TREATMENT OF TREATMENT OF

OSTEOPOROSISOSTEOPOROSIS Prof. Riad AgbariaProf. Riad Agbaria

Physiology of Physiology of CalciumCalcium

Calcium is essential:Calcium is essential:

In intracellular fluidIn intracellular fluid– micromolecular and macroscopic biological functions.micromolecular and macroscopic biological functions.– Ca2+, is an important of current flow across excitable Ca2+, is an important of current flow across excitable

membranes.membranes.– Ca2+ is vital for muscle contractionCa2+ is vital for muscle contraction– Ca2+ is vital for fusion, and release of storage vesicles.Ca2+ is vital for fusion, and release of storage vesicles.– intracellular Ca2+ acts as a critical second messenger intracellular Ca2+ acts as a critical second messenger

In extracellular fluid,In extracellular fluid,– promote blood coagulationpromote blood coagulation– support the formation and continuous remodeling of the support the formation and continuous remodeling of the

skeletonskeleton..– Cross-linking of structural proteins in bone matrix.Cross-linking of structural proteins in bone matrix.

Body content of calciumBody content of calcium

In adult men ~1300g and In adult men ~1300g and 1000g in women, 1000g in women,

99% is in bone and teeth99% is in bone and teeth. .

Normal serum calcium Normal serum calcium con. con. 8.5-10.4 mg/dL8.5-10.4 mg/dL– ionized (50%),ionized (50%),– protein-bound (40%)protein-bound (40%) (Albumin accounts for some 90%) (Albumin accounts for some 90%)

– complexed (10%). complexed (10%).

Calcium StoresCalcium Stores

The The skeleton contains 99%skeleton contains 99% of total body calcium in a of total body calcium in a crystalline form resembling the mineral hydroxyapatite crystalline form resembling the mineral hydroxyapatite [Ca10(PO4)6(OH)2]; [Ca10(PO4)6(OH)2]; other ions, including Na+, K+, Mg2+, and F-, also are other ions, including Na+, K+, Mg2+, and F-, also are present in the crystal lattice.present in the crystal lattice.The steady-state content of calcium in bone reflects the The steady-state content of calcium in bone reflects the net effect of net effect of bone resorption and bone formationbone resorption and bone formationA labile pool of bone Ca2+ exchanges readily with A labile pool of bone Ca2+ exchanges readily with interstitial fluid. This exchange is modulated by interstitial fluid. This exchange is modulated by hormones, vitamins, drugs, and other factorshormones, vitamins, drugs, and other factors that directly that directly alter bone turnover or that influence the Ca2+ level in alter bone turnover or that influence the Ca2+ level in interstitial fluid.interstitial fluid.

Calcium Absorption and ExcretionCalcium Absorption and Excretion

~75% of calcium is from milk and ~75% of calcium is from milk and dairy productsdairy products. . The adequate intake is 1300 The adequate intake is 1300 mg/day in adolescents and 1000 mg/day in adolescents and 1000 mg/day in adults. mg/day in adults. After age 50, the adequate intake After age 50, the adequate intake is 1200 mg/day.is 1200 mg/day.

Ca2+ enters the body only Ca2+ enters the body only through the intestinethrough the intestine. . Active vitamin D–dependentActive vitamin D–dependent transport occurs in the proximal transport occurs in the proximal duodenum,duodenum,

Active vitamin D–dependentActive vitamin D–dependent

Efficiency Of Intestinal Ca2+ AbsorptionEfficiency Of Intestinal Ca2+ Absorption

a diet a diet lowlow in calcium leads to a compensatory in calcium leads to a compensatory increase in fractional absorption owing partly to increase in fractional absorption owing partly to activation of activation of vitamin Dvitamin D. .

Disease associated with Disease associated with diarrhea, BIDdiarrhea, BID or chronic or chronic malabsorption promote fecal loss of calcium, malabsorption promote fecal loss of calcium,

drugs such as drugs such as glucocorticoids and phenytoin glucocorticoids and phenytoin depress intestinal Ca2+ transportdepress intestinal Ca2+ transport..

Urinary CaUrinary Ca2+2+ excretion excretion

About About 9 g9 g of Ca2+ are filtered each day. of Ca2+ are filtered each day.

Tubular reabsorption Tubular reabsorption >98%>98%

Reabsorption is regulated by parathyroid Reabsorption is regulated by parathyroid hormone hormone (PTH) (PTH)

loop of Henle Diuretics (e.g., loop of Henle Diuretics (e.g., furosemidefurosemide) ) increaseincrease calcium excretion. calcium excretion.

By contrast, By contrast, thiazidethiazide diuretics diuretics diminishingdiminishing calcium excretion calcium excretion

PhosphatePhosphateEssential Essential component of all bodycomponent of all body tissues, tissues, present in plasma, extracellular fluid, cell present in plasma, extracellular fluid, cell membrane membrane phospholipidsphospholipids, intracellular fluid, , intracellular fluid, collagen, collagen, and bone tissueand bone tissue..> > 80%80% of body phosphorus is in of body phosphorus is in bonebone, and , and ~15% is in soft tissue~15% is in soft tissuephosphate roles:phosphate roles:– energy metabolismenergy metabolism– key regulator of key regulator of enzyme activityenzyme activity when transferred by when transferred by

protein kinases from ATP to phosphorylatable serine, protein kinases from ATP to phosphorylatable serine, threonine, and tyrosine residues.threonine, and tyrosine residues.

Hormonal Regulation Of Calcium And Phosphate Hormonal Regulation Of Calcium And Phosphate HomeostasisHomeostasis

parathyroid hormone parathyroid hormone (PTH)(PTH)

1,25-dihydroxy 1,25-dihydroxy vitamin Dvitamin D (calcitriol),:(calcitriol),:

which regulate mineral which regulate mineral homeostasis by effects on:homeostasis by effects on:– KidneyKidney– IntestineIntestine– bonebone

Hormonal Interactions Controlling Bone Mineral Hormonal Interactions Controlling Bone Mineral HomeostasisHomeostasis

FGF23 is a recently discovered hormone that stimulates renal phosphate excretion and inhibits renal production of 1,25(OH (2D

Mechanisms of Bone Mineral HomeostasisMechanisms of Bone Mineral Homeostasis

1,25(OH)2D3 (D), Parathyroid hormone (PTH), Calcitonin (CT). Fibroblast Growth Factor 23 (FGF23)

MCSF, macrophage colony-stimulating factor; OPG, osteoprotegerin; RANKL, ligand for receptor for activation of nuclear factor-  B

Osteoclasts functionOsteoclasts functionOsteoclasts move to areas of microfracture in the bone by chemotaxis. Osteoclasts move to areas of microfracture in the bone by chemotaxis. Osteoclasts lie in a small cavity called Howship's lacunae, Osteoclasts lie in a small cavity called Howship's lacunae, Attachment to the bone matrix is facilitated by integrin receptorsAttachment to the bone matrix is facilitated by integrin receptorsThe osteoclast releases hydrogen ions through the action of carbonic The osteoclast releases hydrogen ions through the action of carbonic anhydrase (H2O + CO2 → HCO3- + H+) through the ruffled border into anhydrase (H2O + CO2 → HCO3- + H+) through the ruffled border into the resorptive cavity, acidifying and aiding dissolution of the mineralized the resorptive cavity, acidifying and aiding dissolution of the mineralized bone matrix into Ca2+, H3PO4, H2CO3, water and other substances. bone matrix into Ca2+, H3PO4, H2CO3, water and other substances. Hydrogen ions are pumped against a high concentration gradient by Hydrogen ions are pumped against a high concentration gradient by proton pump vacuolar-ATPase. This enzyme has been targeted in the proton pump vacuolar-ATPase. This enzyme has been targeted in the prevention of osteoporosis. prevention of osteoporosis. In addition, several hydrolytic enzymes, such as members of the In addition, several hydrolytic enzymes, such as members of the cathepsincathepsin and and matrix metalloprotease(MMP)matrix metalloprotease(MMP) groups , are released to groups , are released to digest the organic components of the matrix. These enzymes are digest the organic components of the matrix. These enzymes are released into the compartment by lysosomes. Of these hydrolytic released into the compartment by lysosomes. Of these hydrolytic enzymes, enzymes, cathepsin Kcathepsin K is of most importance. is of most importance.

Parathyroid Hormone (PTH)Parathyroid Hormone (PTH)

PTH regulate plasma Ca2+ by affecting:PTH regulate plasma Ca2+ by affecting:– Bone resorption/formationBone resorption/formation– Renal Ca2+ excretion/reabsorptionRenal Ca2+ excretion/reabsorption– Calcitriol synthesis (thus GI Ca2+ absorption).Calcitriol synthesis (thus GI Ca2+ absorption).

PTH PTH CHEMISTRYCHEMISTRY

PTH - PTH - single polypeptidesingle polypeptide chains of 84 chains of 84 amino acids with molecular masses of amino acids with molecular masses of ~9500 Da.~9500 Da.

Biological activity is associated binding to Biological activity is associated binding to the the PTH receptorPTH receptor..

signaling pathways: signaling pathways: CAMP or IP3–Ca2+.CAMP or IP3–Ca2+.

PTH Physiological FunctionsPTH Physiological Functions

PTH affects a variety of tissues: PTH affects a variety of tissues: – vascular smooth muscle, placenta, liver, vascular smooth muscle, placenta, liver,

pancreatic islets, brain, dermal fibroblasts, pancreatic islets, brain, dermal fibroblasts, and lymphocytes. BY and lymphocytes. BY TWO RECEPTORS: TWO RECEPTORS: PTH1 & PTH2PTH1 & PTH2

PTH Regulation of SecretionPTH Regulation of Secretion

At LOWAt LOW Ca2+ PTH secretion Ca2+ PTH secretion increasesincreases. . hypocalcemiahypocalcemia induces parathyroid induces parathyroid hypertrophyhypertrophy and and hyperplasia. hyperplasia. Ca2+Ca2+ itself appears to regulate itself appears to regulate parathyroid gland growthparathyroid gland growth as well as hormone synthesis and secretion.as well as hormone synthesis and secretion.

Adrenergic Adrenergic receptor agonists and dopamine receptor agonists and dopamine increaseincrease parathyroid cell cyclic AMP levels, and increase PTH parathyroid cell cyclic AMP levels, and increase PTH secretion, secretion, Active Active vitamin Dvitamin D metabolite, 1,25-dihydroxyvitamin D metabolite, 1,25-dihydroxyvitamin D (calcitriol), directly (calcitriol), directly suppressessuppresses PTH gene expression. PTH gene expression.

PTH Effects on BonePTH Effects on Bone

PTH enhances bone PTH enhances bone resorptionresorption and thereby and thereby increases Ca2+ delivery to the extracellular fluid,increases Ca2+ delivery to the extracellular fluid,The primary skeletal target cell for PTH is the The primary skeletal target cell for PTH is the osteoblastosteoblast, , PTH also recruits PTH also recruits osteoclastosteoclast precursor cells to precursor cells to form new bone remodeling units. form new bone remodeling units. PTH PTH in vivoin vivo reflects not only hormone action on reflects not only hormone action on individual cells but also the increased total individual cells but also the increased total number of active osteoblasts, owing to initiation number of active osteoblasts, owing to initiation of new remodeling units. of new remodeling units.

Vitamin DVitamin D

Vitamin D Vitamin D permit efficient absorption of dietary permit efficient absorption of dietary calciumcalcium and to allow full expression of the and to allow full expression of the actions of PTH. actions of PTH. Vitamin D is actually a Vitamin D is actually a hormonehormone rather than a rather than a vitamin;vitamin;synthesized in synthesized in mammals andmammals and, under ideal , under ideal conditions, probably is not required in the diet. conditions, probably is not required in the diet. Receptors for the activated form of vitamin D are Receptors for the activated form of vitamin D are expressed in many cells: expressed in many cells: lymphocyteslymphocytes, , epidermal cells, epidermal cells, hair follicleshair follicles, , adipose tissueadipose tissue, , pancreatic islets, muscle, and neurons.pancreatic islets, muscle, and neurons.

Calcitriol SynthesisCalcitriol Synthesis

The final step in the activation of The final step in the activation of vitamin D to calcitriolvitamin D to calcitriol occurs in occurs in kidney proximal tubule cells. kidney proximal tubule cells.

Pi, PTH, and Ca2+:Pi, PTH, and Ca2+: govern the enzymatic activity of the 25- govern the enzymatic activity of the 25-hydroxyvitamin D3-1-hydroxylase that catalyzes this stephydroxyvitamin D3-1-hydroxylase that catalyzes this stepReducedReduced circulating or tissue circulating or tissue phosphatephosphate content rapidly content rapidly increases increases calcitriol productioncalcitriol production, whereas , whereas hyperphosphatemiahyperphosphatemia or or hypercalcemiahypercalcemia suppresses it. suppresses it. PTHPTH powerfully stimulates powerfully stimulates calcitriol synthesiscalcitriol synthesis. . Thus, when hypocalcemia causes a rise in PTH concentration, both Thus, when hypocalcemia causes a rise in PTH concentration, both the PTH-dependent lowering of circulating Pi and a more direct the PTH-dependent lowering of circulating Pi and a more direct effect of the hormone on the 1-hydroxylase lead to increased effect of the hormone on the 1-hydroxylase lead to increased circulating concentrations of calcitriol.circulating concentrations of calcitriol.

OsteoporosisOsteoporosis

Disease of the skeleton markedDisease of the skeleton markedlow bone mass and microarchitectural degeneration of low bone mass and microarchitectural degeneration of bone tissue, bone tissue, Over Over 2 million2 million osteoporosis-related fractures occur in the osteoporosis-related fractures occur in the United States annually, with an estimated cost of $17 United States annually, with an estimated cost of $17 billion billion The prevalence of osteoporosismay be on the The prevalence of osteoporosismay be on the riserise, in , in part, due to a decrease in the overall routine utilization of part, due to a decrease in the overall routine utilization of hormone replacement therapy hormone replacement therapy (HRT)(HRT) for most for most postmenopausalpostmenopausal women. women. Also, while osteoporosis is less prevalent in men than Also, while osteoporosis is less prevalent in men than women, men account for almost 30% of low bone mass women, men account for almost 30% of low bone mass related (fragility) fracturesrelated (fragility) fractures

Common Risk Factors for OsteoporosisCommon Risk Factors for Osteoporosis

Estrogen deficiency (a result of menopause) Estrogen deficiency (a result of menopause) Amenorrhea (absence of menstrual periods) Amenorrhea (absence of menstrual periods) Advanced age Advanced age Family history of osteoporosis Family history of osteoporosis History of prior fracture (after age 50) History of prior fracture (after age 50) Alcoholism Alcoholism Calcium and/or vitamin D deficiency Calcium and/or vitamin D deficiency Cushing syndrome Cushing syndrome Hypogonadism (low testosterone in men) Hypogonadism (low testosterone in men) Anorexia/eating disorders Anorexia/eating disorders Inflammatory bowel disease (IBD) Inflammatory bowel disease (IBD) Hyperparathyroidism Hyperparathyroidism Hyperthyroidism Hyperthyroidism Rheumatoid arthritis (RA) Rheumatoid arthritis (RA)

11 - -VITAMIN DVITAMIN D

Vitamin DVitamin DGlobulinGlobulin binds V-D, 25(OH)D and 24,25(OH)2D binds V-D, 25(OH)D and 24,25(OH)2D

T1/2 of calcifediol = 23 days,in anephric subjects= T1/2 of calcifediol = 23 days,in anephric subjects= 42 days.42 days.

Liver is principal organ for clearance. Liver is principal organ for clearance.

Excess vitamin D is Excess vitamin D is stored in adipose tissuestored in adipose tissue. .

Calcitriol T1/2= hours. Calcitriol T1/2= hours.

1,25(OH)2D analogs are 1,25(OH)2D analogs are bound poorlybound poorly by the by the vitamin D-binding protein. So vitamin D-binding protein. So clearance is very clearance is very rapidrapid, , T1/2= minutesT1/2= minutes. .

Calcitriol; 1,25(OH)2DCalcitriol; 1,25(OH)2D

Calcitriol; 1,25(OH)2D The Calcitriol; 1,25(OH)2D The most potentmost potent agent stimulates: agent stimulates:– intestinal calcium and phosphate transportintestinal calcium and phosphate transport– in intestine induce: synthesis of calcium-binding protein and in intestine induce: synthesis of calcium-binding protein and

TRPV6, an intestinal calcium channel … TRPV6, an intestinal calcium channel … – Like PTH, calcitriol can induce RANK ligand in osteoblasts and Like PTH, calcitriol can induce RANK ligand in osteoblasts and

proteins such as osteocalcin, which may regulate the proteins such as osteocalcin, which may regulate the mineralization process. mineralization process.

CalcitriolCalcitriol Act on the Specific receptors for 1,25(OH)2D Act on the Specific receptors for 1,25(OH)2D exist in target tissues. exist in target tissues.

25(OH)D25(OH)D appears to be appears to be more potent thanmore potent than 1,25(OH)2D in 1,25(OH)2D in stimulatingstimulating renal reabsorptionrenal reabsorption of calcium and phosphate of calcium and phosphate

Calcitriol; 1,25(OH)2DCalcitriol; 1,25(OH)2D

Calcitriol receptor found in and involves: Calcitriol receptor found in and involves: – PTHPTH secretion from parathyroid gland secretion from parathyroid gland– insulininsulin secretion from the pancreas secretion from the pancreas– cytokinecytokine production by production by macrophages and T cellsmacrophages and T cells– proliferationproliferation and differentiation of a large number of and differentiation of a large number of

cells, including cells, including cancercancer cells. cells. – Thus, the clinical utility of Thus, the clinical utility of 1,25(OH)2D1,25(OH)2D and its and its

analogsanalogs is likely to expand. is likely to expand.

Secondary Hormonal RegulatorsSecondary Hormonal Regulators of Bone Mineral Homeostasis of Bone Mineral Homeostasis

CalcitoninCalcitonin: secreted by thyroid, T: secreted by thyroid, T1/21/2= 10 min,= 10 min, lower lower serum serum calcium and phosphatecalcium and phosphate by actions on by actions on bone and kidneybone and kidneyGlucocorticoidsGlucocorticoids alter bone mineral homeostasis by alter bone mineral homeostasis by antagonizing vitamin D-stimulatedantagonizing vitamin D-stimulated intestinal calcium intestinal calcium transport, by stimulating renal calcium excretion, and by transport, by stimulating renal calcium excretion, and by blocking bone formation.blocking bone formation.Estrogens,Estrogens, prevent accelerated prevent accelerated bone lossbone loss postmenopausal postmenopausal period by:period by:– reduce bone-resorbing action of PTH.reduce bone-resorbing action of PTH.– increased 1,25(OH)2D level in bloodincreased 1,25(OH)2D level in blood– May increased risk of breast cancer from continued May increased risk of breast cancer from continued

estrogen use estrogen use

TREATMENT OF TREATMENT OF OSTEOPOROSISOSTEOPOROSIS

1. Calcitriol and Analouges2. Bisphosphonates3. Calcimimetics: Cinacalcet4. Calcitonin5. Estrogen6. Calcium7. Parathyroid hormone

Drugs for osteoporosis

Hormonal Interactions Controlling Bone Mineral Hormonal Interactions Controlling Bone Mineral HomeostasisHomeostasis

FGF23 is a recently discovered hormone that stimulates renal phosphate excretion and inhibits renal production of 1,25(OH (2D

1- Calcitriol and Analouges1- Calcitriol and Analouges

Available for Available for oraloral administration or administration or injectioninjection..I.V highI.V high doses of doses of calcitriol or one of calcitriol or one of its derivatives. its derivatives. predominant used predominant used for patients with for patients with chronic kidney chronic kidney diseasedisease and and end-end-stage kidney stage kidney disease.disease.

Therapeutic Indications for Vitamin DTherapeutic Indications for Vitamin D

The major therapeutic uses of vitamin D The major therapeutic uses of vitamin D may be divided into four categories:may be divided into four categories:

– ProphylaxisProphylaxis and cure of nutritional and cure of nutritional ricketsrickets (softening of bones in children)(softening of bones in children)

– treatment of treatment of metabolic ricketsmetabolic rickets and and osteomalacia, particularly in the setting of osteomalacia, particularly in the setting of chronic renal failurechronic renal failure

– prevention and treatment of prevention and treatment of osteoporosisosteoporosis

Adverse Effects of Vitamin D TherapyAdverse Effects of Vitamin D Therapy

HypercalcemiaHypercalcemia, with or without , with or without hyperphosphatemia, may limit its use at hyperphosphatemia, may limit its use at doses that effectively suppress PTH doses that effectively suppress PTH secretion.secretion.Hypervitaminosis D is treated by:Hypervitaminosis D is treated by:– immediate withdrawal of the vitaminimmediate withdrawal of the vitamin– low-calcium dietlow-calcium diet– administration of glucocorticoidsadministration of glucocorticoids– loop diuretics is also useful. loop diuretics is also useful.

1. Calcitriol and Analouges

2. Bisphosphonates

3. Calcimimetics: Cinacalcet

4. Calcitonin

5. Estrogen

6. Calcium

Drugs for osteoporosis

22 - -Bisphosphonates MABisphosphonates MA

concentrate at sites of active remodelingconcentrate at sites of active remodeling

Incorporated into the Incorporated into the bone matrixbone matrix

Remain in the matrix until the bone is Remain in the matrix until the bone is remodeledremodeled and then are and then are releasedreleased in the in the acid environment of the resorption lacunae acid environment of the resorption lacunae beneath thebeneath the osteoclast osteoclast as the overlying as the overlying mineral matrix is dissolved.mineral matrix is dissolved.

Induce osteoclast apoptosisInduce osteoclast apoptosis

Bisphosphonates other Cellular EffectsBisphosphonates other Cellular Effects

inhibition of 1,25(OH)2D productioninhibition of 1,25(OH)2D production

inhibition of intestinal calcium transportinhibition of intestinal calcium transport

metabolic changes in bone cells such as metabolic changes in bone cells such as inhibition of glycolysisinhibition of glycolysis

inhibition of cell growthinhibition of cell growth

Changes in acid and alkaline phosphatase.Changes in acid and alkaline phosphatase.

22 - -BisphosphonatesBisphosphonates

First-generation (MCET)First-generation (MCET)::– Medronate; clodronate; etidronate Medronate; clodronate; etidronate

and tiludronate. and tiludronate. Second-generation (AP)Second-generation (AP) aminobisphosphonates:aminobisphosphonates:– Alendronate and pamidronate, Alendronate and pamidronate,

contain a contain a nitrogennitrogen groupgroup in the side in the side chain. chain.

– 10-100 times10-100 times more potentmore potent than first- than first-generation compounds.generation compounds.

Third-generation (RZ)Third-generation (RZ):: risedronate and zoledronate) contain risedronate and zoledronate) contain

a a nitrogen atomnitrogen atom within a heterocyclic within a heterocyclic ring and are up to ring and are up to 10,000 times10,000 times more more potent than first-generation agents.potent than first-generation agents.

BisphosphonatesBisphosphonates Absorption, Fate, and Excretion Absorption, Fate, and Excretion

All oralAll oral, very poorly absorbed from the intestine, , very poorly absorbed from the intestine, low low bioavailabilitybioavailability (<1% [alendronate, risedronate] to 6% (<1% [alendronate, risedronate] to 6% [etidronate, tiludronate]).[etidronate, tiludronate]).FoodFood reduces absorption: Should be administered with reduces absorption: Should be administered with a a full glassfull glass of water following an overnight of water following an overnight FASTFAST and and at least 30 minutes before breakfast.at least 30 minutes before breakfast.Oral bisphosphonates Oral bisphosphonates HAVE NOT BEEN used widely used widely in in CHILDRENCHILDREN or adolescents because of uncertainty or adolescents because of uncertainty of long-term effects of bisphosphonates on the of long-term effects of bisphosphonates on the growing skeletongrowing skeleton..Excreted by kidneys.Excreted by kidneys.

Pamidronate is not available as an oral preparation because it causes gastric irritationHowever, with the possible exception of etidronate, all currently available bisphosphonates have this complication.~50% of absorbed drug accumulates in bone; rest excreted unchanged in the urine. Contraindications: esophageal motility disorders, peptic ulcer renal failer diseaseThe portion bound to bone is retained for months, depending on the turnover of bone itself.

BisphosphonatesBisphosphonates Absorption, Fate, and Excretion Absorption, Fate, and Excretion

Bisphosphonates Adverse EffectsBisphosphonates Adverse Effects

Very safeVery safeAt At higher doseshigher doses: gastric (etidronate) and : gastric (etidronate) and esophageal (pamidronate& alendronate) esophageal (pamidronate& alendronate) irritationirritation Irritation Irritation minimizedminimized by taking the drug with by taking the drug with glass glass of waterof water and remaining and remaining upright for 30upright for 30 minutes. minutes. Rare, Rare, OSTEONECROSISOSTEONECROSIS of the jaw ( of the jaw (ONJONJ), ), 1/100,000 with 1/100,000 with I.VI.V doses of doses of zoledronate zoledronate are are used to control bone used to control bone metastases and cancer-metastases and cancer-inducedinduced hypercalcemia. hypercalcemia.

1. Calcitriol and Analouges

2. Bisphosphonates

3. Calcimimetics: Cinacalcet

4. Calcitonin

5. Estrogen

6. Calcium

Drugs for osteoporosis

33 - -Calcimimetics: Calcimimetics: CinacalcetCinacalcetCinacalcet: Cinacalcet: Cinacalcet blocks PTH secretionCinacalcet blocks PTH secretion

a a new classnew class of drugs that of drugs that activates the calcium activates the calcium sensing receptorsensing receptor (CaR). (CaR).

CaR is widely distributed but has its greatest CaR is widely distributed but has its greatest concentration in the parathyroid gland. concentration in the parathyroid gland.

Approved for the treatment ofApproved for the treatment of secondary secondary hyperparathyroidismhyperparathyroidism in chronic in chronic kidneykidney disease disease and for the treatment of and for the treatment of parathyroid carcinomaparathyroid carcinoma..

1. Calcitriol and Analouges2. Bisphosphonates3. Calcimimetics: Cinacalcet4. Calcitonin5. Estrogen6. Calcium7. Parathyroid hormone

Drugs for osteoporosis

44 - -CALCITONINCALCITONIN

Hormonal Interactions Controlling Bone Mineral Hormonal Interactions Controlling Bone Mineral HomeostasisHomeostasis

FGF23 is a recently discovered hormone that stimulates renal phosphate excretion and inhibits renal production of 1,25(OH (2D

44 - -CALCITONINCALCITONIN Calcitonin lowers plasma Ca2+ and phosphate concentrations in patients with hypercalcemia; by DECREASED BONE RESORPTION. Although calcitonin is effective for up to 6 hours in the initial treatment of hypercalcemia, LESS ACTIVE after a few days due to receptor downregulation.Development of antibodies with prolonged therapy.Salmon calcitonin is available as a NASAL SPRAY, introduced for once-daily treatment of postmenopausal osteoporosis. Side effects: Nausea, hand swelling, urticaria, rarely, intestinal cramping.

1. Calcitriol and Analouges2. Bisphosphonates3. Calcimimetics: Cinacalcet4. Calcitonin5. Estrogen6. Calcium7. Parathyroid hormone

Drugs for osteoporosis

5- Estrogen5- Estrogen

Helping to maintain a Helping to maintain a normal bonenormal bone resorption rate. resorption rate. SUPPRESSES THE PROLIFERATION SUPPRESSES THE PROLIFERATION AND DIFFERENTIATION OF AND DIFFERENTIATION OF OSTEOCLASTSOSTEOCLASTS Increases Increases osteoclast apoptosisosteoclast apoptosis..DecreasesDecreases the production of several the production of several cytokines that are cytokines that are potent stimulators of potent stimulators of osteoclastsosteoclasts (IL-1. IL-6, TNF) (IL-1. IL-6, TNF)Decreases the production of Decreases the production of RANKLRANKL and and increases the production of OPG; both of increases the production of OPG; both of which which reduce osteoclastogenesisreduce osteoclastogenesis. .

EstrogenEstrogenPostmenopausal or estrogen deficiency Postmenopausal or estrogen deficiency increases riskincreases risk for for osteoporosisosteoporosisEstrogen replacementEstrogen replacement effective in effective in conservation of bone and protection conservation of bone and protection against osteoporotic fracture after against osteoporotic fracture after menopausemenopause Side effects: increased risks of Side effects: increased risks of heart heart diseasedisease and and breast cancerbreast cancer were found in were found in chronic treatmentchronic treatment

RALOXIFINE (Evista)RALOXIFINE (Evista)

Selective estrogen receptor modulatorSelective estrogen receptor modulator

Decrease bone resorptionDecrease bone resorption

60mg 1Xday60mg 1Xday

Side effectsSide effects::– Hot flushesHot flushes– leg crampsleg cramps– Thrombolism (monitor INR)Thrombolism (monitor INR)

Contraindicatin:Contraindicatin:– Pregnancy/lactationPregnancy/lactation– Pulmonary embolism & DVTPulmonary embolism & DVT

1. Calcitriol and Analouges2. Bisphosphonates3. Calcimimetics: Cinacalcet4. Calcitonin5. Estrogen6. Calcium7. Parathyroid hormone

Drugs for osteoporosis

66 - -CalciumCalcium

There isThere is controversy controversy about the role of calcium during about the role of calcium during the early years after menopause, when the primary the early years after menopause, when the primary basis for bone loss is estrogen withdrawal. basis for bone loss is estrogen withdrawal.

Patients who are Patients who are unable or unwillingunable or unwilling to increase to increase calcium by dietary means alone may choose from calcium by dietary means alone may choose from many palatable, many palatable, low-cost calcium preparationslow-cost calcium preparations. . ORAL ORAL CALCIUM CARBONATECALCIUM CARBONATE, which , which should be should be taken withtaken with mealsmeals to facilitate dissolution and to facilitate dissolution and absorption. absorption. Traditional dosing of calcium Traditional dosing of calcium is ~1000 mg/dayis ~1000 mg/day, nearly , nearly the amount present in a quart of milk. Adults >50 years the amount present in a quart of milk. Adults >50 years of age need 1200 mg of calcium daily. of age need 1200 mg of calcium daily.

1. Calcitriol and Analouges2. Bisphosphonates3. Calcimimetics: Cinacalcet4. Calcitonin5. Estrogen6. Calcium7. Parathyroid hormone

Drugs for osteoporosis

77 - -Parathyroid hormone:Parathyroid hormone:TERIPATIDE (Forteo)TERIPATIDE (Forteo)

ACTS AS PARATHYROID HORMONE (PTH)ACTS AS PARATHYROID HORMONE (PTH)Increase bone formation by stimulation of Increase bone formation by stimulation of OsteoblastsOsteoblastsIncrease Increase renal reabsorptionrenal reabsorption of calcium of calcium20mg 1xday20mg 1xday

Side effectsSide effects::– Orthostatic hypotensionOrthostatic hypotension– HypercalcemiaHypercalcemia

ContraindicationContraindication::– HypercalcemiaHypercalcemia– HypersinsitivityHypersinsitivity

THE ENDTHE END