Agents that Affect Bone Mineral Homeostasis Agents that Affect Bone Mineral Homeostasis By Dr. Sasan Zaeri (PharmD, PhD) (PharmD, PhD) Department of Pharmacology

Introduction Abnormalities in bone mineral homeostasis can lead to: Abnormalities in bone mineral homeostasis can lead to: A wide variety of cellular dysfunctions: A wide variety of cellular dysfunctions: Tetany Tetany Coma Coma Muscle weakness Muscle weakness Disturbances in structural support of the body: Disturbances in structural support of the body: Osteoporosis with fractures Osteoporosis with fractures Loss of hematopoietic capacity (infantile osteopetrosis) Loss of hematopoietic capacity (infantile osteopetrosis)

Hormonal Regulators of Bone Mineral Homeostasis Primary (principal): Primary (principal): Parathyroid hormone (PTH) Parathyroid hormone (PTH) Vitamin D (metabolites) Vitamin D (metabolites) Fibroblast growth factor 23 (FGF23) Fibroblast growth factor 23 (FGF23) Secondary: Secondary: Calcitonin Calcitonin Glucocorticoids Glucocorticoids Estrogen Estrogen in pharmacologic doses are useful therapeutically

Hormonal Regulators of Bone Mineral Homeostasis (Cont’d) All the principal regulators affect bone, kidney, and intestine and also each other activity or production All the principal regulators affect bone, kidney, and intestine and also each other activity or production The net effect of PTH is to raise serum Ca and reduce serum phosphate The net effect of PTH is to raise serum Ca and reduce serum phosphate The net effect of vitamin D is to raise both The net effect of vitamin D is to raise both The net effect of FGF23 is to decrease phosphate The net effect of FGF23 is to decrease phosphate

Hormonal interactions controlling bone mineral homeostasis

Parathyroid Hormone PTH is the most important stimulator for renal production of the active metabolite of vitamin D: 1,25(OH) 2 D PTH is the most important stimulator for renal production of the active metabolite of vitamin D: 1,25(OH) 2 D PTH promotes both bone formation and resorption by stimulating the osteoblasts and osteoclasts PTH promotes both bone formation and resorption by stimulating the osteoblasts and osteoclastsbone formation and resorptionbone formation and resorption PTH enhances renal retention of Ca PTH enhances renal retention of Ca It promotes renal phosphate excretion It promotes renal phosphate excretion

Bone Formation versus Resorption

Parathyroid Hormone (Cont’d) Ca is the principal regulator of PTH secretion Ca is the principal regulator of PTH secretion The net effect of excess PTH is to increase bone resorption The net effect of excess PTH is to increase bone resorption However, PTH in low and intermittent doses increases bone formation 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 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 This led to recombinant form of PTH 1-34 (Teriparatide) for the treatment of osteoporosis

Vitamin D (metabolites) Vitamin D is produced in the skin from 7- dehydrocholesterol under the influence of UV radiation Vitamin D is produced in the skin from 7- dehydrocholesterol under the influence of UV radiationUV radiationUV radiation Both the natural form (cholecalciferol) (D 3 ) and the plant-derived form (ergocalciferol) (D 2 ) are present in the diet Both the natural form (cholecalciferol) (D 3 ) and the plant-derived form (ergocalciferol) (D 2 ) are present in the diet

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. Vitamin D 25(OH)D 1,25(OH) 2 D

Chemical and Generic NamesAbbreviation Vitamin D3; cholecalciferolD3 Vitamin D2; ergocalciferolD2 D2 25-Hydroxyvitamin D3; calcifediol25(OH)D3 1,25-Dihydroxyvitamin D3; calcitriol1,25(OH) 2 D3 24,25-Dihydroxyvitamin D3; secalcifediol24,25(OH) 2 D3 DihydrotachysterolDHT Calcipotriene (calcipotriol)None 1-Hydroxyvitamin D 2 ; doxercalciferol1(OH)D 2 19-nor-1,25-Dihydroxyvitamin D 2 ; paricalcitol19-nor-1,25(OH)D 2 Vitamin D and Its Major Metabolites and Analogs

Vitamin D (metabolites) Cont’d 1,25(OH) 2 D stimulates the intestinal absorption of Ca and phosphate. 1,25(OH) 2 D stimulates the intestinal absorption of Ca and phosphate. It promotes both bone formation and resorption by stimulating the osteoblasts and osteoclasts. It promotes both bone formation and resorption by stimulating the osteoblasts and osteoclasts. Calcitriol enhances renal retention of Ca. Calcitriol enhances renal retention of Ca.

Vitamin D (metabolites) Cont’d 1,25(OH) 2 D directly inhibits PTH secretion 1,25(OH) 2 D directly inhibits PTH secretion This is by a direct action on PTH gene transcription and independent of its effect on Ca 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 This ability is being exploited using calcitriol analogs that have less effect on Ca Such analogs have little of the hypercalcemic, hypercalciuric effects of calcitriol Such analogs have little of the hypercalcemic, hypercalciuric effects of calcitriol This is an important aspect of their use for secondary hyperparathyroidism This is an important aspect of their use for secondary hyperparathyroidism

Vitamin D (metabolites) Cont’d Doxercalciferol and paricalcitol are used for secondary hyperparathyroidism in patients with chronic kidney disease Doxercalciferol and paricalcitol are used for secondary hyperparathyroidism in patients with chronic kidney disease Calcipotriene (calcipotriol), is being used for psoriasis Calcipotriene (calcipotriol), is being used for psoriasis

Calcitonin Human calcitonin has a half-life of 10 minutes 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 Salmon calcitonin (as nasal spray) half-life is 43 min, making it more useful as a therapeutic agent Salmon It lowers Ca and P and inhibits osteoclastic bone resorption 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 At first, bone formation is not impaired, but with time both formation and resorption of bone are reduced

Calcitonin (Cont’d) No major problem develops in cases of calcitonin deficiency (thyroidectomy) or excess (medullary carcinoma of the thyroid) 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 Paget's disease, osteoporosis and hypercalcemia Its ability to block bone resorption and lower Ca is used in Paget's disease, osteoporosis and hypercalcemia

Glucocorticoids Glucocorticoids antagonize vitamin D-stimulated intestinal Ca transport Glucocorticoids antagonize vitamin D-stimulated intestinal Ca transport Glucocorticoids do that by stimulating renal Ca excretion, and by blocking bone formation 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 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 Their prolonged administration causes osteoporosis in adults and stunted skeletal growth in children

Estrogens Estrogens can prevent accelerated bone loss during the immediate postmenopausal period Estrogens can prevent accelerated bone loss during the immediate postmenopausal periodaccelerated bone lossaccelerated bone loss Estrogens increase 1,25(OH) 2 D in blood Estrogens increase 1,25(OH) 2 D in blood Estrogen receptors have been found in bone, and estrogen has direct effects on bone remodeling Estrogen receptors have been found in bone, and estrogen has direct effects on bone remodeling Long-term use of estrogen has some adverse effects Long-term use of estrogen has some adverse effects Selective estrogen receptor modulators (SERMs) retain the beneficial effects while minimizing the adverse effects Selective estrogen receptor modulators (SERMs) retain the beneficial effects while minimizing the adverse effects

Estrogens (Cont’d) Raloxifene is the first SERM used for the prevention of osteoporosis Raloxifene is the first SERM used for the prevention of osteoporosis It doses not increase the risk of breast or endometrial cancer It doses not increase the risk of breast or endometrial cancer It may actually reduce the risk of breast cancer It may actually reduce the risk of breast cancer

Non-Hormonal Regulators of Bone Mineral Homeostasis Bisphosphonate Bisphosphonate Thiazides Thiazides …

Bisphosphonates Bisphosphonates consist of : Etidronate, Pamidronate, Alendronate, Risedronate etc. Bisphosphonates consist of : Etidronate, Pamidronate, Alendronate, Risedronate etc. They increase bone density and reduce fractures over at least 5 years They increase bone density and reduce fractures over at least 5 years5 years5 years Trials between alendronate and calcitonin indicated a greater efficacy of alendronate. Trials between alendronate and calcitonin indicated a greater efficacy of alendronate.

Bisphosphonates (Cont’d) The exact mechanism by which they selectively inhibit bone resorption is not clear 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 Food reduces the absorption of these drugs, so should be administered on an empty stomach Gastric irritation, is the complication of all bisphosphonates Gastric irritation, is the complication of all bisphosphonates Contraindications are: decreased renal function, esophageal motility disorders, and peptic ulcer Contraindications are: decreased renal function, esophageal motility disorders, and peptic ulcer They are useful for the treatment of paget's disease, hypercalcemia of malignancy, and osteoporosis They are useful for the treatment of paget's disease, hypercalcemia of malignancy, and osteoporosis

Thiazides The principal application of thiazides is in reducing renal Ca excretion 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. In the distal tubule, thiazides block sodium reabsorption, increasing the Ca-sodium exchange, thus enhancing Ca reabsorption into the blood.distal tubuledistal tubule Thiazides are useful in reducing the hypercalciuria and incidence of stone formation in idiopathic hypercalciuria Thiazides are useful in reducing the hypercalciuria and incidence of stone formation in idiopathic hypercalciuria

Calcitonin

Calcipotriol

Teriparatide