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Agents That Affect Bone Mineral Homeostasis Dr Safaeian Bone Principal structural support for body and provides space for hematopoiesis. Major mineral constituents: Calcium (98% of 1–2 kg) and Phosphorus (85% of 1 kg) Complex set of mechanisms for homeostasis of calcium and phosphate Bone cells: Osteoclast (bone resorption: removing mineralized matrix and breaking up organic bone) Osteoblasts (bone formation) Bone Remodeling Growth and development of endochondral bone are driven by a process called modeling. Once new bone is laid down, it is subject to a continuous process of breakdown and renewal called remodeling, by which bone mass is adjusted throughout adult life. Abnormalities in bone mineral homeostasis Cellular dysfunctions (tetany, coma, muscle weakness) Disturbances in structural support of body (osteoporosis with fractures) Loss of hematopoietic capacity Calcium and Phosphate Enter body from intestine. Ca: absorption → principally in duodenum and upper jejunum, secretion →principally in ileum) P: absorption → principally in jejunum 98% of filtered Ca and 85% of filtered P reabsorbed by kidney. Intestinal absorption and Renal excretion of Ca and P is closely regulated. Principal hormonal regulators of bone mineral homeostasis Parathyroid hormone (PTH) Fibroblast growth factor 23 (FGF23) Vitamin D Parathyroid Hormone (PTH) 1. 2. 3. Parathormon 100 uspU/ml AMP Teriparatide 250 mcg/ml, Prefilled Disposable Injectional Pen (Recombinant PTH 1-34) PTH: a single-chain peptide hormone (84 amino acids) Regulation of PTH: Cleavage of PTH in the gland through a Ca-sensitive protease ↓ PTH production and secretion through Ca-sensing receptor Parathyroid gland contains Vit D receptor and also activates Vit D ► suppress PTH production. Parathyroid Hormone (PTH) Rapid metabolic clearance in liver and kidney Regulates Ca and P flux across cellular membranes in bone and kidney PTH ►↑Serum Ca and ↓Serum P PTH in the bone PTH ► both catabolic and anabolic effects on bone. Excess endogenous PTH ► ↑Activity and number of osteoclasts, ↑bone turnover indirectly through induction of a protein called RANK (receptor for activation of nuclear factor-κB) ligand Denosumab: An antibody that inhibits action of RANKL has been developed for treatment of excess bone resorption in osteoporosis and certain cancers. Low and intermittent exogenous PTH ► ↑ bone formation indirectly through insulin-like growth factor 1 (IGF-1) ► Teriparatide: for treatment of osteoporosis. PTH in the kidney ↑Ability of nephron to reabsorb Ca and Mg ↓Ability to reabsorb phosphate, amino acids, bicarbonate, Na, Cl, and sulfate Stimulation of 1,25-dihydroxyvitamin D (1,25[OH]2D) production Vitamin D (Vit D3) A secosteroid produced in skin from 7dehydrocholesterol under influence of UV. Also found in diet as natural form (Vit D3: Cholecalciferol) and plant-derived form (Vit D2: Ergocalciferol [less potent]) A prohormone is first hydroxylated in liver to 25hydroxyvitamin D3 (25[OH]D: Calcifediol): major circulating form of Vit D3. Further converted in kidney to 1,25dihydroxyvitamin D3 (1,25[OH]2D: Calcitriol) and 24,25-dihydroxyvitamin D3 (24,25[OH]2D: Secalcifediol). Conversion of 7-dehydrocholesterol to Vit D3 and its metabolism Vitamin D Preparations Vitamin D3 300,000 U AMP Vitamin D3 50,000 U CAP (Pearl) Calcitriol 0.25 mcg, 1, 2 mcg/ml CAP, AMP Dihydrotachysterol 1 mg/ml Oral Solution Calcipotriol (Calcipotriene) Topical Gel, OINT, Solution (for psoriasis) Vitamin D The recommended dietary allowance of vit D for infants and children is 400 IU, or 10 g, daily. The adult dose was set arbitrarily at 200 IU. Maximum daily intake: up to 4000 IU/day In osteoporosis ► Vit D: 600-800 IU daily In hypocalcemia due to vit D deficiency ► 50,000 U D2 or D3 orally once per week for 6-8 weeks, and then 800 to 1000 U of D3 daily. Vitamin D Vit D and its metabolites tightly bound to vit Dbinding protein in plasma. Principal organ for clearance: liver Prolonged terminal half-life = weeks to months (store in fat depots). Biological actions of vit D are mediated by a nuclear receptor. Vit D: Mechanism of action Calcitriol: most potent agent in stimulation of intestinal Ca and P transport and bone resorption. Supplementation with cholecalciferol (D3) is suggested because D3 increases serum 25[OH]D more efficiently than ergocalciferol (D2). Acts on intestine through intracellular receptor by induction of new protein synthesis (Ca-binding protein and intestinal Ca channel) and by modulation of Ca flux across membranes. On bone like PTH, regulate mineralization process. Vit D: Mechanism of action Calcifediol (25(OH)D) is more potent than 1,25(OH)2D in stimulating renal reabsorption of Ca and P and regulating Ca flux and contractility in muscle. Vit D ►↑Serum Ca and ↑Serum P Vit D: Side effects Safe Upper Limit for vit D: 4000 IU/day However, higher doses are sometimes required for initial treatment of vit D deficiency. Excessive vit D, especially + Ca ► hypercalcemia, hypercalciuria, kidney stones. (weakness, headache, somnolence, nausea, cardiac rhythm disturbance) Fibroblast Growth Factor 23 (FGF23) A single-chain protein produced primarily by osteoblasts and osteocytes in bone. Inhibits 1,25(OH)2D3 production and phosphate reabsorption (via Na phosphate co-transporters) in kidney ► ↓Serum P and ↓circulating 1,25(OH)2D3 Actions of PTH, Vit D, and FGF23 on Gut, Bone, and Kidney PTH Intestine ↑Ca and P absorption (by ↑1,25[OH]2D production) Vitamin D FGF23 Kidney ↓Ca excretion, ↑P excretion ↓Ca and P excretion ↑P excretion by 25(OH)D and 1,25(OH)2D1 Bone ↑Ca and P resorption high doses. Low doses may increase bone formation. ↑Ca and P resorption ↓mineralization due by 1,25(OH)2D; to ↑bone formation by hypophosphatemia 1,25(OH)2D and 24,25(OH)2D Net effect on serum levels ↑Serum Ca ,↓Serum P ↑Serum Ca and P ↓Serum P ↑Ca and phosphate ↓Ca and P absorption by 1,25 absorption by ↓1,25(OH)2 (OH)2D production Secondary Hormonal Regulators of Bone Mineral Homeostasis Calcitonin Glucocorticoids Estrogens Calcitonin Calcitonin 50, 100 IU/ml AMP Calcitonin, Salmon100, 200 IU/dose NASAL SPRAY A single-chain peptide hormone secreted by parafollicular cells of thyroid. Half-life of human calcitonin monomer=10 min Salmon calcitonin: longer half-life and a ↓metabolic clearance → more attractive as a therapeutic agent. Much of clearance occurs in kidney. Calcitonin Principal effects ►↓Serum Ca and P by actions on bone and kidney. Inhibits osteoclastic bone resorption at first after its administration, with time►↓both formation and resorption of bone. In kidney► ↓Ca, P, Na, K and Mg reabsorption Useful in treatment of Paget's disease, hypercalcemia, and osteoporosis. Glucocorticoids Alter bone mineral homeostasis. Antagonize Vit D-stimulated intestinal Ca transport. Stimulate renal Ca excretion. Block bone formation. Prolonged administration ► Osteoporosis Useful in reversing hypercalcemia associated with lymphomas or in Vit D intoxication. Estrogens Prevent accelerated bone loss during immediate postmenopausal period and at least transiently increase bone in postmenopausal woman. Reduce bone-resorbing action of PTH. Lead to ↑1,25(OH)2D level in blood. Estrogen receptors have been found in bone ► direct effects on bone remodeling. Estrogens Long-term use of estrogen is discouraged because of its deleterious adverse effects. But, selective estrogen receptor modulators (SERMs) such as Raloxifene have beneficial effects on bone while minimizing these deleterious adverse effects on breast, uterus. Nonhormonal agents Bisphosphonates Calcimimetics Thiazides Fluoride Other drugs Gallium nitrate Plicamycin (Mithramycin) Strontium Ranelate Bisphosphonates: Analogs of pyrophosphate Etidronate TAB Pamidronate AMP AlendronateTAB Risedronate TAB Zoledronate AMP Bisphosphonates: Pharmacodynamic Retard formation and dissolution of hydroxyapatite crystals within and outside skeletal system. Localize to regions of bone resorption and so exert their greatest effects on osteoclasts. Amino bisphosphonates such as alendronate and risedronate ►block farnesyl pyrophosphate synthase, an enzyme in mevalonate pathway is critical for osteoclast survival. Bisphosphonates: Pharmacokinetics Less than 10% of an oral dose is absorbed. Food reduces absorption. Pamidronate is not available as an oral preparation due to gastric irritation. ½ Absorbed drug accumulates in bone for months. Remainder is excreted unchanged in urine. Bisphosphonates: Clinical Application Hypercalcemia associated with malignancy Paget's disease Osteoporosis Contraindications: ↓Renal function, esophageal motility disorders, and peptic ulcer disease→ can be used IV administration of pamidronate. Bisphosphonates: Adverse Effects Remarkably free of ADR in doses for osteoporosis. Etidronate → Mineralization defect in higher doses All (exception of etidronate) have gastric and esophageal irritation ►taking drug with a full glass of water and remaining upright for 30 min. Rare osteonecrosis of jaw (1/100,000 patient-years) by high iv doses of zoledronate Rare femur fractures after long-term treatment due to over-suppressing bone turnover. ↑Risk of new-onset atrial fibrillation (AF), especially in IV therapy (zoledronate)- UpToDate 2016. Calcimimetics: Cinacalcet TAB Activates calcium sensing receptor (CaR) especially in parathyroid gland. Blocks PTH secretion. Approved for treatment of secondary hyperparathyroidism in chronic kidney disease and for treatment of parathyroid carcinoma. Thiazides Reduce renal Ca excretion. Increase effectiveness of PTH in stimulating renal Ca reabsorption. In distal tubule: block Na reabsorption,↑Ca-Na exchange ►↑Ca reabsorption into blood Useful in reducing hypercalciuria and incidence of stone formation in idiopathic hypercalciuria ►↓Stone formation by ↓urine oxalate excretion Fluoride Effective for prophylaxis of dental caries. Accumulated by bones and teeth ► stabilizes hydroxyapatite crystal. Optimum concentration in drinking water supplies = 0.5–1 ppm. Excess fluoride in drinking water leads to mottling of enamel. Calcium Preparations Calcium Citrate Calcium Gluconate 10%, 10ml, AMP, GEL Calcium Carbonate 500 mg TAB, Eff TAB Calcium Carbonate+Vit D3 500 mg+200IU TAB, Eff Calcium Forte (Carbonate 0.3 g, Lactate Gluconate 2.94 g) TAB, Eff TAB Calcium (Glubionate, Lactobionate): 500 mg Syrup The intake recommendations refer to amount of elemental calcium in the calcium supplement. Calcium Optimal intake of Ca: 1200 mg (total of diet and supplement) should not routinely exceed 2000 mg/day. The most widely available Ca supplements: calcium carbonate and calcium citrate. Calcium carbonate is cheapest► good first choice in most individuals when taken with meals. Calcium citrate is well absorbed in fasting state, is first line in patients taking proton pump inhibitors or H2 blockers or who have achlorhydria. Intravenous Calcium Indication Acutely symptomatic patients (acute hypoparathyroidism following surgery) Asymptomatic hypocalcemia with acute ↓serum Ca to ≤7.5 mg/dL (1.9 mmol/L) may develop serious complications if untreated Patients with milder or chronic hypocalcemia unable to take or absorb oral supplements (after complex surgical procedures) Calcitriol (0.25 to 0.5 mcg BID) is preferred for patients with severe acute hypocalcemia because of its rapid onset of action. Intravenous Calcium Indication 10% Ca gluconate (90 mg of elemental Ca/10 mL) can be infused over 10 to 20 mins ► because of risk of serious cardiac dysfunction, including systolic arrest. Ca should be diluted in 5% dextrose or saline because of irritating effect to veins. IV solution should not contain bicarbonate or phosphate, which can form insoluble calcium salts. Another IV line (in another limb) could be used. Calcium Preparations: Side effects of high calcium intake Headache, anorexia, weakness, dry mouth, metallic taste, dyspepsia and constipation, abdominal cramps, ataxia, ↑risk of nephrolithiasis Cardiovascular disease (CVD) is controversial. Interfere with absorption of iron and thyroid hormone ► should be taken at different times. Side effects following IV administration: dizziness, flushing, sensation of warmth, irregular heartbeat, nausea or vomiting, skin redness, rash, pain, or burning at injection site, sweating, tingling sensation Phosphate Preparations For treatment of Hypophosphatemia Phosphate (Organic) AMP Phosphate, Potassium AMP Phosphate, Potassium Monobasic Bulk, TAB Phosphate, Sodium Monobasic, Dibasic Bulk Phosphate, Sodium TAB, EFFERVESCENT Treatment of Hyperphosphatemia Dialysis Glucose and insulin infusions (seldom necessary) Restriction of dietary phosphate plus use of phosphate-binding gels (Sevelamer 800mg, TAB) Ca supplements.