nd

Medicine II 6.02a 2 Sem/A.Y. 2016-2017

Calcium Metabolism and Disorders
JM Co, MD, FPCP, FPSEDM March 16, 2017

OUTLINE A. CALCIUM AND PHOSPHATE

I. Introduction III. Disorders of Calcium Metabolism
II. Hormones That Regulate Calcium IV. Osteoporosis

LEGEND:
! & 4 «
Recording Harrison’s 2018B Trans Remember

CALCIUM METABOLISM AND DISORDERS

I. INTRODUCTION

! Endocrinology – study of hormones and the glands that

produce them

Two ways by which the organs of the body communicate

with each other: !
Figure 1. Location of Calcium and Its Functions. ! Take
1. HORMONES
note that calcium is primarily found extracellularly. It also has a
o Chemical messengers that allow one organ of the
lot of functions as enumerated above.
body to speak to another organ
o All hormones pass through the blood, if it does not
Why do we need calcium? What is it good for? !
pass through the blood, it is not a hormone
ü Exocrine glands – their secretions are not • Lay person’s answer: strong bones.
released into the bloodstream, they do not belong • Medical student’s answer: Some people would even say
to the endocrine system. that the bones are just the storage places for calcium. It
ü e.g. If the brain feels that it is getting dehydrated, plays a bigger role than producing stronger bones
what will it do? Since the osmolality is increasing, • For muscle contraction, neuron activation, hormone
the brain will secrete arginine vasopressin into the secretion, bone mineral, blood coagulation, and membrane
bloodstream. Arginine vasopressin will then go to excitability.
the kidneys because they have receptors for it
(which allows the hormones to exert their action B. CALCIUM RECOMMENDATIONS
on the target organ). It targets the V2 receptors of Table 1. 2002 Food and nutrition research institute of the
the kidneys; its activation leads to the migration of Philippines (FNRI) recommended energy and nutrients
aquaporins to the cell membrane to reabsorb intake (RENI). ! For 19-49yo, 750 mg of calcium is
water. recommended per day.
ü Remember that arginine vasopressin exerts its
action on water; aldosterone acts on sodium.
o You can control the amount of hormones released in
the blood
ü e.g. If the brain is slightly dehydrated, small
amounts of arginine vasopressin are released; the
opposite is true if the brain is severely dehydrated
ü If the pancreas detects small amounts of sugar in
the blood, small amounts of insulin are secreted;
higher sugar levels, higher insulin produced
o Snail mail of the body
2. NERVOUS SYSTEM (CNS or PNS)
o Allows faster communication of the organs
o Referred to as the e-mail of the body
o All-or-none (on or off) principle applies: once the
threshold is hit, action potential will occur
ü e.g. If the brain wants you to raise our hand, it’s
automatic through electrical signals.
ü If you touched something hot, the receptors will
send signals to the brain that the object is hot and
the brain will in turn send signals back to the hand
causing you to let go of the hot object.

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Medicine II 6.02a: Calcium Metabolism and Disorders
II. HORMONES THAT REGULATE CALCIUM

Parathyroid Hormone-related Protein (PTHrP)

Parathyroid Hormone (PTH)
Vitamin D
Calcitonin
! Our body is very efficient in maintaining blood levels of
calcium in such a narrow range of 2.1 – 2.5mmol/L, unlike
sodium where the range is 135 – 153mmol/L.

A. PARATHYROID HORMONE-RELATED PROTEIN (PTHRP)

! Hormone seen in the pathologic state
• Exhibit considerable functional and structural homology
with PTH
• Bind to and activate PTH/PTHrP receptor
• May be produced by tumors, especially of the squamous
Figure 2. The Bone Health Pyramid Food Guide; cell type
Conceptualized by Sanirose S. Orbeta, MS, RD, FADA. • Paraneoplastic syndromes are disorders that accompany
! Calcium comes from: benign or malignant tumors but are not directly related to
o 1 cup of milk (300 mg) mass effects or invasion
o 2oz cheese (350mg) ! From paraneoplastic syndromes, which are responsible for
o 1 cup yogurt (490mg) most instances of hypercalcemia of malignancy (e.g.
o Fish with bones (assuming you eat the bones (500- lung tumor, squamous cell tumor resulting in high levels of
1000mg) calcium)
o Leafy vegetables (250mg)
o Rice (1 cup 65mg) B. VITAMIN D
! Recently recognized as a hormone because our bodies
C. DISTRIBUTION OF CALCIUM IN THE PLASMA can produce them on our own (remember that our bodies
cannot produce vitamins)
! D3 – Cholecalciferol (animal source)
o Produced when sunlight hits our skin, which converts
7-deoxycholesterol to cholecalciferol
o Cholecalciferol à goes to the liver where it is
hydroxylated à 25 hydroxycholecalciferol à goes to
the kidney and with the help of parathyroid hormone,
25 hydroxycholecalciferol becomes à 1,25
dihydroxycholecalciferol
ü 1,25 dihydroxycholecalciferol
o Increases calcium absorption in the GIT
! D2 – Ergocalciferol (plant source)
Figure 3. Distribution of ionized calcium, diffusible but non-
ionized calcium complexed to anions, and non-diffusable
protein-bound in the plasma.
! Calcium in the blood is bound to albumin (41%); ionized
calcium is the free form (50%).
! This is important because sometimes in the laboratory, we
just request for the ionized calcium. If we request for total
calcium and the patient is malnourished, s/he has low
albumin, the total calcium may look smaller than what it
actually is because there is less albumin.
! To make it easier to interpret calcium than computing for
corrected calcium, request for ionized calcium but it is
much expensive.

How to compute for corrected calcium?

Figure 4. Formula for Corrected Calcium. NOTE: No need to

memorize this for the exam but please take note of the formulae Figure 5. Activation of Vitamin D3 to form 1,25-
above as you will need this a lot to clerkship. You can also dihydroxycholecalciferol and the role of vitamin D in
download the app and just input the values for convenience. controlling the plasma calcium concentration.

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Medicine II 6.02a: Calcium Metabolism and Disorders
o In the kidneys, it will tell the kidneys to excrete
phosphorus but this is not an effect on calcium levels.
• Actions:
o Induces bone calcium resorption
o Stimulates calcium reabsorption in the distal tubule
o Stimulate synthesis of 1,25-dihydroxyvitamin D in the
kidneys à increases calcium absorption in the
intestine
! Converts 25 hydroxycholecalciferol to 1,25
dihydroxycholecalciferol in the kidneys
! Reabsorbs calcium in the kidneys
o Inhibits phosphate transport in the proximal tubule
! In exchange for calcium, phosphorus will be
released in the urine
• Chronic exposure to PTH: increased osteoclast-mediated
bone resorption «
• Intermittent exposure to PTH: net stimulation of bone
formation «
! May be used as treatment for osteoporosis – give it by
subcutaneous injection once a day
§ Half life is 7 minutes
§ One of the most effective treatments in
osteoporosis

Figure 6. Schematic representation of the hormonal control

loop for vitamin D metabolism and function. & A reduction
in the serum calcium below ~2.2 mmol/L (8.8 mg/dL) prompts a
proportional increase in the secretion of parathyroid hormone
(PTH) and so mobilizes additional calcium from the bone. PTH
promotes the synthesis of 1,25(OH)2D in the kidney, which in
turn stimulates the mobilization of calcium from bone and
intestine and regulates the synthesis of PTH by negative
feedback.

QUESTION: Which of the following is not a direct action of

parathyroid hormone?
A. Bone calcium resorption
B. Increased renal calcium reabsorption
C. Increased production of 1,25 dihydroxyvitamin D Figure 7. Parathyroid Gland. The four parathyroid glands lie
D. Increased intestinal absorption of calcium immediately behind the thyroid gland. Almost all of the PTH is
synthesized and secreted by the chief cells. The function of the
C. PARATHYROID HORMONE (PTH) oxyphil cells is uncertain, but they may be modified or depleted
! Main hormone for calcium regulation chief cells that no longer secrete PTH.
• Produced by four parathyroid glands located posterior to
the thyroid gland
! Sometimes removed in thyroidectomies, and patient
becomes hypoparathyroid.
• Primary regulator of calcium physiology
! Its secretion is stimulated by low levels of calcium in the
blood
! How does the parathyroid gland know if the calcium is low?
Does a higher order organ just like in the cases of the
pituitary gland, adrenals, and thyroid control it?
o NO, it is not controlled or it does not need any other
organ to tell it to produce the parathyroid. The
parathyroid gland has calcium-sensing receptors Figure 8. Efficiency of PTH maintaining calcium at a narrow
that detect the levels of the calcium in the blood. range. ! As calcium starts to go to the low side, PTH starts to
! In response to low levels of blood calcium, the parathyroid increase. This shows the inverse relationship of PTH and
gland will release parathyroid hormone to the bloodstream calcium.
and it will attach to the receptors. Where?
o In the bone, where it will tell the bone to donate QUESTION: PL, a 74/M diagnosed with squamous cell
calcium to the blood to increase its levels. carcinoma of the lungs is admitted for decreased sensorium.
o Where else? GI tract, it will produce an indirect effect. His serum calcium is markedly elevated. Which of the following
hormonal abnormalities is the likely cause of his
hypercalcemia?

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Medicine II 6.02a: Calcium Metabolism and Disorders
A. Increased parathyroid hormone (PTH) Table 3. Functional Classification of Hypocalcemia. !
B. Increased parathyroid hormone-related peptide Cases often seen locally: Acquired hypoparathyroidism (after
(PTHrP) thyroid surgery), chronic kidney disease, and active vitamin D
C. Increased calcitonin lacking.
D. Increased 1,25-OH vitamin D

D. CALCITONIN
• Hypocalcemic peptide hormone
• Produced by parafollicular (C-cells) of the thyroid gland
! Lowers calcium levels
! Not sure if calcitonin has a physiologic role (because
even if you perform total thyroidectomy, calcium levels
do not increase), but it has a medical role
• Actions:
o Inhibits osteoclast-mediated bone resorption
o Stimulates renal calcium clearance
• Limited physiologic significance in humans
• Of medical significance
o As a tumor marker in medullary thyroid carcinoma
o As an adjunctive treatment in:
§ Severe hypercalcemia
§ Paget’s diseases of bone
§ Osteoporosis

III. DISORDERS OF CALCIUM METABOLISM QUESTION: Which of the following ECG changes is seen in
patients with hypocalcemia? «
A. HYPOCALCEMIA A. Prolonged QT interval
B. Short QT interval
CAUSES C. Prolonged PR interval
D. Short PR interval
Table 2. Factors causing low blood calcium levels.
• Often does not need treatment
MANIFESTATIONS
• Causes
o Severe sepsis • Muscle spasm
o Burns • Carpopedal spasm
ACUTE, o Acute renal failure ! What we look out for in post thyroidectomy patients
TRANSIENT o Extensive transfusions with • Facial grimacing
HYPOCALCEMIA citrated blood • Prolonged QT interval on ECG «
o Acute pancreatitsis • Arrhythmias
o Medications • Intestinal cramps
o (e.g. protamine, heparin, and • Chronic malabsorption
glucagon) • (+) Chvostek’s sign
• Usually symptomatic and needs ! Tapping the facial nerve on the cheek and seeing
treatment twitching of muscles around the lips and around the
• Causes face
o Chronic renal failure • (+) Trousseau’s sign
! Not enough active form of ! Cuff is applied to upper arm and inflated up to
vitamin D. Even if you give 20mmHg above systolic, keep it there for 3 minutes
cholecalciferol, it will not ! Expected response: carpal spasm
improve because it is not • In severe cases, laryngeal spasm, convulsions, respiratory
converted to 1,25- arrest, increased intracranial pressure, irritability,
CHRONIC
dihydroxycholecalciferol depression, psychosis
HYPOCALCEMIA
! Do not request for 25-
hydroxycholecalciferol TREATMENT
because this is always • High doses of oral calcium intake
elevated ! Some are given 12 tablets of caltrate plus per day to
o Hereditary and acquired normalize calcium
hypoparathyroidism • Replacement with Vitamin D or 1,25-dihydroxyvitamin D,
o Vitamin D deficiency also called calcitriol (active form)
o Pseudo-hypoparathyroidism o For those with renal failure, give 1,25-
o Hypomagnesemia. dihydroxyvitamin D
o For post-parathyroidectomy patients – give 1,25
dihydroxy vitamin D
! Active form is given because you need
parathyroid hormone to convert vitamin D to the
active form
• Thiazide diuretics
o Decrease calcium excretion

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Medicine II 6.02a: Calcium Metabolism and Disorders
! Increase calcium reabsorption • Recently, we had a patient with increased
! Monitor sodium and potassium levels of calcium but the PTH levels are low,
! Side effect: increase levels of calcium in the blood so it could be because of a tumor (a
• Correct hypomagnesemia, if present mediastinal tumor for this patient). We didn’t
o Parenteral repletion have to get PTHrP, because we know that the
hypercalcemia is from the tumor, so we treat
B. HYPERCALCEMIA her for hypercalcemia of malignancy.
CHRONIC DURATION
CAUSES HIGH PTH • Hyperparathyroidism
Table 4. Possible causes of HYPERcalcemia. ! • Rare causes that we hardly see
• One of the complications of o FHH: Familial Hypocalciuric
Medications patients taking Hypercalcemia
(e.g. Thiazide hydrochlorothiazide, which is a LOW PTH • Hyperthyroidism can cause hypercalcemia
diuretics) very commonly prescribed because there is an increase in reabsorption
antihypertensive drug of calcium in the GIT from the thyroid
Malignancy, solid hormone
• Can increase production of
tumors, squamous
PTHrP § Rule out false-positive causes
cell tumors
• Fat soluble vitamin (unlike B and o Hemoconcentration during blood collection
C), it needs high doses of o Elevated serum proteins such as albumin
Hypervitaminosis D ! Prolonged tourniquet time or rapid blood extraction
Vitamin D to have
hypervitaminosis ! Can cause hemolysis leading to hypercalcemia.
• Which could lead to secretion of Request for repeat extraction and give orders to
Hyperparathyroidism parathyroid hormone, leading to avoid prolonged tourniquet time or rapid
increased calcium in the blood extraction.
! One of the most common causes of
• Remember! There is NO such thing as
hypercalcemia is actually lab error.
HYPERCALCITOnemia or HYPOCALCITOnemia.
! If we take out the thyroid glands, blood levels of calcium
FEATURES
do not increase, so we don’t know the physiologic role.
• Fatigue • Constipation
• Depression • Reversible renal tubular defects
• Mental Confusion • Increased urination
• Anorexia Short QT interval in ECG «
• Nausea • Cardiac arrhythmias
• Vomiting • Severe: coma and cardiac
arrest

Table 6. SYMPTOMS OF HYPERCALCEMIA

• Deposition of calcium in the renal
STONES parenchyma
(Kidney) • Recurrent nephrolithiasis (calcium
oxalate or calcium phosphate)
• Osteitis fibrosa cystica (subperiosteal
resorption, bone cyst)
BONES
• Increased skeletal turnover à decreased
bone density
• May include vague abdominal complaints
Figure 9. Evaluation of Patients with HYPERcalcemia. ABDOMINAL and disorders of the stomach and
GROANS pancreas
Table 5. Algorithm Explanation !
• Pancreatitis
§ First step: Confirm if increase in calcium is chronic.
• Neuropsychiatric manifestations
ACUTE DURATION
PSYCHIC • Proximal muscle weakness
• Primary hyperparathyroidism: consider MEN MOANS • Easy fatigability
(Multiple Endocrine Neoplasia) Syndrome.
• Atrophy of muscles
o MEN 1 (3Ps): Parathyroid hormone
(parathyroid adenoma), Pancreas
(pancreatic tumor, insulinoma), Pituitary
(prolactinoma, etc.)
HIGH PTH
o MEN 2A: Parathyroid adenoma,
Medullary thyroid carcinoma,
Pheochromocytoma
o MEN 2B: Medullary thyroid carcinoma,
Pheochromocytoma, Ganglionomas (NO
PARATHYRIOD INVOLVEMENT)
• Consider malignancy
LOW PTH • You can get a PTHrP assay but is not
available locally, so we can assume.

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Medicine II 6.02a: Calcium Metabolism and Disorders
TREATMENT FOR SEVERE HYPERCALCEMIA D. All of the above
Table 7. Therapies for severe hypercalcemia (larger photo in E. Only A and B
the apperndix).
2. SECONDARY HYPERPARATHYROIDISM
• Usually occurs in the setting of renal failure
! Because they can’t make enough vitamin D they
become hypocalcemic
• Adaptive response to ↓Ca
• Partial resistance to the metabolic actions of PTH leads to
excessive production of the hormone
• May develop bone pain, ectopic calcification and pruritus
! In the efforts to normalize the calcium levels
• May develop renal osteodystrophy
o Osteomalacia
o Osteitis fibrosa cystica

! For acute treatment of patients with hypercalcemia, TREATMENT:

hydrate and diurese. « That should be automatic. Hook • Reduce dietary phosphates
the patient to plain NSS, fast drip 200=250cc/hr and give • Vitamin D (calcitriol)
forced diuresis with a LOOP diuretic (i.e. Furosemide). A • Phosphate binders (e.g. sevelamer)
loop diuretic will make you pee out calcium while a thiazide
diuretic will increase its reabsorption. 3. TERTIARY HYPERPARATHYROIDISM
! If patients have severe hypercalcemia (vomiting, abdominal • Progression of secondary hyperparathyroidism to a state of
pain, arrhythmia etc) give calcitonin because it works very severe hyperparathyroidism (autonomous parathyroid
fast. However, the problem is its rapid tachyphylaxis (it function)
effect ends quickly too). Thus, at the start you should give • PTH no longer suppressed by ↑ Calcium
something with long duration of action and slow onset such ! Sometimes in renal failure patients, already with secondary
as Bisphosponates. hyperparathyroidism, their calcium levels already
! Give Glucocorticoids if patient has cancer. normalized but the parathyroid hormone is still elevated.
! Start Dialysis for those with hypercalcemia and renal For some reason, PTH is still excessive, it becomes
failure. Be careful if they have renal failure, because you autonomous.
might keep hydrating these patients but since their kidneys
are damaged it will lead to congestion. TREATMENT
• Parathyroidectomy
C. HYPERPARATHYROIDISM • Cinacalcet (calcium mimetic)

1. PRIMARY HYPERPARATHYROIDISM 4. MANAGEMENT AND TREATMENT FOR

• With wider use of screening tests, diagnosis is frequently HYPERPARATHYROIDISM
made in patients who have no symptoms and minimal 4 Either through surgery or medical management
signs of disease 4 Medical surveillance without operation for patients with
o Classic “stones, bones, abdominal groans and psychic mild, asymptomatic disease is, however, still preferred by
moans” seen less often some physicians and patients, more particularly in the
o Half or more of patients are asymptomatic elderly.
• Commonly caused by solitary adenoma (8-%) that is rarely 4 More recently, evidence favoring surgery is growing
a carcinoma because of concerns about skeletal cardiovascular and
• Parathyroid carcinoma is often not aggressive neuropsychiatric disease, even in mild hyperparathyroidism
• May be part of hereditary syndrome (in non-surgically managed patients).
o MEN1 (Wermer’s syndrome)
o MEN2A Table 8. Guidelines for surgery in asymptomatic primary
o Hyperparathyroidism jaw tumor hyperparathyroidism.
o Nonsyndromic familial isolated hyperparathyroidism

DIAGNOSIS
• ↑ Calcium
• ↑ intact PTH (iPTH)
• Elevated 24-h urine calcium
• Note: Familial Hypocalciuric Hypercalcemia (FHH),
presents with ↑ Calcium, ↑ iPTH, but ↓ 24-h urine calcium. ! Age less than 50 because they found out that monitoring a
FHH presents with few clinical signs or symptoms and patient through long term is actually more costly than
surgery is not indicated in these patients having it removed.
! Even if the patient is asymptomatic, if the following
QUESTION: Which is an indication for parathyroid surgery in a parameters are present then surgery is indicated.
patient with asymptomatic hyperparathyroidism?
A. Age <50
B. Calcium >1mg/dl above normal
C. T-score <-2.5

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Medicine II 6.02a: Calcium Metabolism and Disorders
Table 9. Guidelines for monitoring in asymptomatic primary acting. If you give it today, its effects are after 3-4 days.
hyperparathyroidism. ! In case patients don’t meet the For those with osteoporosis, zoledronic acid is given once
criteria for surgery, these are how to monitor them. Every year, a year. That’s how long its effect is.
get serum calcium, serum creatinine, and Bone density. • Calcitonin is short acting so you need to give this with a
drug that has a long duration of action.

-- From 2018B --
4 MEDICAL MANAGEMENT OF HYPERPARATHYROIDISM
• The main goal of management is hydration and forced
diuresis. «
• Medical monitoring rather than corrective surgery is still
acceptable, but it is clear that surgical intervention is the
QUESTION: JD is a 35/F diagnosed with primary more frequently recommended option.
hyperparathyroidism. To aid the surgeon in identifying the • Remember: Thiazide diuretics promote absorption of
hyperfunctioning gland, which combination of imaging calcium; Loop diuretics promote urinary excretion of
modalities is most useful? calcium.
A. Ultrasound + Tc99m sestamibi scanning • Therapies used for Severe Hypercalcemia
B. CT scan + 131-Iodine scintigraphy o Hydration with saline
C. MRI + 125-Iodine scintigraphy o Saline plus loop diuretic
D. PET + Spect CT scanning o Pamidronate – Bisphosphonate
o Zoledronate – Bisphosphonate o Calcitonin
Notes: o Therapies with Special Use:
A - In localizing a hyperfunctioning parathyroid gland, you § PhosphateOral
combine ultrasound and Tc99m sestamibi scanning. One is § Glucocorticoids
an imaging the other is a functional scan. Ultrasound will § Dialysis
just tell you if there are large adenomas -- end of part from 2018B --
B and C - Iodine goes to the thyroid
D - if you are considering a malignancy D. PSEUDOHYPOPARATHYROIDISM
• It’s a hereditary disorder
SURGICAL TREATMENT OF HYPERPARATHYROIDISM • Deficient end-organ response to PTH
• Localization of hyperfunctioning parathyroid gland o Calcium is low despite elevated PTH
o Ultrasound • Typically associated with distinctive skeletal and
o Tc99m sestamibi scan developmental defects:
• Surgical removal of the affected gland o Short stature
• Intraoperative determination of intact PTH (iPTH) to o Round face
determine if appropriate gland has been removed o Skeletal anomalies (brachydactyly)
! If the surgeon is unsure and there is no available o Heterotropic ossification
nuclear imaging modality, the surgeon can take out • Presents with signs and symptoms of hypoparathyroidism
one. Then after few minutes (t½ of PTH is 7 minutes), ! Rare especially in the Philippines; just 1 case in the past 15
get the blood levels of parathyroid hormone. If it years
lowers, the surgeon closes. If levels still persist, the
surgeon would take out another gland. Then test IV. OSTEOPOROSIS
again. If it still persists, take another one or if needed • Most common bone disease in humans
take everything out. • A silent disease until it is complicated by fractures
• Multiple gland hyperplasia approaches (fractures that can occur even with minimal trauma)
o Remove 3.5 glands • It is characterized by:
! Surgeons would take 3 ½ glands and if the patient o Low bone mass
is still hypercalcemic, the remaining 0.5 gland is o Deterioration of bone tissue and disruption of bone
also removed architecture
o Total parathyroidectomy with transplantation of a o Compromised bone strength
removed gland into the muscle of the forearm.
! All 4 parathyroid glands are roved and implanted
into the forearm. If the patient is still
hypercalcemic, it is easier to remove the
implanted parathyroid gland. Surgery could be
performed in the clinic or outpatient.

QUESTION: Which of the following agents used in the

management of hypercalcemia has the advantage of long
duration of action, but the disadvantage of slow onset?
A. Calcitonin
B. Zoledronic acid
C. Plicamycin
D. Allium nitrate Figure 10. Epidemiology of vertebral, hip, and Colles’
fractures with age.
Notes: ! Colles’ fracture: fracture in the distal forearm upon falling
! Zoledronic Acid (Bisphosphonate) is slow in onset and long on an outstretched arm – this is how they fall below 70
years old but beyond 70 years old they fall backwards.

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Medicine II 6.02a: Calcium Metabolism and Disorders
! After 70 years old, hip fractures are more common. ! If there is something that slows down bone formation or
increases osteoclast activity, it can lead to osteoporosis.

B. PATHOPHYSIOLOGY

Figure 11. Estimated number of hip fractures.

! Hip fractures are expected to rise in the next years because
people now live longer. Figure 14. Gross appearance of osteoporotic bone.
! By 2050, there will be 6.26 million with hip fractures.
• Balance of bone remodeling is altered, resulting in greater
bone removal than replacement.
& Loss of bone tissue is associated with deterioration in
skeletal microarchitecture.

C. RISK FACTORS

QUESTION: Which of the following is NOT a risk factor for the

development of osteoporosis?
A. Hypothyroidism
B. Chronic glucocorticoid intake
C. Low body weight
D. Alcoholism
E. Presently smoking
Figure 12. Hip fractures’ sequelae.
! We have to treat osteoporosis not just to decrease the risk • It is HYPERthyroidism that is a risk factor for osteoporosis
of hip fracture, but also to decrease the risk of dying one because there is increase in bone resorption.
year after the fracture.
• Age
A. BONE REMODELING • Sex
• LOW BODY MASS INDEX: ! stress on bone is a stimulus
for bone growth
• Previous fragility fracture, particularly of the hip, wrist and
spine, including morphometric vertebral fracture in adult life
• Parental history of hip fracture
• Glucocorticoid treatment (≥5 mg prednisolone daily or
equivalent for 3 months or more)
• Current smoking
• Alcohol intake 3 or more units daily
! Hyperthyroidism
Figure 13. Bone Remodeling Process.
• Bone is continuously remodeled at discrete sites in the
skeleton in order to maintain the integrity of the tissue.
• During the process, old bone is resorbed by osteoclasts
and replaced with new osteoid, secreted by osteoblasts.
First osteoclasts are activated, and the resorption phase
takes approximately 10 days.
• Following resorption, unclassified macrophage-like cells are
found at the remodeling site in the intermediate, or reversal
phase.
• Osteoblast precursors are then recruited, which proliferate
and differentiate into mature osteoblasts, before secreting
new bone matrix.
• The matrix then mineralizes to generate new bone and this
completes the remodeling process.

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Medicine II 6.02a: Calcium Metabolism and Disorders

D. DIAGNOSTIC TOOLS FOR OSTEOPOROSIS E. DEFINITION AND DIAGNOSIS OF OSTEOPOROSIS

Definition of osteoporosis for POSTmenopausal women

and MEN >50yo: «
Table 10. Definition of osteopenia.

*T-score: comparing to younger patients of same sex and race.

Figure 15. Asian Screening Tool. ! Familiarize yourself with Diagnosis in PREmenopausal women, and in MEN <50yo,
this Table.This is an osteoporotic screening tool made by South and CHILDREN «
East Asians countries. It is based on one’s weight and age. If a • Z-scores should be used, with Z-scores:
person falls under “high” red zone, then you can start treating o - 2.0 or LOWER
for osteoporosis. No need for further testing. § Low bone mineral density for chronological age
§ Below the expected range for age
o ABOVE - 2.0
§ Within the expected range for age

QUESTION: RS is a 60/F who underwent bone densitometry

(DXA) scanning. Her L1-L4 spine results showed a Z-score of -
1.8 and a T-score of -2.0. She has:
A. Bone mineral density within the expected range for
age
B. Low bone mineral density for chronological age
C. Osteopenia
D. Osteoporosis

F. NONPHARMACOLOGIC TREATMENT OF OSTEOPOROSIS

• Adequate Calcium (1200mg/day)
• Adequate vitamin D3 (800 to 1000 IU/day for adults>50)
• Regular weight-bearing exercise
Figure 16. WHO Fracture Assessment Tool (FRAX) • Fall prevention (! clean spills on floor, remove toys, wires
http://www.shef.ac.uk/FRAX. etc. on the floor, put handle bars in the bathroom and
! Another way to diagnose osteoporosis for free is using stairs. Walkway is well lit.)
FRAX. This is country specific. • Avoidance of tobacco use and excessive alcohol intake
! Magic number here: 20% risk for major osteoporotic
fracture or 3% risk for hip fracture, patients will need PREVENTING FALLS STEP BY STEP
treatment. « • Among older adults, falls are a leading cause for
! FRAX is available on iOS (Php299) and android hospitalization and emergency care.
(Php260.34) • Falls can lead to potentially severe injuries such as hip
fractures and head traumas, and can even increase the risk
Indications for BMD Testing « of early death.
Consider BMD testing in the following individuals: • During Falls Prevention Awareness Week, Amedisys Home
• Women age 65 and older and men age 70 and older, Health and Hospice offers the following tips to reduce the
regardless of clinical risk factors risk of falling so seniors can live healthier, more
• Younger postmenopausal women, women in the independent lives.
menopausal transition and men age 50 to 69 with clinical
risk factors for fracture IN THE HOME: YOURSELF:
• Adults who have a fracture after age 50 • Know about any side • Exercise to improve
• Adults with a condition (e.g. rheumatoid arthritis) or taking a effects of medications strength, balance, and
medication (e.g. glucocorticoids in daily dose > 5mg that could potentially coordination. Always
prednisone or equivalent for > three months) associated lead to a fall. check with your doctor
with low bone mass or bone loss • Use non-slip rubber before starting a new
mats in the bathtub and exercise routine.
shower. • Wear sturdy shoes and
• Keep your home well-lit, or non-skid socks.

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Medicine II 6.02a: Calcium Metabolism and Disorders
placing lights in • If you live in region that Table 12. Anti-fracture efficacy of the most frequently used
hallways, stairwells, and gets wintery weather, treatments for postmenopausal osteoporosis when given
bathrooms. consider putting special with calcium and vitamin D, as derived from randomized
• Clean up spills once cleats on your shoes to controlled trials. (Larger photo in the appendix)
they happen. prevent you from
• Use handrails on the slipping on the snow and
stairway and in the ice.
bathroom.
• Clear walkways of
clutter, electrical cords,
etc.
• Get rid of throw rugs or
use double-sided tape to
secure them.

G. PHARMACOLOGIC TREATMENT OF OSTEOPOROSIS

QUESTION: Which of the following agents is a selective

estrogen response modulator (SERM) used in the prevention « NOTE: Please study the AACE/ACE 2016 Postmenopausal
and treatment of osteoporosis? Osteoporosis Treatment Algorithm in the Appendix. «
A. Tamoxifen
B. Raloxifene H. OTHER BONE PATHOLOGY
C. Teriparatide
D. Strontium ranelate
1. PAGET DISEASE OF BONE
Table 11. Pharmacologic therapy for osteoporosis. • Localized bone disorder that affects widespread areas of
• Alendronate, Risedronate, the skeleton through increased bone remodeling
Ibandronate, Zoledronate • Overactive osteoclastic bone resorption followed by
• Specifically impair osteoclast compensatory increase in osteoblastic bone formation
Bisphosphonates • New bone is structurally disorganized and more
function and reduce osteoclast
number, in part by the induction susceptible to deformities and fractures
of apoptosis
4 Rarely used weak evidence TREATMENT:
Calcitonin Bisphosphonates
and very expensive •
Estrogen/Hormone ! For early postmenopausal • Calcitonin
Therapy women
o Selective Estrogen Receptor 2. OSTEOPETROSIS
Estrogen
Modulators • Group of disorders caused by severe impairment of
Agonist/Antagonist
o Raloxifene osteoclast-mediated bone resorption
Parathyroid • Teriparatide (Forteo) • Loss of osteoclastic bone resorption and preservation of
Hormones ! Very expensive normal osteoblastic bone formation
! Now being removed from the
Strontium Renalate market due to cardiac adverse a. SEVERE OSTEOPETROSIS
events • Paralysis of one or more cranial nerves may occur due to
Antibody to RANK-L • Denosumab narrowing of the cranial foramina
NOTE: Refer to appendix for Table 12. Anti-fracture Efficacy • Inadequate marrow space, leading to extramedullary
of the Treatments for Osteoporosis. ! Look for the ones with hematopoiesis with hypersplenism and pancytopenia
pluses all over: HRT, Strontium Ranelate and Denosumab. • Hypocalcemia due to lack of osteoclastic bone resorption
However only given for early post-menopausal • Untreated infantile disease is fatal, often before age 5

b. ADULT OSTEOPETROSIS
• Usually benign but may be accompanied by loss of vision,
deafness, psychomotor delay, mandibular osteomyelitis,
and other complications usually associated with the
juvenile form

TREATMENT: Bone Marrow Transplant

3. FIBROUS DYSPLASIA
• Sporadic disorder characterized by the presence of
one or more expanding fibrous skeletal lesions
composed of bone-forming mesenchyme
o McCune-Albright syndrome: polyostotic form of
fibrous dysplasia associated with café-au-lait spots
and hyperfunction of an endocrine system such as
pseudo-precocious puberty of ovarian origin

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Medicine II 6.02a: Calcium Metabolism and Disorders
MANIFESTATIONS
• Expanding bone lesions (most commonly involve the
maxilla and other craniofacial bones, ribs, and metaphyseal
or diaphyseal portions of the proximal femur or tibia) may
cause pain, deformity, fractures, and nerve entrapment.
• Hypophosphatemia

TREATMENT
• No established effective treatment
• IV bisphosphonate therapy
• Surgical stabilization

REFERENCES
1. Co MD’s Lecture Recording and PowerPoint Presentation
(March 16, 2017; University Auditorium 2 UERMMMCI)
th
2. Harrison’s 19 Edition
3. 2018B Trans

GUIDE QUESTIONS
1. Chronic use of aldactone and furosemide
A. Inc. potassium C. Breast enlargement
B. Inc. calcium D. Liver cirrhosis

2. 25/F with elevated serum calcium. has pulmonary

tuberculosis. What will be your next step?
A. Check if PTH is intact C. Perform VitD assay
B. Check phosphorus levels D. Repeat test

3. Old man with lung cancer with anorexia, headache,

vomiting, HR=110, BP=90/60, increased Ca levels, and
increased creatinine. What is the management?
A. Bisphosphonates
B. Infuse with saline
C. Infuse with saline and furosemide

4. Mr P has had repeatedly high serum calcium. He has a

history of recurrent nephrolithiasis. He comes to you
complaining of muscle weakness and easy fatigability (I’m
not sure if he had these symptoms, can’t remember). He
denies vomiting, nausea, or diarrhea. Sestamibi scan
revealed a solitary enlargement at the right inferior pole of
the thyroid. What is your management?
A. Calcimimetic
B. Remove abnormal parathyroid
C. Remove 3.5 of the parathyroids
D. Remove all 4 and transplant portion of one gland to
forearm

5. Which of the following diseases/medicines is associated

with excess Vitamin D production leading to
hypercalcemia?
A. Hyperthyroidism C. Tuberculosis
B. Lithium use D. Thiazides

6. Which of the following therapeutics used in the treatment of

severe hypercalcemia has a delayed onset of action?
A. Bisphosphonates C. Dialysis
B. Calcitonin D. Hydration

7. Approved in prevention of osteoporosis in women

A. Calcitonin C. Estrogen
B. Denosumab D. Teriparatide

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 nd
Medicine II 6.02a 2 Sem/A.Y. 2016-2017
Calcium Metabolism and Disorders
JM Co, MD, FPCP, FPSEDM March 16, 2017

Table 7. Therapies for severe hypercalcemia.

Table 12. Anti-fracture efficacy of the most frequently used treatments for postmenopausal osteoporosis when given with
calcium and vitamin D, as derived from randomized controlled trials.

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Medicine II 6.02a: Calcium Metabolism and Disorders

«Figure 22. AACE/ACE 2016 Postmenopausal Osteoporosis Treatment Algorithm.

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Medicine II 6.02a: Calcium Metabolism and Disorders

« Figure 23. AACE/ACE 2016 Postmenopausal Osteoporosis Treatment Algorithm cont..

«Figure 24. AACE/ACE 2016 Postmenopausal Osteoporosis Treatment Algorithm cont..

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