Annals of Internal MedicineT

In the ClinicT

Osteoporosis
O
steoporosis is a common systemic skeletal
disorder resulting in bone fragility and
increased fracture risk. Evidence-based
screening strategies improve identification of
patients who are most likely to benefit from drug
treatment to prevent fracture. In addition, careful
Screening and Prevention
consideration of when pharmacotherapy should be
started, choice of medication, and duration of Diagnosis
treatment maximizes the benefits of fracture pre-
vention while minimizing potential harms of long-
term drug exposure. Treatment for Fracture
Prevention
CME/MOC activity available at Annals.org.

Practice Improvement
Physician Writers doi:10.7326/AITC202401160
Kristine E. Ensrud, MD, MPH
Carolyn J. Crandall, MD, MS This article was published at Annals.org on 9 January 2024.
University of Minnesota, CME Objective: To review current evidence for screening, prevention, diagnosis,
Minneapolis, Minnesota (K.E.E.) and treatment of osteoporosis.
David Geffen School of
Medicine at UCLA, Los Angeles, Funding Source: American College of Physicians.
California (C.J.C.) Disclosures: All relevant financial relationships have been mitigated. Disclosures
can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.
do?msNum¼M23-0284.

With the assistance of additional physician writers, the editors of Annals of

Internal Medicine develop In the Clinic using MKSAP and other resources of
the American College of Physicians.
In the Clinic does not necessarily represent official ACP clinical policy. For ACP
clinical guidelines, please go to https://www.acponline.org/clinical_information/
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 Osteoporosis is a systemic skeletal dis- loss of independence, and increased
ease characterized by low bone mass mortality, especially after hip and clini-
and microarchitectural deterioration in cal vertebral fractures (3).
bone tissue, leading to bone fragility
1. Sarafrazi N, Wambogo EA,
Shepherd JA. Osteoporosis and increased fracture risk. The opera- The goal of screening, diagnosis, and
or Low Bone Mass in Older
Adults: United States, tional definition of osteoporosis is treatment of osteoporosis is to prevent
2017–2018. NCHS Data based on bone mineral density (BMD) clinical fractures. There is strong evi-
Brief no. 405. March 2021.
Accessed at www.cdc.gov/ measurement. In 2017–2018, the age- dence that osteoporosis drug treat-
nchs/products/databriefs/
db405.htm on 28 July adjusted prevalence of osteoporosis ment reduces clinical fracture risk
2022. among adults aged 50 years or older among postmenopausal women with
2. Singer AJ. Chapter 29 -
Economics of osteoporosis. was 12.6% (1). The clinical and eco- existing vertebral fractures or BMD-
In: Dempster DW, Cauley
JA, Bouxsein ML, et al, eds. nomic burden of osteoporosis-related defined osteoporosis and among
Marcus and Feldman's fractures is substantial (2). An esti- adults aged 50 years or older with
Osteoporosis (Fifth Edition).
Academic Pr; 2021:693- mated 2 million incident osteoporotic recent hip fracture (4–6). However,
704. Accessed at www.
sciencedirect.com/science/ fractures at a total cost of $17 billion management of osteoporosis and frac-
article/pii/ occur each year in the United States. ture prevention strategies are often not
B9780128130735000290
on 22 February 2023. Adverse fracture-related consequen- addressed by primary care clinicians,
3. Center JR, Bliuc D. Chapter
28 - Imminent fracture risk ces include functional impairment, even in older patients with recent frac-
and disability post fracture. chronic pain, reduced quality of life, tures (7).
In: Dempster DW, Cauley
JA, Bouxsein ML, et al, eds.
Marcus and Feldman's
Osteoporosis (Fifth Edition).
Academic Pr; 2021:669-
691. Accessed at www.
sciencedirect.com/science/
Screening and Prevention
article/pii/ Who is at risk for osteoporosis? osteoporosis drug treatment (14–17), is
B9780128130735000289
on 1 March 2023. Osteoporosis may be due to aging and a web-based calculator designed to
4. Ayers C, Kansagara D, Lazur
decreased gonadal function (primary estimate 10-year probabilities of hip
B, et al. Effectiveness and
safety of treatments to pre- osteoporosis) or specific clinical disor- and major osteoporotic fracture, with
vent fractures in people
with low bone mass or pri- ders or medications (secondary osteo- or without incorporation of BMD infor-
mary osteoporosis: a living
systematic review and net- porosis). Among U.S. adults aged 50 mation. FRAX has several strengths
work meta-analysis for the years or older, the prevalence of pri- (18): Country-specific models are avail-
American College of
Physicians. Ann Intern mary osteoporosis is higher among able, its performance has been eval-
Med. 2023;176:182-195.
[PMID: 36592455] women than men (15.4% vs. 4.3%) and uated in studies, and the algorithm is
5. Ensrud KE, Crandall CJ. lower among non-Hispanic Black adults regularly revised and updated. How-
Bisphosphonates for post-
menopausal osteoporosis. than among Asian, Hispanic, and non- ever, FRAX also has limitations (19, 20).
JAMA. 2019;322:2017- There are no randomized clinical trial
2018. [PMID: 31621799] Hispanic White adults (8, 9). Common
6. Ensrud KE, Schousboe JT. risk factors for primary osteoporosis (RCT) data showing a benefit of phar-
Anabolic therapy for osteo-
porosis. JAMA. include older age, female biological macotherapy for clinical fracture pre-
2021;326:350-351. [PMID:
34313699] sex, low body weight, cigarette smok- vention in patients enrolled on the
7. National Committee for
ing, and parental history of osteoporo- basis of FRAX intervention thresholds
Quality Assurance.
Osteoporosis Management sis or osteoporotic fracture. recommended by some organizations
in Women Who Had a
Fracture (OMW). Accessed (14–17). The way in which FRAX scores
How should fracture risk be assessed?
at www.ncqa.org/hedis/
measures/osteoporosis-
are derived is not transparent. FRAX
management-in-women-
Fracture risk can be qualitatively assessed generates fracture risk probabilities
who-had-a-fracture on 25 by considering osteoporosis risk factors using femoral neck BMD and underes-
January 2023.
8. Noel SE, Santos MP, Wright and fall propensity (10). Formal fracture timates fracture probability in persons
NC. Racial and ethnic dis-
risk assessment tools (11–13) are available
parities in bone health and with markedly lower spine BMD. FRAX
outcomes in the United that estimate a patient’s absolute risk for
States. J Bone Miner Res. does not account for the existing dose–
2021;36:1881-1905. fracture. However, the benefit of includ-
[PMID: 34338355] response relationship for some clinical
ing these tools into shared clinical deci-
9. Wright NC, Looker AC, risk factors. For example, prior fracture
Saag KG, et al. The recent sion making is uncertain.
prevalence of osteoporosis is a FRAX clinical risk factor, but the
and low bone mass in the
United States based on The Fracture Risk Assessment Tool algorithm does not consider recency,
bone mineral density at the
femoral neck or lumbar (FRAX) (11), the most commonly number, or site of prior fractures, all of
spine. J Bone Miner Res. endorsed tool in the United States to which affect subsequent risk. Fall his-
2014;29:2520-2526.
[PMID: 24771492] aid decision making about initiation of tory or propensity is not a component

© 2024 American College of Physicians ITC2 In the Clinic Annals of Internal Medicine January 2024

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of FRAX; the tool may underestimate years, when it begins to increase expo-
fracture risk in a patient with a higher nentially (27). Evidence is also lacking
10. Qaseem A, Hicks LA,
propensity for falls. Although the U.S. on the benefits versus the harms of ini- Etxeandia-Ikobaltzeta I,
FRAX tool generates race-specific frac- tiating drug treatment at age 50 to 64 et al; Clinical Guidelines
Committee of the
ture probabilities for Asian, Black, His- years. American College of
Physicians. Pharmacologic
panic, and White adults, little evidence Some guidelines (14, 15, 26) encour- treatment of primary
osteoporosis or low bone
supports the need to differentially as- age BMD measurement for younger mass to prevent fractures
sess fracture risk based on race and postmenopausal women with risk fac-
in adults: a living clinical
guideline from the
ethnicity. Finally, FRAX is designed to tors for fracture, but there is no consen- American College of
Physicians. Ann Intern
aid in clinical decision making about sus on which specific risk factors to Med. 2023;176:224-238.
[PMID: 36592456]
drug treatment initiation and should be consider. The USPSTF (25) recom- 11. Centre for Metabolic Bone
used to estimate fracture risk only in mends using a formal risk assessment Diseases. FRAX WHO
Fracture Risk Assessment
treatment-naive patients. tool in younger postmenopausal wo- Tool. Accessed at www.
shef.ac.uk/FRAX on 20
Systematic reviews (21, 22) of observa- men who are at risk for osteoporosis July 2022.
12. ClinRisk Ltd. QFracture®-
tional studies in postmenopausal women based on medical history to select candi- 2016 risk calculator.

found that no fracture risk assessment dates for BMD testing (Appendix Table 1, Accessed at https://
qfracture.org on 22
tool is optimal and concluded that sim- available at Annals.org). Four of the 5 August 2022.
13. Garvan Institute of
ple tools or BMD alone often perform as tools suggested by the USPSTF, including Medical Research. Bone

well as more complex ones, including the Osteoporosis Self-Assessment Tool Fracture Risk Calculator.
Accessed at www.garvan.
FRAX. Although a decision aid incorpo- (OST) (a simple instrument based on age org.au/bone-fracture-risk
on 22 August 2022.
rating FRAX probability may improve and weight alone) (25), were designed to 14. Camacho PM, Petak SM,

patient knowledge, effects on rates of identify postmenopausal women with low Binkley N, et al. American
Association of Clinical
treatment initiation and adherence are BMD. FRAX without BMD (11), designed Endocrinologists/
American College of
uncertain (23, 24). to estimate 10-year fracture probabilities, Endocrinology clinical
is the fifth tool suggested by the USPSTF. practice guidelines for the
diagnosis and treatment
Who should be screened with a For each tool, the USPSTF suggests a of postmenopausal osteo-
BMD test? porosis–2020 update.
specific threshold to select younger post- Endocr Pract. 2020;26:1-
The U.S. Preventive Services Task Force menopausal women for screening with 46. [PMID: 32427503]
15. LeBoff MS, Greenspan SL,
(USPSTF) (25) and professional soci- BMD testing. Of these tools, use of the Insogna KL, et al. The
clinician's guide to pre-
eties (14, 15, 26) universally recom- OST (threshold score <2) is recommen- vention and treatment of
mend that women aged 65 years or ded because it is the most parsimonious osteoporosis. Osteoporos
Int. 2022;33:2049-2102.
older should be screened for osteopo- and time-efficient tool, does not include a [PMID: 35478046]
16. Watts NB, Adler RA,
rosis with BMD measurement at the hip component based on race or ethnicity, Bilezikian JP, et al;
and lumbar spine using dual-energy x- and performs better than the more com- Endocrine Society.
Osteoporosis in men: an
ray absorptiometry (DXA). The preva- plex FRAX tool in identifying women with Endocrine Society clinical
practice guideline. J Clin
lence of osteoporosis in older U.S. BMD-defined osteoporosis (Appendix Endocrinol Metab.
women is 27% (1). The USPSTF recom- Table 2, available at Annals.org) (28). 2012;97:1802-1822.
[PMID: 22675062]
mendation is based on the high preva- Before ordering a BMD test in younger 17. Eastell R, Rosen CJ, Black
DM, et al.
lence and convincing evidence that BMD postmenopausal women, clinicians should Pharmacological manage-
is accurate for detecting osteoporosis counsel patients about the lack of evidence ment of osteoporosis in
postmenopausal women:
and predicting osteoporotic fractures and on the benefits versus the harms of initiating an Endocrine Society clini-
cal practice guideline. J
that drug therapies reduce subsequent osteoporosis drug treatment at this life Clin Endocrinol Metab.
fracture rates in this population. stage. 2019;104:1595-1622.
[PMID: 30907953]
18. Kanis JA, Hans D, Cooper
The optimal risk assessment strategy to Osteoporosis screening in older men C, et al; Task Force of the
FRAX Initiative.
select younger postmenopausal women has been proposed because it is an Interpretation and use of
for osteoporosis screening is uncertain. accepted strategy in older women. FRAX in clinical practice.
Osteoporos Int.
Despite rapid rates of spinal bone loss However, the prevalence of osteoporo- 2011;22:2395-2411.
[PMID: 21779818]
during the menopausal transition, abso- sis among men aged 65 years or older 19. Collins GS, Michaëlsson
lute fracture risk for any given BMD is is only 5.7% (1). Importantly, data are K. Fracture risk assess-
ment: state of the art,
much lower in younger postmeno- lacking on the efficacy of pharmaco- methodologically
unsound, or poorly
pausal women than in older women. therapy to prevent clinical fractures in reported? Curr
The absolute 5-year hip fracture proba- men. Thus, although some guidelines Osteoporos Rep.
2012;10:199-207.
bility is less than 1.0% until age 70 to 79 (15, 16, 26) recommend BMD testing in [PMID: 22688862]

January 2024 Annals of Internal Medicine In the Clinic ITC3 © 2024 American College of Physicians

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 all men aged 70 years or older and in What is the role of calcium and
those aged 50 to 69 years with risk fac- vitamin D in preventing osteoporosis?
tors, the USPSTF (25) does not recom- The recommended dietary allowance
mend for or against screening in men, (RDA) is calculated to meet intake
citing insufficient evidence. requirements of more than 97% of the
20. van den Bergh JPW, van
Geel TACM, Lems WF, et U.S. population. For women, the RDA
al. Assessment of individ- A study (29) in 4043 community-dwelling for calcium is 1000 mg/d for those
ual fracture risk: FRAX and
beyond. Curr Osteoporos men aged 70 years or older reported aged 19 to 50 years and 1200 mg/d for
Rep. 2010;8:131-137.
[PMID: 20563901]
that the OST approach (cutoff <2) per- those older than 50 years; for men, the
21. Rubin KH, Friis-Holmberg formed slightly better than a more com- RDA is 1000 mg/d for those aged 19 to
T, Hermann AP, et al. Risk
assessment tools to iden- plex FRAX-based strategy in identifying 70 years and 1200 mg/d for those
tify women with increased
risk of osteoporotic frac- a BMD T-score of 2.5 or lower (area older than 70 years (34). Intake above
ture: complexity or sim-
plicity? A systematic
under the curve, 0.68 for OST strategy vs. 2500 mg/d should be avoided because
review. J Bone Miner Res. 0.62 for FRAX strategy); use of either tool of a dose-dependent increased risk for
2013;28:1701-1717.
[PMID: 23592255] substantially reduced the proportion of nephrolithiasis. Preferred sources of
22. Beaudoin C, Moore L,
Gagne M, et al.
men referred for BMD measurement com- calcium are calcium-rich foods and
Performance of predictive pared with universal screening. beverages.
tools to identify individu-
als at risk of non-traumatic
fracture: a systematic How often should older women be The RDA for vitamin D is 600 IU/d for
review, meta-analysis, and
meta-regression.
screened? men and women aged 19 to 70 years
Osteoporos Int. A single hip BMD measurement in and 800 IU/d for older adults (34).
2019;30:721-740. [PMID:
30877348] older women is a robust predictor of Vitamin D in the U.S. diet is primarily pro-
23. LeBlanc A, Wang AT,
Wyatt K, et al. Encounter long-term fracture risk with little degra- vided by fortified foods. Multiple RCTs
decision aid vs. clinical
dation over time (30). Prospective stud- have shown no benefit of vitamin D sup-
decision support or usual
care to support patient- ies in postmenopausal (31) and older plementation in fracture risk reduction;
centered treatment deci- thus, screening for vitamin D deficiency
sions in osteoporosis: the women (32) with widely varying initial
Osteoporosis Choice or supplemental vitamin D in the general
Randomized Trial II. PLoS BMD suggest that repeating BMD mea-
One. 2015;10:e0128063. population is not recommended (35,
surement 3 to 8 years after the initial
[PMID: 26010755] 36).
24. Montori VM, Shah ND,
Pencille LJ, et al. Use of a
measurement does not meaningfully
decision aid to improve improve fracture prediction. However, What other nonpharmacologic
treatment decisions in
osteoporosis: the other evidence indicates that the opti- lifestyle measures are recommended
Osteoporosis Choice
mal screening interval in older women for prevention?
Randomized Trial. Am J
Med. 2011;124:549-556. without osteoporosis at the initial assess- Although definitive evidence from
[PMID: 21605732]
25. Curry SJ, Krist AH, Owens ment depends on baseline BMD; those RCTs is not available, other lifestyle
DK, et al; US Preventive
Services Task Force. with lower BMD at baseline should have measures recommended for preven-
Screening for osteoporosis
a shorter rescreening interval because of tion include maintaining a healthy
to prevent fractures: US
Preventive Services Task higher incidence of osteoporosis and body weight (for example, body mass
Force recommendation
statement. JAMA. related fractures. index >20 kg/m2) and adequate die-
2018;319:2521-2531.
[PMID: 29946735]
tary protein intake (0.8 g/kg of body
26. International Society for A longitudinal study (33) in 4957 com- weight per day) and avoiding cigarette
Clinical Densitometry.
ISCD Adult Positions. munity-dwelling women aged 67 years smoking and excessive alcohol intake.
June 2019. Accessed at
https://iscd.org/learn/
or older without osteoporosis at the ini- Physical activity is widely recommended
official-positions/adult- tial assessment estimated the cumula- to improve skeletal health, but RCTs
positions on 28 July
2022. tive incidence of osteoporosis and have not been conducted to identify the
27. Doherty DA, Sanders KM,
Kotowicz MA, et al. reported that fewer than 10% became type, frequency, or duration necessary
Lifetime and five-year
age-specific risks of first
osteoporotic during follow-up if rescre- to prevent osteoporosis. Some guide-
and subsequent osteopor- ening intervals were 15 years for those lines (14, 15) endorse lifelong physical
otic fractures in post-
menopausal women. with normal BMD (T-score ≥1.0) or activity (both weight-bearing exercise
Osteoporos Int.
2001;12:16-23. [PMID: mild osteopenia (T-score <1.0 and and muscle-strengthening exercise) for
11305078]
28. Crandall CJ, Ensrud KE.
>1.5), 5 years for those with moderate osteoporosis prevention, typically 30 to
Osteoporosis screening in osteopenia (T-score ≤1.5 and >2.0), 40 minutes of walking per day plus a
younger postmenopausal
women. JAMA. and 1 year for those with advanced few minutes of gentle resistance exer-
2020;323:367-368.
[PMID: 31917384] osteopenia (T-score ≤2.0 and >2.5). cises 3 to 4 days per week.

© 2024 American College of Physicians ITC4 In the Clinic Annals of Internal Medicine January 2024

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 Screening and Prevention... Fracture risk can be assessed by considering osteoporo-
sis risk factors and fall propensity. No optimal fracture risk assessment tool is available.
Women aged 65 years or older should be screened for osteoporosis with hip and spine 29. Diem SJ, Peters KW,
BMD measurements. Use of an OST cutoff less than 2 is a reasonable strategy to identify Gourlay ML, et al;
Osteoporotic Fractures in
younger postmenopausal women for BMD testing if there is agreement that drug treat- Men Research Group.
ment will be initiated for a BMD T-score of 2.5 or lower. Data are insufficient to endorse Screening for osteoporo-
sis in older men: operat-
a specific screening strategy in older men. The initial BMD T-score is the major determi- ing characteristics of
nant of the screening interval among older women without osteoporosis at the initial proposed strategies for
assessment. Adequate exercise and intake of protein, calcium, and vitamin D at RDA lev- selecting men for BMD
testing. J Gen Intern
els are recommended for bone health. Med. 2017;32:1235-
1241. [PMID: 28815485]
30. Black DM, Cauley JA,
Wagman R, et al. The
CLINICAL BOTTOM LINE ability of a single BMD
and fracture history
assessment to predict
fracture over 25 years in
postmenopausal women:
the Study of Osteoporotic

Diagnosis Fractures. J Bone Miner

Res. 2018;33:389-395.
[PMID: 28719727]
What elements of the history and (posterior–anterior view of the L1–L4 31. Crandall CJ, Larson J,
Wright NC, et al. Serial
examination should be part of the vertebrae) using DXA. bone density measure-
ment and incident frac-
evaluation?
BMD results are reported as T-scores ture risk discrimination in
postmenopausal women.
Although osteoporosis cannot be diag- and Z scores (Box: Classification of JAMA Intern Med.
nosed on the basis of the history and BMD by DXA). The T-score is reported
2020;180:1232-1240.
[PMID: 32730575]
examination, the history should assess in postmenopausal women and men 32. Hillier TA, Stone KL, Bauer
DC, et al. Evaluating the
common risk factors for osteoporosis aged 50 years or older and compares value of repeat bone min-
and related fractures (for example, fam- the patient’s BMD in terms of the SD
eral density measurement
and prediction of fractures
ily history of osteoporosis, history of below or above the mean BMD for a in older women: the
Study of Osteoporotic
fracture, or recent falls) and screen for young adult reference population. Be- Fractures. Arch Intern
possible secondary causes (such as gas- cause fracture risk in women and men
Med. 2007;167:155-160.
[PMID: 17242316]
tric bypass surgery or use of medications is similar at the same absolute value of 33. Gourlay ML, Fine JP,
Preisser JS, et al; Study of
with adverse skeletal effects) (Box: Selec- BMD (grams per square centimeter), Osteoporotic Fractures
Research Group. Bone-
ted Conditions and Medications Asso- non-Hispanic White women aged 20 to density testing interval
ciated With Secondary Osteoporosis). 29 years from NHANES III (Third Natio- and transition to osteopo-
rosis in older women.
The physical examination may reveal nal Health and Nutrition Examination N Engl J Med.
2012;366:225-233.
height loss or hyperkyphosis possibly Survey) serve as the universal reference [PMID: 22256806]
related to unrecognized vertebral frac- group (26). No internationally recom- 34. Ross AC, Taylor CL,
Yaktine AL, et al, eds;
tures or signs of secondary causes of mended reference group exists for Institute of Medicine (US)
Committee to Review
osteoporosis (such as tremor or tachycar- lumbar spine measurements; thus, the Dietary Reference Intakes
dia [hyperthyroidism] or moon facies or reference group for calculation of spine for Vitamin D and
Calcium. Dietary
striae [glucocorticoid excess]). BMD T-scores is the DXA manufacturer- Reference Intakes for
Calcium and Vitamin D.
How should osteoporosis be specific reference database of young National Academies Pr;
2011. Accessed at www.
diagnosed? White women. BMD within 1 SD of this ncbi.nlm.nih.gov/books/
reference group is classified as normal NBK56070 on 22 August
The diagnosis of osteoporosis can be 2022.
BMD, 1.0 to 2.5 SDs below is classified 35. Kahwati LC, LeBlanc E,
made in adults aged 50 years or older Weber RP, et al.
with a history of hip or clinical vertebral as osteopenia or low bone mass, and Screening for vitamin D
deficiency in adults:
fracture not due to excessive trauma, 2.5 or more SDs below is defined as updated evidence report
those with existing vertebral fractures osteoporosis. and systematic review for
the US Preventive
identified on the basis of a spinal imag- Services Task Force.
When should clinicians consider JAMA. 2021;325:1443-
ing study alone (radiographic vertebral 1463. [PMID: 33847712]
fractures), and those with a BMD at or laboratory testing to assess for 36. LeBoff MS, Chou SH,
Ratliff KA, et al.
below the cutoff value (≥2.5 SDs below secondary causes? Supplemental vitamin D
and incident fractures in
that of a young White woman). BMD The clinical utility of laboratory testing midlife and older adults.
should be measured at the total hip to identify secondary causes of osteo- N Engl J Med.
2022;387:299-309.
and femoral neck and the lumbar spine porosis is unclear. On the basis of [PMID: 35939577]

January 2024 Annals of Internal Medicine In the Clinic ITC5 © 2024 American College of Physicians

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 Selected Conditions and Medications Associated With Secondary Osteoporosis
Conditions*
37. Jamal SA, Leiter RE, • Alcoholism
Bayoumi AM, et al. • Anorexia nervosa
Clinical utility of labora- • Athletic amenorrhea
tory testing in women
with osteoporosis. • Celiac disease
Osteoporos Int. • Chronic obstructive pulmonary disease
2005;16:534-540. [PMID: • Cushing syndrome
15340801]
• Type 1 diabetes mellitus
38. Fink HA, Litwack-Harrison
S, Taylor BC, et al; • Gastric bypass surgery
Osteoporotic Fractures in • Hematologic cancer (e.g., multiple myeloma, lymphoma)
Men (MrOS) Study Group. • Hyperparathyroidism
Clinical utility of routine
laboratory testing to iden-
• Hyperprolactinemia
tify possible secondary • Hyperthyroidism
causes in older men with • Inflammatory bowel disease
osteoporosis: the • Malabsorption syndromes
Osteoporotic Fractures in
Men (MrOS) Study. • Premature ovarian failure
Osteoporos Int. • Rheumatoid arthritis
2016;27:331-338. [PMID: • Systemic lupus erythematosus
26458388]
39. Ensrud KE. Epidemiology Medications
of fracture risk with • Androgen deprivation therapy
advancing age. J Gerontol
A Biol Sci Med Sci.
• Antiepileptic drugs
2013;68:1236-1242. • Aromatase inhibitors
[PMID: 23833201] • Chemotherapeutic agents
40. Bhasin S, Gill TM, Reuben • Cyclosporine
DB, et al; STRIDE Trial
Investigators. A random- • Excessive doses of L-thyroxine
ized trial of a multifacto- • Gonadotropin-releasing hormone agonists
rial strategy to prevent • Heparin (prolonged treatment)
serious fall injuries. N • Methotrexate (high-dose)
Engl J Med.
2020;383:129-140. • Selective serotonin reuptake inhibitors
[PMID: 32640131] • Systemic glucocorticoids
41. Guirguis-Blake JM, • Tacrolimus
Michael YL, Perdue LA, et
al. Interventions to pre- * Clinicians should consider referring patients with conditions presumed to cause secondary
vent falls in older adults:
updated evidence report
osteoporosis to a subspecialist for further evaluation and treatment.
and systematic review for
the US Preventive
Services Task Force.
JAMA. 2018;319:1705-
1716. [PMID: 29710140]
expert opinion and small studies of ter- Measurement of serum 25-hydroxyvita-
42. de Souto Barreto P, tiary care populations, some organiza- min D (25-(OH)D) is widely recommen-
Rolland Y, Vellas B, et al.
Association of long-term tions (14–16) recommend ordering labo- ded in patients with osteoporosis (14,
exercise training with risk
of falls, fractures, hospital-
ratory tests in “patients with osteoporosis 15). However, there is no evidence that
izations, and mortality in or high fracture risk” or “patients in whom vitamin D supplementation at doses
older adults: a systematic
review and meta-analysis. a specific secondary, treatable cause of needed to achieve a target level (for
JAMA Intern Med.
2019;179:394-405.
osteoporosis is being considered.” How- example, 30 ng/mL) is superior to a
[PMID: 30592475] ever, large studies of community-dwelling more conservative approach (for exam-
43. Grossman DC, Curry SJ,
Owens DK, et al; US postmenopausal women (37) and older ple, supplementation if needed to
Preventive Services Task
Force. Interventions to
men (38) found that the prevalence of a achieve the RDA of 600 to 800 IU/d) in
prevent falls in commu- specific laboratory test abnormality was reducing risk for falls or fractures. The
nity-dwelling older adults:
US Preventive Services generally similar between persons with clinical utility of this measurement is likely
Task Force recommenda-
tion statement. JAMA.
and without osteoporosis. to be greatest in patients with problems
2018;319:1696-1704.
[PMID: 29710141]
44. Black DM, Bauer DC,
Vittinghoff E, et al;
Foundation for the
Classification of BMD by DXA
National Institutes of In postmenopausal women and men aged ≥50 years, BMD should be reported as T-scores:
Health Bone Quality
Project. Treatment-related • Normal: T-score ≥1.0
changes in bone mineral • Low bone mass (osteopenia): T-score <1.0 and >2.5
density as a surrogate bio- • Osteoporosis: T-score ≤2.5
marker for fracture risk
reduction: meta-regres- In premenopausal women and men aged <50 years, BMD should be reported as Z scores:
sion analyses of individual • Z score ≤2.0 is defined as “below the expected range for age”
patient data from multiple
randomised controlled tri- • Z score >2.0 is “within the expected range for age”
als. Lancet Diabetes
Endocrinol. 2020;8:672-
BMD ¼ bone mineral density; DXA ¼ dual energy x-ray absorptiometry.
682. [PMID: 32707115]

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absorbing or metabolizing vitamin D or medications that may cause hypocalcemia,
patients who will be initiating osteoporosis such as denosumab.
45. Chen P, Miller PD,
Delmas PD, et al. Change
Diagnosis... The diagnosis of osteoporosis in adults aged 50 years or older can be in lumbar spine BMD and
vertebral fracture risk
made if they have a history of hip or clinical vertebral fracture not due to excessive reduction in teriparatide-
trauma; existing radiographic vertebral fractures; or a BMD T-score at the femoral neck, treated postmenopausal
women with osteoporosis.
total hip, or lumbar spine that is 2.5 or less relative to the reference population of J Bone Miner Res.
young adult women. Current evidence is insufficient to support routine laboratory test- 2006;21:1785-1790.
ing in patients with osteoporosis to identify possible secondary causes. [PMID: 17002571]
46. Cummings SR, Karpf DB,
Harris F, et al.
Improvement in spine
CLINICAL BOTTOM LINE bone density and reduc-
tion in risk of vertebral
fractures during treatment
with antiresorptive drugs.
Am J Med.
2002;112:281-289.
[PMID: 11893367]
Treatment for Fracture Prevention 47. Panday K, Gona A,
Humphrey MB.
Medication-induced
What measures should be taken to The USPSTF (43) recommends exercise osteoporosis: screening
reduce fall risk? interventions (moderate benefit) and and treatment strategies.
Ther Adv Musculoskelet
Osteoporotic fractures are the major multifactorial interventions (small benefit) Dis. 2014;6:185-202.
[PMID: 25342997]
source of morbidity and mortality asso- to prevent falls in community-dwelling 48. Cummings SR, Black DM,
older adults at increased risk. A reasona- Thompson DE, et al. Effect
ciated with osteoporosis. Most frac- of alendronate on risk of
tures result from falls, but only 10% to ble strategy is to request physical therapy fracture in women with
low bone density but
15% of falls in older adults result in frac- evaluation (for example, gait assessment, without vertebral frac-
tures: results from the
tures. Several factors are associated balance training, and lower-extremity Fracture Intervention Trial.
with increased fall risk in older adults, strengthening programs) in older patients JAMA. 1998;280:2077-
2082. [PMID: 9875874]
including age-related deficits in visual, with deconditioning, reduced mobility, or 49. McClung MR, Geusens P,
Miller PD, et al; Hip
proprioceptive, and vestibular systems; balance or gait abnormalities. Intervention Program
Study Group. Effect of
decreased lower-extremity performance; What are the goals of osteoporosis risedronate on the risk of
medical conditions and comorbidity bur- drug treatment?
hip fracture in elderly
women. N Engl J Med.
den; use of certain medications and The primary goal of osteoporosis drug 2001;344:333-340.
[PMID: 11172164]
polypharmacy; and environmental fac- treatment is to reduce risk for clinical 50. McClung MR, Boonen S,
Törring O, et al. Effect of
tors (39). fractures (symptomatic fractures requir- denosumab treatment on
the risk of fractures in
ing medical attention), especially those
Some guidelines (14, 15) recommend subgroups of women with
of the hip and vertebrae. Although postmenopausal osteopo-
evaluation of risk factors for falls in all rosis. J Bone Miner Res.
treatment-related BMD changes have 2012;27:211-218.
patients with osteoporosis. Although [PMID: 21976367]
been strongly associated with fracture
minimizing use of medications associ- 51. Reid IR, Horne AM, Mihov
risk reductions across RCTs of pharma- B, et al. Fracture preven-
ated with increased fall risk is appropri- tion with zoledronate in
cotherapies (44), the applicability of older women with osteo-
ate, the extent to which other risk
this finding to individual patients is penia. N Engl J Med.
2018;379:2407-2416.
factors may be mitigated by home
uncertain. Evidence suggests that most [PMID: 30575489]
safety evaluation and fall prevention 52. Ensrud KE, Taylor BC,
of the reduction in fracture risk with a Peters KW, et al;
programs is controversial. Multifactorial Osteoporotic Fractures in
specific agent is not explained by its Men Study Group.
interventions (customized strategies
effect on BMD (45, 46). Implications of expanding
based on initial comprehensive individ- indications for drug treat-
ment to prevent fracture
ualized assessment of fall risk) modestly Clinicians should emphasize to patients in older men in United
States: cross sectional and
reduce fall incidence but not other fall- that the goal of treatment is to prevent longitudinal analysis of
related outcomes, such as injurious falls disabling fractures. A single fracture prospective cohort study.
BMJ. 2014;349:g4120.
(40, 41). Long-term exercise training during treatment is not necessarily evi- [PMID: 24994809]
53. Wright NC, Saag KG,
reduces fall risk, including injurious falls, dence of treatment failure, but it does Dawson-Hughes B, et al.
and may modestly reduce fracture risk indicate a higher risk for future fractures. The impact of the new
National Bone Health
(42). Trials of vitamin D supplementation Patients who have fractures while receiv- Alliance (NBHA) diagnos-
tic criteria on the preva-
in fall prevention have reported mixed ing drug treatment should be assessed lence of osteoporosis in
results, with high doses resulting in higher for adherence, underlying medical con- the USA. Osteoporos Int.
2017;28:1225-1232.
rates of fall-related outcomes (41). ditions (Box: Selected Conditions and [PMID: 27966104]

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 Medications Associated With Secon- ded in this patient population. On the
dary Osteoporosis), concomitant medi- basis of data from trials in women, men
cations (to determine whether use of with osteoporosis according to these
those with adverse effects on bone criteria likely also benefit from drug
54. Cummings SR, Ferrari S, health can be reduced or discontinued treatment.
Eastell R, et al. Vertebral
fractures after discontinua- [47]), and fall propensity with considera- Evidence that pharmacotherapy reduces
tion of denosumab: a
post hoc analysis of the
tion of preventive measures. In patients clinical fracture risk in postmenopausal
randomized placebo-con- who have had multiple fractures or dis- women with osteopenia (BMD T-score
trolled FREEDOM trial and
its extension. J Bone abling fractures during treatment, clini- between 2.5 and 1.0) is sparse.
Miner Res. 2018;33:190-
198. [PMID: 29105841]
cians may consider starting an alternate Pivotal trials of alendronate, risedronate,
55. Lyu H, Yoshida K, Zhao therapy (for example, switching from a and denosumab found that treatment
SS, et al. Delayed denosu-
mab injections and frac- less potent to a more potent antiresorp- did not reduce risk for clinical fractures in
ture risk among patients
with osteoporosis: a popu-
tive agent) or referring the patient to a postmenopausal women without a BMD
lation-based cohort study. subspecialist (for example, for consider- T-score of 2.5 or lower or existing ver-
Ann Intern Med.
2020;173:516-526. ation of anabolic therapy). tebral fractures (48–50). In contrast, a trial
[PMID: 32716706] of zoledronate in older women with
56. Mangione CM, Barry MJ, Which patients should take calcium osteopenia or osteoporosis (51) repor-
Nicholson WK, et al; US
Preventive Services Task and vitamin D supplementation? ted that treatment reduced risk for clini-
Force. Hormone therapy
for the primary prevention No RCTs have evaluated the efficacy of cal fractures, including nonvertebral frac-
of chronic conditions in
postmenopausal persons:
calcium and vitamin D supplementa- tures. There are no data on antifracture
US Preventive Services tion in reducing clinical fracture risk in efficacy of drug treatment in men with
Task Force recommenda-
tion statement. JAMA. adults with osteoporosis, but several osteopenia.
2022;328:1740-1746. trials of osteoporosis medications pro-
[PMID: 36318127]
57. Shoback D, Rosen CJ, vided calcium and vitamin D supple- Some guidelines (14–17) endorse use
Black DM, et al.
mentation to participants in both active of specific FRAX intervention thresh-
Pharmacological manage-
ment of osteoporosis in treatment and placebo groups. Clini- olds to aid in deciding whether to rec-
postmenopausal women:
cians should follow the Institute of ommend drug treatment in adults
an Endocrine Society
guideline update. J Clin Medicine’s 2011 recommendations on aged 50 years or older with osteope-
Endocrinol Metab.
2020;105:dgaa048. levels of calcium and vitamin D intake nia. These guidelines recommend ini-
[PMID: 32068863]
to optimize skeletal health (34) and en- tiating drug treatment if the FRAX-
58. Khan AA, Morrison A,
Kendler DL, et al; courage patients to obtain these nutri- estimated 10-year absolute probability
International Task Force
ents through dietary sources, adding is 3% or higher for hip fracture or 20%
on Osteonecrosis of the
Jaw. Case-based review of supplementation only in patients who or higher for major osteoporotic frac-
osteonecrosis of the jaw
(ONJ) and application of do not meet intake levels. Excessive ture. However, there is no evidence
the international recom-
calcium intake can result in nephroli- from RCTs demonstrating antifracture
mendations for manage-
ment from the thiasis, and high-dose vitamin D sup- benefit of this strategy, and it greatly
International Task Force expands the proportion of older adults
on ONJ. J Clin Densitom. plementation may increase fracture risk
2017;20:8-24. [PMID: identified as drug treatment candi-
(34). Thus, combined calcium and vita-
27956123] dates (52, 53).
59. Gedmintas L, Solomon min D supplementation should be rec-
DH, Kim SC.
Bisphosphonates and risk ommended at prudent doses in speci- What is the initial pharmacologic
of subtrochanteric, femo- fic patient populations, such as older agent for patients with treatment
ral shaft, and atypical fe-
mur fracture: a systematic institutionalized adults and adults with indications?
review and meta-analysis.
J Bone Miner Res.
osteoporosis and inadequate dietary Several drug therapies are available to
2013;28:1729-1737. intake. treat osteoporosis. Antiresorptive agents,
[PMID: 23408697]
60. Black DM, Abrahamsen B,
Bouxsein ML, et al. Which patients are candidates for including bisphosphonates (alendronate,
Atypical femur fractures: drug treatment? risedronate, ibandronate, zoledronate),
review of epidemiology,
relationship to bisphosph- Several medications (Table) reduce denosumab, and raloxifene, inhibit osteo-
onates, prevention, and
clinical management. clinical fracture risk in postmenopausal clast-mediated bone resorption. In contrast,
Endocr Rev. women with osteoporosis defined by a anabolic therapies (teriparatide and
2019;40:333-368. [PMID:
30169557] hip or spine BMD T-score of 2.5 or abaloparatide) stimulate bone forma-
61. Black DM, Geiger EJ,
Eastell R, et al. Atypical fe-
lower or a history of a fragility fracture tion earlier and to a greater degree
mur fracture risk versus (for example, hip, clinical vertebral, or than bone resorption. Romosozumab,
fragility fracture preven-
tion with bisphospho- radiographic vertebral fracture) (5, 6). an agent with dual action, increases
nates. N Engl J Med.
2020;383:743-753.
Thus, guidelines universally agree that bone formation while simultaneously
[PMID: 32813950] drug treatment should be recommen- decreasing bone resorption.

© 2024 American College of Physicians ITC8 In the Clinic Annals of Internal Medicine January 2024

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 Table. Pharmacologic Agents for Treatment of Osteoporosis
Medication* Method and Dosage Fracture Risk Reduction Adverse Effects and Risks
Bisphosphonates† Oral therapy:
Alendronate Oral, 70 mg weekly Vertebral, nonvertebral, Common: upper gastrointestinal irritation,
hip musculoskeletal problems; uncommon:
esophageal ulcer, bone pain; rare: ONJ,
Ibandronate Oral, 150 mg monthly; IV, Vertebral AFFs
3 mg every 3 mo Contraindications: CrCl <30–35 mL/min/
Risedronate Oral, 35 mg weekly or Vertebral, nonvertebral, 1.73 m2, esophageal stricture, achalasia,
150 mg monthly hip Barrett esophagus
Zoledronate IV, 5 mg annually Vertebral, nonvertebral, IV therapy:
hip Common: flu-like symptoms, bone pain
(with first dose of zoledronate), musculo-
skeletal problems; rare: hypocalcemia,
ONJ, AFFs
Contraindications: CrCl <30–35 mL/min/1.73 m2

RANKL inhibitor
Denosumab‡ Subcutaneous, 60 mg Vertebral, nonvertebral, Common: eczema, nausea, injection site
every 6 mo§ hip reactions; rare: hypocalcemia, ONJ, AFFs
Contraindications: known hypersensitivity to
denosumab/component of formulation,
preexisting hypocalcemia, patient unwill-
ingness to initiate bisphosphonate therapy
if denosumab therapy discontinued

SERMs
Raloxifene|| Oral, 60 mg daily Vertebral Common: leg cramps, hot flashes; uncom-
mon: uterine polyps, deep venous throm-
bosis
Contraindications: active or history of venous
thromboembolism

Parathyroid hormone and

related peptide analogues
Teriparatide¶ Subcutaneous, 20 mcg Vertebral, nonvertebral Common: nausea, dizziness, headache,
daily for 1–2 y**†† arthralgia (teriparatide), palpitations (abalo-
Abaloparatide¶ Subcutaneous, 80 mcg Vertebral, nonvertebral paratide); uncommon: hypotension with
daily for 1–2 y†† first few doses
Contraindications: primary or secondary hy-
perparathyroidism, hypercalcemic disor-
ders, hypercalciuria, urolithiasis, elevated
risk for osteosarcoma

Sclerostin inhibitor
Romosozumab‡‡ Subcutaneous, 210 mg Vertebral, nonvertebral, Common: arthralgia, headaches; uncom-
monthly for 1 y†† hip mon: hypocalcemia; rare: hypersensitivity
(followed by 12 mo of reactions, ONJ, AFFs
alendronate) Contraindications: myocardial infarction or
stroke in past year or high risk for cardio-
vascular disease

AFF ¼ atypical femur fracture; CrCl ¼ creatinine clearance; IV ¼ intravenous; ONJ ¼ osteonecrosis of the jaw; RANKL ¼ receptor acti-
vator of nuclear factor kappa-B ligand; SERM ¼ selective estrogen receptor modulator.
* Bisphosphonates, denosumab, and raloxifene are antiresorptive medications; teriparatide and abaloparatide are anabolic thera-
pies; and romosozumab is a therapy with dual action (increases bone formation while simultaneously decreasing bone resorption).
† Approved by the U.S. Food and Drug Administration (FDA) for treatment of postmenopausal osteoporosis; all except ibandronate
are approved for treatment of osteoporosis in men. All bisphosphonates are available in generic form.
‡ FDA-approved for treatment of osteoporosis in postmenopausal women and men.
§ Bisphosphonate therapy must be initiated upon discontinuation.
|| FDA-approved for treatment of postmenopausal osteoporosis; available in generic form.
¶ FDA-approved for treatment of osteoporosis in postmenopausal women and men at high risk for fracture.
** Use of teriparatide for >2 years during a lifetime should be considered only in a patient who remains at or has reverted to a very
high risk for fracture.
†† Antiresorptive medication (bisphosphonate or denosumab) must be initiated upon discontinuation.
‡‡ FDA-approved for treatment of osteoporosis in postmenopausal women at high risk for fracture.

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 Bisphosphonates (Table) are the first- medications. Common adverse effects
line pharmacologic therapy for osteo- include upper gastrointestinal tract irri-
porosis due to their efficacy in fracture tation and musculoskeletal problems.
prevention, availability of long-term Gastrointestinal irritation is minimized
safety data, and cost advantage com- by adherence to dosing instructions.
pared with several other agents. Candidates for IV zoledronate include
patients with gastrointestinal contrain-
A systematic review found high-cer-
dications or adverse effects to oral
tainty evidence that bisphosphonate
bisphosphonates and those with (or
treatment for 3 to 4 years in postmeno-
likely to have) poor adherence to oral
pausal women with osteoporosis reduces
bisphosphonates. Adverse reactions
risk for hip fracture by 36% (6 fewer
include flu-like symptoms or bone pain
events per 1000 treated women), clinical
(typically with the initial infusion and
vertebral fracture by 62% (18 fewer
events per 1000 treated women), and minimized by administration of acet-
any clinical fracture by 21% (24 fewer aminophen) and myalgia and arthral-
events per 1000 treated women) (4). gia. Rare but serious adverse effects of
both oral and IV bisphosphonates
Treatment of postmenopausal osteo- include osteonecrosis of the jaw (ONJ),
porosis with alendronate, risedronate, exposed bone in the maxillofacial
or zoledronate reduces risk for verte- region that does not heal within 8
bral and nonvertebral fractures, includ- weeks, and atypical femur fractures
ing hip fractures (4, 5). In addition, (AFFs), which are low-trauma subtro-
zoledronate reduces clinical fracture chanteric or femoral shaft fractures with
risk among adults aged 50 years or unusual radiographic features, includ-
older with recent hip fracture. Differen- ing a transverse morphology and thick-
ces in effectiveness of these 3 bi- ened cortices.
sphosphonates are likely to be small
(5). Ibandronate is rarely prescribed What alternative pharmacologic
because there is no evidence that it agents can be considered for
reduces risk for hip or other nonverte- osteoporosis treatment?
62. Fink HA, MacDonald R,
bral fractures. Denosumab, a biologic therapy,
Forte ML, et al. Long-term
drug therapy and drug reduces risk for vertebral and nonverte-
discontinuations and holi- Bisphosphonates are not recom- bral fractures, including hip fractures
days for osteoporosis frac-
ture prevention: a mended for patients with severe renal (4, 5). Denosumab is administered
systematic review. Ann
Intern Med.
impairment. Renal function should be twice yearly by subcutaneous injection
2019;171:37-50. [PMID: assessed to ensure a creatinine clear- by a health care professional. Candi-
31009947]
63. Adler RA, El-Hajj FG, ance of 30 to 35 mL/min/1.73 m2 or dates include patients with contraindi-
Bauer DC, et al.
Managing osteoporosis in
higher. Transient hypocalcemia may cations (such as severe renal impair-
patients on long-term occur after bisphosphonate administra- ment) or intolerance to oral or IV
bisphosphonate treat-
ment: report of a task tion, especially after intravenous (IV) bisphosphonates. Because denosu-
force of the American infusion; hypocalcemia and vitamin D
Society for Bone and mab reduces calcium mobilization
Mineral Research. J Bone deficiency (serum 25-(OH)D level <15
Miner Res. 2016;31:16- from the bone into the bloodstream,
35. [PMID: 26350171] to 20 ng/mL) should be corrected
64. Kline GA, Morin SN,
hypocalcemia and vitamin D deficiency
before initiation of bisphosphonates.
Feldman S, et al. must be corrected before denosumab
Diminishing value from
multiple serial bone den- Oral bisphosphonates (such as alen- is started. Common adverse effects
sitometry in women
receiving antiresorptive dronate and risedronate) should be include eczema, nausea, and injection
medication for osteoporo- taken with a glass of water on an empty site reactions. Rare but serious adverse
sis. J Clin Endocrinol
Metab. 2021;106:2718- stomach to maximize absorption. effects include ONJ and AFFs. Dis-
2725. [PMID: 33784384]
65. Bell KJ, Hayen A, Contraindications include esophageal continuation leads to rapid reversal of
Macaskill P, et al. Value of stricture, achalasia, or Barrett esopha- denosumab’s therapeutic effect and
routine monitoring of
bone mineral density after gus; bisphosphonates are often toler- may result in “rebound” fractures, espe-
starting bisphosphonate
treatment: secondary ated in patients with a remote history of cially clinical vertebral fractures (54, 55).
analysis of trial data. BMJ.
2009;338:b2266. [PMID:
peptic ulcer disease or those with gas- Patients should be counseled before
19549996] troesophageal reflux controlled with denosumab initiation on the importance

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of not delaying or abruptly discontinu- specimen for calcium–creatinine ratio)
ing injections. should be checked before administra-
tion. Because transient hypotension
Raloxifene, a selective estrogen recep- has been reported with initial doses (6),
tor modulator, reduces risk for vertebral the first dose should be administered
fractures in postmenopausal women
in a setting where the patient can lie
with osteoporosis but has no effect on
down if symptoms occur. Adverse reac-
risk for nonvertebral fractures (4, 5).
Thus, it is not considered a first- or sec- tions include nausea, headache, dizzi-
ond-line agent for treatment of post- ness, arthralgia (teriparatide), and palpi-
menopausal osteoporosis. Raloxifene is tations (abaloparatide). Previous black
sometimes prescribed because long- box warnings of a dose-dependent in-
term treatment reduces risk for breast crease in osteosarcoma incidence in
cancer among women at higher risk for animal studies have been removed by
this condition, although potential harms the U.S. Food and Drug Administration
include higher risk for venous throm- (FDA) because findings were not con-
boembolic events. firmed in postmarketing surveillance
studies. Treatment with teriparatide or
Medications with anabolic effects (teri- abaloparatide is contraindicated in pa-
paratide, abaloparatide, and romosozu- tients with elevated risk for osteosar-
mab) (6) are not first-line treatments
coma (for example, skeletal radiation).
because of their substantial cost, need for
subcutaneous administration, and con-
Romosozumab is administered by a
cerns about long-term safety. These med-
ications may be considered in treatment- health care professional via subcutane-
naive patients with very high risk for frac- ous injection once monthly. Compared
ture (for example, BMD T-score ≤3.5 or with treatment with 12 months of pla-
recent hip or clinical vertebral fracture cebo followed by 12 months of deno-
with BMD T-score ≤2.5) or those who sumab, treatment of postmenopausal
experience treatment failure (for example, osteoporosis with romosozumab for 12
≥2 fractures or while receiving and adher- months followed by 12 months of
ent to potent antiresorptive therapy). denosumab reduces risk for vertebral
but not nonvertebral fractures (4, 6).
Therapy with daily self-administered
However, compared with 24 months of
subcutaneous injections of teriparatide
alendronate alone, treatment with 12
or abaloparatide for 18 to 21 months
months of romosozumab followed by
reduces vertebral and nonvertebral
12 months of alendronate reduces risks
fracture risk among women with post-
menopausal osteoporosis who are at for vertebral, nonvertebral, and hip
very high risk for fracture (4, 6), but tri- fractures in postmenopausal women
als were not adequately powered to with osteoporosis who are at very high
test their efficacy in preventing hip frac- risk for fracture (4, 6). Because of a
tures. Because hypercalcemia and higher incidence of major adverse car-
hypercalciuria have been reported with diac events in the romosozumab group
both drugs, primary or secondary hy- (2.0%) compared with the alendronate
perparathyroidism, other hypercalce- group (1.1%) (4, 6), the FDA issued a
mic disorders, hypercalciuria, and uro- black box warning for an increased risk
lithiasis are contraindications (6). These for cardiovascular disease events. Pa-
agents should be used with caution in tients with myocardial infarction or
patients with a history of gout because stroke in the past year or high cardio-
of treatment-related increases in serum vascular disease risk should not be
uric acid level. Levels of serum calcium, treated with romosozumab. Serum cre-
albumin, 25-(OH)D, intact parathyroid atinine, calcium, and 25-(OH)D should be
hormone, phosphorus, creatinine, alka- checked before romosozumab admini-
line phosphatase, and 24-hour urine stration; calcium intake should meet RDA
calcium and creatinine (or fasting urine levels, and vitamin D deficiency should be

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corrected. Adverse reactions in- (conditional recommendation, Although ONJ prevalence has
clude arthralgia and headaches. low-certainty evidence) diag- been reported to be 1% to 15%
ONJ and AFFs have been reported nosed with osteoporosis who in oncology patients receiving
rarely during or after romosozu- have contraindications to or ex- high-dose bisphosphonates or
mab treatment. perience adverse effects of bis- denosumab, estimates are sub-
phosphonates. Romosozumab stantially lower (0.001% to 0.01%)
Combination pharmacotherapy (moderate-certainty evidence) in patients with osteoporosis re-
for osteoporosis is not recom- or teriparatide (low-certainty ceiving lower doses of either
mended. The antifracture effi- evidence) followed by a bis- medication (58). Risk factors in-
cacy of combination medication phosphonate is suggested only clude poor oral hygiene, concom-
regimens has not been eval- in women with primary osteo- itant use of systemic glucocorti-
uated, and safety has not been porosis who are at very high coids or chemotherapy, smoking,
adequately assessed. risk for fracture (conditional diabetes, and recent history of
What is the role of estrogen recommendation). invasive dental procedures.
therapy in the treatment of
The Endocrine Society recom- AFFs are rare and typically occur
osteoporosis?
mends use of bisphosphonates with little or no antecedent
Estrogen therapy or combined trauma, may be preceded by
or denosumab as initial treat-
hormone therapy (estrogen plus thigh or groin pain, and may
ment in postmenopausal women
progestin) is not recommended occur bilaterally. They are rare in
who are at high fracture risk (de-
or FDA-approved for treatment the general population and have
fined by the presence of osteo-
of postmenopausal osteoporo- a markedly lower incidence than
penia with estimated fracture risk
sis. Although use of estrogen hip fractures. Although bisphosph-
above a FRAX threshold) or have
plus progestin or estrogen alone onate use is associated with a 1.7-
osteoporosis and teriparatide,
is moderately beneficial in reduc- fold higher relative risk for AFFs
abaloparatide, or romosozumab
ing clinical fracture risk in post- (59), the absolute risk among users
for postmenopausal women with
menopausal women not selec- is very low. It is estimated that for
osteoporosis who are at very high
ted on the basis of osteoporosis, every 10 000 women treated with
risk for fracture (17, 57).
these benefits do not outweigh
bisphosphonates for 3 years, 130
the harms in most women (56). The Bone Health & Osteoporo- hip fractures will be prevented at a
What do professional societies sis Foundation guidelines state cost of 1 AFF (60). However, AFF
recommend for pharmacologic that the pharmacologic treat- incidence increases with longer
treatment of osteoporosis? ment plan in patients with osteo- duration of bisphosphonate use
The American College of Physi- porosis should be individualized and decreases with longer time
cians (ACP) (10) recommends because no uniform recommen- since discontinuation.
clinicians use bisphosphonates dation applies to all patients, but
the guidelines note that a ther- In an analysis of 196 129 women
for initial pharmacologic treat- aged 50 years or older receiving
ment to reduce fracture risk in apy that has been shown to
reduce risk for both vertebral and bisphosphonates, AFF incidence
postmenopausal women (strong rates increased from 0.07 per
recommendation, high-certainty nonvertebral fractures should be
considered over one that has not 10 000 person-years among wo-
evidence) and men (conditional
(15). men with less than 3 months of
recommendation, low-certainty evi-
use to 13.10 per 10 000 person-
dence) diagnosed with primary
How long should patients be years among those with 8 or more
osteoporosis but suggests that
treated, and when should years of use and decreased from
clinicians take an individualized
clinicians consider instituting a 4.50 per 10 000 person-years am-
approach to starting treatment
drug holiday? ong current users to 0.50 per
in women with osteopenia aged
10 000 person-years among for-
65 years or older (conditional re- The ideal duration of antiresorp-
mer users with more than 15
commendation, low-certainty evi- tive treatment is uncertain, espe-
months since discontinuation (61).
dence). Denosumab is suggested cially because ONJ and AFFs
as a second-line drug treatment in are rare but serious potential Thus, although the benefits of
postmenopausal women (condi- harms of longer-term treatment bisphosphonates likely outwei-
tional recommendation, moderate- with potent agents (bisphospho- gh the risk for AFFs early in treat-
certainty evidence) and men nates and denosumab). ment, this benefit is less clear for

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long-term users, especially for should consider stopping bi- every 1 to 3 years until findings
Asian patients, in whom AFF sphosphonate treatment after 5 stabilize. However, no RCTs have
rates are higher than in White years unless the patient has a shown that this practice improves
patients. AFFs have also been strong indication for treatment fracture risk prediction. Evidence
reported in patients receiving de- continuation. suggests that among women
nosumab, but whether AFF risk who are adherent to antiresorp-
Unlike bisphosphonates, denosu-
increases with longer treatment tive medications with 3 sequen-
mab and medications with ana-
duration is unknown. tial BMD measures, a very small
bolic effects produce BMD gains
percentage (1.5%) sustain BMD
Bisphosphonates have a long that rapidly wane after treatment
losses on repeated measures
half-life in bone. Thus, unlike discontinuation. Discontinuation
(64).
most drugs, stopping use of or delayed denosumab adminis-
them does not result in cessation tration leads to accelerated bone Secondary data analysis of annual
of action. Two RCTs have eval- turnover and rapid bone loss and BMD measurements in 6459 post-
uated the benefits on fracture risk increases risk for rebound frac- menopausal women with low
of continuing versus discontinu- tures (especially multiple vertebral BMD in a large placebo-controlled
ing bisphosphonate treatment. fractures) (54, 55). Thus, patients RCT of alendronate (65) found that
After 3 to 5 years of treatment, treated with denosumab should the within-person (measurement-
bisphosphonate continuation ver- either continue treatment indefi- related) variation in treatment ef-
sus discontinuation reduced radi- nitely or transition to a potent fects on BMD was large compared
ographic vertebral fractures (zole- bisphosphonate upon discontinu- with the smaller between-person
dronate) and clinical vertebral ation. Physicians should avoid treatment-related variation.
fractures (alendronate) but not prescribing teriparatide or aba-
nonvertebral fractures (62). Thus, Thus, because BMD changes on
loparatide in patients discontin-
evidence is lacking to support a treatment are often modest com-
uing use of denosumab because
benefit of bisphosphonate use for pared with errors in measure-
BMD loss has been reported
more than 5 years for prevention ment of BMD change, routine
with the switch from denosumab
of nonvertebral fractures. monitoring of BMD change may
to teriparatide.
lead clinicians to make inappro-
Some organizations suggest a Because of waning of bone for- priate decisions about response
drug holiday (for example, tem- mation effects and the treatment to therapy. Monitoring BMD is
porary discontinuation for up to period of 18 to 21 months in tri- also likely a suboptimal method
5 years, followed by reassess- als, treatment duration with teri- of detecting nonadherence to
ment) in certain patients receiv- paratide or abaloparatide is us- treatment. There is no RCT evi-
ing bisphosphonate therapy. A ually limited to 2 years during a dence showing that serial BMD
task force of the American So- lifetime. Longer use of teripara- monitoring improves adherence
ciety for Bone and Mineral Re- tide may be considered in a to treatment compared with a
search (63) recommends clini- patient who remains at or has more pragmatic approach (such
cians consider a drug holiday in reverted to a very high risk for as simply asking patients in a
postmenopausal women after 5 fracture. The duration of romo- nonjudgmental manner whether
or more years of oral bisphosph- sozumab therapy is limited to 1 they have problems taking treat-
onate therapy (or ≥3 years of IV year. After discontinuation of ment or reviewing pharmacy
bisphosphonate therapy) if the agents with anabolic effects, use records).
patient satisfies 3 criteria: 1) they of a potent antiresorptive agent
have had no hip, spine, or multi- When should consultation be
(bisphosphonate or denosu-
ple other osteoporotic fractures considered?
mab) is recommended because
before or during the initial treat- of the ensuing rapid bone loss. Primary care clinicians may con-
ment period; 2) their hip BMD T- sider referring treatment-naive
score is above 2.5 after the ini- Should patients receiving drug patients with osteoporosis who
tial treatment period; and 3) treatment be monitored with are at very high fracture risk or
they are not at high fracture risk. serial BMD measurements? patients who have treatment fail-
The task force also suggested To monitor response to drug ure while adherent to potent
that patients on a drug holiday treatment, some organizations antiresorptive therapy to an
be reassessed every 2 to 3 years. (14–17, 26) recommend spine osteoporosis specialist for con-
ACP (10) suggests that clinicians and hip DXA BMD measurements sideration of medications with

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anabolic effects. Consultation bisphosphonate therapy or for should be initiated. Referral is also
may be warranted for patients patients completing a 3- to 5-year indicated in patients with specific
at the time of denosumab ther- bisphosphonate drug holiday to presumed secondary causes of
apy discontinuation to deter- determine whether to resume osteoporosis and those with com-
mine timing and duration of medication and which medication plex diagnostic issues.

Treatment for Fracture Prevention... Reducing risk for clinical fractures is the primary goal of treatment.
Among patients with primary osteoporosis, alendronate, risedronate, and zoledronate are first-line pharmaco-
therapies and denosumab is a second-line agent to reduce fracture risk. A treatment period of 5 years with oral
bisphosphonates (3 years for IV bisphosphonates) is a reasonable strategy. Patients using denosumab must con-
tinue indefinitely or transition to bisphosphonate therapy. Short-term treatment with medications with anabolic
effects should be considered only in postmenopausal women with osteoporosis who are at very high risk for frac-
ture; these patients should receive antiresorptive treatment upon discontinuation of anabolic therapy. Calcium
and vitamin D supplementation at prudent doses should be recommended in patients with inadequate dietary
intake. Potentially reversible risk factors for falls, with particular attention to polypharmacy, should be addressed
in patients at increased fall risk. Evidence does not support routine serial BMD measurements to monitor response
or adherence to medication therapy.

CLINICAL BOTTOM LINE

Practice Improvement
What measures do U.S. What do professional Endocrinologists (14), the Bone
stakeholders use to evaluate the organizations recommend with Health & Osteoporosis Foun-
quality of care? regard to screening, diagnosis, dation (15), and ACP (10), have
The Healthcare Effectiveness Data and treatment of osteoporosis? published guidelines on screen-
and Information Set includes 2 ing, diagnosis, or treatment of osteo-
The USPSTF (25) and several
measures in the domain of osteo- porosis. Specific recommenda-
professional societies, including
porosis in women aged 65 to 85 tions from these organizations
the Endocrine Society (16, 17,
on screening, diagnosis, and
years: osteoporosis testing, and 57), the International Society for
treatment are summarized in
osteoporosis management in Clinical Densitometry (26), the
relevant sections of this article.
women who had a fracture. American Association of Clinical

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 Patient Information
In the Clinic https://medlineplus.gov/osteoporosis.html

Tool Kit https://medlineplus.gov/languages/

osteoporosis.html
Information on osteoporosis in English and
other languages from the National
Institutes of Health’s MedlinePlus.
Osteoporosis
www.niams.nih.gov/health-topics/
osteoporosis
Information on osteoporosis from the
National Institute of Arthritis and
Musculoskeletal and Skin Diseases.

www.bonehealthandosteoporosis.org/
patients

In the Clinic
Educational materials on osteoporosis from
the Bone Health & Osteoporosis
Foundation.
Information for Health Professionals
www.acpjournals.org/doi/full/10.7326/
M22-1034
The American College of Physicians’ living
clinical guideline on pharmacologic treat-
ment of primary osteoporosis or low bone
mass to prevent fractures in adults.

www.uspreventiveservicestaskforce.org/
uspstf/recommendation/osteoporosis-
screening
U.S. Preventive Services Task Force recom-
mendation statement on screening for
osteoporosis to prevent fractures.

www.endocrinepractice.org/article/S1530-
891X(20)42827-7/fulltext
Clinical practice guidelines for the diagnosis
and treatment of postmenopausal osteopo-
rosis from the American Association of
Clinical Endocrinologists and the
American College of Endocrinology.

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 In the Clinic
WHAT YOU SHOULD KNOW Annals of Internal Medicine
ABOUT OSTEOPOROSIS
What Is Osteoporosis?
Osteoporosis is a disease that reduces the density
of bones, which can cause them to weaken.
Weak bones can easily break. These breaks,
called fractures, can be painful and may make it
hard to take care of yourself. The risk for osteo-
porosis increases with age.

Who Should Be Screened?

• All women aged 65 years or older.
• Women younger than 65 years may need screen-
ing if they have certain risk factors, including low How Can It Be Prevented?
weight, cigarette smoking, and history of bone • Keep a healthy body weight.
fractures. Talk to your doctor about other risks • Exercise regularly.
you may have. • Eat enough protein.
• Eat foods with calcium and vitamin D. These include
dairy, tofu, leafy greens, fatty fish like salmon, and
How Is It Diagnosed? foods fortified with calcium and vitamin D.
• Avoid drinking heavily.
• Your doctor can check for bone loss using a test • Don’t smoke.
called a DXA scan. This test takes pictures of your
bones.
• If your DXA results are below a certain number,
your doctor may diagnose you with osteoporosis Questions for My Doctor
and you may need treatment. • How do I know if I am at risk for osteoporosis?
• Should I take calcium or vitamin D supplements?
• I was diagnosed with osteoporosis. Can I still do
How Is It Treated? the things I like to do?
• Should I make changes to my diet?

Patient Information
• There are medicines for osteoporosis called • What can I do to prevent falls?
bisphosphonates that help prevent fractures. • What side effects does the medicine have?
• They are usually prescribed for 3 to 5 years. • How much will the medicine cost?
• After 3 to 5 years, you may have another DXA scan • Will my osteoporosis ever go away?
and your treatment may be stopped or changed. • What will happen if I stop taking the medicine?

For More Information

MedlinePlus
https://medlineplus.gov/osteoporosis.html
https://medlineplus.gov/languages/osteoporosis.html
National Institute of Arthritis and Musculoskeletal and Skin
Diseases
www.niams.nih.gov/health-topics/osteoporosis
Bone Health & Osteoporosis Foundation
www.bonehealthandosteoporosis.org/patients

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 Appendix Table 1. Tools to Identify Postmenopausal Women Aged <65 Years for Osteoporosis Screening With BMD
Testing
Risk Factor, by Tool Scoring Threshold
Fracture Risk Assessment Tool (FRAX)
Age (years) Proprietary formula Screen if predicted MOF risk ≥8.4%
Sex
Body weight (kg)
Height (cm)
Prior fracture
Parental history of hip fracture
Current smoking
Corticosteroid use*
Rheumatoid arthritis
Secondary osteoporosis
≥3 alcoholic units/day

Osteoporosis Risk Assessment Instrument (ORAI)

Age 55–64 y 5 points Screen if score ≥9
Age 45–54 y 0 points
Body weight <60 kg 9 points
Body weight 60–69 kg 3 points
Body weight ≥70 kg 0 points
No current estrogen use 0 points

Osteoporosis Index of Risk (OSIRIS)

Age (years) Age  0.2 points Screen if score <1
Body weight (kg) Weight  0.2 points
Current estrogen use 2 points
Prior low-impact fracture 2 points

Osteoporosis Self-Assessment Tool (OST)

Body weight (kg) (Weight  age)  0.2 points† Screen if score <2
Age (years)

Simple Calculated Osteoporosis Risk Estimation (SCORE)

Age (years) 3  first digit of age Screen if score ≥6
Body weight (lb) 1  (weight / 10)†
No estrogen use 1
Non-Black race 5
Rheumatoid arthritis 4
Prior fracture after age 45 y (nontraumatic rib, wrist, hip) 4 for each type (maximum of 12)

BMD ¼ bone mineral density; MOF ¼ major osteoporotic fracture.

* Currently exposed to oral glucocorticoids or has been exposed to oral glucocorticoids for >3 months at a dose of prednisolone ≥5
mg daily (or equivalent doses of other glucocorticoids).
† Truncate to integer.

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Appendix Table 2. Comparison of OST Versus FRAX Strategies Recommended by the USPSTF for Identifying
Osteoporosis in Women Aged 50 to 64 Years*
Identification of Osteoporosis (Femoral Neck BMD T-Score ≤2.5) Among Untreated Women
(n ¼ 2163)
Strategy Sensitivity (95% CI), % Specificity (95% CI), % PPV (95% CI), % AUC (95% CI)
Strategy based on OST 79 (73–85) 70 (68–72) 15 (12–17) 0.75 (0.72–0.78)†
(screen if score <2)
Strategy based on FRAX 33 (26–40) 86 (85–88) 14 (10–17) 0.60 (0.56–0.63)†
(screen if predicted MOF risk ≥8.4%)

AUC ¼ area under the curve; BMD ¼ bone mineral density; FRAX ¼ Fracture Risk Assessment Tool; MOF ¼ major osteoporotic frac-
ture; OST ¼ Osteoporosis Self-Assessment Tool; PPV ¼ positive predictive value; USPSTF ¼ U.S. Preventive Services Task Force.
* 36% (OST strategy) vs. 15% (FRAX strategy) of women were selected for BMD testing.
† AUC results for each strategy were similar in a secondary analysis with the outcome of a BMD T-score ≤2.5 at the hip or spine.

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