Agents that affect bone mineral homeostasis

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  • Osteopetrosis, literally "stone bone", also known as marble bone disease and Albers-Schonberg disease is an extremely rare inheriteddisorder (1 in every 200,000 birth) whereby the bones harden, becoming denser, in contrast to more prevalent conditions like osteoporosis, in which the bones become less dense and more brittle, or osteomalacia, in which the bones soften.
  • Ca homeostasis. Schematic illustration of Ca content of extracellular fluid (ECF) and bone as well as of diet and feces; magnitude of Ca flux per day as calculated by various methods is shown at sites of transport in intestine, kidney, and bone. Ranges of values shown are approximate and chosen to illustrate certain points discussed in text. In conditions of Ca balance, rates of Ca release from and uptake into bone are equal.
  • The hormonal interactions controlling bone mineral homeostasis. In the body (A), 1,25(OH)2D is produced by the kidney under the control of parathyroid hormone (PTH), which stimulates its production, and fibroblast growth factor 23 (FGF23), which inhibits its production. 1,25(OH)2D in turn inhibits the production of PTH by the parathyroid glands and stimulates FGF23 release from bone. 1,25(OH)2D is the principal regulator of intestinal Ca and phosphate absorption. At the level of the bone (B), both PTH and 1,25(OH)2D regulate bone formation and resorption, with each capable of stimulating both processes. This is accomplished by their stimulation of preosteoblast proliferation and differentiation into osteoblasts, the bone forming cell. PTH and 1,25(OH)2D stimulate the expression of RANKL by the osteoblast, which, with MCSF, stimulates the differentiation and subsequent activation of osteoclasts, the bone resorbing cell. FGF23 in excess leads to osteomalacia by inhibiting 1,25(OH)2D3 production and lowering phosphate levels. MCSF, macrophage colony-stimulating factor; OPG, osteoprotegerin; RANKL, ligand for receptor for activation of nuclear factor-B.
  • Vitamin D synthesis and activation. Vitamin D is synthesized in the skin in response to ultraviolet radiation and is also absorbed from the diet. It is then transported to the liver, where it undergoes 25-hydroxylation. This metabolite is the major circulating form of vitamin D. The final step in hormone activation, 1-hydroxylation, occurs in the kidney.
  • Conversion of 7-dehydrocholesterol to vitamin D3 and metabolism of D3 to 1,25(OH)2D3 and 24,25(OH)2D3. Control of the latter step is exerted primarily at the level of the kidney, where low serum phosphorus, low serum Ca, and high parathyroid hormone favor the production of 1,25(OH)2D3, whereas fibroblast growth factor 23 inhibits its production. The inset shows the side chain for ergosterol. Ergosterol undergoes similar transformation to vitamin D2 (ergocalciferol), which, in turn, is metabolized to 25(OH)D2, 1,25(OH)2D2, and 24,25(OH)2D2. In humans, corresponding D2 and D3 derivatives have equivalent effects and potency. They are therefore referred to in the text without a subscript.
  • Some mechanisms contributing to bone mineral homeostasis. Direct actions are shown and feedback may alter the net effect. Ca (Ca) and phosphorus (P) concentrations in the serum are controlled principally by three hormones, 1,25(OH)2D3 (D), fibroblast growth factor 23 (FGF23), and parathyroid hormone (PTH), through their action on absorption from the gut and from bone and on excretion in the urine. PTH and 1,25(OH)2D3 increase input of Ca and phosphorus from bone into the serum and stimulate bone formation. 1,25(OH)2D3 also increases Ca and phosphate absorption from the gut. 1,25(OH)2D3 decreases urinary excretion of both Ca and phosphorus, whereas PTH reduces Ca but increases phosphorus excretion. FGF23 stimulates renal excretion of phosphate. Calcitonin (CT) is a less critical hormone for Ca homeostasis, but in pharmacologic concentrations can reduce serum Ca and phosphorus by inhibiting bone resorption and stimulating their renal excretion. Feedback may alter the effects shown; for example, vitamin D usually increases urinary Ca excretion because of effects on Ca absorption from the gut and effects on PTH.
  • Schematic representation of the hormonal control loop for vitamin D metabolism and function. A reduction in the serum Ca below ~2.2 mmol/L (8.8 mg/dL) prompts a proportional increase in the secretion of parathyroid hormone (PTH) and so mobilizes additional Ca from the bone. PTH promotes the synthesis of 1,25(OH)2D in the kidney, which, in turn, stimulates the mobilization of Ca from bone and intestine and regulates the synthesis of PTH by negative feedback.
  • The hormonal interactions controlling bone mineral homeostasis. In the body (A), 1,25(OH)2D is produced by the kidney under the control of parathyroid hormone (PTH), which stimulates its production, and fibroblast growth factor 23 (FGF23), which inhibits its production. 1,25(OH)2D in turn inhibits the production of PTH by the parathyroid glands and stimulates FGF23 release from bone. 1,25(OH)2D is the principal regulator of intestinal Ca and phosphate absorption. At the level of the bone (B), both PTH and 1,25(OH)2D regulate bone formation and resorption, with each capable of stimulating both processes. This is accomplished by their stimulation of preosteoblast proliferation and differentiation into osteoblasts, the bone forming cell. PTH and 1,25(OH)2D stimulate the expression of RANKL by the osteoblast, which, with MCSF, stimulates the differentiation and subsequent activation of osteoclasts, the bone resorbing cell. FGF23 in excess leads to osteomalacia by inhibiting 1,25(OH)2D3 production and lowering phosphate levels. MCSF, macrophage colony-stimulating factor; OPG, osteoprotegerin; RANKL, ligand for receptor for activation of nuclear factor-B.
  • Vitamin D and Its Major Metabolites and Analogs
  • osteoporosis (abnormal loss of bone; remaining bone histologically normal)osteomalacia (abnormal bone formation due to inadequate mineralization)osteitis fibrosa (excessive bone resorption replaced with fibrotic tissue)
  • Epidemiology of vertebral, hip, and Colles' fractures with age.The term Colles fracture is classically used to describe a fracture at the distal end of the radius, at its cortico-cancellous junction. The classic Colles fracture has the following characteristics:[3]Transverse fracture of the radius1 inch (2.54 cm) proximal to the radio-carpal jointdorsaldisplacement and angulation
  • Typical changes in bone mineral density with time after the onset of menopause, with and without treatment. In the untreated condition, bone is lost during aging in both men and women. Fluoride, strontium (Sr2+), and parathyroid hormone (PTH) promote new bone formation and can increase bone mineral density in subjects who respond to it throughout the period of treatment, although PTH also activates bone resorption. In contrast, estrogen, calcitonin, and bisphosphonates block bone resorption. This leads to a transient increase in bone mineral density because bone formation is not initially decreased. However, with time, both bone formation and bone resorption are decreased with these pure antiresorptive agents, and bone mineral density reaches a new plateau.
  • Microcomputed tomography images of trabecular bone from the vertebrae of an osteoporotic individual (left) and a healthy age-matched normal woman (right).
  • The hormonal interactions controlling bone mineral homeostasis. In the body (A), 1,25(OH)2D is produced by the kidney under the control of parathyroid hormone (PTH), which stimulates its production, and fibroblast growth factor 23 (FGF23), which inhibits its production. 1,25(OH)2D in turn inhibits the production of PTH by the parathyroid glands and stimulates FGF23 release from bone. 1,25(OH)2D is the principal regulator of intestinal Ca and phosphate absorption. At the level of the bone (B), both PTH and 1,25(OH)2D regulate bone formation and resorption, with each capable of stimulating both processes. This is accomplished by their stimulation of preosteoblast proliferation and differentiation into osteoblasts, the bone forming cell. PTH and 1,25(OH)2D stimulate the expression of RANKL by the osteoblast, which, with MCSF, stimulates the differentiation and subsequent activation of osteoclasts, the bone resorbing cell. FGF23 in excess leads to osteomalacia by inhibiting 1,25(OH)2D3 production and lowering phosphate levels. MCSF, macrophage colony-stimulating factor; OPG, osteoprotegerin; RANKL, ligand for receptor for activation of nuclear factor-B.
  • Results of hormone therapy regimens on bone mineral density (BMD) of the spine (A) and hip (B). Unadjusted mean percent change in BMD in the hip by treatment assignment and visit: adherent PEPI participants only. Results from the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. Estrogen, conjugated equine estrogen 0.625 mg/d; progestin, medroxyprogesterone acetate 10 mg/d.
  • The structure of pyrophosphate and of the first three bisphosphonates—etidronate, pamidronate, and alendronate—that were approved for use in the USA.
  • Cumulative proportions of women with osteoporosis who suffered clinical fracture (vertebral, hip, or wrist) during 3 years of treatment with alendronate or placebo (FIT 1).
  • Ion transport pathways across the luminal and basolateral membranes of the distal convoluted tubule cell. As in all tubular cells, Na+/K+ ATPase is present in the basolateral membrane. NCC is the primary sodium and chloride transporter in the luminal membrane. (R, parathyroid hormone [PTH] receptor.)
  • Some mechanisms contributing to bone mineral homeostasis. Direct actions are shown and feedback may alter the net effect. Ca (Ca) and phosphorus (P) concentrations in the serum are controlled principally by three hormones, 1,25(OH)2D3 (D), fibroblast growth factor 23 (FGF23), and parathyroid hormone (PTH), through their action on absorption from the gut and from bone and on excretion in the urine. PTH and 1,25(OH)2D3 increase input of Ca and phosphorus from bone into the serum and stimulate bone formation. 1,25(OH)2D3 also increases Ca and phosphate absorption from the gut. 1,25(OH)2D3 decreases urinary excretion of both Ca and phosphorus, whereas PTH reduces Ca but increases phosphorus excretion. FGF23 stimulates renal excretion of phosphate. Calcitonin (CT) is a less critical hormone for Ca homeostasis, but in pharmacologic concentrations can reduce serum Ca and phosphorus by inhibiting bone resorption and stimulating their renal excretion. Feedback may alter the effects shown; for example, vitamin D usually increases urinary Ca excretion because of effects on Ca absorption from the gut and effects on PTH.
  • Hormonal control of bone resorption.A. Proresorptive and calcitropic factors; B. Anabolic and antiosteoclastic factors. RANKL expression is induced in osteoblasts, activated T cells, synovial fibroblasts, and bone marrow stromal cells. It binds to membrane-bound receptor RANK to promote osteoclast differentiation, activation, and survival. Conversely, osteoprotegerin (OPG) expression is induced by factors that block bone catabolism and promote anabolic effects. OPG binds and neutralizes RANKL, leading to a block in osteoclastogenesis and decreased survival of preexisting osteoclasts. RANKL, receptor activator of nuclear factor NFB; PTH, parathyroid hormone; PGE2, prostaglandin E2; TNF, tumor necrosis factor; LIF, leukemia inhibitory factor; TPO, thrombospondin; PDGF, platelet-derived growth factor; OPG-L, osteoprotegerin-ligand; IL, interleukin; TGF-β, transforming growth factor β
  • Hormonal control of bone resorption.A. Proresorptive and calcitropic factors; B. Anabolic and antiosteoclastic factors. RANKL expression is induced in osteoblasts, activated T cells, synovial fibroblasts, and bone marrow stromal cells. It binds to membrane-bound receptor RANK to promote osteoclast differentiation, activation, and survival. Conversely, osteoprotegerin (OPG) expression is induced by factors that block bone catabolism and promote anabolic effects. OPG binds and neutralizes RANKL, leading to a block in osteoclastogenesis and decreased survival of preexisting osteoclasts. RANKL, receptor activator of nuclear factor NFB; PTH, parathyroid hormone; PGE2, prostaglandin E2; TNF, tumor necrosis factor; LIF, leukemia inhibitory factor; TPO, thrombospondin; PDGF, platelet-derived growth factor; OPG-L, osteoprotegerin-ligand; IL, interleukin; TGF-β, transforming growth factor β
  • Agents that affect bone mineral homeostasis

    1. 1. Agents that AffectBone Mineral Homeostasis By M.H.Farjoo M.D. , Ph.D. Shahid Beheshti University of Medical Science
    2. 2. Agents that Affect Bone Mineral Homeostasis Introduction Regulator Hormones Parathyroid Hormone Vitamin D (metabolites) Fibroblast Growth Factor 23 Hormone Interactions Clinical Pharmacology  Osteoporosis  Hypercalcemia  Hypocalcemia  Pagets Disease Drug Pictures
    3. 3. Introduction Abnormalities in bone mineral homeostasis can lead to:  A wide variety of cellular dysfunctions:  Tetany  Coma  Muscle weakness  Disturbances in structural support of the body:  Osteoporosis with fractures  Loss of hematopoietic capacity (infantile osteopetrosis).
    4. 4. Introduction (Cont’d) To regulate Ca level, both Ca absorption (in the duodenum and upper jejunum) and secretion (in the ileum) occur. P absorption occurs in the jejunum, ranging from 70% to 90%, depending on intake. Intrinsic disease of the intestine (nontropical sprue) or kidney (CRF) disrupts bone mineral homeostasis. In the steady state, renal excretion of Ca and phosphate balances intestinal absorption.
    5. 5. Ca homeostasis. Schematic illustration of Ca content of extracellularfluid (ECF) and bone as well as of diet and feces; magnitude of Caflux per day as calculated by various methods is shown at sites oftransport in intestine, kidney, and bone. Ranges of values shown areapproximate and chosen to illustrate certain points discussed in text.In conditions of Ca balance, rates of Ca release from and uptake intobone are equal.
    6. 6. Regulator Hormones Primary (principal):  Parathyroid hormone (PTH)  Vitamin D (metabolites)  Fibroblast growth factor 23 (FGF23) Secondary: in pharmacologic doses are  Calcitonin useful therapeutically.  Glucocorticoids,  Sex steroids (estrogen)  Other less important: Prolactin, growth hormone, insulin, thyroid hormone
    7. 7. Regulator Hormones (Cont’d) All the principal regulators affect bone, kidney, and intestine and also each other activity or production. The net effect of PTH is to raise Ca and reduce phosphate. The net effect of vitamin D is to raise both. The net effect of FGF23 is to decrease phosphate.
    8. 8. Parathyroid Hormone PTH is the most important stimulator for renal production of the active metabolite of vitamin D, 1,25(OH)2D. PTH promote both bone formation and resorption by stimulating the osteoblasts and osteoclasts. PTH enhances renal retention of Ca and Mg. It promotes renal phosphate excretion and also that of amino acids, bicarbonate, Na, Cl, and sulfate.
    9. 9. The hormonal interactions controlling bone mineral homeostasis. In the body(A), 1,25(OH)2D is produced by the kidney under the control of parathyroidhormone (PTH), which stimulates its production, and fibroblast growth factor23 (FGF23), which inhibits its production. 1,25(OH)2D in turn inhibits theproduction of PTH by the parathyroid glands and stimulates FGF23 releasefrom bone. 1,25(OH)2D is the principal regulator of intestinal Ca andphosphate absorption. At the level of the bone (B), both PTH and 1,25(OH)2Dregulate bone formation and resorption, with each capable of stimulating bothprocesses. This is accomplished by their stimulation of preosteoblastproliferation and differentiation into osteoblasts, the bone forming cell. PTHand 1,25(OH)2D stimulate the expression of RANKL by the osteoblast, which,with MCSF, stimulates the differentiation and subsequent activation ofosteoclasts, the bone resorbing cell. FGF23 in excess leads to osteomalacia byinhibiting 1,25(OH)2D3 production and lowering phosphate levels. MCSF,macrophage colony-stimulating factor; OPG, osteoprotegerin; RANKL, ligandfor receptor for activation of nuclear factor-B.
    10. 10. Parathyroid Hormone (Cont’d) Ca is the principal regulator of PTH secretion. It binds to the Ca sensing receptor (CaR) and links changes in intracellular Ca to changes in extracellular Ca. Phosphate regulates PTH secretion directly and indirectly by forming complexes with Ca. P levels ↑ => ionized Ca ↓ => PTH ↑.
    11. 11. Parathyroid Hormone (Cont’d) The net effect of excess PTH is to increase bone resorption. However, PTH in low and intermittent doses increases bone formation. The biologic activity of PTH resides in the last 34 amino acids of amino terminal. This led to recombinant form of PTH 1-34 (teriparatide) for the treatment of osteoporosis.
    12. 12. Parathyroid Hormone (Cont’d) Teriparatide, unlike other drugs for osteoporosis, stimulates bone formation rather than inhibiting bone resorption. The drawback is that it must be given daily by SC injection. Its efficacy in preventing fractures is at least similar to that of bisphosphonates. In all cases, adequate intake of Ca and vitamin D needs to be maintained.
    13. 13. Vitamin D (metabolites) Vitamin D is produced in the skin from 7- dehydrocholesterol under the influence of UV radiation. Both the natural form (cholecalciferol) and the plant- derived form (ergocalciferol) are present in the diet. In humans, this difference is not important. Only vitamin D3 and 1,25(OH)2D (calcitriol) are available for clinical use. Both Ca and P at high levels reduce 1,25(OH)2D and increase of 24,25(OH)2D.
    14. 14. Vitamin D Vitamin D synthesis and activation. Vitamin D is synthesized in the skin in response to ultraviolet radiation and is also absorbed from the diet. It is thenVitamin D transported to the liver, where it undergoes 25-hydroxylation. This metabolite is the major circulating form of vitamin D. The final step in hormone activation, 1-hydroxylation, 25(OH)D occurs in the kidney. 1,25(OH)2D
    15. 15. Conversion of 7-dehydrocholesterol to vitamin D3 and metabolism ofD3 to 1,25(OH)2D3 and 24,25(OH)2D3. Control of the latter step isexerted primarily at the level of the kidney, where low serumphosphorus, low serum Ca, and high parathyroid hormone favor theproduction of 1,25(OH)2D3, whereas fibroblast growth factor 23inhibits its production. The inset shows the side chain for ergosterol.Ergosterol undergoes similar transformation to vitamin D2(ergocalciferol), which, in turn, is metabolized to25(OH)D2, 1,25(OH)2D2, and 24,25(OH)2D2. Inhumans, corresponding D2 and D3 derivatives have equivalent effectsand potency. They are therefore referred to in the text without asubscript.
    16. 16. Vitamin D and Its Major Metabolites and Analogs Chemical and Generic Names AbbreviationVitamin D3; cholecalciferol D3Vitamin D2; ergocalciferol D225-Hydroxyvitamin D3; calcifediol 25(OH)D31,25-Dihydroxyvitamin D3; calcitriol 1,25(OH)2D324,25-Dihydroxyvitamin D3; secalcifediol 24,25(OH)2D3Dihydrotachysterol DHTCalcipotriene (calcipotriol) None1-Hydroxyvitamin D2; doxercalciferol 1(OH)D219-nor-1,25-Dihydroxyvitamin D2; paricalcitol 19-nor-1,25(OH)D2
    17. 17. Vitamin D (metabolites) Cont’d 1,25(OH)2D stimulates the intestinal absorption of Ca and phosphate. It promotes both bone formation and resorption by stimulating the osteoblasts and osteoclasts. Calcitriol enhances renal retention of Ca. It regulates PTH, and insulin secretion, cytokine production, and differentiation of cancer cells. 25(OH)D is the major metabolite regulating Ca flux and contractility in muscle.
    18. 18. Vitamin D (metabolites) Cont’d 1,25(OH)2D directly inhibits PTH secretion. This is by a direct action on PTH gene transcription and independent of its effect on Ca. This ability is being exploited using calcitriol analogs that have less effect on Ca . The receptor for 1,25(OH)2D exists in a wide variety of "nonclassic" tissues. Thus, the clinical utility in nonclassic conditions for calcitriol and its analogs is expanding.
    19. 19. Vitamin D (metabolites) Cont’d Vitamin D and its metabolites circulate in plasma tightly bound to the vitamin D-binding protein. The half-life of calcifediol and 24,25(OH)2D is 23 days, that of calcitriol is measured in hours. 1,25(OH)2D analogs are bound poorly by the binding protein so have a half-life of minutes. Such analogs have little of the hypercalcemic, hypercalciuric effects of calcitriol. This is an important aspect of their use for psoriasis and hyperparathyroidism.
    20. 20. Vitamin D (metabolites) Cont’d They can be used for secondary and some cases of primary hyperparathyroidism. Doxercalciferol and paricalcitol are used for secondary hyperparathyroidism in patients with chronic kidney disease. Calcipotriene (calcipotriol), is being used for psoriasis. Other analogs are being investigated for various cancers.
    21. 21. Fibroblast Growth Factor 23 Fibroblast growth factor 23 (FGF23) is the most important inhibitor for renal production of 1,25(OH)2D. It stimulates P excretion in the kidney. This leads to hypophosphatemia and low levels of 1,25(OH)2D3. Osteoblasts and osteocytes in bone are its primary site of production.
    22. 22. Schematic representation of thehormonal control loop for vitamin Dmetabolism and function. A reduction inthe serum Ca below ~2.2 mmol/L (8.8mg/dL) prompts a proportional increasein the secretion of parathyroid hormone(PTH) and so mobilizes additional Cafrom the bone. PTH promotes thesynthesis of 1,25(OH)2D in thekidney, which, in turn, stimulates themobilization of Ca from bone andintestine and regulates the synthesis ofPTH by negative feedback.
    23. 23. The hormonal interactions controlling bone mineral homeostasis. In the body(A), 1,25(OH)2D is produced by the kidney under the control of parathyroidhormone (PTH), which stimulates its production, and fibroblast growth factor23 (FGF23), which inhibits its production. 1,25(OH)2D in turn inhibits theproduction of PTH by the parathyroid glands and stimulates FGF23 releasefrom bone. 1,25(OH)2D is the principal regulator of intestinal Ca andphosphate absorption. At the level of the bone (B), both PTH and 1,25(OH)2Dregulate bone formation and resorption, with each capable of stimulating bothprocesses. This is accomplished by their stimulation of preosteoblastproliferation and differentiation into osteoblasts, the bone forming cell. PTHand 1,25(OH)2D stimulate the expression of RANKL by the osteoblast, which,with MCSF, stimulates the differentiation and subsequent activation ofosteoclasts, the bone resorbing cell. FGF23 in excess leads to osteomalacia byinhibiting 1,25(OH)2D3 production and lowering phosphate levels. MCSF,macrophage colony-stimulating factor; OPG, osteoprotegerin; RANKL, ligandfor receptor for activation of nuclear factor-B.
    24. 24. Actions of PTH, Vitamin D, and FGF23 on Gut, Bone, and Kidney PTH Vitamin D FGF23 Increased Ca and PTH Increased Ca and Decreased Ca and Serum Ca increased, serum absorption by phosphate absorption (by phosphate absorption by phosphate Net effectIntestine increased 1,25[OH]2D phosphateD 1,25 (OH)2 decreased 1,25(OH)2 decreased production production) Decreased Ca excretion, Ca and phosphate Increased phosphate increased phosphate excretion may be excretionKidney excretion decreased FGF23 and by 25(OH)D 1,25(OH)2D1 Net effect Serum phosphate decreased mineralization Ca and phosphate Increased Ca and Decreased resorption increased by phosphate resorption by due to hypophosphatemia high doses. Low doses 1,25(OH)2D; boneBone may increase bone formation may be formation. increased by 1,25(OH)2D and 24,25(OH)2D Vitamin D Serum Ca increased, Serum Ca and phosphate Decreased serum Serum Ca and phosphateNet serum Net effect phosphate both increased phosphateeffect decreased both increased1Direct effect. Vitamin D often increases urine Ca owing to increased Ca absorption from the intestine and resulting decreased PTH.
    25. 25. Clinical Pharmacology Bone and kidney play central roles in bone mineral homeostasis. This alteration in this homeostasis will affect one or both of these tissues. Effects on bone results in: osteoporosis, osteomalacia, or osteitis fibrosa . Patients generally have abnormality in serum or urine Ca (or both) and often have abnormal serum P levels. This may cause emergency conditions eg: coma in malignant hypercalcemia and tetany in hypocalcemia.
    26. 26. Clinical Pharmacology (Cont’d) Biochemical markers of skeletal involvement include:  Changes in serum levels of the skeletal isoenzyme of alkaline phosphatase and osteocalcin (reflecting osteoblastic activity).  Urine levels of hydroxyproline and pyridinoline cross-links (reflecting osteoclastic activity).
    27. 27. Clinical Pharmacology (Cont’d) The kidney becomes involved when:  The Ca x P product in serum exceeds the point at which ectopic calcification occurs (nephrocalcinosis).  The Ca x oxalate (or phosphate) product in urine exceeds saturation (nephrolithiasis). Kidney can affect bone by alterations in Ca and P, 1,25(OH)2D, and secondary hyperparathyroidism.
    28. 28. Osteoporosis Osteoporosis is a very common and preventable disease of the bone with 2 kinds of treatment: Hormonal treatment:  Calcitonin  Glucocorticoids  Estrogen Non-hormonal treatments:  Bisphosphonates  Plicamycin  Thiazides  Fluoride  Strontium
    29. 29. vertebral, hip, and Colles fractures with age
    30. 30. Typical changes in bone mineral density with time after the onset ofmenopause, with and without treatment. In the untreatedcondition, bone is lost during aging in both men and women.Fluoride, strontium (Sr2+), and parathyroid hormone (PTH) promotenew bone formation and can increase bone mineral density in subjectswho respond to it throughout the period of treatment, although PTHalso activates bone resorption. In contrast, estrogen, calcitonin, andbisphosphonates block bone resorption. This leads to a transientincrease in bone mineral density because bone formation is notinitially decreased. However, with time, both bone formation andbone resorption are decreased with these pure antiresorptiveagents, and bone mineral density reaches a new plateau.
    31. 31. Microcomputed tomography images of trabecular bone from thevertebrae of an osteoporotic individual (right) and a healthy age-matchednormal woman (left).
    32. 32. Calcitonin Human calcitonin has a half-life of 10 minutes. Salmon calcitonin (as nasal spray) half-life is 43 min, making it more useful as a therapeutic agent. It lowers Ca and P and inhibits osteoclastic bone resorption. At first bone formation is not impaired, but with time both formation and resorption of bone are reduced.
    33. 33. Calcitonin (Cont’d) Calcitonin in pharmacologic amounts decreases gastrin secretion and reduces gastric acid. Pentagastrin and hypercalcemia are potent stimulators of calcitonin. No major problem develops in cases of calcitonin deficiency (thyroidectomy) or excess (medullary carcinoma of the thyroid). Its ability to block bone resorption and lower Ca is used in Pagets disease, osteoporosis and hypercalcemia.
    34. 34. Glucocorticoids Glucocorticoids antagonize vitamin D-stimulated intestinal Ca transport. Glucocorticoids do that by stimulating renal Ca excretion, and by blocking bone formation. They are used in reversing the hypercalcemia associated with lymphomas, sarcoidosis, or in vitamin D intoxication. Their prolonged administration causes osteoporosis in adults and stunted skeletal growth in children.
    35. 35. Estrogens Estrogens can prevent accelerated bone loss during the immediate postmenopausal period. Estrogens increase 1,25(OH)2D in blood. Estrogen receptors have been found in bone, and estrogen has direct effects on bone remodeling. Long-term use of estrogen has some adverse effects. Selective estrogen receptor modulators (SERMs) retain the beneficial effects while minimizing the adverse effects.
    36. 36. Results of hormone therapy regimens on bone mineral density (BMD)of the spine and hip.
    37. 37. Estrogens (Cont’d) Raloxifene is the first serms used for the prevention of osteoporosis. It doses not increase the risk of breast or endometrial cancer. It may actually reduce the risk of breast cancer. Although not as effective as estrogen, raloxifene reduces vertebral fractures.
    38. 38. Bisphosphonates Bisphosphonates are analogs of pyrophosphate and consist of : etidronate, pamidronate, alendronate, and risedronate. They increase bone density and reduce fractures over at least 5 years. They retard formation and dissolution of hydroxyapatite crystals within and outside the skeletal system. Trials between alendronate and calcitonin indicated a greater efficacy of alendronate. They localize to regions of bone resorption and so exert their greatest effects on osteoclasts.
    39. 39. The structure of pyrophosphate and of the firstthree bisphosphonates—etidronate, pamidronate,and alendronate—that were approved for use in theUSA.
    40. 40. Bisphosphonates (Cont’d) The exact mechanism by which they selectively inhibit bone resorption is not clear. Food reduces the absorption of these drugs, so should be administered on an empty stomach. Gastric irritation, is the complication of all bisphosphonates. Contraindications are: decreased renal function, esophageal motility disorders, and peptic ulcer. They are useful for the treatment of pagets disease, hypercalcemia of malignancy, and osteoporosis.
    41. 41. Bisphosphonates (Cont’d) Farnesyl pyrophosphate synthase is an enzyme in the mevalonate pathway which is critical for osteoclasts. Amino bisphosphonates such as alendronate and risedronate block this enzyme. Statins, which block mevalonate synthesis, stimulate bone formation at least in animal studies. Thus the mevalonate pathway is important in bone function. This pathway may provides new targets for drug development.
    42. 42. Plicamycin Plicamycin is a cytotoxic antibiotic used for Pagets disease and hypercalcemia. Its mechanism of action is unclear. It may relate to the need for protein synthesis to sustain bone resorption. The doses required to treat these diseases are one tenth that of cytotoxic effects.
    43. 43. Thiazides The principal application of thiazides is in reducing renal Ca excretion. In the distal tubule, thiazides block sodium reabsorption, increasing the Ca-sodium exchange. Thus enhancing Ca reabsorption into the blood. Thiazides are useful in reducing the hypercalciuria and incidence of stone formation in idiopathic hypercalciuria. They ↓ urine oxalate excretion and ↑ urine Mg2+ and Zn levels, both of which inhibit Ca oxalate stone formation.
    44. 44. Fluoride Fluoride prevents dental caries, so why not osteoporosis? Drinking fluoridated water (1–2 ppm) decreases vertebral compression fractures. Fluoride stabilizes the hydroxyapatite crystal. This explains decrease of dental caries, but does not explain new bone growth.
    45. 45. Fluoride (Cont’d) Fluoride in water is most effective for dental caries if consumed before the eruption of the permanent teeth. Topical application is most effective if done just as the teeth erupt. There is little further benefit to give fluoride after the permanent teeth are fully formed. However, studies of the ability of fluoride to reduce fractures reach opposite conclusions. At present, fluoride is not approved by the FDA for use in osteoporosis.
    46. 46. Strontium Ranelate Strontium ranelate (in Iran chloride) is used in Europe for the treatment of osteoporosis. It blocks osteoclast differentiation while promoting their apoptosis and thus inhibiting bone resorption. At the same time, it promotes bone formation. Unlike bisphosphonates or teriparatide, the drug increases bone formation markers while inhibiting bone resorption markers. Its efficacy is demonstrated in increasing bone mineral density and decreasing fractures in the spine and hip.
    47. 47. Hypercalcemia Bisphosphonates  Pamidronate, is used for the hypercalcemia of malignancy. Calcitonin  Calcitonin is an ancillary treatment. Gallium Nitrate (in Iran Citrate)  Is used for hypercalcemia of malignancy.  This drug acts by inhibiting bone resorption.  It is superior to calcitonin in reducing Ca in cancer.
    48. 48. Hypercalcemia (Cont’d) Phosphate  IV phosphate is the fastest and surest way to reduce serum Ca.  It is a hazardous procedure if not done properly.  IV phosphate should be used only after other methods have failed.  Phosphate must be given over 6–8 hours and switched to oral form as soon as symptoms have cleared.
    49. 49. Hypercalcemia (Cont’d) Phosphate (Cont’d)  The risks of IV phosphate include: sudden hypocalcemia, ectopic calcification, ARF, and hypotension.  Oral phosphate can also lead to ectopic calcification and renal failure, but the risk is less and the time of onset much longer.
    50. 50. Hypercalcemia (Cont’d) Glucocorticoids:  They have no clear role in the immediate treatment of hypercalcemia.  The chronic hypercalcemia of sarcoidosis, vitamin D intoxication, and certain cancers.  Response is seen within several days.
    51. 51. Hypocalcemia Treatment of severe hypocalcemia is with slow infusion of 5–20 mL of 10% Ca gluconate. Generic form in Iran is calcium gluconate injection 10%, in 10ml. Rapid infusion can lead to cardiac arrhythmias. Less severe hypocalcemia is best treated with oral forms. Oral forms should provide 400–1200 mg of elemental Ca. Dosage must be adjusted to avoid hypercalcemia and hypercalciuria.
    52. 52. Hypocalcemia (Cont’d) Vitamin D:  When rapidity of action is required, 1,25(OH)2D3 (calcitriol), is the metabolite of choice.  It is capable of raising serum Ca within 24–48 hr.  To prevent ectopic calcification, careful monitoring of both Ca and P is important
    53. 53. Pagets Disease Pagets disease is a localized bone disease. There is uncontrolled osteoclastic bone resorption with secondary increases in bone formation. But the new bone is poorly organized. Calcitonin and bisphosphonates are the first-line agents for this disease.
    54. 54. Calcitonin
    55. 55. Calcipotriol
    56. 56. Calcium tab.
    57. 57. Fluoride
    58. 58. Teriparatide
    59. 59. Summary In English
    60. 60. Thank you Any question?

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