-
butter, and fatty acids. tion from alcoholic solutions to washes, gels, or more moisturizing
creams or lotions might help.
6 7 First-line, second-line, and third-line therapies should
be selected and altered as appropriate for the severity and staging
TREATMENT of the clinical presentation. Treatment is directed at control, not
cure. Regimens should be tapered over time, adjusting to response.
The first step in determining a safe and efficacious treatment regi- Combine the smallest number of agents at the lowest possible dos-
men for acne vulgaris is to establish desired outcomes for the patient, ages to ensure efficacy, safety, avoidance of resistance, and patient
regarding both short- and long-term goals. adherence. Once control is achieved, simplify the regimen but
continue with some suppressive therapy. As it takes 8 weeks for a
Desired Outcomes (Goals of Treatment) microcomedone to mature, therapy must be continued beyond this
4 Acne vulgaris is treated as a chronic disease, as it demonstrates duration to assess efficacy. With the exception of topical antibiotics,
typical chronicity characteristics: manifests as either acute outbreaks most topical preparations may be used for years as needed.
or slow onset; patterns of recurrence or relapse; a prolonged course; Lesions typically recur for years. Microcomedones signifi-
and psychologic and social impact. There are two governing prin- cantly decrease during therapy but rebound almost immediately
ciples: the chronic nature warrants early and aggressive treatment, after therapy is discontinued. The strategy for treating acne
and maintenance therapy is often needed for optimal outcomes. includes an induction phase followed by a maintenance phase,
Acne requires long-term control. This must be stressed with further supported by adjunctive treatments and/or cosmetic
the patient to encourage adherence to lengthy treatment regimens, routines. Routine maintenance therapy involves regular use of
which address management of current symptoms and signs and pre- appropriate agents to ensure remission and reduce potential for
ventive measures. recurrence of visible lesions.
Basic goals of treatment include alleviation of symptoms by For successful long-term treatment, maintenance therapy must
reducing the number and severity of lesions (objective and subjec- be tolerable, appropriate for the patient’s lifestyle and convenience,
tive grading) and improving appearance, slowing progression, limit- continuing months to years, depending on age. Education about
ing duration and recurrence, prevention of long-term disfigurement pathophysiology of acne and the psychosocial benefits of clearer skin
associated with scarring and hyperpigmentation, and avoidance of are compelling reasons for patient adherence to consistent therapy
psychologic suffering. to sustain remission.
A significant percentage change in lesion counts is desirable:
most patients empirically validate a margin of 10% to 15% reduction Nonpharmacologic Therapy
in facial lesion counts as appropriate. Patient global self-assessment 8 9 Encourage patients with acne to discontinue or avoid aggra-
of acne improvement is a primary outcome. vating factors, including occlusion from mechanical factors or cos-
metics, maintain a balanced, low-glycemic-load diet, and control
General Approach to Treatment stress. By being empathic and informative during counseling, the
5 The most critical treatment target is the microcomedone. health professional may motivate the patient to continue long-term
Eliminating follicular occlusion will arrest the whole acne cas- therapy.1,4,43 One of the first approaches to nondrug management
cade. Nondrug and pharmacologic treatment and preventive mea- of acne is attention to cleansing techniques. Shaving recommen-
sures should be directed toward cleansing, reducing triggers, and dations, comedone extraction, dietary considerations, issues relat-
combination therapy targeting all four pathogenic mechanisms. ing to ultraviolet light, and prevention of cosmetic acne should be
Combination therapy is often more effective than single therapy and reviewed with patients.

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Considerations) (eg, hormonal or adrenal anomalies:

presence of vellus hair on females; in children: early age of
onset [age 1-7 years], body odor, hair in axillary and pubic

CHAPTER        Acne Vulgaris
areas; and adrenal: rapid growth in children)
• Severity: number, type, and region of lesions; presence of
scarring
• Hyperpigmentation of healed lesions (postinflammatory
hyperpigmentation)
• Ability/willingness to adhere to long-term therapy 117
• Emotional status (eg, presence of anxiety, depression)

Plan*
• Goals: clear existing and prevent new lesions; reduce
scarring, hyperpigmentation, and psychological impact
• Discontinuation of provoking habits, botanicals, or drug or
nondrug measures
• Cleansing routine
• Drug therapy regimen including dietary, nonpharmacologic,

Patient Care Process for Acne Vulgaris •

and pharmacologic approaches
Monitoring parameters including efficacy (eg, improvement
The image shows the five fundamental steps included in or resolution of lesions and time frame) and safety (eg, sign
The Pharmacist’s Care Process endorsed by the Joint and symptoms worsening, irritation, or allergy); frequency
Commission for Pharmacy Practitioners (2014). The tagline of and timing of follow-up
this process reads collaborate, communicate, and document. • Patient education (eg, purpose of treatment, dietary and
The five fundamental steps listed here are collect, assess, plan, lifestyle modification, drug-specific information, medication
implement, and follow-up: monitor and evaluate. All these administration, or application technique)
steps are listed in a circular block diagram. • Self-monitoring for resolution of acne symptoms,
occurrence of scarring, when to seek emergency medical
Collect attention
• Patient characteristics (eg, age, race, sex, weight [body mass • Referrals to other providers when appropriate (eg,
index], pregnant) behavioral health, dietitian)
• Patient medical history (personal and family history,
especially of acne or scarring, adrenal abnormalities) Implement*
• Social history (eg, psychosocial issues) and dietary habits • Provide patient education regarding all elements of
including intake of glycemic foods, dairy, and sugary drinks treatment plan
(see Clinical Presentation/Diagnostic and Assessment • Use motivational interviewing and coaching strategies to
Considerations; also section “Etiology”) maximize adherence
• Current medications including OTC drug and nondrug • Schedule follow-up, adherence assessment
measures, prescription drugs (eg, contraceptives)
sunscreens, herbal products, dietary supplements, and prior Follow-up: Monitor and Evaluate
acne medication use • Improvement or resolution of acne symptoms
• Current cosmetic use, including makeup, coverups, and (eg, noninflammatory or inflammatory lesions)
cleansers • Prevention of complications (eg, scarring, infection)
• Current use of devices (eg, comedone extractors) • Slow progression
• Inhaled systemic or contact allergies to drugs, cosmetics, • Presence of adverse effects
foods, vehicle ingredients or excipients
• Patient adherence to treatment plan using multiple sources
• Objective data of information
oo Fitzpatrick phototype • Reevaluate duration of therapy every 3 months
oo Labs if relevant to monitoring for hepatic or renal
function Collaborate with patient, caregivers, and other healthcare professionals.
*

Assess
• Presence of provoking factors or contributing factors
(see Clinical Presentation/Diagnostic and Assessment

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Cleansing as possible, using a sharp blade and being careful to avoid nicking
A systematic review of clinical evidence for washing and cleansers lesions. Strokes should be in the direction of hair growth, shaving
reported that they are common interventions. Cleansers are indi- each area only once, to minimize irritation.
cated in all patients with acne. However, the clinical evidence for
Comedone Extraction
their efficacy is not well understood.49
Twice-daily face washing may be superior to either once-daily Comedone extraction has not been widely tested in clinical trials
despite long-standing clinical use; however, it is painless and results
SECTION     Dermatologic Disorders

or more frequent washing. Washing too frequently in an attempt to

remove surface oils has no added benefit and is not likely helpful, as in immediate cosmetic improvement. Pretreatment with a peeler
surface lipids do not affect acne. Contributory lipids are deep in the for 4 to 6 weeks often facilitates the procedure.47 Following cleans-
follicle and are not removed through washing. Antiseptic cleansers, ing with hot water, a comedone extractor is placed over the lesion
while producing a clean, refreshed feeling, remove only surface dirt, and gentle pressure applied until the contents are expressed. This
oil, and aerobic bacteria. They do not affect P. acnes. Patients should removes unsightly lesions, preventing progression to inflamma-
16 wash no more than twice daily with a mild, nonfragranced opaque tion. A correctly sized extractor allows the central keratin plug to
or glycerin soap or a soapless cleanser. extrude through the opening. The small end of a plastic eye dropper,
Bar soaps are subclassified into true soaps, comprising an alkali with bulb removed, may also be used. These instruments should be
and a fatty acid, syndet bars, which use synthetic surfactants, and cleaned with alcohol after each use. Some initial reddening may be
combars, which include features of both. A study has suggested syn- apparent. If the contents are not expressed with modest pressure,
det bars may be superior to true soaps as an acne vulgaris cleansing patients should not continue since improper extraction may further
agent.50 irritate the skin. A physician should be consulted if this technique is
Soapless cleansers are an alternative to soaps.51 Soaps are the too difficult for the patient to manage. Since the follicle is difficult to
most widely used cleansing products, but do not lend themselves remove completely, comedones may recur between 25 and 50 days
to efficient delivery of active drug. Two main disadvantages exist. following expression. Fewer than 10% of comedone extractions are
As soaps are rinsed off, the deposit of active agent is limited, and a complete success, but the process is useful when done properly.31
the high pH required in soaps may degrade some active ingredients Comedo removal may be helpful in the management of come-
and be less tolerable on sensitive skin. Soaps produce a drying effect dones resistant to other therapies. While the procedure cannot affect
on the skin due to detergent action. As medicated cleansers require the clinical course of the disease, it can improve the patient’s appear-
increased contact time, this drying action is pronounced, especially ance, which may encourage adherence with the treatment program.
with peeling agents.
Ultraviolet Light
Gentle liquid cleansers often contain surfactant systems to
remove dirt, sebum, bacteria, and corneocytes from the skin surface. Although ultraviolet light was recommended in the past for des-
Oil is dispersed from the skin into the surfactant system; however, quamation, the practice is no longer advisable because of the
the active ingredient is sometimes trapped and removed upon rins- well-­established carcinogenic and photoaging effects of ultraviolet
ing. The balance between cleanliness and drying or irritation should exposure. Moreover, inflamed skin is more susceptible to the dam-
also be considered. Most patients prefer products with foaming aging effects of ultraviolet light. Patients taking tretinoin may show
action, and these must contain additional secondary surfactants to heightened sensitivity.52
enhance the foam and condition the skin. Before exposure to sunlight, patients with acne should apply
There is no evidence that any particular washing regimen is sunscreens (sun protection factor [SPF] 15) in alcohol- or oil-free
superior. Evidence-based studies on the use of cleanser or medi- bases and avoid using the acnegenic benzophenones. Sunscreen
cated cleansers are lacking or poorly designed with small numbers should be applied as the first product.
of patients.52 It is also difficult to compare studies of different non-
Prevention of Cosmetic Acne
prescription formulations even when the same active ingredient is
used, as differences in the composition of vehicle may affect cuta- Persistent low-grade acne is frequently caused by heavy cosmetic
neous penetration and vehicles themselves may affect acne. Avoid use in women after their mid-twenties. Adolescent acne in younger
cream-based cleansers. Scrubbing should be minimized to prevent women may be exacerbated with makeup overuse. The problem
follicular rupture. is perpetuated when resultant blemishes are concealed with more
Because the acid pH of skin has an antimicrobial effect, it has cosmetics.
been proposed that lowering lesional surface pH (with products Patients should be advised to discontinue oil-containing cosmet-
such as Herpifix, marketed in Europe) may be correlated to the num- ics and avoid cosmetic multistep regimens applying various cream-
ber of acne lesions. Studies are planned. based cleansers and cover-ups. These are commercially advertised and
Synthetic polyester cleansing sponges abrade the skin surface, often available with promotional bonuses through Internet shopping.
removing superficial debris. Considering the structure of comedo- Three-step basic systems usually combine medicated and nonmedi-
nes, they are unlikely to unseat these lesions. Sponges are available cated ingredients. The product names used in marketing these prepara-
in soft or coarse textures, with or without soap. Circular or rubbing tions may not make apparent the inclusion of therapeutic agents. Initial
motions will increase irritation. Instruct patients to use single, gen- steps usually involve cleansers, in lotions or creams, which may contain
tle, continuous strokes on each side of the face, from the midline out a multitude of unnecessary ingredients, including medicated peelers,
toward the ears. oils, fragrances, and preservatives. Active ingredients including salicylic
Cationic-bond strips are activated by water. As the strip dries, acid, sulfur, or benzoyl peroxide are often included in subtherapeutic or
the cation bonds with the anionic dirt and oil in the pores and low doses. The second step is generally a water- or alcohol-based “toner”
removes it when the strip is peeled off. or “refresher,” which might contain medicated mild comedolytic agents
such as α-hydroxy acids (eg, glycolic acid), or even a humectant such as
glycerin. The final product, often called intensive or repairing solutions,
Shaving usually contains the lowest strength of peelers such as benzoyl peroxide,
Boys and men with acne should try electric and safety razors to sulfur, or salicylic acid; plus potentially sensitizing fragrances and pre-
determine which is more comfortable for shaving. When using a servatives; or oil-soluble sunscreens not identified on the label. Bases
safety razor, the beard should be softened with soap and warm water may have significant oil content. There may be additional products such
or shaving gel. Shaving should be done as lightly and infrequently as masks or spot treatments that supplement the base routine of three

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steps. Multiple-step cosmetic programs are often costly and should be Solutions are simpler formulations. They are often used as the
avoided in favor of simple cleansers and more effective single-ingredient soaking liquid for fibrous cloth wipe products. The shelf life depends
peelers at optimal concentrations. upon whether multiple wipe packages are resealable, and whether
The term noncomedogenic may refer to either water-based vehi- the solvent volatility will affect storage and active agent availabil-
cles or products that are free of substances known to induce come- ity or cause crystallization. Solutions are used mainly with topical
dones. They are not necessarily oil-free. Water-based cosmetics may antibiotics, which are often dissolved in specific types of alcohol.

CHAPTER        Acne Vulgaris
contain significant amounts of oil in the form of undiluted vegetable Although some antibiotics are only soluble in ethyl alcohol, iso-
oils, lanolin, fatty acid esters (butyl stearate, isopropyl myristate), propyl alcohol is generally better able to remove oil from the skin
fatty acids (stearic acid), fatty acid alcohols, cocoa butter, coconut surface and is preferred for nonmedicated vehicles. Solutions and
oil, red veterinary petrolatum, and sunscreens containing benzophe- washes can be more easily applied to large areas such as the back.60
nones. Water-based products are more likely to contribute to pore Nongreasy solutions, gels, lotions, and creams should be selected as
blockage than oil-free products. bases for topical acne preparations. Lotions and creams will contain
Oil-free makeups are well tolerated and lipstick, eye shadow, some oil-phase ingredients. Discourage moisturizers and oil-based 117
eyeliner, eyebrow pencils, and loose face powders are relatively products. Lotions are slightly less drying than gels, and creams are
innocuous. Heavier, oil-based preparations, particularly moisturiz- more emollient. Gels are very useful as they are mixtures of water or
ers and hairsprays, clog pores and accelerate comedone formation.53 alcohol and totally oil free. Many gels contain ethanol or isopropyl
Patients should restrict cosmetic use including makeup, mois- alcohol. Propylene glycol is sometimes present in small amounts to
turizers, or sunscreens to products labeled oil-free rather than water- add viscosity and lessen the drying effects of strong peeling agents.
based. Cover-up cosmetics for acne are available in several skin Gels are drying but may cause a burning irritation in some patients
tones and in lotion and cream forms. They often contain peeling and may prevent certain kinds of cosmetics from adhering to the
agents, antibacterial agents, or hydroquinone. Most contain sulfur. skin.53 Propylene glycol gels are easy to apply and dry without a vis-
They may be applied as cosmetics two or three times daily, over the ible or sticky film. Nonalcoholic gels may be so effective and less
entire face or to individual lesions. Because the spread time of oil- drying than alcoholic solutions. Alcoholic or acetone gels are usually
free makeup is decreased, best results are achieved if applied to one- more drying and provide better penetration of the active ingredient.
quarter of the face at a time. Topical medication should be applied Consider the patient’s skin type and preferences in the choice
after gentle cleansing and a foundation lotion may be used sparingly of vehicle for topical agents. Patients with oily skin often prefer vehi-
as a concealer.54-56 cles with higher proportions of alcohol (solutions and gels), while
Because the action of most therapeutic acne agents is to dry the those with dry or sensitive skin prefer nonirritating lotions and
skin, the use of nonspecific moisturizers is counterproductive. Active creams. Hydrating and emollient products are often recommended
agents, such as α-hydroxy acids (glycolic, lactic, pyruvic, and citric to patients using drying treatment therapies, such as isotretinoin, to
acids), may be present in a cosmetic formulation, since they reduce control adverse effects and improve adherence to treatment. Lotions
corneocyte adhesion.57 Patients with acne should be restricted to oil- can be used with any skin type and can be easily spread over hair-
free α-hydroxy acid products unless necessary because of treatment bearing skin, but they will cause burning or dryness if they contain
with strong drying agents or isotretinoin. propylene glycol. Compatibility of vehicles and agents with cosmet-
Cosmetics, if correctly prescribed, may improve the perfor- ics should also be considered.
mance of the therapy, whereas incorrect procedures and/or inade- The focus of innovation has been optimal formulations of prob-
quate cosmetics may worsen acne. Clinicians should make informed lematic drugs. A fixed topical alcohol-free aqueous gel combination
decisions about the role of various cosmetics and to identify the of clindamycin phosphate 1.2% and tretinoin 0.025% given once
appropriate indications and precautions. The choice of the most daily simplifies administration and encourages adherence. Creamy
effective product should take into consideration the ongoing phar- wash and gel hydrophase options for benzoyl peroxide reduce the
macologic therapy and acne type/severity as well.58 irritation of this drug.61
The importance of vehicle effects in topical therapy has been
demonstrated in placebo effect literature.61 The percent contribution
Vehicles of vehicle (placebo) toward efficacy of reduction of lesions counts of
Topical medication is a staple in treating mild-to-moderate acne eight commonly prescribed topical preparations at the end of 10 to
because it is an efficient way to deliver medication to the site of 12 weeks of daily administration has been reported as a mean value
action and involves decreased risk of exposure to ingredients. Since of 55% (range 35%-82%).
local irritation from the vehicle can lead to poor adherence and out-
comes, it is essential to choose a vehicle which is effective and well How to Use Topical Preparations
tolerated. Topical agents are absorbed primarily through passive dif- Topical preparations should not be applied to individual lesions but to
fusion via appendageal transcellular or intracellular pathways. As the whole area affected by acne to prevent new lesions from develop-
the active drug travels, it may undergo chemical changes in the skin ing. Care should be advised in applying around the eyelid, mouth, and
or by the vehicle.59 neck (to avoid chafing). Lotions should be applied with a cotton swab
The formulation of an acne vehicle must consider the techni- once or twice a day after washing or at bedtime if they leave a visible
cal characteristics of maintaining and delivering the drug in an active residue. Skincare products may cause skin dryness and redness particu-
state together with the need for an elegant product that is well tolerated larly at the early stages of the treatment. Should this occur, the product
and the patient will enjoy using, so that it is more likely to be applied as should be applied more infrequently, the treatment should be stopped
required and deliver the full benefit. Physically and chemically, the vehi- for a while or another topical product tried. To reduce irritation a topi-
cle will be used with one or more of the following goals: reduce excess cal vehicle with high water content may be applied over the medicinal
oil, control bacteria associated with acne, reduce the effects of hyperke- product after a few minutes; the irritation usually subsides as the skin
ratinization, and unclog pores. Performance, safety, and stability should becomes accustomed to the topical skincare product.
be maximized while addressing technical and commercial factors.
Immiscible liquids might be delivered in oil-in-water or water- Psychologic Approaches, Hypnosis, and
in-oil emulsions. In addition to having undesirable oil content, these Biofeedback
vehicles also contain humectants, thickeners, preservatives, and fra- The psychologic effects of acne may be profound. The American
grance, all of which may be problematic. Academy of Dermatology expert workgroup unanimously

CH117.indd 1619 13-12-2022 15:23:50

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concluded that effective acne treatment can improve the emotional the generation of its extracellular products and inflammatory effects.
outlook of patients.62 There is weak evidence of the possible benefit Either the fixed-dose combination (adapalene and benzoyl perox-
of biofeedback-assisted relaxation and cognitive imagery.63,64 ide) or benzoyl peroxide or topical retinoid or azelaic acid is strongly
recommended as first choice therapy (high strength recommenda-
Dressings tion).24,32,67 In case of more widespread disease, for the treatment
A pilot double-blind, randomized study of 20 patients has shown of moderate papulopustular inflammatory acne, the fixed-dose
some benefit of treatment with a hydrocolloid acne dressing when combination is preferred, with or without hormonal therapy and/or
SECTION     Dermatologic Disorders

compared with tape dressings for improving mild-to-moderate antibiotic, particularly if the trunk is involved.67
inflammatory acne vulgaris. Results showed greater reduction over Low-strength recommendations are offered as considerations
3 to 7 days in the overall severity of acne and inflammation, along for treatment if there are limitations that apply in selecting a first-
with greater improvement in redness, oiliness, dark pigmentation, choice agent. The choices would be blue light monotherapy, alternate
and sebum casual level. Less ultraviolet B light reaches the skin sur- combination therapy (such as fixed-dose combination of erythro-
16 face with the hydrocolloid dressing in place.65,66 mycin and tretinoin, fixed-dose combination of isotretinoin and
erythromycin) or oral zinc. In case of more widespread disease, a
Pharmacologic Therapy combination of a systemic antibiotic with either benzoyl peroxide or
Successful pharmacologic therapy must address one of the four with adapalene in fixed combination with benzoyl peroxide can be
mechanisms involved in the pathogenesis of acne. Numerous agents considered.24,32
are available that prove one or more of these actions and are there- For moderately severe or severe papulopustular or moderate
fore effective. However, the choice of active pharmacologic therapy nodular acne The fixed-dose combination with an oral antibiotic is
depends on severity. preferred. Alternatively, oral isotretinoin or oral hormonal therapy
Mechanisms of drug action relating to acne pathogenesis are can also be added.68 If there are limitations to use these agents, con-
illustrated in Fig. 117-2. siderations could be given to oral antiandrogens in combination with
oral antibiotics or topical treatments, or systemic antibiotics in com-
Drug Treatments of First Choice bination with benzoyl peroxide (low strength recommendation).
There is concordance among key opinion leaders in different set-
tings regarding recommendations for drugs of choice for manage- Managing Very Severe Acne
ment of acne—the Global Alliance 2018 and the 2016 European For nodular or conglobate acne In males, monotherapy with oral
Guidelines.24,32,67 isotretinoin is strongly recommended as the drug of first choice
(high strength recommendation).24,32 As alternative agents, a reti-
Managing Acne noid fixed combination or oral antibiotics can be recommended. For
For comedonal, noninflammatory acne Active agents of first females, oral isotretinoin plus antiandrogenic hormonal therapy is
choice include those that correct the defect in keratinization by pro- preferred. Alternatively a fixed combination retinoid with oral anti-
ducing exfoliation most efficaciously. Topical retinoids, in particu- biotics (consider high dose) and/or oral antiandrogenic hormonal
lar, adapalene, or a fixed combination with a retinoid (eg, adapalene therapy can be recommended.68
plus benzoyl peroxide) can be recommended as drugs of choice.24,32 For maintenance therapy for acne The most frequently rec-
Benzoyl peroxide or azelaic acid or salicylic acid can be considered, ommended agents are topical retinoids or retinoid and benzoyl
as alternatives (lower strength recommendation).24,32 Limitations peroxide fixed dose combinations.67 The most extensively studied
can apply that may necessitate the use of a treatment with a lower maintenance treatment (four controlled trials) has been adapalene
strength of recommendation as a first-line therapy (eg, financial regimens.24,32 Other published options include tazarotene or treti-
resources and reimbursement limitations, legal restrictions, avail- noin. In general, maintenance therapy is begun after a 12-week
ability, drug licensing). Because the comedone is the initial lesion induction and continues for 3 to 4 months. Continuing improve-
even in inflammatory acne, these agents are used to correct the ment using this schema is achieved, with relapse occurring when
defect in keratinization in all cases of acne. patients stop treatment, suggesting a longer duration of maintenance
For mild-to-moderate papulopustular inflammatory acne It therapy is likely to be beneficial. Topical azelaic acid is an alterna-
is important to reduce the population of P. acnes in the follicle and tive to topical retinoids for acne maintenance therapy, with advanta-
geous efficacy and safety profiles for long-term therapy. To minimize
antibiotic resistance, long-term therapy with antibiotics is not rec-
ommended as an alternative to topical retinoids. If an antimicrobial
effect is desired, the addition of benzoyl peroxide to topical retinoid
Benzoyl peroxide Abnormal Salicylic acid therapy is preferred.
Topical/oral keratinization Benzoyl peroxide
antibiotics of follicle Topical retinoids Published Guidelines
Isotretinoin Isotretinoin
In general, recommendations should be based on critical appraisal
Acne and interpretation of the literature combined with clinical experi-
pathogenesis Abnormal ence. There is considerable heterogeneity in the acne literature.
P. acnes sebum The large number of products and product combinations, and the
proliferation &
scarcity of comparative studies, has led to disparate opinions and
drug
few recommendations are evidence based. Various evidence-based
mechanisms guidelines, available from multiple American, Canadian, European,
Intralesional Antiandrogens
corticosteroids Isotretinoin
Scandinavian, and South African sources from 2005 to 2018, do not
Oral Topical/oral provide concordance or clarity on all issues.
corticosteroids Inflammatory antibiotics The 2016 European Guidelines for the Treatment of Acne focus
Topical/oral response Corticosteroids primarily on major treatments, but do not review general manage-
antibiotics Estrogens ment issues such as psychologic determinants, scarring, and diet.24,69
Where relevant, specific information from multiple sources will be
FIGURE 117-2 Acne pathogenesis and drug mechanisms. integrated into the therapy section that follows.

CH117.indd 1620 13-12-2022 15:23:51

 1621
An expert committee of the American Academy of Dermatology the Global Alliance published a further update providing relevant
redefined guidelines for acne therapy in 2016 (Table 117-1).68 clinical guidance to healthcare practitioners managing patients with
These guidelines address the management of adolescent and adult acne, with an emphasis on areas where the evidence base may be
patients presenting with acne but not the consequences of disease, sparse or needs interpretation for daily practice. They provided 10
including the scarring, postinflammatory erythema, or postin- consensus recommendations, based on the 2016 American Academy
flammatory hyperpigmentation. In 2009, the Global Alliance to and European Guidelines.67

CHAPTER        Acne Vulgaris
Improve Outcomes in Acne updated their 2003 recommendations The Alliance recommendations statements were as follows67:
to review new information about pathophysiology and treatment   1. Retinoids have an essential role in treatment of acne. For
and included current published data on relevant issues.70 In 2018, most patients with inflammatory acne, comedonal acne, or
both, a topical retinoid plus benzoyl peroxide is first-line
therapy.24,68,69
TABLE 117-1  Evidence Chart for Recommendations for   2. The role of antibiotics in acne therapy has changed. Neither
Managing Acne Vulgaris topical nor systemic antibiotics should be used as mono-
117
Strength of Level of therapy for acne treatment.69,71
Recommendation Recommendation Evidence  3. Oral isotretinoin should be first-line therapy for very
Grading/classification system B II, III severe (cystic and conglobate) acne.69
Microbiologic testing B II, III   4. Oral isotretinoin therapy should proceed until full clear-
Endocrinologic testing B I, II ance of acne. Additional studies are needed to define a total
Topical therapies cumulative dose that maintains remission.
Benzoyl peroxide A I, II   5. Acne flare with oral isotretinoin can be minimized by ini-
Topical antibiotics (eg, clindamycin, A I, II tiating therapy at a low dose.
minocycline, and erythromycin)
  6. Most patients with acne should receive maintenance ther-
Combination of topical antibiotics A I apy with a topical retinoid.
and benzoyl peroxide
Topical retinoids (eg, tretinoin, A I, II
  7. Azelaic acid cream 20% or gel 15% is a useful acne treat-
adapalene, tazarotene, and ment in pregnant women and patients with acne and PIH.
trifarotene)   8. At present, devices that use laser, intense pulsed light, or
Combination of topical retinoids and A I, II photodynamic therapy should not be considered first-line
benzoyl peroxide/topical antibiotic treatment for inflammatory acne.
Azelaic acid A I
  9. A minority of women 25 years of age have acne lesions
Dapsone A I, II localized only to the lower face. Topical retinoids with or
Salicylic acid B II without benzoyl peroxide are important components in
Systemic antibiotics therapy of adult acne.
Tetracyclines (eg, doxycycline, A I, II 10. Early and effective treatment is important to minimize
minocycline, and sarecycline) potential risk for acne scarring.
Macrolides (eg, azithromycin and A I
erythromycin)
General Information Regarding Efficacy and Safety
Trimethoprim (with or without B II
sulfamethoxazole)
The guidelines and recommendations of the American Academy
of Dermatology considered the efficacy and safety of various treat-
Limiting treatment duration and A I, II
concomitant/maintenance topical
ments, such as topical agents, systemic antibacterial agents, hor-
therapy monal agents, isotretinoin, miscellaneous therapies, complementary
Hormonal agents and alternative therapies, and dietary restriction, based on levels
of evidence and best clinical practice.68 More specific information
Combined oral contraceptives A I
about the efficacy and safety of each of these specific modalities is
Spironolactone B II, III
outlined below in sections on each individual agent.
Oral corticosteroids B II
Isotretinoin Alternative Drug Treatments
Conventional dosing A I, II Complementary and Alternative Medications People with acne
Low-dose treatment for moderate A I, II often turn to complementary and alternative medicine (CAM), such
acne as herbal medicine, acupuncture, and dietary modifications, because
Monitoring B II of their concerns about the adverse effects of conventional medi-
cines. Although these products might be well tolerated, very limited
iPLEDGE and contraception A II
data exist regarding their safety and efficacy.
Miscellaneous therapies and physical
modalities
There is increasing interest in the use of CAM as adjuvant or
single therapies: in America, 7% people report using a complemen-
Chemical peels B II, III
tary medicine, and 2% report seeing a complementary medicine
Intralesional steroids C III practitioner.72 Traditional Chinese medicine has been widely used
Complementary and alternative B II to treat acne for many years, based on a diagnosis from a traditional
therapies (eg, tea tree oil, herbal,
Chinese medicine perspective according to the different syndromes
and biofeedback)
of acne.
Role of diet in acne effect of glycemic B II
The Cochrane collaboration undertook a systematic review,
index
reported in 2015, to assess the effectiveness and safety of any CAM
Dairy consumption B II
in the management of acne vulgaris. This included 35 studies, with a
Data from Reference 68. total of 3,227 participants in parallel-group randomized controlled

CH117.indd 1621 13-12-2022 15:23:51

 1622
trials (or the first phase data of randomized cross-over trials) of depigmentation lasts for 2 to 6 months but is reversible. While effec-
any kind of CAM, compared with no treatment, placebo, or other tive in the removal of melanin, hydroquinone has been clinically
active therapies, in people with a diagnosis of acne vulgaris. The pri- found to be a possible carcinogen and causes a blue-black discolor-
mary outcome was improvement of clinical signs assessed through ation known as ochronosis.76
skin lesion counts. Some evidence from single studies showed low- After considering new data and information on the safety of
glycemic-load diet, tea tree oil, and pollen bee venom (PBV) may hydroquinone, the FDA issued a proposed ruling in 2006 about
have an effect reducing total skin lesion counts and acne severity hydroquinone products. The FDA proposed reversing earlier rules
SECTION     Dermatologic Disorders

scores. However, small sample sizes and poor methodological qual- that hydroquinone is generally recognized as safe and effective. The
ity limited the strength of the evidence. Evidence from other exist- FDA has not yet issued a final ruling on the status of nonprescrip-
ing randomized controlled trials does not support the use of herbal tion hydroquinone, and many physicians consider a ban unneces-
medicine, acupuncture, or wet-cupping therapy for the treatment sary, given the lack of convincing evidence of carcinogenic risk to
of acne vulgaris. The evidence for a secondary outcome (number of humans and the rarity of ochronosis occurrence.
16 participants with remission) for herbal medicine versus antibiotic
Treatment of Scarring Drug and nondrug measures for scar
was uncertain. Two trials reported QOL showed the benefit of herbal
resolution are important in acne vulgaris because many patients are
medicine compared with western drugs. From the review of 31 stud-
scarred despite adequate treatment and scarring carries an emo-
ies, the Cochrane review cautioned there is a lack of evidence to sup-
tional toll. Interventions for atrophic scars might be aided through
port the use of other CAMs, such as aloe vera, copaiba essential oil,
early identification of patients at risk using a risk assessment tool
dried fruit of Berberis vulgaris, or seaweed oligosaccharides for the
for scar development. One such tool incorporates four factors: worst
treatment of this condition. Most studies were done in a traditional
ever severity of acne, duration of acne, family history of atrophic
Chinese medicine context; therefore, results might be less generaliz-
acne scars, and lesion manipulation behaviors.77
able to western medicine. The review highlights potential adverse
Effective procedures for treatment of scarring focus on resur-
effects from herbal medicine (dizziness, dry mouth, nausea, diar-
facing techniques. For patients with mild scarring, nonprescription
rhea, or stomach upset); acupuncture (pain, itchiness, or redness);
α-hydroxy acids may be used, while severe scarring may be cor-
and tea tree oil gel (pruritus, dryness, burning sensations, and skin
rected with other treatment modalities that require consultation
flaking).73
with a dermatologist. Dermabrasion, local or subcuticular excision,
A 2018 review focused on the use of essential oils and aroma-
collagen implants, chemical peels (eg, 70% glycolic acid, trichloro-
therapy in acne, examining existing evidence from small pilot stud-
acetic acid), and laser therapy have been used to improve scarring.
ies.74 It reaffirmed there is only weak clinical evidence that tea tree oil
Atrophic scars can be treated with laser resurfacing. Usually the
5% may be used as an alternative acne therapy. Several agents may
scar is not completely removed, but a more cosmetically acceptable
be helpful as complementary therapy due to biologic plausibility,
result is achieved. Keloids and hypertrophic scars can be treated with
including lactobacillus-fermented Chamaecyparis obtuse, copaiba,
intralesional triamcinolone, cryotherapy, topical steroids, and sili-
sandalwood oil, rosemary extract, jeju essential oil, and Korean cit-
cone sheeting. Surgical options for scars include excision, augmenta-
rus, but concluded there is little supportive clinical evidence.
tion with collagen or fat, chemical peels, subcision, and injection of
The use of botanical preparations that are nonstandardized
autologous fibroblasts.
should be discouraged in favor of traditional quality-controlled
preparations that have evidence of efficacy. The lack of appropriate
data, absence of quality assessment, and inconsistencies in search Special Populations
methodology suggest that CAM cannot be recommended for acne About 20% of young infants (2-3 months of age) develop papules,
therapy now. pustules, and less commonly closed or open comedones, primar-
ily on the cheeks, due to placental transfer of maternal androgens
Glycolic Acid Another agent considered alternative therapy
(neonatal acne). The acne subsides within a few months with regu-
for acne vulgaris is glycolic acid. The efficacy and tolerability of a
lar maturation. Boys are affected more often than girls because of
0.1% retinaldehyde/6% glycolic acid combination (Diacneal) has
a transient increase in testosterone secretion during the third and
been evaluated for mild-to-moderate acne vulgaris.75 Physician and
fourth month of intrauterine life. Malassezia spp. may be involved
patient ratings of acne symptom severity and tolerance performed at
in pathogenesis.31 Resolution occurs without therapy.78 Infants with
baseline and months 1, 2, and 3 showed mean numbers of papules,
neonatal acne may have more severe teenage acne.31
pustules, and comedones were significantly reduced from month 1
The treatment of acne in children is similar to treatment for
on, demonstrating that glycolic acid is effective and well tolerated in
adults. Because topical therapies may be more irritating in children,
mild-to-moderate acne vulgaris.
initiation with low concentrations is preferred. Systemic treatments
Both glycolic acid–based, salicylic acid or salicylic acid deriva-
should be reserved for more extensive cases. Erythromycin is pre-
tive–based (eg, lipohydroxyacid), and amino fruit acid–peeling
ferred over tetracyclines for children younger than 9 years of age
preparations have been used in the treatment of acne. There is very
because tetracyclines can affect growing cartilage and teeth.
little evidence from clinical trials published in peer-reviewed litera-
Although treatment with isotretinoin has numerous potential
ture supporting the efficacy of peeling regimens.62 Topical corneo-
minor adverse effects in patients of all ages, an uncommon compli-
lytics, including retinaldehyde/glycolic acid or lactic acid, induce a
cation in young patients is premature epiphyseal closure. This gen-
comedolytic effect and may also facilitate skin absorption of topi-
erally occurs when isotretinoin is administered in high doses, thus
cal drugs.58 Further research on the use of peeling in the treatment
limiting long-term therapy.
of acne needs to be conducted to establish best practices for this
There is a growing population of women seeking acne therapy
modality.
and a clinical perception that acne in women requires systemic treat-
Hydroquinone To control pigmentation, hydroquinone, which ment. Analyses of clinical trials have shown that topical therapy can
reversibly damages melanocytes, has been used as a hypopigment- be efficacious in this group. Most patients have an acne presenta-
ing agent in concentrations of 2% to 4%, in preparations of clear tion similar to adolescent acne, with mixed inflammatory and non-
or tinted gels, which are more drying, and as vanishing or opaque, inflammatory lesions on multiple facial areas (not limited to the
flesh-tinted creams, with or without α-hydroxy acids or sun- mandibular area). Topical therapy with a retinoid and antimicrobial
screens. Hydroquinone causes fading of epidermal but not dermal can be a good option. Data support the use of retinoids, including
pigmentation. Onset of response is usually 3 to 4 weeks, and the adapalene/benzoyl peroxide in both 0.1% and 0.3% concentrations,

CH117.indd 1622 13-12-2022 15:23:51

 1623
tretinoin 0.04%, and a retinaldehyde 0.1%/glycolic acid/6% cream. acid (tretinoin) was most active, compared with benzoyl peroxide
Among antimicrobial agents, both dapsone and clindamycin/ben- and salicylic acid, which were respectively less active. Data from
zoyl peroxide have efficacy if a topical retinoid is added. Azelaic acid peer-reviewed literature regarding the efficacy of sulfur, resorcinol,
15% gel has also shown good results in a small study. Hormonal sodium sulfacetamide, aluminum chloride, and zinc are limited.
therapy, including oral contraceptives (OCs), can play an important Traditional nonprescription exfoliants, including phenol, resorcinol,
role in management of acne in women and is typically used in com- beta-naphthol, sulfur, Vleminckx solution, and sodium thiosulfate,

CHAPTER        Acne Vulgaris
bination with topical acne therapy.67 are weak or ineffective. These agents are not comedolytic given that
Selecting appropriate treatment in pregnant women can be they affect the superficial epidermis rather than the hair canal. They
challenging because many acne therapies are teratogenic; all topi- have been supplanted by superior effective agents. Linoleic acid–rich
cal and especially oral retinoids should be avoided. Oral therapies, phosphatidylcholine combined with 4% nicotinamide is suggested
such as tetracyclines and antiandrogens, are also contraindicated in as an emulsion treatment that may be effective in normalization of
pregnancy. Topical and oral treatment with erythromycin may be follicular hyperkeratinization, and also provide anti-inflammatory
considered. effects.80,81 117
Acne in skin of color is an increasing problem, presenting
Resorcinol Although sulfur and resorcinol have been used for many
unique challenges. Postinflammatory hyperpigmentation (PIH), a
years in the treatment of acne, evidence from peer-reviewed litera-
hypermelanotic reaction to skin inflammation, is a common occur-
ture supporting their efficacy is lacking.67 The phenol derivative res-
rence in patients with acne, particularly in those with darker skin
orcinol is less keratolytic than salicylic acid. It is noted to be both
and those who excoriate their lesions, affecting all genders and
bactericidal and fungicidal. Products containing resorcinol 1% to
ages. It has a prolonged duration and can be more bothersome than
2% have been used for acne, often in combination with other peeling
active acne lesions. Prevention (including sun protection) and early
agents such as sulfur or salicylic acid. The FDA considers resorcinol
treatment of underlying acne-associated inflammation effectively
2% and resorcinol monoacetate 3%, in combination with sulfur 3%
is a primary approach to PIH management. Chemical peels, lasers,
to 8%, to be safe and effective and that the combination may enhance
and other light therapies may also be used for PIH; however, these
the activity of sulfur. However, the FDA is not convinced that resor-
methods can also cause pigmentation problems so should be used
cinol and resorcinol acetate are safe and effective when used as single
with care. Topical retinoids also improve pigmentation by inhibit-
ingredients, and has placed such products in category II (not gener-
ing melanosome transfer to keratinocytes and increasing epidermal
ally recognized as safe and effective, or misbranded).81
turnover, lessening pigmentation. It is important for the patient to
Resorcinol is an irritant and sensitizer and should not be
be aware that many PIH lesions resolve spontaneously, but slowly.67
applied to large areas of the skin or on broken skin. It produces a
A variety of topical agents have studies that specifically included
reversible, dark brown scale on some dark-skinned individuals.
patients with skin of color, confirming their safe use in this popula-
Protective packaging is important as resorcinol is reactive to
tion. These include all the currently available topical retinoids, ben-
light and oxygen. It has good solubility in both water and alcohol
zoyl peroxide, azelaic acid, clindamycin, dapsone, and clascoterone.
and is heat stabile. Thus, it is incorporated into a variety of products,
A key goal of therapy in this population is to minimize postinflam-
including emulsions.82
matory hyperpigmentation from irritating topical agents, with
an emphasis on use of hydrating cleansers and non-comedogenic Salicylic Acid Salicylic acid, a β-hydroxy acid, is a comedolytic
moisturizers.79 agent that is available over the counter in 0.5% to 2% strengths.
Another important counseling point is to emphasize sun pro- Clinical trials demonstrating the efficacy or safety of salicylic acid in
tective measures to minimize the darkening effects of UV irradia- acne are limited, although it has been used for many years.67 It is a
tion on postinflammatory hyperpigmentation. Recommendations natural ingredient in many plants such as willow tree or willow bark,
include use of a broad-spectrum sunscreen, protective clothing, and and it penetrates the pilosebaceous unit. The comedolytic action
inclusion of vitamin D–rich foods or supplementation.76 depends on concentration: concentrations in commercial prepa-
rations (<2%-3%) are generally low. Concentrations less than 2%
Drug Class Information may in fact increase keratinization, while those between 3% and 6%
This section reviews the pharmacology and mechanisms as related are keratolytic, softening the horny layer and producing shedding
to pathophysiology for pharmacologic options recommended in the of scales. Its mechanism remains unresolved, attributed to either
guidelines for mild, moderate, and severe acne. It will also review reduced cohesion of corneocytes or shedding of epidermal cells,
evidence of efficacy and safety as well as kinetics, interactions, dos- rather than breakdown of keratin.
ing, and administration when relevant. Salicylic acid has no effect on the mitotic activity of normal
epidermis and does not influence disordered cornification.83 It may
Topical Therapies Topical therapy agents are available over the
provide mild antibacterial value, as it is active against P. acnes. It
counter or by prescription. The choice of therapy can be influenced
offers slight anti-inflammatory activity at concentrations ranging
by age of the patient, site of involvement, extent and severity of dis-
from 0.5% to 5%. Its efficacy against comedones helps to prevent
ease, and patient preference. Topical therapies may be used as mono-
development of inflamed lesions, thus providing a delayed efficacy.84
therapy, in combination with other topical agents, or in combination
Salicylic acid is effective. As a peeling agent, its relative strength
with oral agents in both initial control and maintenance. Strength
compared with others in this class varies according to the model
of recommendations for treatment of acne with topical therapies is
used in measurement. It is slightly less potent than equal-strength
shown in Table 117-2.
benzoyl peroxide when measured with the rabbit ear animal model,
Exfoliants (Peeling Agents) Exfoliants induce continuous mild and slightly more potent when measured with a biologic micro-
drying and peeling by primary irritation, damaging the superficial comedone model.84 Its anti-inflammatory properties may help dry
layers of the skin, and inciting inflammation. This stimulates mito- inflammatory lesions.82 Its comedolytic properties are considered
sis, thickening the epidermis, and increasing horny cells, scaling, less potent than topical retinoids. It is often used when patients can-
and erythema. A decrease in sweating results in a dry, less oily sur- not tolerate a topical retinoid because of skin irritation.85
face and may superficially resolve pustular lesions. Its keratolytic effect may enhance the absorption of other
In the past, a rabbit model was used to study the efficacy of agents. Salicylic acid is a mild irritant and may cause some degree
topical exfoliants in retarding tar-induced comedone formation and of local skin peeling and discomfort (burning or reddening). It is
accelerating their loss (comedolysis). In this animal model, retinoic not a sensitizer. Although the FDA recognizes salicylic acid as safe

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TABLE 117-2 Monitoring of Medications Used in Acne Treatment and Maintenance Therapy
Medications Adverse Drug Effects Monitoring Parameters Comments
Exfoliants
Resorcinol Irritant and sensitizer Degree and/or changes in signs or symptoms Should not be applied to large areas of
of irritancy (redness, discomfort, peeling, skin the skin or on broken skin
breakdown, or dermatitis)
SECTION     Dermatologic Disorders

Sulfur Avoid eye contact—slight Degree and/or changes in signs or symptoms

ophthalmic and skin irritation of irritancy (redness, discomfort, peeling, skin
breakdown, or dermatitis).
Discontinue use if excessive irritation results
Salicylic acid Mild irritant—burning and Degree and/or changes in signs or symptoms Begin with a low concentration and
reddening, local skin peeling of irritancy (redness, discomfort, peeling, skin increase as tolerance develops
16 breakdown, or dermatitis) Not a sensitizer
Retinoids
Isotretinoin Side effects: mucocutaneous Test for pregnancy twice before starting Drying agents must be discontinued
(most common), Contraceptive measures must be started 1 month Sun-avoidance strategies and sunscreen
musculoskeletal, and prior, continued during the 2 months of treatment use recommended
ophthalmic systems and for at least 1 month after stopping treatment Vitamin A supplementation
Common: dryness of mucus (but normally 4 months) Use moisturizers (lip balm, nasal
membranes (lips, mouth, eyes, Laboratory monitoring during therapy should include moisturizers, eye lubricants,
nose) dry skin, itching, hair triglycerides, cholesterol, transaminases, and temporary removal of contacts)
loss, thirst, back pain, myalgia, complete blood counts (before, during, and after Most adverse effects, such as cheilitis,
headaches, and central nervous treatment) and dry nose, eyes and mouth, are
system effects Degree and/or changes in signs or symptoms of temporary and resolve after the drug
Increased cholesterol irritancy to skin (redness, discomfort, peeling, skin is discontinued
Teratogenic breakdown, or dermatitis) Advise patients about a possible risk of
Sun sensitivity Degree and/or changes in signs or symptoms of depression and suicidal behavior
Depression and irritancy to mucous membranes (mouth, nose,
suicide—controversial eyes)
Instances of headache or central nervous system
symptoms
Note prior psychiatric symptoms, monitor patients at
each visit for early recognition of changes in mood
or psychological well-being (before, during, and
after treatment)
Tretinoin/retinoic Common: erythema, dryness, Degree and/or changes in signs or symptoms of Additive effects with concomitant
acid burning, photosensitization irritancy to skin (redness, discomfort, peeling, skin topical drying medications, such as
Rare: true contact allergy breakdown, or dermatitis) products with high concentrations of
Use cautiously in pregnancy Skin changes in areas of sun exposure—dermatitis alcohol, astringents, or abrasive soaps
(Irritation: tazarotene > retinoic or hives Gels and creams are less irritating than
acid > adapalene) solutions
Sun-avoidance strategies and sunscreen
use recommended
Adapalene Side effects include erythema, Degree and/or changes in signs or symptoms of Less photosensitivity than other agents
xerosis, burning and irritancy to skin (redness, discomfort, peeling, skin Sun-avoidance strategies and sunscreen
desquamation breakdown, or dermatitis) use recommended
Less irritation than other retinoids Skin changes in areas of sun exposure—dermatitis
Photoirritation or sensitization or hives
Tazarotene Side effects include irritation, Skin changes in areas of sun exposure—dermatitis Contraindicated in pregnancy due to the
erythema, xerosis, burning, and or hives large surface area
desquamation Short contact therapy, 1-5 minutes every
other night, gradually increasing to
overnight advocated for dosing in
patients with sensitive skin
Oily complexions may tolerate twice
daily, short contact time
Topical Antimicrobial Agents
Benzoyl peroxide Dryness and peeling appear after Once tolerance is achieved, the strength may be Increased skin irritation or drying effect
a few days, erythema, burning, increased to 5% or the base changed to the with other medications, soaps, and
pruritus acetone or alcohol gels, or to paste cosmetics with strong drying effect
Rare reports of contact allergic Degree and/or changes in signs or symptoms of Chemically incompatible with retinoic
dermatitis irritancy to skin (redness, discomfort, peeling, skin acid
May bleach hair and clothing breakdown, or dermatitis) Cross-reactions with other sensitizers,
Body odor, odor on clothes and Hives such as Peruvian balsam, cinnamon,
bedsheets and other benzoic acid derivatives
Irritation is concentration (topical anesthetics)
dependent—most frequent
with 10% gel
Irritation from gels used as
vehicles—water-based
< alcohol = acetone
Clindamycin Erythema, peeling, itching, Signs or symptoms of irritancy to skin (redness,
dryness, and burning discomfort, peeling, skin breakdown, or dermatitis)

(continued)

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TABLE 117-2 Monitoring of Medications Used in Acne Treatment and Maintenance Therapy (Continued)
Medications Adverse Drug Effects Monitoring Parameters Comments
Oral Antibiotics
Erythromycin Gastrointestinal upset (nausea, If gastrointestinal adverse effects occur, monitor Drug interactions:
vomiting, diarrhea) hydration Inhibits CYP1A2 and CYP3A4:
Vaginal candidiasis Vaginal discharge carbamazepine, cyclosporine,

CHAPTER        Acne Vulgaris
theophylline, and warfarin
Safe in pregnant women and children
Tetracyclines Gastrointestinal intolerance: Vaginal discharge Contraindicated in pregnant women
(tetracycline > erythromycin > Skin changes in areas of sun exposure—dermatitis or in children younger than 9 years
doxycycline = minocycline) or hives of age
Vaginal candidiasis Absorption decreased by food, chelated
Photosensitivity is dose- by antacids and milk
dependent (doxycycline > To be taken on an empty stomach 117
tetracycline)
Minocycline Drug-induced lupus Vaginal discharge Contraindicated in pregnant women
Pigment changes in skin, mucous Skin changes in areas of sun exposure—dermatitis or in children younger than 9 years
membranes, and teeth or hives of age
Hepatitis Changes or discoloration of skin, teeth, or mucous Decreased gastrointestinal absorption
Urticaria membranes with Fe, Ca, Mg, Al
Dose-related dizziness (resolves Monitor degree of dizziness as dose is titrated Sun-avoidance strategies and sunscreen
with dose titration) Signs of hypersensitivity syndrome: fever, dermatitis, use recommended
Autoimmune hepatitis and blistering reactions; systemic symptoms such
hypersensitivity syndrome as malaise, changes in blood pressure, or renal
function
Doxycycline Gastrointestinal upset If gastrointestinal side effects occur, monitor Contraindicated in pregnant women
Photosensitizer (especially at hydration or in children younger than 9 years
higher doses) Skin changes in areas of sun exposure—dermatitis of age
or hives Sun-avoidance strategies and sunscreen
use recommended
Antisebum
Combination oral Breakthrough bleeding, headache Spotting or bleeding Oral antibiotics may decrease
contraceptives Serious: venous contraceptive efficacy—(significance
thromboembolism, controversial)
hepatotoxicity
Spironolactone Common: hyperkalemia, Menstrual signs
menstrual irregularity, Breast changes
gynecomastia, breast
tenderness
Anti-inflammatory
Azelaic acid Primary: pruritus, burning, Skin changes in areas of sun exposure—dermatitis Adverse reactions are generally transient
stinging, and tingling or hives and mild in nature
Other: erythema, dryness, rash,
peeling, irritation, dermatitis,
and contact dermatitis in less
than 1% of patients
Dapsone Short- and long-term safety and Skin changes in areas of sun exposure—dermatitis Does not induce phototoxicity or
efficacy demonstrated or hives photoallergy in human dermal safety
Peeling, dryness, and erythema studies
Medications such as rifampin,
anticonvulsants, trimethoprim/
sulfamethoxazole, and St John’s wort
may increase formation of dapsone
hydroxylamine (toxicity)

Al, aluminum; Ca, calcium; CYP, cytochrome P450; Fe, iron; Mg, magnesium.

and effective, the compound offers no advantages over more modern after peel, but it must be applied under strict control to offer this
topical agents such as benzoyl peroxide.81,83,85 adjunctive benefit when treating acne vulgaris.86
Salicylic acid products are often used as first-line therapy for
mild acne because of their widespread availability without a pre- Sulfur Sulfur medications often lessen the severity of acne, presum-
scription in a variety of formulations. Both wash-off and leave-on ably because of keratolytic and antibacterial action. Sulfur helps to
preparations are well tolerated. Lower concentrations are some- resolve comedones by an exfoliant action. Its popularity is due to
times combined with sulfur to produce an additive keratolytic effect. its ability to quickly resolve pustules and papules, mask and conceal
Concentrations up to 5% to 10% can be used for acne, beginning lesions (as a thick foundation lotion), and produce irritation lead-
with a low concentration and increasing as tolerance to the irritation ing to skin peeling and mild antibacterial action. Sulfur is used in
develops. However, the maximum strength allowed in nonprescrip- the precipitated or colloidal form in concentrations of 2% to 10%,
tion acne products is 2%. In high concentrations of 20% to 30% in because it is practically insoluble in water and must be well dis-
hydroethanolic vehicles, salicylic acid, either alone or in combina- persed. Its stability depends on effective maintenance of the disper-
tion, can be used as a peeling agent for comedonal acne and hyper- sion.82 Sulfur compounds (eg, sulfides, thioglycolates, sulfites, thiols,
pigmentation. It extrudes closed and open comedones several days cysteines, and thioacetates) are also available and somewhat weaker.

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Sulfur can cause slight ophthalmic and dermatologic irritation, and combinations in specialized gel vehicles with benzoyl peroxide to
patients should be cautioned to avoid eye contact. Use should be increase the efficacy in comparison with monotherapies. This strat-
discontinued if excessive irritation results. Although it is often com- egy allows for the synergy of adapalene effects on normalizing des-
bined with salicylic acid or resorcinol to increase its effect, its use quamation with reduction of inflammation due to benzoyl peroxide
is limited by its offensive odor and the availability of more effective action against P. acnes. Adapalene gel 0.1% is approved in the United
agents.87 States as a nonprescription product for once-daily application by
patients aged 12 years and older.
SECTION     Dermatologic Disorders

Topical Retinoids Topical retinoids are prescription vitamin Tazarotene has superior efficacy to parent retinoids, reduc-
A derivatives with well-documented, randomized, double-blind, ing both noninflammatory and ILs. While its exact mechanism is
placebo-controlled trials supporting their use for acne treatment.68 unknown, it is thought to activate retinoid receptors and thereby
Multiple agents are available in a variety of strengths and formula- affect keratinocyte differentiation, and inhibit proinflammatory
tions: tretinoin, adapalene, tazarotene, and trifarotene. Each retinoid transcription factors to decrease cell proliferation and inflamma-
16 binds to a different set of retinoic acid receptors conferring slight tion.47 It penetrates skin but accumulates in the upper dermis. It is as
differences in activity, tolerability, and efficacy: tretinoin to alpha, effective as adapalene in reducing noninflammatory and IL counts
beta, and gamma; tazarotene and adapalene, selectively, to beta when applied half as frequently. Compared with tretinoin, it is
and gamma; and trifarotene to gamma. Binding to specific nuclear as effective for comedonal and more effective for inflammatory
receptors reduces inflammation, and inhibits sebocyte proliferation lesions when applied once daily. Tazarotene foam 0.1% can be used
and differentiation, which reduces sebum production. as an alternative vehicle to the gel with less systemic absorption and
Retinoids are the most powerful available peeling agents since is a safe and effective formulation.87,97,98 Tazarotene is not degraded
normal epithelial cell differentiation is a vitamin A–dependent pro- by sunlight.26
cess. There is no consensus about the relative efficacy of currently Trifarotene is a topical selective agonist of RAR-γ, a receptor
available topical retinoids and oral isotretinoin. They are the core expressed in skin and not in internal organs. It was evaluated in two
of topical therapy because of their ability to target key stages in the vehicle-controlled, 12-week, randomized double-blind studies of
development of the disease: they are comedolytic, resolve the pre- more than 2,000 patients aged 9 years and older, with 20% to 30%
cursor microcomedone lesion, and are anti-inflammatory. decrease in both noninflammatory and inflammatory lesions on the
Retinoids act to reduce obstruction within the follicle and face and trunk. In an open-label extension of continued use, more
therefore are useful in the management of both comedonal and than 70% of patients achieved an Investigator Global Assessment
inflammatory acne. As a group, they are highly active peelers as score of 0 or 1 by 52 weeks. It is approved in the United States as a
they reverse abnormal keratinocyte desquamation.88 They improve once-daily application to the trunk and face in patients 9 years and
acne vulgaris by inhibiting microcomedone formation, diminish- older.99
ing the number of mature comedones and subsequently, inflamma- Isotretinoin is a systemic retinoid that is reviewed separately
tory lesions. They also normalize follicular epithelium maturation below.
and desquamation. Topical retinoids, unlike isotretinoin, do not Retinoids tend to produce remissions that are maintained for
decrease production of sebum, but primarily decrease inflamma- extended periods of time, provided the accompanying irritation
tion, normalize keratinocyte differentiation, and increase keratino- does not impede patient adherence. Side effects, including dryness,
cyte proliferation and migration.88 peeling, erythema, and irritation, can be mitigated by reduced fre-
Retinoids also facilitate acne lesion clearance through second- quency of application. Given any single agent, higher concentrations
ary effects of loosening and decreasing corneocytes. This increases may be more efficacious, but with greater side effects. The vehicle of
skin permeability, facilitates absorption of other agents, such as anti- any particular retinoid may also decrease tolerability.91,92 Most reti-
microbials or benzoyl peroxide, and increases penetration of oral noids are unstable and insoluble in water.
antibiotics into the follicular canal. As a result, the overall duration Topical retinoids should be used cautiously in pregnancy and
of antibiotic treatment decreases, and the possibility of resistance tazarotene is contraindicated. Tretinoin and adapalene are in FDA
lessens. Therefore, combination products with oral or topical anti- category C, while tazarotene, based on large-surface-area use in
microbials are available for increased efficacy, faster onset of effects, psoriasis (see Chapter 118, “Psoriasis”), is in FDA category X.31
decreased total antibiotic use and risk of resistance, and shorter Trifarotene should be avoided in pregnancy. Cases of birth defects
duration of treatment.88 Retinoids may also improve and prevent in the babies of females using trifarotene have been reported, as has
postinflammatory hyperpigmentation often seen in people with adverse effects in pregnant rabbits given trifarotene orally during
darker complexions who have acne. the period of organogenesis. The drug is also present in the breast
Retinoic acid (vitamin A acid or tretinoin) is a powerful exfoli- milk of rats being fed the medications, and the manufacturer there-
ant that slows the desquamation process, reducing numbers of both fore recommends caution, with application only to small areas that
microcomedones and comedones.26 Gels and creams are less irritat- would be unlikely to result in systemic absorption and avoidance of
ing than solutions. application to the nipples.
Stable and fast acting, adapalene has significant anti-inflammatory Skin type and age may influence tolerability in addition to the
and comedolytic properties.88-92 It causes epidermal and follicular epi- choice of vehicle. Oily skin may be more resistant, and darker skin is
thelium hyperplasia, increased desquamation, keratinocyte differentia- more prone to postinflammatory hyperpigmentation due to retinoid
tion, and loosening of corneocyte connections. Its anti-inflammatory dermatitis. To decrease irritation, start with the lowest concentra-
effect is due to the inhibition of oxidative metabolism of arachidonic tion and increase as tolerated. Application of retinoids should be at
acid and inhibition of chemotactic reponses.92 It is better at reducing night, a half hour after cleansing, starting with every other night for
inflammatory lesions and total lesion count91 and causes less local irrita- 1 to 2 weeks to adjust to irritation. Short contact time starting with
tion because of its mechanisms and receptor specificity than tretinoin 2 minutes and adding 30 seconds per dose can be advised for patients
or tazarotene.90-96 Release from lotions and hydroalcoholic gels is more with sensitive skin or in the winter, discontinuing and resuming after
effective than from creams and aqueous gels and a microsphere gel a 3-day rest if undue irritation results. Doses can be increased after 4
formulation may be less irritating.88,93 It is a good first-line therapy for to 6 weeks if there is no irritation. Gels and creams are less irritating
colder climates or in patients with sensitive skin.76 than solutions.
Adapalene is generally regarded as effective but less irritat- Some formulations of tretinoin are not photostable and should
ing than other topical retinoids.54,70 It is available in fixed-dose be applied in the evening. Tretinoin also may be oxidized and

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inactivated by the coadministration of benzoyl peroxide. It is recom- reducing free fatty acids, which are comedogenic agents and triggers
mended that the two agents be applied at different times. Tretinoin of inflammation.101 Topical benzoyl peroxide 5% lowers free fatty
microsphere formulation, adapalene, and tazarotene do not have acids 50% to 60% after daily application for 14 days and decreases
similar restrictions. Topical retinoids have been associated with an aerobic bacteria by 84% and anaerobic bacteria (primarily P. acnes)
increased risk of photosensitivity; concurrent daily sunscreen can be by 98%.
used to reduce the risk of sunburn. Benzoyl peroxide is also comedolytic. While earlier rabbit

CHAPTER        Acne Vulgaris
Adapalene and tazarotene are photo-irritants (not photosensi- model studies showed a benzoyl peroxide effect greater than that
tizers), and sun avoidance and sunscreen use are imperative.88 of salicylic acid, these animal comedones were not physiologic but
These agents enhance any other topical acne regimen and allow induced by tar. More recent studies using native microcomedones
for maintenance of clearance after discontinuation of oral therapy. show an anticomedogenic effect that is only comparatively slight,
Since retinoids are ideal for comedonal acne, when used in combina- compared with tretinoin or salicylic acid.102-104
tion with other agents, they can address all acne variants. Adapalene Finally, a supplementary benefit of benzoyl peroxide is an indi-
is available in combination with benzoyl peroxide, and tretinoin rect anti-inflammatory action, which is due either to its antibacterial 117
is available combined with clindamycin phosphate 1.2%/tretinoin or oxidizing effects. This has been reported in several studies and
0.025% gel, approved for those age 12 years or older.67 thus can be used to support treatment of predominantly inflamed
The therapy of acne in children younger than 12 years of age lesions.101 The drug’s antiacne effect is augmented by increased blood
with products approved by the FDA has expanded. Fixed combina- flow, dermal irritation, local anesthetic properties, and promotion of
tion benzoyl peroxide 2.5%/adapalene 1% gel and trifarotene are healing.105-108 Because the primary effect of benzoyl peroxide is anti-
approved for patients 9 years of age or older, and tretinoin 0.05% bacterial, it is most effective for inflammatory acne. Many patients
micronized tretinoin gel for patients 10 years of age or older. All with noninflammatory comedonal acne will respond to its peeling
other retinoids are approved by the FDA for patients 12 years of age action.
or older. Current data show that retinoids in younger patients are Benzoyl peroxide is available in a variety of preparations with-
effective and are not associated with increased irritation or risk.67 out a prescription such as topical washes, foams, creams, or gels,
Overall, topical retinoids are the cornerstone of acne treatment and can be used as leave-on or wash-off agents. There is no clear
and provide safe, effective, and economical means of treating all superiority of different preparations in terms of effectiveness. Newer
but the most severe cases of acne vulgaris. They should be the first delivery systems to enhance efficacy and tolerability are also being
step in moderate acne, alone or in combination with antibiotics and investigated. Strengths available for acne therapy range from 2.5%
benzoyl peroxide, reverting to retinoids alone for maintenance once to 10%. Total skin contact time and formulation can affect efficacy.
adequate results are achieved. Their lack of effect in inducing bacte- Lower concentrations (eg, 2.5%-5%), water-based, and wash-off
rial resistance enables long-term maintenance of remission. agents may be better tolerated in patients with more sensitive skin.
Cleansers containing benzoyl peroxide are available as non-
Antibacterial Agents Choices for antibacterial therapy include
prescription liquid washes and solid bars of various strengths. The
benzoyl peroxide, prescription topical and systemic antibiotics, and
desquamative and antibacterial effectiveness in a soap or wash is
combination products. These drugs kill P. acnes and inhibit the pro-
minimized by limited contact time and removal with proper rinsing.
duction of proinflammatory mediators by organisms that are not
Alcohol and acetone gels facilitate bioavailability and may be more
killed.26
effective, while water-based vehicles are less irritating and better tol-
Benzoyl Peroxide Benzoyl peroxide is a bactericidal agent that has erated. Paste vehicles are stiffer and more drying than ointments or
proven effective in the treatment of acne. It kills P. acnes through creams, which facilitate absorption and allow the active ingredients
the release of free oxygen radicals and is also mildly comedolytic. to stay localized.
No resistance to this agent has been reported, and the addition of Concentrations of 2.5%, 5%, and 10% in a water-based gel
benzoyl peroxide to regimens of antibiotic therapy enhances results have been compared with the vehicle alone. The 2.5% formulation is
and may reduce resistance development. equivalent to the 5% and 10% formulation in reducing the number
Benzoyl peroxide is a derivative of coal tar and was first used of inflammatory lesions. The lower strength may not be as effective
for acne vulgaris in the mid-1960s, becoming popular once stable a peeler compared to higher strengths, which is due to an irritancy
formulations aimed at its heat-lability were developed in the mid- reaction. Thus, irritant side effects with the 2.5% gel are less frequent
1970s.95 These preparations are the single most useful group of topi- than with the 10% gel but are equivalent to the 5% gel. The low-
cal nonprescription drugs. Used alone or in combination, benzoyl est concentration of benzoyl peroxide should be used for treating
peroxide is the standard of care for mild-to-moderate papular- patients with easily irritated skin and may lessen irritation when
pustular acne. It is an agent of first choice when combined with ada- used in combination topical therapy with comedolytic agents.
palene for most patients with mild-to-moderate inflammatory acne Therapy is limited by staining and bleaching of hair, bedsheets,
vulgaris and a second choice alternative for patients with noninflam- and clothing, concentration-dependent irritation, and uncommonly
matory comedonal acne.24,32,67 A systematic review of 22 trials using contact allergy. It produces a mild primary irritant dermatitis that
benzoyl peroxide for acne vulgaris provided evidence that it reduces subsides with continued use and is more likely to occur in those with
acne-lesion count, although high-quality evidence is not robust fair complexions, a tendency to irritancy, or propensity to sunburn.
enough for firm conclusions.100 This irritation is dependent on the concentration and the vehicle,
Benzoyl peroxide is well absorbed through the stratum cor- being higher with alcoholic gels compared with emulsion bases.102
neum and concentrates in the pilosebaceous unit.101 It has three There are rare reports of contact allergic dermatitis. Cross-reactions
principal actions useful in both noninflammatory and inflamma- with other sensitizers, notably Peruvian balsam and cinnamon, are
tory acne. It produces powerful anaerobic antibacterial activity due well established. It may cross-sensitize to other benzoic acid deriva-
to slow release of oxygen, thereby acting against gram-positive and tives such as topical anesthetics. Concomitant use of an abrasive
gram-negative bacteria, yeasts, and fungi. This nonspecific antibac- cleanser may initiate or enhance sensitization.109
terial mechanism does not induce resistance with long-term use.101 Another side effect is body odor from breakdown of the ben-
It has a rapid (within 2 hours) bactericidal effect that lasts at least zoyl peroxide that remains on clothing and bedsheets.
48 hours. As a result, it may decrease the number of inflamed lesions Benzoyl peroxide has been combined with prescription agents
within 5 days. As an indirect effect, it induces suppression of sebum to improve efficacy, reduce dosing strengths, decrease irritation, and
production; it does not reduce skin surface lipids, but is effective in reduce resistance of antibiotics.110-113

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Benzoyl peroxide is combined with topical retinoids for an Stable, fixed-combination agents are available with erythromycin
antimicrobial effect or used in conjunction with an antimicrobial. It 3%/benzoyl peroxide 5%, clindamycin 1%/benzoyl peroxide 5%,
reduces the likelihood of antibiotic resistance. For long-term main- and clindamycin 1%/benzoyl peroxide 3.75%. Combination agents
tenance therapy, it is recommended as a highly efficient bactericidal may enhance adherence with treatment regimens. Some topical
agent to be added to a topical retinoid.24,32 antibiotic–benzoyl peroxide combinations require refrigeration.62
The adjunctive use of clindamycin/benzoyl peroxide gel with Tolerance with these agents is excellent; clindamycin alone is preg-
tazarotene cream promotes greater efficacy and may also enhance nancy category B.68
SECTION     Dermatologic Disorders

tolerability. Increased tolerability might be attributed to emollients Other topical antibiotics that are being studied include fluoro-
in the clindamycin/benzoyl peroxide gel formulation.114 A patented quinolones, such as nadifloxacin and minocycline, but these are not
gel formulation of benzoyl peroxide 5%/clindamycin phosphate 1% approved for use in patients with acne by FDA. Minocycline 4% foam
(clindamycin) containing dimethicone and glycerin was studied is approved by FDA for topical treatment of patients aged 9 years and
both as a monotherapy and in combination with topical retinoid use. older with inflammatory lesions of nonnodular moderate-to-severe
16 Certain additives, such as silicates and specific humectants, reduced acne vulgaris. Its use has been evaluated in 3 large randomized,
irritation by maintaining barrier integrity.115 double-blind, vehicle-controlled study in patients with moderate-
When using single-agent preparations of benzoyl peroxide, to-severe acne. Once-daily application for 12 weeks was associated
the weakest concentration (2.5%) in a water-based formulation is with a decrease in inflammatory lesion count of approximately 13%
preferred for anyone with a history of skin irritation.115 There are to 17% compared with 10% to 17% with vehicle alone. It is generally
many suggested routines to initiate therapy. One is to gently cleanse well tolerated, with the most common adverse effects including head-
the skin and apply the preparation for 15 minutes the first evening, ache (3%), mild erythema (14.2%), inflammatory/postinflammatory
avoiding the eyes and mucous membranes. A mild stinging and red- hyperpigmentation (12.4%), and xerosis (6.8%).120
dening will appear. Each evening the time should be doubled until Minocycline is formulated in a yellow base, which can stain fab-
the product is left on for 4 hours and subsequently all night. Dryness rics but does not permanently stain skin, and there are no reports to
and peeling will appear after a few days. Once tolerance is achieved, date of drug-induced pigmentation associated with topical applica-
the strength may be increased to 5% or the base changed to the ace- tion. There are additionally no reports to date of bacterial resistance
tone or alcohol gels, or to paste. Alternatively, benzoyl peroxide can with topical minocycline. It is broken down by benzoyl peroxide;
be applied for 2 hours for four nights, 4 hours for four nights, and they should be applied 8 hours apart when used concurrently.
then left on all night. It is important to wash the product off in the
morning. Other drying agents should be discontinued. Patients with Oral Antibacterials Overview: a systematic evidence-based
very sensitive skin or demonstrated sensitivity to benzoyl peroxide review of scientific evidence of the efficacy of oral antibiotics for
should not use the product, and it should be discontinued if irri- acne was published in 2017. Due to heterogeneity in trials, there is
tation becomes severe upon use. Contact with eyes, lips, or mouth insufficient evidence to support one type, dose, or duration of oral
should be avoided. antibiotic over another in terms of efficacy and summarized key
A sunscreen is recommended if benzoyl peroxide is used. To points.121
avoid interactions, apply the sunscreen during the day and the ben- • The use of oral antibiotics is reserved for patients with
zoyl peroxide at night. moderate-to-severe inflammatory acne.

Topical Antibacterials Topical antibiotics for acne accumulate in • Tetracyclines are considered first-line therapy, while mac-
the follicle, where they can have antibacterial effects (the primary rolides and trimethoprim/sulfamethoxazole are acceptable
mechanism for efficacy in acne) and anti-inflammatory actions. alternative agents.
These agents are best used in combination with benzoyl peroxide • It is recommended that oral antibiotics be prescribed with
(wash-off or leave-on), which increases efficacy and decreases the concurrent topical therapy for improved efficacy and to
development of resistant bacterial strains. Monotherapy with topical combat antibiotic resistance.
antibiotics in the management of acne is not recommended because • The choice of antibiotic should be determined based on the
of the development of antibiotic resistance.116,117 Macrolides, includ- side effect profile, resistance, cost, and consensus guidelines.
ing topical erythromycin and topical clindamycin, are effective and
• Oral antibiotics used in the treatment of acne may have
well-tolerated, well-established acne treatments.
unintended effects on nontarget bacteria, and the clinical
Clindamycin is available as a single agent for topical acne ther-
implications of this warrant further exploration.
apy. Topical erythromycin has reduced efficacy in comparison with
clindamycin because of resistance of cutaneous staphylococci and Systemic antibiotics are a standard of care in the management of mod-
P. acnes.68 More than 50% of P. acnes strains are resistant to topical erate and severe acne and treatment-resistant forms of inflammatory
macrolides. Resistant strains are usually resistant to all macrolides.118 acne. There is evidence to support the use of tetracycline, doxycy-
Current recommendations discourage topical antibiotic mono- cline, minocycline, erythromycin, trimethoprim-sulfamethoxazole,
therapy in favor of combination therapy with benzoyl peroxide and trimethoprim, and azithromycin. Studies do not exist for the use of
topical retinoids. Addition of benzoyl peroxide or topical retinoids ampicillin, amoxicillin, or cephalexin. However, any antibiotic that
to the macrolide antibiotic regimen is more effective than monother- can reduce the P. acnes population in vivo and interfere with the
apy and mitigates against survival of resistant P. acnes populations. organism’s ability to generate inflammatory agents should be effec-
Clindamycin is the preferred macrolide because of potent tive.62 Although erythromycin is effective, use should be limited to
action, lack of absorption, and its systemic use is limited because it those who cannot use one of the tetracyclines (ie, pregnant women
can cause pseudomembranous colitis when given orally or by injec- or children under 8 years of age because of the potential for damage
tion. It is available as a single ingredient topical preparation and to the skeleton or teeth). Ciprofloxacin, trimethoprim-sulfamethox-
can also be combined with benzoyl peroxide. A topical fixed-dose azole, and trimethoprim alone are also effective in instances where
clindamycin phosphate 12% and benzoyl peroxide 30% combination other antibiotics cannot be used or for patients who do not respond
gel once daily was more effective and twice daily at least as effective to conventional treatment.81,122
as clindamycin alone twice daily, with an early onset of action and an The tetracycline antibiotic family has multiple modes of action,
acceptable safety and tolerability profile.119 Erythromycin is available well-understood antibacterial effects, and anti-inflammatory effects
alone and in combination with retinoic acid or benzoyl peroxide. that target an additional aspect of pathogenesis.116,122,123 Through

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calcium chelation, they inhibit neutrophil and monocyte chemo- The most likely consequence of resistance is decreased clinical
taxis. Concentrations below the antibiotic threshold still inhibit efficacy of antibiotic-based treatment regimens compared with that
inflammation and improve both acne vulgaris and acne rosacea. in patients with fully susceptible flora.
Tetracycline is no longer the drug of choice in this family; dis- Studies on P. acnes resistance have highlighted the need for
advantages include diet-related effects on absorption and the drug’s treatment guidelines to restrict the use of antibiotics to limit the
lower anti-inflammatory and antibacterial activity. emergence of resistant strains. Patients with less severe forms of acne

CHAPTER        Acne Vulgaris
The incidence of significant adverse effects with oral antibiotic should not be treated with oral antibiotics, and where possible such
use is low. However, adverse effect profiles may be helpful for each therapy should be limited to the shortest feasible duration (eg, 6-8
systemic antibiotic used in the treatment of acne. Vaginal candidiasis weeks). Local patterns of resistance should be considered. The use
may complicate the use of all oral antibiotics.62 Doxycycline is very of systemic antibiotics should be limited (both indication and dura-
commonly a photosensitizer especially at higher doses. tion) and topical antibiotic monotherapy should be avoided.
Minocycline has been associated with pigment deposition in Guidelines advocate early use of combination therapy with reti-
the skin, mucous membranes, and teeth, particularly among patients noids. Often, when oral antibiotics are combined with topical agents, 117
receiving long-term therapy and/or higher doses of the medica- the antibiotic may be discontinued after 6 months of therapy. Nearly
tion. In some instances this is irreversible. Pigmentation occurs 70% of patients with acne require antibiotics for 12 weeks or less if
most often in acne scars, anterior shins, and mucous membranes. aggressive retinoid therapy is introduced during that time.116
Minocycline may cause dose-related dizziness, which resolves with Another potential strategy is to eliminate the use of antibiotics and
dose titration; urticaria; hypersensitivity syndrome, autoimmune combine other topical agents. Neither retinoids nor benzoyl peroxide
hepatitis, a systemic lupus erythematosus-like syndrome; and serum creates selective pressure for resistance and is one combination option.
sickness-like reactions.62,116 Although this approach has been evaluated for efficacy and safety, there
The Cochrane collaboration has conducted a review into the is limited evidence of its effect on microbial resistance. In one open label
efficacy and safety of minocycline, examining 39 randomized con- study of adapalene and benzoyl peroxide, baseline counts of antibiotic
trolled trials. These studies show that minocycline is an effective resistant strains of P. acnes were reduced by week 4.116
treatment for moderate-to-severe inflammatory acne but present no Stricter cross-infection control measures are recommended
evidence to support the first-line use of minocycline in acne treat- when assessing acne. Any topical or systemic antibiotic therapy
ment. The drug is more lipophilic, may act more quickly, and can be should be combined when possible with broad-spectrum antibacte-
taken once daily. However, people treated with minocycline are at rial agents such as benzoyl peroxide. In addition, isotretinoin use
a significantly greater risk of developing an autoimmune syndrome should be initiated earlier in indicated patients, rather than prolong-
than those given tetracycline or no treatment.124 ing antibiotic courses.24,69
Sarecycline (Seysara) is a new, oral, narrow-spectrum tetracycline-
derived antibiotic with anti-inflammatory properties. It is specifically Other Topical Agents A tyrosine kinase inhibitor, azelaic acid
indicated for the treatment of inflammatory lesions of non-nodular has been used in patients with sensitive skin or of Fitzpatrick skin
moderate-to-severe acne vulgaris in patients 9 years of age or older. The types IV or greater because of the lightening effect of the product on
mechanism of action in treating acne vulgaris is not known. Sarecycline dyspigmentation.67
should be taken with or without food once daily at a weight-based tiered Azelaic acid possesses activity against all four pathogenic fac-
dosage (60 mg if 33-54 kg, 100 mg if 55-84 kg, and 150 mg if 85-136 kg). tors that produce acne. It has anti-inflammatory and antibacte-
To reduce the risk of esophageal irritation and ulceration, sarecycline rial activities. Azelaic acid also normalizes keratinization, which
should be administered with adequate amounts of fluid. accounts for its anticomedogenic effect. It is a competitive inhibitor
The FDA approval of sarecycline in October 2018 was based of mitochondrial oxidoreductases and of 5-α-reductase, inhibiting
on two identically designed, large, multicenter, randomized, double- the conversion of testosterone to 5-dehydrotestosterone. It also pos-
blind, placebo-controlled, phase III studies that assessed use in a sesses bacteriostatic activity to both aerobic and anaerobic bacteria
total of 2,002 participants 9 years of age or older with moderate- including P. acnes. Azelaic acid is an antikeratinizing agent, display-
to-severe facial acne vulgaris. Data demonstrated that once-daily ing antiproliferative cytostatic effects on keratinocytes and modulat-
sarecycline 1.5 mg/kg significantly improved acne severity based ing the early and terminal phases of epidermal differentiation.103 It
on Investigator’s Global Assessment (IGA) success and significantly may produce hypopigmentation. Inhibition of thioredoxin reductase
reduced inflammatory lesion count versus placebo at week 12. Study by azelaic acid provides a rationale for its depigmenting property.
1: IGA success, 21.9% versus 10.5%, and mean absolute reduction in Azelaic acid 20% cream is used in the treatment of mild-to-
number of inflammatory lesions, 15.3 versus 10.2. Study 2: IGA suc- moderate inflammatory acne, has an excellent safety profile with
cess, 22.6% versus 15.3%, and mean absolute reduction in inflamma- minimal adverse effects, and is well tolerated in comparison with
tory lesions, 15.5 versus 11.1.125-127 other acne treatments. The most common adverse effects are pruri-
Bacterial resistance to antibiotics is an increasing problem in tus, burning, stinging, and tingling; these are reported in 1% to 5%
acne therapy, particularly because treatments are used over a long of patients. These are generally transient and mild in nature. Other
period of time.116 The development of strains with unidentified muta- adverse reactions, such as erythema, dryness, rash, peeling, irrita-
tions suggests new evolving mechanisms of resistance. Combined tion, dermatitis, and contact dermatitis, were reported in fewer than
resistance to clindamycin and erythromycin is much more common 1% of patients.
than resistance to tetracycline. Use of topical antibiotics can lead to Azelaic acid has been effective in clinical trials studied with top-
resistance largely confined to the skin of treated sites, whereas oral ical 2% erythromycin, topical 5% benzoyl peroxide gel, and topical
antibiotics can lead to resistance in commensal flora at all body 0.05% tretinoin cream in the treatment of mild-to-moderate inflam-
sites. Resistance is more common in patients with moderate-to- matory acne. However, the agent has limited efficacy, compared with
severe acne and in countries with high outpatient antibiotic sales. other antiacne therapies.62 It is an alternative to first choice therapy
Resistance is disseminated primarily by person-to-person contact, for comedonal and all types inflammatory acne, particularly in com-
and thus the spread occurs frequently. bination. It is an alternative to topical retinoids for maintenance
There have been an increasing number of reports of systemic therapy as its efficacy and safety profile are advantageous for long-
infections caused by resistant P. acnes in nonacne patients after term therapy.24,32,67
surgery. A transmission of factors conferring resistance to bacteria Azelaic acid should be applied twice a day, in the morning
other than P. acnes has been described. and evening. A majority of patients with inflammatory lesions may

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experience an improvement in their acne within 4 weeks of begin- from baseline to −19.4 (both trials) versus −13.0 and −10.8 with
ning treatment. However, treatment may be continued over several vehicle, respectively, as well as a reduction in inflammatory lesions
months, if necessary. from baseline to −19.3 and −20.0 versus −15.5 and −12.6 with
Azelaic acid is in a pregnancy category B and should only be used vehicle, respectively. The most common side effects were erythema,
in pregnant women if medically necessary. Patients with dark com- pruritus, edema, stinging, and burning.133
plexions should be monitored for early signs of hypopigmentation. In contrast to systemic spironolactone, topical clascoterone can
Dapsone, a synthetic sulfone, is available topically as 5% be used in both males and females. There are no human data on
SECTION     Dermatologic Disorders

and 7.5% gels for acne, and may be used in sulfonamide-allergic use in pregnancy, but subcutaneous exposure to doses 8 to 39 times
patients. Dapsone’s utility is attributable to its anti-inflammatory maximal recommended human doses resulted in increased malfor-
and antimicrobial properties that improve both inflammatory and mations in rats and postimplantation loss and resorptions in rab-
noninflammatory acne, with more prominent effects occurring in bits. There are no data on safety in lactation or detection of drug or
inflammatory lesions. In clinical trials, topical dapsone showed metabolite in human milk.134
16 modest-to-moderate efficacy, primarily in the reduction of inflam-
Oral Contraceptives Estrogen-containing oral contraceptives can
matory lesions. Short- and long-term safety and efficacy have been
be useful in the treatment of acne in some women. Those approved
demonstrated.128
by the FDA for the management of acne contain norgestimate with
In a study of 101 adult women with mild-to-moderate inflam-
ethinyl estradiol and norethindrone acetate with ethinyl estradiol.
matory facial acne and sensitive skin for 12 weeks, topical 5% dap-
There is good evidence and consensus opinion that other estrogen-
sone gel was effective and minimally irritating. Response to dapsone
containing oral contraceptives are also equally effective.62
appears to be influenced by gender, with female patients experi-
The mechanism of action of combination oral contraceptives
encing a significantly greater reduction in acne lesion counts and
(COCs) in the treatment of acne is based on their antiandrogenic
a significantly higher clinical success rate following 12 weeks of
properties. These hormones decrease androgen production at the
treatment.129
level of the ovary and also increase sex hormone-binding globulin,
Topical 5% dapsone gel is recommended to be used twice daily
binding free circulating testosterone and rendering it unavailable to
for acne. Conversely, dapsone 7.5% gel is indicated once daily. It
bind and activate the androgen receptor. In addition, COCs reduce
received FDA approval for use in patients aged 12 years and older
5-α-reductase activity and block the androgen receptor.68
based on a pair of 12-week, double-blind, placebo-controlled, ran-
The risks of COCs must be weighed against the risks of the con-
domized trials that included more than 4,300 participants with acne.
dition that they are treating or preventing. If COCs are used exclu-
In these studies, a Global Acne Assessment Score of 0 or 1 with at
sively for acne, their risks must be compared to the risks of acne. It
least a two-grade improvement was achieved in 30% of patients
is important to remember that FDA approval of all COCs for acne
assigned to dapsone 7.5% gel, compared with 21% of vehicle-treated
specifies that they are approved for the treatment of acne in women
controls. It was extremely well tolerated, with application site dry-
who also desire contraception. COCs carry cardiovascular risks, and
ness and itching rates similar to placebo.130
breast cancer risks in some women, and low estrogen may affect
Topical dapsone is especially beneficial for patients exhibiting
bone mass. However, decreased risks of colorectal, ovarian, and
sensitivities or intolerance to conventional antiacne agents.131
endometrial cancers have been shown.
Combination therapy with dapsone and topical retinoids may
Oral contraceptives may improve acne for many women with
be indicated if comedonal components are present. Topical dapsone
clinical and laboratory findings of hyperandrogenism and in women
5%, alone or in combination, with adapalene 0.1% or benzoyl perox-
without these findings.68
ide 4% has been safe and efficacious but may be more irritating than
The Cochrane collaboration conducted a review in 2012 to
other topical agents.131,132
determine the effectiveness of COCs for the treatment of facial acne
Intralesional Steroids Intralesional corticosteroid injections compared with placebo or other active therapies. Thirty-one trials
are effective for individual inflammatory acne nodules. The effect with a total of 12,579 women were reviewed.134
of intralesional injection with corticosteroids (eg, triamcinolone Combination oral contraceptive use reduced inflammatory
acetonide) is a well-established and recognized treatment for large and noninflammatory facial lesion counts, severity grades, and self-
inflammatory lesions. Cystic acne improved in patients receiving assessed acne in nine placebo comparison trials, according to the
intralesional steroids.62 Rapid improvement and decreased pain are review.
noted. Most studies assessed women over six treatment cycles, which
Systemic absorption of steroids may occur with intralesional might not be adequate for a chronic condition like acne. In two
injections. Adrenal suppression was observed in one study. The trials, patients were more likely to discontinue because of adverse
injection of intralesional steroids may be associated with local atro- events, suggesting even if COCs improve acne, women might not be
phy. Lowering the concentration and/or volume of steroid may min- willing to accept long-term use for acne because of other side effects.
imize these complications. The review concluded that COCs should be considered for
women with acne who also want an oral contraceptive.
Hormonal Agents Two topical antiandrogen treatments are
A meta-analysis review of 32 randomized controlled trials
now available: clascoterone and topical spironolactone. Systemic
comparing use of antibiotics to oral contraceptive agents for acne
antiandrogen agents include oral contraceptives and systemic
concluded that although antibiotics may be superior at 3 months,
spironolactone.
oral contraceptive agents are equivalent to antibiotics at 6 months
Clascoterone is an androgen receptor inhibitor with a greater
in reducing acne lesions and may be a better first-line alternative to
ability to inhibit inflammatory cytokine synthesis from sebocytes
systemic antibiotics for long-term acne management in women.135
compared to spironolactone. It has been approved in a 1% cream
formulation for topical treatment of acne vulgaris in patients 12 Spironolactone Spironolactone is an antiandrogenic compound
years and older based on two randomized, double-blind, vehicle- that decreases testosterone production and competitively inhibits
controlled trials of 1,421 participants 12 years and older with moder- binding of testosterone and dihydrotestosterone to androgen recep-
ate-to-severe facial acne vulgaris. Overall, 62% of participants were tors in the skin. Spironolactone may cause hyperkalemia, primarily
female, and 91% were White, with a mean age of 19.7 years. After with higher doses or in patients with cardiac or renal compromise.
12 weeks of twice-daily application, clascoterone cream 1%, pro- Routine use occasionally causes menstrual irregularity. A 5% spi-
duced a significant reduction in absolute noninflammatory lesions ronolactone gel, studied in patients with increased sebum secretion,

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resulted in a decrease in the total acne lesions with no significant used for longer time periods, with a total cumulative dose of 120
efficacy under the acne severity index.136,137 to 150 mg/kg or the dose can be lowered to 20 mg on alternate
A single center review of 80 female patients with acne treated days after an initial 2 months of therapy with higher dosage.142-144
with systemic spironolactone (median age 19 years; range 14-20) Reports suggest that low-dose regimens are superior to other regi-
reported complete response in 22.5% of patients, and complete or mens (conventional or intermittent) in terms of patient satisfac-
partial response greater than 50% in 58.8% of subjects. The median tion, tolerability, and efficacy in patients with moderate acne. In

CHAPTER        Acne Vulgaris
dose was 100 mg, and median time to initial and maximal responses patients with severely inflamed acne, an even greater initial dose
were 3 and 5 months, respectively. Responders were more likely reduction may be required or pretreatment with oral corticoste-
to have jawline distribution of acne (70.3% vs 56.3%) and cyclic roids considered.
flares (75% vs 56.3%), although this was not significant. Only three Some patients experience a relapse of acne after the first
patients experienced side effects (rash, breast tenderness, diarrhea, course of treatment with isotretinoin. A retrospective review com-
and headache) and discontinued treatment. There were no reports of pared 82 patients who completed two courses of isotretinoin to 160
symptoms of hypotension, although blood pressure and potassium patients with only one course. Patients receiving a second course 117
were not routinely checked in the cohort.138 had shorter time from clear date to end of the treatment (32.0 ±
Although not currently FDA approved for the treatment of 43.3 days compared with 65.4 ± 65 days).145 Despite the small
acne, the 2016 AAD work group supports the use of spironolactone number of patients and retrospective nature of these data, waiting
in the management of acne in select women.68 for 2 months without new lesions has been adopted by some prac-
titioners to minimize risk of relapse after achieving target cumula-
tive dosing.
Oral Corticosteroids Oral corticosteroids have two potential
The 2016 AAD guidelines support initiation of isotretinoin at
modes of activity in the treatment of acne. One study demonstrated
0.5 mg/kg/day when appropriate, subsequently increasing to a full
that low-dose corticosteroids suppress adrenal activity in patients
dose of 1 mg/kg/day after the first month as tolerated, with a goal
who have proven adrenal hyperactivity.139 Low-dose prednisone in
cumulative dose between 120 and 150 mg/kg. One recent study of
doses ranging from 5 to 15 mg daily, administered alone or with high
116 patients found that a cumulative dose of 220 mg/kg or more may
estrogen containing COCs, has efficacy in the treatment of acne and
result in lower relapse rates, but confirmation will require study in
seborrhea. Expert opinion is that short courses of higher dose oral
larger populations.68
corticosteroids may be beneficial in patients with highly inflamma-
Isotretinoin is highly lipophilic and best absorbed when taken
tory disease. Long-term adverse effects of corticosteroids prohibit
with food. One novel formulation is less dependent on the presence
use as a primary therapy for acne.68
of fat in the gut for absorption.146 When prescribed, drying agents
Oral Isotretinoin Isotretinoin has been revolutionary for acne treat- must be discontinued and replaced with moisturizers.
ment. The risk of potential adverse effects must be weighed against Because isotretinoin is a vitamin A derivative, it interacts with
its ability to prevent lifelong and permanent physical and psycho- many of the biologic systems of the body, and consequently has a
logic scarring.140 significant pattern of adverse effects. The pattern is similar to that
Oral isotretinoin is an isomer of retinoic acid that has been seen in hypervitaminosis A. Side effects include those of the muco-
used for many years and is approved by the FDA for the treatment of cutaneous (most common), musculoskeletal, and ophthalmic sys-
severe recalcitrant acne vulgaris. Its use results in decreased sebum tems, as well as headaches and central nervous system effects. Most
production, acne lesions, and acne scarring, along with a decrease adverse effects, including cheilitis and dry nose, eyes, and mouth,
in symptoms of anxiety and depression. The 2016 AAD guidelines are transient and resolve with drug discontinuation.140 Laboratory
recommend use of oral isotretinoin in patients with moderate acne monitoring during therapy should include triglycerides, cholesterol,
that is treatment-resistant or that produces physical scarring or sig- transaminases, and complete blood counts.
nificant psychosocial distress. Mood disorders, depression, suicidal ideation, and suicides
Oral isotretinoin is a natural metabolite of vitamin A. Its mech- have been reported sporadically in patients taking this drug. A
anism is elusive, as it does not bind to retinoid receptors. It reduces causal relationship has not been established. These symptoms are
sebogenesis and may also inhibit sebaceous gland activity, growth quite common in adolescents and young adults, the age range of
of P. acnes, and inflammation, and improve follicular epithelial dif- patients who are likely to receive isotretinoin.
ferentiation.141 Systemic isotretinoin exerts a primary effect on com- Issues regarding responsible and informed use Published data
edogenesis, causing a decrease in size and reduction in formation of and expert opinion differ with respect to the use of isotretinoin as
new comedones.26 Isotretinoin is the only drug treatment for acne first-line or reserve therapy, optimal dosing, and risk of depression.140
that produces prolonged remission. Although some persist in reserving isotretinoin use only for
The teratogenic effects of oral retinoid therapy are well docu- severe acne, nodular or conglobate acne that has not responded
mented, and it should be prescribed only by those physicians to appropriate antibiotics and topical therapy, delaying use of
knowledgeable in its appropriate administration and monitoring. isotretinoin, the most effective choice, poses an ethical problem.147
Individuals capable of becoming pregnant who are of child-bearing Opinions vary on whether or not to restrict use to patients under
potential must enroll in the approved pregnancy prevention and 12 years and whether to avoid lasers, peelers, or wax epilation for at
management program (ie, iPLEDGE) to be treated with isotreti- least 6 months after discontinuation of therapy.148
noin. Two different forms of contraception must be started 1 month The causal relationship between the use of isotretinoin and
before and continue at least 1 month (but normally 4 months) after risk of depression continues to be scrutinized with no consensus.
therapy and pregnancy monitoring undertaken before, during, and The issue is complex as depression and suicidal ideation occur with
after therapy.140 severe acne in the absence of isotretinoin.
The efficacy of conventional isotretinoin treatment (0.5-1.0 There are instances in which withdrawal of isotretinoin has
mg/kg/day for 16-32 weeks, reaching a cumulative dose of 120-150 resulted in improved mood, and reintroduction of isotretinoin has
mg/kg) for acne has been well established. The approved dosage of resulted in the return of mood changes. Treatment of severe acne
isotretinoin is 0.5 to 2.0 mg/kg/day. with isotretinoin is often associated with mood improvement.62
Initial flaring can be minimized by initiation of lower doses There is epidemiologic evidence that the incidence of these events
(ie, 0.5 mg/kg/day or less). Many reports document efficacy of low- is lower in patients treated with isotretinoin than in an age-matched
dose and intermittent isotretinoin treatment. Lower doses can be general population. There is also evidence that the risk of depressed

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mood is no greater during isotretinoin therapy than during therapy Pharmacologic Cleansing Options
of an age-matched acne group treated with conservative therapy.62 Medicated Soaps and Washes Medicated soaps, washes, and
A 2016 review on isotretinoin controversies, facts, and recom- foams may contain topical antiseptics such as triclosan; peeling
mendations concluded despite common misperceptions, there is agents such as salicylic acid, sulfur; antimicrobials such as benzoyl
weak evidence for increased incidence of depression, suicidality, or peroxide, clindamycin, or azelaic acid, alone or in combination in
inflammatory bowel disease with isotretinoin use, and data indicate low concentrations. They may be nonprescription or prescription
that transient increases in transaminases and lipid levels do not typi-
SECTION     Dermatologic Disorders

status.160 Most washes should remain on the skin from 15 seconds to

cally necessitate discontinuation of therapy.149 5 minutes followed by thorough rinsing. This limits the amount of
In 2017, a systematic review and meta-analysis of the litera- time the active ingredient is in contact with the skin. Other cleansers
ture, with 31 studies, concluded isotretinoin treatment for acne are applied after washing and left on the skin without rinsing.
did not appear to be associated with an increased risk for depres- Quaternary ammonium compounds are cationic detergents
sion and that the treatment of acne appears to ameliorate depres- that are inactivated quickly in the presence of organic material such
16 sive symptoms.150 Current literature regarding the association with as sebum. The duration of action of these products is short.
depression and suicide was reexamined in 2018. It reconfirmed Antiseptic cleansers that have been studied include hexachlo-
that while those with a personal or family history of mental disor- rophene, chlorhexidine, and povidone-iodine. Use of hexachloro-
der might be at risk, further studies are needed and no conclusions phene has since been banned in nonprescription products by the
can be drawn.151 The current literature is insufficient to support a UFDA because of neurotoxicity concerns. Bacteriostatic soaps con-
meaningful causative association, but important study limitations taining hexachlorophene, carbanilides, and salicylanilides (halo-
exist. In the absence of definitive evidence, an idiosyncratic effect genated hydroxyphenols) may alter normal flora or be acnegenic.
cannot be excluded. This disputed association remains an impor- Few ordinary soaps induce acne. However, acne patients are par-
tant area for future research. Given the prevalence of depression, ticularly susceptible to comedogenic contactants, and if these soaps
anxiety, and suicidal ideation/suicide in the general population, are applied several times daily for long periods, they may become
and especially the adolescent population who may be candidates troublesome.
for isotretinoin therapy, the prescribing physician should continue Soaps containing coal tar, which can induce folliculitis, are not
to monitor for these symptoms at each visit for early recognition, indicated for acne.
advise patients about a possible risk of depression and suicidal In a very small group of patients in an 8-week, double-blind,
behavior, and make therapeutic decisions within the context of randomized clinical trial, a combination cleanser containing triclo-
each individual patient.68 san, azelaic acid, and salicylic acid produced a greater histopathologic
decrease in inflammatory response compared with a nonmedicated
Light Therapy cleanser, but there was no significant difference in noninflamma-
Light therapies are believed to work by killing P. acnes and by dam- tory lesions in either group.161 A rebound tendency was noted for
aging and shrinking sebaceous glands, reducing sebum output and the nonmedicated cleanser with respect to inflammatory lesions at
have few152 or temporary153,154 adverse effects. Light therapies may 4 weeks. Authors concluded that nonmedicated cleansers were an
be used once or twice weekly as a course of 6 to 10 treatments, with easier and cheaper way of managing patients with mild acne.
each irradiation lasting 10 to 20 minutes.154 P. acnes produce endog- Chlorhexidine inhibits in vitro growth of P. acnes.162 A 4%
enous porphyrins that absorb light to form highly reactive singlet chlorhexidine gluconate preparation in a detergent base is as effec-
oxygen, which destroys the bacteria.154 There is still debate about tive as benzoyl peroxide washes in patients with mild acne, and both
the effectiveness of different wavelengths.154 Since porphyrins have preparations reduced the number of inflammatory and noninflam-
peak absorption at blue light wavelengths, blue light is often used matory lesions after 8 and 12 weeks, compared with vehicle alone.161
to treat acne. Red light is also absorbed by porphyrins and can pen- However, further evidence is lacking, and irritation is a side effect.49
etrate deeper into the skin,155 where it may directly affect inflam- Glycolic 1%, an alpha-hydroxy acid (AHA), has been used as
matory mediators. Other light therapies attempt to selectively target a cleanser. AHAs cause desquamation by decreasing basal corneo-
and damage sebaceous glands directly, reducing their size and thus cyte cohesion and limiting follicular occlusion. AHA-containing
sebum output.156 These include infrared lasers, low-energy pulsed formulations may be considered in the treatment of acne in light
dye lasers, and radiofrequency devices.154 of mechanistic similarities with better validated antikeratinization
Photodynamic therapy (PDT) uses specific light-activating agents such as retinoids.49
creams, which are absorbed into the skin and amplify the response Alcohol-detergent medicated pads, impregnated with salicylic
to light therapy but tend to produce more severe adverse effects. acid 0.5%, have reduced inflammatory lesions and open comedones
There are concerns that PDT may interfere with the skin’s natural in mild-to-moderate acne. This type of medication is less abrasive,
immune mechanisms157,158 and cause long-term skin damage. not rinsed off, and convenient.163
Light therapies, previously expensive and accessed privately via Alcohol-detergent wipes, swabs, or “pledgets” impregnated
dermatologists or clinics, are increasingly popular. Home-use blue with antibiotics, such as clindamycin or lincomycin, are available.
light therapy is now available. Patients find it easier to comply with The antibiotic is deposited in low concentrations on the surface of
light treatments because of their short duration. the skin and may not penetrate to the depths of the pilosebaceous
Very few trials compare light therapy with conventional acne duct. Although patients may like the convenience and perception of
treatments. The European evidence-based guidelines concluded using an active agent, they should not be recommended over simple
published evidence is scarce and standardized treatment proto- cleansing.
cols and widespread experience are lacking. Due to conflicting or Abrasives consist of finely divided particles of fused aluminum
insufficient evidence, these guidelines did not make a recommen- or plastic together with cleansing and wetting agents. Abrasives peel
dation for or against treatment of comedonal, MMPP, or severe and remove surface debris and may assist resorption of papules and
papulopustular/nodular acne with monotherapy visible light, vis- pustules. Despite vigorous rubbing, removal of comedones is not
ible or infrared wavelength lasers, or intense pulsed light or PDT. accomplished. Particles containing active agents, such as sodium
Blue light has a low strength recommendation as a consideration tetraborate decahydrate, dissolve on use, and their abrasiveness is
for MMPP.24,69 An ongoing Cochrane review protocol continues to therefore limited.163 The effectiveness of an abrasive cleanser with
investigate the current state of evidence for use of light therapy in and without polyethylene granules showed no difference in results
acne.159 in patients with mild-to-moderate acne. These products are not

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TABLE 117-3 Monitoring Therapy for Acne: Parameters and Frequency
Person Responsible and Frequencies for Monitoring:
Patient: daily while on drug therapy; Pharmacist: every 4-8 weeks of therapy or next pharmacy visit
Parameter Time Frame/Degree of Change Actions
Short-Term Effectiveness End Points (Acne Resolution/Control)

CHAPTER        Acne Vulgaris
Lesion count Decrease by 10%-25% within 4-8 weeks, with If end points are not achieved, refer to a physician for
control, or more than a 50% decrease within further therapy
2-4 months
Comedones Resolve by 3-4 months
Inflammatory lesions Resolve within a few weeks
Anxiety, depression Achieve control or improvement within 2-4 months
Long-Term Effectiveness End Points (Acne Resolution/Control) 117
Progression of severity No progression of severity If end points are not achieved, refer to a physician for
further therapy
Recurrent episodes Lengthening of acne-free periods throughout
therapy
Scarring or pigmentation No further scarring or pigmentation throughout
therapy
Safety End Points (Treatment Side Effects)
Dermatitis, increased dryness, No adverse effects Refer to a physician for alternate therapy, dose
gastrointestinal upset, photosensitivity reduction, discontinuation or additive palliative
treatment, or preventative measures for adverse
effects

TABLE 117-4 Monitoring Care Plans for Acne Types I Through IV

Adjustment in Therapy
Follow-up Action If Patient Does Not
Acne Follow-up Action If Patient If Patient Does Not Respond Adequately
Type Description Suggested Options Responds Respond in 3 Months to Previous Action
Type I Mainly comedones Topical retinoid or a fixed Continue until lesions are Treat as Type II acne
with an occasional combination with a retinoid completely cleared and
small inflamed is the drug of choice; can also then stop or taper therapy
papule or pustule; consider benzoyl peroxide or
no scarring present azelaic acid or salicylic acid
Type II Comedones and more Fixed-dose combination Continue until lesions are Treat as Type III acne
numerous papules (adapalene and benzoyl completely cleared and
and pustules peroxide) or benzoyl then stop or taper therapy
(mainly facial); mild peroxide or topical retinoid
scarring or azelaic acid; if more severe,
fixed-dose combination is
preferred, with or without
hormonal therapy and/or
antibiotic, particularly if the
trunk is involved
Type III Numerous Fixed-dose combination with Oral antibiotics typically are Add oral contraceptive Oral isotretinoin
comedones, an oral antibiotic is preferred; prescribed for daily use or antiandrogen (except in women
papules and oral isotretinoin or oral over 4-6 months, with (women only) who are or who may
pustules, spreading hormonal therapy can also subsequent tapering and become pregnant);
to the back, chest, be added discontinuation as acne consider safety end
and shoulders, improves. Other agents points (potential
with an occasional can also be stopped or adverse effects)
cyst or nodule; tapered now before initiating
moderate scarring therapy
Type IV Numerous large cysts For males, monotherapy with Oral antibiotics typically are If no response after
on the face, neck, oral isotretinoin or a retinoid prescribed for daily use 3-6 months, oral
and upper trunk; fixed combination or oral over 4-6 months, with isotretinoin (except
severe scarring antibiotics; for females, subsequent tapering and in women who are
oral isotretinoin plus discontinuation as acne or who may become
antiandrogenic hormonal improves pregnant). Consider
therapy is preferred, or a safety end points
fixed combination retinoid Other agents can also be (potential adverse
with oral antibiotics (consider stopped or tapered now effects) before
high dose) and/or oral initiating therapy
antiandrogenic hormonal
therapy

CH117.indd 1633 13-12-2022 15:23:52

 1634
indicated in most cases but may be used in a patient who responds GHQ general health quality
empirically.164 HGL high glycemic load
IGF insulin-like growth factor
EVALUATION OF THERAPEUTIC MMPP mild-to-moderate papulopustular
P. acnes Propionibacterium acnes
OUTCOMES PAPA pyogenic arthritis, pyoderma gangrenosum, acne
PBV pollen bee venom
SECTION     Dermatologic Disorders

Provide a monitoring framework for patients with acne.

Parameters should be monitored by the patient and recorded in PDT photodynamic therapy
a diary. Therapy should be appropriately tapered in response to QOL quality of life
improvement or resolution. The healthcare professional should be SAPHO synovitis, acne, pustulosis, hyperostosis, osteitis
responsible for ensuring that the treatment plan remains on sched- syndrome
ule and is effective with no adverse effects. The patient should be SPF sun protection factor
16 contacted within 2 to 3 weeks to determine progress. TTO time trade-off
Acne is poorly understood by adolescents. These patients often
lack knowledge of the cause of the disorder and aggravating factors,
indications for self-care versus prescription treatment, expected
onset of effect, sequence of the healing process, duration of treat-
ment, appropriate application of topical agents, maximal achievable
effects, expected adverse effects, safety concerns, and the benefit to
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