Agents That Agents That Affect Bone Affect Bone

Mineral Mineral HomeostasisHomeostasis

Functions of the bone:

1. Principal structural support for the body

2. Ca and PO4 reservoir

3. Space for hematopoesis

Two hormones serve as Two hormones serve as principal principal regulatorsregulators of Ca & P homeostasis: of Ca & P homeostasis: parathyroid hormone (PTH) & parathyroid hormone (PTH) & vitamin D (active metabolite) vitamin D (active metabolite)

Certain of Certain of secondary regulatorssecondary regulators— — calcitonin, glucocorticoids & calcitonin, glucocorticoids & estrogens—are useful therapeuticallyestrogens—are useful therapeutically

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Some mechanisms contributing to bone mineral homeostasis.

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Actions of PTH & vitamin D on gut, bone, & kidney.

  PTH Vitamin D

Intestine ↑ Ca & P absorption (by ↑ 1,25 [OH]2D production)

↑ Ca & P absorption by 1,25(OH)2D

Kidney ↓ Ca excretion, ↑ P excretion

Ca & P excretion may be ↓ by 25(OH)D & 1,25(OH)2D

Bone Ca & P resorption ↑ by high doses. Low doses may ↑ bone formation

↑ Ca & P resorption by 1,25(OH)2D; bone formation may be ↑ by 24,25(OH)2D

Net effect on serum levels

Serum Ca↑, serum P ↓

Serum Ca & P both ↑

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CLINICAL CLINICAL PHARMACOLOGY PHARMACOLOGY

Conditions that alter bone mineral Conditions that alter bone mineral homeostasis:homeostasis:

Effects on bone can result in:Effects on bone can result in: osteoporosis (osteoporosis (abnormal loss of bone; abnormal loss of bone;

remaining bone histologically normal)remaining bone histologically normal) osteomalaciaosteomalacia (abnormal bone formation (abnormal bone formation

due to inadequate mineralization) due to inadequate mineralization) osteitis fibrosaosteitis fibrosa (excessive bone resorption (excessive bone resorption

with fibrotic replacement of resorption with fibrotic replacement of resorption cavities) cavities)

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Osteomalacia Osteitis Osteomalacia Osteitis fibrosa cysticafibrosa cystica 9

ABNORMAL SERUM ABNORMAL SERUM Ca & P LEVELS Ca & P LEVELS

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HYPERCALCEMIA HYPERCALCEMIA Hypercalcemia Hypercalcemia causescauses CNS depression, CNS depression,

including coma, & is potentially lethalincluding coma, & is potentially lethal ArrhythmiaArrhythmia cardiovascular collapse cardiovascular collapse give give

MgSO4 (IV) to offset the dynamic effect MgSO4 (IV) to offset the dynamic effect Major Major causescauses (other than thiazide therapy) (other than thiazide therapy)

are hyperparathyroidism & cancer with or are hyperparathyroidism & cancer with or without bone metastases without bone metastases

Less commonLess common causes are hypervitaminosis D, causes are hypervitaminosis D, sarcoidosis, thyrotoxicosis, milk-alkali sarcoidosis, thyrotoxicosis, milk-alkali syndrome - seldom require emergency syndrome - seldom require emergency ↓ ↓ of of serum Ca (serum Ca (with exception of hypervitaminosis D)with exception of hypervitaminosis D)

Ca X PO4 must be < 55 mgCa X PO4 must be < 55 mg22/dL/dL22 in order to in order to prevent ectopic calcification in soft vital prevent ectopic calcification in soft vital tissuestissues

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Treatment of Treatment of hypercalcemiahypercalcemia

1. Saline Diuresis1. Saline Diuresis 500-1000 mL/h of saline to reverse 500-1000 mL/h of saline to reverse dehydration & restore urine flow + loop dehydration & restore urine flow + loop diuretic to diuretic to ↑↑urine flow but also urine flow but also ↓Ca↓Ca reabsorption in ascending limb of loop of reabsorption in ascending limb of loop of Henle Henle

2. If more 2. If more prolonged treatmentprolonged treatment of of hypercalcemia is required:hypercalcemia is required:1. 1. BisphosphonatesBisphosphonates Etidronate in saline IV for 3 days. Etidronate in saline IV for 3 days. Pamidronate appears to be more effectivePamidronate appears to be more effective

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BisphosphonatesBisphosphonates MOA:MOA: inhibit bone resorption inhibit bone resorption less than 10% of an oral dose of these drugs is less than 10% of an oral dose of these drugs is

absorbed. absorbed. Food reduces absorption even further Food reduces absorption even further empty empty

stomach.stomach. That’s why: pamidronate is not available as an oral That’s why: pamidronate is not available as an oral

preparation.preparation. all currently available bisphosphonates have this all currently available bisphosphonates have this

complication (with the possible exception of complication (with the possible exception of etidronate) etidronate)

Nearly half of the absorbed drug accumulates in bone;Nearly half of the absorbed drug accumulates in bone; C/I: Decreased renal function, esophageal motility C/I: Decreased renal function, esophageal motility

disorders, and peptic ulcer disease are the main disorders, and peptic ulcer disease are the main

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3. Calcitonin: 3. Calcitonin: ancillary treatment.ancillary treatment. effect lasts for 6-10 hours. effect lasts for 6-10 hours. Calcimar (salmon calcitonin) is Calcimar (salmon calcitonin) is

available for parenteral & nasal available for parenteral & nasal administration (preferred)administration (preferred)

MOA: (1) inhibits osteoclastic bone MOA: (1) inhibits osteoclastic bone resorption (resorption ((although with time both resorption and (although with time both resorption and firmation of bone are reduced) firmation of bone are reduced)

(2) In kidney: Reduces Ca and PO4 (2) In kidney: Reduces Ca and PO4 reabsorptionreabsorption

Useful for the treament of Paget’s disease, Useful for the treament of Paget’s disease, Hypercalcemia and osteoporossisHypercalcemia and osteoporossis 14

4. Gallium Nitrate (IV)4. Gallium Nitrate (IV) Acts by (-) bone resorptionActs by (-) bone resorption Due to nephrotoxicity, patients Due to nephrotoxicity, patients

should be well-hydrated & have should be well-hydrated & have good renal output before starting good renal output before starting infusion infusion

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5. 5. Plicamycin(Mithramycin):Plicamycin(Mithramycin): (risk of (risk of thrombocytopenia followed by thrombocytopenia followed by hemorrhage), hepatic & renal toxicityhemorrhage), hepatic & renal toxicity

6. 6. Phosphate:Phosphate: IV is IV is hazardous hazardous procedure if not done properly: procedure if not done properly: sudden hypocalcaemia, ectopic sudden hypocalcaemia, ectopic calcification, acute renal failure, calcification, acute renal failure, hypotensionhypotension

Must be given slowly (6-8 hrs) then Must be given slowly (6-8 hrs) then switch to oral phosphateswitch to oral phosphate

Very risky16

7. 7. Glucocorticoids:Glucocorticoids: Glucocorticoid hormones alter bone Glucocorticoid hormones alter bone

mineral homeostasis by:mineral homeostasis by: 1. 1. antagonizing vitamin D-stimulated antagonizing vitamin D-stimulated intestinal calcium transport, 2. by intestinal calcium transport, 2. by stimulating renal calcium excretion, and stimulating renal calcium excretion, and by 3. blocking bone formationby 3. blocking bone formation

no clear role in acute treatment of no clear role in acute treatment of hypercalcemia. hypercalcemia.

However, chronic hypercalcemia may respond However, chronic hypercalcemia may respond within several days to glucocorticoid therapywithin several days to glucocorticoid therapy

Prednisone (30-60 mg/day)Prednisone (30-60 mg/day)

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HYPOCALCEMIA HYPOCALCEMIA

Main features (neuromsucular)Main features (neuromsucular): tetany, : tetany, paresthesias, laryngospasm, muscle cramps, paresthesias, laryngospasm, muscle cramps, & convulsions& convulsions

Major causes in adultMajor causes in adult: hypoparathyroidism, : hypoparathyroidism, vitamin D deficiency, chronic kidney disease vitamin D deficiency, chronic kidney disease & malabsorption, infusions of citrated blood & malabsorption, infusions of citrated blood

Neonatal hypocalcemiaNeonatal hypocalcemia usually resolves usually resolves without therapywithout therapy

Treatment: Ca & vitamin D (or its Treatment: Ca & vitamin D (or its metabolites)metabolites)

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Treatment of Treatment of Hypocalcemia Hypocalcemia

1. Calcium:1. Calcium: IVIV: gluceptate, gluconate, chloride. Gluconate is : gluceptate, gluconate, chloride. Gluconate is

the preferred form (less irritating to veins)the preferred form (less irritating to veins) Rapid infusion can lead to cardiac arrhythmias Rapid infusion can lead to cardiac arrhythmias OralOral: carbonate, lactate, phosphate, citrate : carbonate, lactate, phosphate, citrate

Carbonate is preparation of choice: high % of Ca, Carbonate is preparation of choice: high % of Ca, ready availability, low cost, & antacid properties ready availability, low cost, & antacid properties

Treatment:Treatment: Severe symptomatic hypocalcemia: slow infusion of 5-20 mL Severe symptomatic hypocalcemia: slow infusion of 5-20 mL

of 10% Ca gluconate. Avoid rapid infusion (cardiac of 10% Ca gluconate. Avoid rapid infusion (cardiac arrhythmias)arrhythmias)

Less severe cases: oral Ca (carbonate to provide 400-Less severe cases: oral Ca (carbonate to provide 400-1200mg of elemental Ca1200mg of elemental Ca

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2. Vitamin D2. Vitamin D

1,25(OH)2D3 (calcitriol), is the 1,25(OH)2D3 (calcitriol), is the metabolite of choice for rapid action metabolite of choice for rapid action ((↑↑serum Ca within 24-48 hrs). Also serum Ca within 24-48 hrs). Also ↑↑ serum P but usually not observed serum P but usually not observed early in treatmentearly in treatment

Combined effects of calcitriol on both Combined effects of calcitriol on both Ca & P make careful monitoring of Ca & P make careful monitoring of serum Ca × P product important to serum Ca × P product important to avoid ectopic calcificationavoid ectopic calcification

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HYPERPHOSPHATEMIA HYPERPHOSPHATEMIA

CausesCauses: renal failure, : renal failure, hypoparathyroidism & vitamin D hypoparathyroidism & vitamin D intoxicationintoxication

Emergency treatmentEmergency treatment: by dialysis or : by dialysis or glucose & insulin infusionsglucose & insulin infusions

Chronic treatmentChronic treatment: : 1.↓1.↓ dietary phosphate dietary phosphate2. Ca supplements2. Ca supplements3. Al(OH)3-containing antacids (potential 3. Al(OH)3-containing antacids (potential

to induce Al-associated bone disease) to induce Al-associated bone disease) 4. Phosphate-binding gels (4. Phosphate-binding gels (Sevelamer)Sevelamer) 21

Diet Management of Diet Management of hyperphosphatemiahyperphosphatemia

MinimizeMinimize (but not avoid: cheese (no more (but not avoid: cheese (no more than 1 oz per day, milk (250 mL per day), egg than 1 oz per day, milk (250 mL per day), egg (no more than 1 per day- maximum 3-4 per (no more than 1 per day- maximum 3-4 per week), heart, liver, kidney (no more than once week), heart, liver, kidney (no more than once per fortnightper fortnight

Avoid:Avoid: Pilchards, Sardines, Kippers, Pilchards, Sardines, Kippers, Herrings, Whitebait, Sprats, Fish Roe, Prawns Herrings, Whitebait, Sprats, Fish Roe, Prawns or Crab, All Bran., Cocoa powder, Horlicks or Crab, All Bran., Cocoa powder, Horlicks and Ovaltine, Evaporated milk, Chocolate and Ovaltine, Evaporated milk, Chocolate (especially milk) and Fudge, Chocolate (especially milk) and Fudge, Chocolate spread, Peanut butter, Nuts, popcorn. spread, Peanut butter, Nuts, popcorn.

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HypophosphatemiaHypophosphatemia Causes: e.g. hyperparathyroidism, vitamin D Causes: e.g. hyperparathyroidism, vitamin D

deficiency, idiopathic hypercalciuria, vitamin D-deficiency, idiopathic hypercalciuria, vitamin D-resistant rickets, various other forms of renal resistant rickets, various other forms of renal phosphate wasting phosphate wasting

Leads to:Leads to: 1.1. reduction in the intracellular levels of ATP, reduction in the intracellular levels of ATP, 2.2. interfere with normal hemoglobin-to-tissue interfere with normal hemoglobin-to-tissue

oxygen transfer, andoxygen transfer, and3.3. RhabdomyolysisRhabdomyolysis

Treatment: Treatment: Depending on the clinical situation, Depending on the clinical situation, replacement options include dietary phosphate, replacement options include dietary phosphate, oral phosphate preparations, and IV phosphateoral phosphate preparations, and IV phosphate

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SPECIFIC DISORDERS SPECIFIC DISORDERS INVOLVING THE BONE INVOLVING THE BONE MINERAL-REGULATING MINERAL-REGULATING

HORMONES HORMONES

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NUTRITIONAL VITAMIN NUTRITIONAL VITAMIN D DEFFICIENCYD DEFFICIENCY

Vitamin D deficiency in pediatric & Vitamin D deficiency in pediatric & geriatric populations on vegetarian diets geriatric populations on vegetarian diets & with & with ↓↓sunlight exposure sunlight exposure

PreventionPrevention: 800-1200 units/d of vitamin D : 800-1200 units/d of vitamin D TreatmentTreatment: higher dosages (4000 units/d) : higher dosages (4000 units/d) 25(OH)D 25(OH)D No other metabolite is No other metabolite is

indicated indicated Diet should also contain adequate amounts Diet should also contain adequate amounts

of Ca & Pof Ca & P

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CHRONIC RENAL CHRONIC RENAL FAILUREFAILURE

MajorMajor problems problems: loss of 1,25(OH): loss of 1,25(OH)22D & D & 24,25(OH)24,25(OH)22D production, retention of P D production, retention of P →↓→↓ionized Ca levels ionized Ca levels →→ 2 2ryry hyperparathyroidism hyperparathyroidism

With loss of 1,25(OH)2D production, < Ca is With loss of 1,25(OH)2D production, < Ca is absorbed from intestine & < bone is resorbed absorbed from intestine & < bone is resorbed under influence of PTH under influence of PTH → → hypocalcemia hypocalcemia →→ exacerbation of hyperparathyroidismexacerbation of hyperparathyroidism

BonesBones show mixture of osteomalacia & osteitis show mixture of osteomalacia & osteitis fibrosafibrosa

Less commonly hypercalcemia (adynamic Less commonly hypercalcemia (adynamic bone disease)bone disease)

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Vitamin DVitamin D in patients with substantial in patients with substantial degree of renal failure cannot be degree of renal failure cannot be converted to its active metabolitesconverted to its active metabolites

Two analogs of calcitriol, Two analogs of calcitriol, doxercalciferol & paricalcitoldoxercalciferol & paricalcitol, are , are approved for the treatment of 2ry approved for the treatment of 2ry hyperparathyroidism of chronic renal hyperparathyroidism of chronic renal failure. They are less likely to induce failure. They are less likely to induce hypercalcemia hypercalcemia

Use of Vitamin D Use of Vitamin D Preparations Preparations

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1,25(OH)1,25(OH)22DD33 (calcitriol (calcitriol) rapidly corrects ) rapidly corrects hypocalcemia & at least partially reverses hypocalcemia & at least partially reverses 22ryry hyperparathyroidism & osteitis fibrosa. ↑ hyperparathyroidism & osteitis fibrosa. ↑ serum Ca in 1-2 daysserum Ca in 1-2 days

DihydrotachysterolDihydrotachysterol, analog of 1,25(OH)2D, , analog of 1,25(OH)2D, is equally effective. ↑Ca in 1-2 weeks is equally effective. ↑Ca in 1-2 weeks

Neither calcitriol, nor dihydrotachysterol Neither calcitriol, nor dihydrotachysterol correct osteomalacia, & neither should be correct osteomalacia, & neither should be used in patients with hypercalcemiaused in patients with hypercalcemia

CalcifediolCalcifediol (25[OH]D3) is < effective than (25[OH]D3) is < effective than calcitriol in stimulating intestinal calcium calcitriol in stimulating intestinal calcium transport → < hypercalcemiatransport → < hypercalcemia

requires several weeks to restore requires several weeks to restore normocalcemia normocalcemia

Use of Vitamin D Use of Vitamin D Preparations Preparations

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INTESTINAL INTESTINAL OSTEODYSTROPHY OSTEODYSTROPHY

Malabsorption of Ca & vitamin D Malabsorption of Ca & vitamin D →c→combination of osteoporosis & ombination of osteoporosis & osteomalacia osteomalacia

Liver disease may:Liver disease may:1.1. ↓↓production of 25(OH)D from vitamin D production of 25(OH)D from vitamin D 2.2. Impaired secretion into bile of vitamin Impaired secretion into bile of vitamin

D metabolites & conjugates D metabolites & conjugates → → deplete deplete body of endogenous vitamin D & body of endogenous vitamin D & metabolites metabolites

In mild forms of malabsorption, vitamin In mild forms of malabsorption, vitamin D can be used. In severe disease: D can be used. In severe disease: calcitriol & calcifediol calcitriol & calcifediol 30

INTESTINAL INTESTINAL OSTEODYSTROPHY OSTEODYSTROPHY

Malabsorption of Ca & vitamin D Malabsorption of Ca & vitamin D →c→combination of osteoporosis & ombination of osteoporosis & osteomalacia osteomalacia

Liver disease may:Liver disease may:1.1. ↓↓production of 25(OH)D from vitamin D production of 25(OH)D from vitamin D 2.2. Impaired secretion into bile of vitamin Impaired secretion into bile of vitamin

D metabolites & conjugates D metabolites & conjugates → → deplete deplete body of endogenous vitamin D & body of endogenous vitamin D & metabolites metabolites

In mild forms of malabsorption, vitamin In mild forms of malabsorption, vitamin D can be used. In severe disease: D can be used. In severe disease: calcitriol & calcifediol calcitriol & calcifediol 31

OSTEOPOROSIS OSTEOPOROSIS

Osteoporosis is abnormal loss of Osteoporosis is abnormal loss of bone predisposing to fractures. bone predisposing to fractures.

Occurs inOccurs in:: postmenopausal women postmenopausal women older menolder men Chronic/long term glucocorticoids Chronic/long term glucocorticoids

therapytherapy hyperparathyroidism hyperparathyroidism malabsorption syndrome malabsorption syndrome

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Postmenopausal Postmenopausal osteoporosisosteoporosis

may be accompanied by may be accompanied by ↓↓1,25(OH)1,25(OH)22D levels D levels & & ↓↓intestinal Ca transport intestinal Ca transport

Estrogen deficiency Estrogen deficiency → → best treated with best treated with cyclic doses of cyclic doses of estrogenestrogen

The most rapid loss of bone occurs within The most rapid loss of bone occurs within the the first 5 yearsfirst 5 years after menopause after menopause → → administration of estrogens after this time administration of estrogens after this time may be < effective. may be < effective.

If estrogens are discontinued, accelerated If estrogens are discontinued, accelerated bone loss may occur bone loss may occur →→ treatment with treatment with estrogens should be started shortly after estrogens should be started shortly after onset of menopause & may need to be onset of menopause & may need to be continued for life continued for life 33

Risk of endometrial carcinoma is Risk of endometrial carcinoma is minimized by addition of a progestin minimized by addition of a progestin

Estrogen therapy may be Estrogen therapy may be reservedreserved for for women with women with ↓↓bone mineral content at bone mineral content at the time of menopause or those who the time of menopause or those who lose bone rapidly in the first year after itlose bone rapidly in the first year after it

Treatment may Treatment may reinitiate menstrual reinitiate menstrual bleedingbleeding. .

Other complications: Other complications: hypertension & hypertension & thrombophlebitis thrombophlebitis

Small Small ↑↑risk (if it exists at all) of risk (if it exists at all) of breast breast cancercancer is outweighed by is outweighed by ↓ ↓ risk of risk of osteoporosis osteoporosis

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Vitamin DVitamin D is often employed + is often employed + dietary Cadietary Ca supplementation supplementation

In several large studies, vitamin D In several large studies, vitamin D supplementation (400-800 IU/d) has supplementation (400-800 IU/d) has been shown to be useful been shown to be useful

Calcitriol Calcitriol & its analog & its analog 1α(OH)D1α(OH)D33 ↑↑bone mass & bone mass & ↓ ↓ fractures fractures

Use of these agents for osteoporosis Use of these agents for osteoporosis is not FDA-approved, though they is not FDA-approved, though they are used in other countriesare used in other countries

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Fluoride: Fluoride: the only agent that can the only agent that can directly (+) bone formation directly (+) bone formation →↑ →↑ bone bone densitydensity

CalcitoninCalcitonin is approved for use in is approved for use in treatment of postmenopausal treatment of postmenopausal osteoporosis. Reduces bone resorptionosteoporosis. Reduces bone resorption

Bisphosphonates: AlendronateBisphosphonates: Alendronate & & most recently, most recently, risedronaterisedronate, are , are approved for treatment of osteoporosis approved for treatment of osteoporosis

RaloxifeneRaloxifene, SERM, without adverse , SERM, without adverse effects on breast or uterus, has been effects on breast or uterus, has been approved for approved for preventionprevention (not treatment) (not treatment) of osteoporosis Like estrogen, of osteoporosis Like estrogen, ↑↑bone bone density & density & ↓↓fractures in spine. However, fractures in spine. However, ↑↑risk of thrombophlebitis risk of thrombophlebitis

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PAGET'S DISEASE OF PAGET'S DISEASE OF BONE BONE

This is a This is a disease of of bone that initially that initially results in the in the excessive resorption of bone of bone (by (by osteoclasts) followed by the ) followed by the replacement of of normal bone marrow with with vascular and and fibrous tissue. .

Many Many patients are are asymptomatic and and diagnosed by routine diagnosed by routine X-rays. .

The The goal of treatmentgoal of treatment: : ↓↓ bone pain & bone pain & prevent progressive deformity, hearing prevent progressive deformity, hearing loss, high-output cardiac failure, & loss, high-output cardiac failure, & immobilization hypercalcemiaimmobilization hypercalcemia

Calcitonin & bisphosphonatesCalcitonin & bisphosphonates are DOC are DOC Treatment failures may respond to Treatment failures may respond to

plicamycin (highly toxic)plicamycin (highly toxic) 37

Paget’s disease of bonePaget’s disease of bone38

Calcitonin is administered intranasally, SC or Calcitonin is administered intranasally, SC or IMIM

Sodium etidronate, alendronate, risedronate, Sodium etidronate, alendronate, risedronate, & tiludronate are & tiludronate are bisphosphonatebisphosphonates s currently approved for this condition in the currently approved for this condition in the USA USA

Pamidronate is used in other countries Pamidronate is used in other countries Etidronate, but not pamidronate & Etidronate, but not pamidronate &

alendronate can cause osteomalacia & alendronate can cause osteomalacia & ↑↑incidence of fractures incidence of fractures

Alendronate & newer bisphosphonates cause Alendronate & newer bisphosphonates cause gastric irritation when used at high dosesgastric irritation when used at high doses

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