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Dr. S. A. Ziai 98% of the 1-2 kg of calcium and 85% of the 1 kg of phosphorus in the human adult are found in bone Dynamic, with constant remodeling Tetany, coma, muscle weakness, osteoporosis with fractures, loss of hematopoietic capacity From 600-1000 mg of calcium of diet per day ~100-250 mg is absorbed Absorption (principally in the duodenum and upper jejunum) and secretion (principally in the ileum) In diet P= Ca The efficiency of absorption (principally in the jejunum) is greater, (70% to 90%) Renal excretion of calcium and phosphate balances intestinal absorption Over 98% of filtered calcium and 85% of filtered phosphate is reabsorbed by the kidney The movement of Ca & P across the intestinal and renal epithelia is closely regulated nontropical sprue, or CRF disrupts bone mineral homeostasis Major Players ◦ Vitamin D (1,25(OH)2D) ◦ PTH (parathyroid hormone) ◦ Fibroblast growth factor 23 (FGF23) Minor Players (secondary regulators) ◦ ◦ ◦ ◦ ◦ ◦ ◦ Calcitonin (CT) Prolactin Growth hormone Insulin Thyroid hormone Glucocorticoids Sex steroids Calcium-sensitive protease Synthetic 1-34 PTH is fully active. Loss of the first two amino terminal amino acids eliminates most biologic activity Increases serum calcium and decreases serum phosphate Increases bone turnover or bone remodeling (RANKL) The net effect of excess PTH is to increase bone resorption In low and intermittent doses recombinant PTH 1-34 (teriparatide) for the treatment of osteoporosis (indirect by IGF-1) In the kidney, PTH ↑the ability of the nephron to reabsorb calcium and magnesium but ↓ its ability to reabsorb phosphate, amino acids, bicarbonate, sodium, chloride, and sulfate. Another important action of PTH on the kidney is its stimulation of 1,25dihydroxyvitamin D (1,25[OH]2D) production. Teriparatide must be given daily by subcutaneous injection Vitamin D and its major metabolites and analogs. Chemical and Generic Names Abbreviation Vitamin D3; cholecalciferol D3 Vitamin D2; ergocalciferol D2 25-Hydroxyvitamin D3; calcifediol 25(OH)D3 1,25-Dihydroxyvitamin D3; calcitriol 24,25-Dihydroxyvitamin D3; secalcifediol Dihydrotachysterol Calcipotriene (calcipotriol) 1,25(OH)2D3 24,25(OH)2D3 DHT None 1a-Hydroxyvitamin D2; doxercalciferol 1a(OH)D2 19-nor-1,25-Dihydroxyvitamin D2; paricalcitol 19-nor1,25(OH)D2 Only vitamin D and 1,25(OH)2D (as calcitriol) are available for clinical use (natural basis) Calcipotriene (calcipotriol), is being used to treat psoriasis Doxercalciferol and paricalcitol have recently been approved for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease The vitamin D-binding protein This a-globulin binds 25(OH)D and 24,25(OH)2D with comparable high affinity and vitamin D and 1,25(OH)2D with lower affinity Vitamin D rapidly cleared by liver Excess vitamin D is stored in adipose tissue The clinical utility of 1,25(OH)2D analogs is likely to expand: ◦ insulin secretion from the pancreas, cytokine production by macrophages and T cells, and proliferation and differentiation of a large number of cells, including cancer cells Actions of parathyroid hormone (PTH) and vitamin D on gut, bone, and kidney. PTH Vitamin D Intestine Increased calcium and phosphate Increased calcium and phosphate absorption (by increased absorption by 1,25 (OH)2D 1,25[OH]2D production) Kidney Decreased calcium excretion, increased phosphate excretion Calcium and phosphate excretion may be decreased by 25(OH)D and 1,25(OH)2D1 Bone Calcium and phosphate resorption increased by high doses. Low doses may increase bone formation. Increased calcium and phosphate resorption by 1,25(OH)2D; bone formation may be increased by 1,25 (OH)2D and 24,25(OH)2D Net effect on serum levels Serum calcium increased, serum phosphate decreased Serum calcium and phosphate both increased effect. Vitamin D often increases urine calcium owing to increased calcium absorption from the intestine and resulting decreased PTH. 1Direct Heterogen Human calcitonin monomer has a halflife of about 10 minutes Salmon calcitonin has a longer half-life Lowers serum calcium and phosphate by actions on bone and kidney Calcitonin inhibits osteoclastic bone resorption No readily demonstrable problem develops in cases of calcitonin deficiency (thyroidectomy) or excess (medullary carcinoma of the thyroid) The ability of calcitonin to block bone resorption and lower serum calcium makes it a useful drug for the treatment of Paget's disease, hypercalcemia, and osteoporosis Antagonizing vitamin D-stimulated intestinal calcium transport Stimulating renal calcium excretion Blocking bone formation useful in: ◦ Hypercalcemia (lymphomas and granulomatous diseases such as sarcoidosis (in which production of 1,25[OH]2D is increased) ◦ Vitamin D intoxication Reduce the bone-resorbing action of PTH increases 1,25(OH)2D level in blood (no direct effect) It has direct effects on bone remodeling It has effects in men HRT (side effects on breast, uterus, and the cardiovascular system) Selective estrogen receptor modulators (SERMs) It may actually reduce the risk of breast cancer Raloxifene has been shown to reduce vertebral fractures In all cases, adequate intake of calcium and vitamin D needs to be maintained BISPHOSPHONATES CALCIMIMETICS (Cinacalcet) PLICAMYCIN (MITHRAMYCIN) THIAZIDES FLUORIDE Etidronate pamidronate alendronate risedronate tiludronate ibandronate zoledronate Retard formation and dissolution of hydroxyapatite crystals within and outside the skeletal system Their greatest effects on osteoclasts less than 10% of an oral dose of these drugs is absorbed Food reduces absorption Nearly half of the absorbed drug accumulates in bone Decreased renal function, esophageal motility disorders, and peptic ulcer disease are the main contraindications to the use of these drugs Useful for the treatment of hypercalcemia associated with ◦ malignancy ◦ Paget's disease ◦ osteoporosis Alendronate appears to increase bone mineral density well beyond the 2-year period The bisphosphonates exert a variety of other cellular effects ◦ ◦ ◦ ◦ ◦ inhibition of 1,25(OH)2D production inhibition of intestinal calcium transport metabolic changes in bone cells (inhibition of glycolysis) inhibition of cell growth changes in acid and alkaline phosphatase Amino bisphosphonates such as alendronate have recently been found to block farnesyl pyrophosphate synthase, an enzyme in the mevalonate pathway that appears to be critical for osteoclast survival (Statins role) These drugs have proved to be remarkably free of adverse effects when used at the doses recommended for the treatment of osteoporosis. Induction of a mineralization defect by higher than approved doses of etidronate Gastric and esophageal irritation by pamidronate and by high doses of alendronate, Higher doses used in the treatment of hypercalcemia have been associated with renal deterioration and osteonecrosis of the jaw. Esophageal irritation can be minimized by taking the drug with a full glass of water and remaining upright for 30 minutes Cinacalcet Activates the calcium sensing receptor (CaR) Cinacalcet blocks PTH secretion is approved for the treatment of: ◦ Secondary hyperparathyroidism in chronic kidney disease ◦ Treatment of parathyroid carcinoma. A cytotoxic antibiotic that has been used clinically for two disorders of bone mineral metabolism: (1/10 cytotoxic doses) ◦ Paget's disease and ◦ Hypercalcemia Interruption of DNA-directed RNA synthesis Reduces renal calcium excretion ◦ Increasing the calciumsodium exchange in distal tubules ◦ May increase the effectiveness of parathyroid hormone Idiopathic hypercalciuria Reducing stone formation ◦ decrease urine oxalate excretion ◦ increase urine magnesium and zinc levels Prophylaxis of dental caries Under investigation for the treatment of osteoporosis In naturally fluoridated water (1-2 ppm) there are less dental caries and fewer vertebral compression fractures It may stabilize the hydroxyapatite crystal Useful before permanent teeth are fully formed > 1 ppm Fluorosis At present, fluoride is not approved by the FDA for use in osteoporosis CNS depression (coma) It is potentially lethal major causes ◦ Hyperparathyroidism ◦ cancer ◦ thiazide therapy Less common causes ◦ Hypervitaminosis D, sarcoidosis, thyrotoxicosis, milk-alkali syndrome, adrenal insufficiency, and immobilization Saline Diuresis Bisphosphonates Calcitonin ◦ prerenal azotemia ◦ 500-1000 mL/h of saline + furosemide ◦ Beware of heart failure and pulmonary edema ◦ Pamidronate, 60-90 mg, infused over 2-4 hours, and zoledronate, 4 mg, infused over at least 15 minutes ◦ replaced the less effective etidronate ◦ hypercalcemia of malignancy ◦ 7-day interval ◦ self-limited flu-like syndrome, ◦ Repeated doses renal deterioration and osteonecrosis of the jaw ◦ ◦ ◦ ◦ ancillary treatment refractoriness frequently develops Calcimar (salmon calcitonin) An effect on serum calcium is observed within 4-6 hours and lasts for 610 hours Gallium Nitrate Plicamycin (Mithramycin) ◦ Inhibit bone resorption ◦ hypercalcemia of malignancy ◦ potential nephrotoxicity ◦ ◦ ◦ ◦ is not the drug of first choice sudden thrombocytopenia followed by hemorrhage Hepatic and renal toxicity can also occur Hypocalcemia, nausea, and vomiting may limit therapy Phosphate Glucocorticoids ◦ should be used only after other methods of treatment ◦ sudden hypocalcemia, ectopic calcification, acute renal failure, and hypotension ◦ no clear role in the acute treatment ◦ the chronic hypercalcemia of sarcoidosis, vitamin D intoxication, and certain cancers may respond within several days to glucocorticoid therapy ◦ The malignancies responding best to glucocorticoids INJECTION PARENTERAL (KH2PO4 225mg+ K2HPO4 236mg) / ml Phosphate, Potassium Monobasic * UNKNOWN UNASSIGNED **(KH2po4)** Phosphate, Potassium Monobasic* 500 mg TABLET ORAL - Phosphate, Sodium Dibasic * UNKNOWN UNASSIGNED **(Na2hpo4)** Phosphate, Sodium monobasic * UNKNOWN UNASSIGNED **(Nah2po4)** Phosphate, Potassium Phosphate, Sodium* TABLET, EFFERVESCENT ORAL NaH2PO4 1936 mg+ NaHCO3 350 mg+KHCO3 315 mg Neuromuscular-tetany, paresthesias, laryngospasm, muscle cramps, and convulsions The major causes in the adult are: ◦ ◦ ◦ ◦ hypoparathyroidism vitamin D deficiency chronic kidney disease Malabsorption Neonatal hypocalcemia is a common disorder that usually resolves without therapy. Calcium ◦ intravenous, intramuscular, and oral ◦ I.v.: Calcium gluceptate (0.9 mEq calcium/mL), calcium gluconate (0.45 mEq calcium/mL), and calcium chloride (0.68-1.36 mEq calcium/mL) ◦ Oral: calcium carbonate (40% calcium), calcium lactate (13% calcium), calcium phosphate (25% calcium), and calcium citrate (21% calcium) ◦ slow infusion of 5-20 mL of 10% calcium gluconate Vitamin D ◦ Rapid action: 1,25(OH)2D3 (calcitriol), 0.25-1 mcg daily (raising serum calcium within 24-48 hours) ◦ Calcitriol also raises serum phosphate common complication of renal failure also found in all types of hypoparathyroidism (idiopathic, surgical, and pseudo-), vitamin D intoxication, and the rare syndrome of tumoral calcinosis Seldom emergency treatment ◦ dialysis or glucose and insulin infusions Restriction of dietary phosphate plus the use of phosphate-binding gels such as sevelamer and of calcium supplements Aluminum antacids aluminum-associated bone disease clinically significant acute effects of hypophosphatemia are seldom seen primary hyperparathyroidism vitamin D deficiency idiopathic hypercalciuria vitamin D-resistant rickets various other forms of renal phosphate wasting (eg, Fanconi's syndrome) overzealous use of phosphate binders parenteral nutrition with inadequate phosphate content. PRIMARY HYPERPARATHYROIDISM HYPOPARATHYROIDISM NUTRITIONAL VITAMIN D DEFICIENCY OR INSUFFICIENCY CHRONIC KIDNEY DISEASE INTESTINAL OSTEODYSTROPHY OSTEOPOROSIS X-LINKED & AUTOSOMAL DOMINANT HYPOPHOSPHATEMIA VITAMIN D-DEPENDENT RICKETS TYPES I & II NEPHROTIC SYNDROME IDIOPATHIC HYPERCALCIURIA PAGET'S DISEASE OF BONE ENTERIC OXALURIA Asymptomatic patients may be left untreated Cinacalcet approved for secondary hyperparathyroidism It is in clinical trials for the treatment of primary hyperparathyroidism Absence of PTH (idiopathic or surgical hypoparathyroidism) Abnormal target tissue response to PTH (pseudohypoparathyroidism) calcium falls and serum phosphate rises lack of stimulation by PTH of 1,25(OH)2D production pseudohypoparathyroidism ◦ Normal or high PTH levels ◦ Have bone response (have osteitis fibrosa), but not renal response (diminished excretion of cAMP or phosphate) Restore normocalcemia and normophosphatemia ◦ Vitamin D (25,000-100,000 units three times per week) and dietary calcium supplements Disadvantage: Episodes of hypercalcemia ◦ Calcitriol more rapid action Advantage: In patients tend to have hypercalcemia crises Vitamin D deficiency 25(OH)D levels < 10 ng/mL ◦ In the pediatric and geriatric populations on vegetarian diets and with reduced sunlight exposure Vitamin D insufficiency 25(OH)D levels between 10 ng/mL and 32 ng/mL (common) ◦ Decreased bone mineral density and predisposition to falls and fractures in the elderly Avoided by daily intake of 800-1200 units of vitamin D Treated by higher dosages (4000 units per day or 50,000 units per week for several weeks) The diet should also contain adequate amounts of calcium and phosphate The major problems: ◦ ◦ ◦ ◦ Loss of 1,25(OH)2D production (less calcium absorbed) Retention of phosphate Reduces ionized calcium Secondary hyperparathyroidism The bones show a mixture of osteomalacia and osteitis fibrosa (low vitamin D and high PTH) Some patients may become hypercalcemic: ◦ overzealous treatment with calcium ◦ severe secondary (tertiary) hyperparathyroidism with high ALP parathyroidectomy ◦ Adynamic bone disease: decrease in bone cell activity with sensitivity to vitaminD and normal PTH & ALP (high aluminum in bones) Defroxamine Vitamin D preparation ◦ Choice depends on the type and extent of bone disease and hyperparathyroidism ◦ 25(OH)D levels restored to normal (above 32 ng/mL) with vitamin D ◦ 1,25(OH)2D3 (calcitriol) rapid action correct hyperparathyroidism and osteitis fibrosa ◦ Doxercalciferol & paricalcitol they are less likely than calcitriol to induce hypercalcemia for any given reduction in PTH A calcium x phosphate product (in mg/dL units) less than 55 is desired with both calcium and phosphate in the normal range ◦ Calcium adjustments in the diet and dialysis bath ◦ Phosphate restriction (dietary and with oral ingestion of phosphate binders) should be used along with vitamin D metabolites Some GI & hepatic disease ◦ malabsorption of calcium & malabsorption of vitamin D ◦ Reduction in reabsorption of endogenous vitamin D metabolites as well as limit absorption of dietary vitamin D (distal jejunum and ileum) Disordered calcium & phosphate homeostasis osteoporosis & osteomalacia Treatment: ◦ vitamin D (25,000-50,000 units three times per week) ◦ Dietary calcium supplementation and monitoring of serum calcium and phosphate levels Abnormal loss of bone $13.8 billion in 1996 Postmenopausal Long term glucocorticoids Thyrotoxicosis Hyperparathyroidism Malabsorption syndrome Alcohol abuse Cigarette smoking Idiopathic Postmenopausal osteoporosis ◦ lower 1,25(OH)2D levels ◦ reduced intestinal calcium transport Estrogen deficiency ◦ HRT ◦ Side effects: increases the risk of breast cancer and fails to reduce the development of heart disease Selective estrogen receptor modulators (SERMs) Raloxifene reduce the risk of breast and uterine cancer protects against spine fractures but not hip fractures does not prevent hot flushes same increased risk of thrombophlebitis ◦ vitamin D therapy is often used in addition to dietary calcium supplementation ◦ calcitriol and its analog 1a(OH)D3 increase bone mass and reduce fractures (not FDA approved) ◦ Fluoride remains controversial ◦ Teriparatide 20 mcg subcutaneously daily stimulates new bone formation ◦ Calcitonin increases bone mass and reduce fractures only in the spine ◦ Bisphosphonates potent inhibitors of bone resorption. They increase bone density and reduce the risk of fractures in the hip, spine, and other locations alendronate 10 mg/d, risedronate 5 mg/d, ibandronate 2.5 mg/d alendronate 70 mg/wk, risedronate 35 mg/wk ibandronate 150 mg/mo These drugs are effective in men as well as women and for various causes of osteoporosis Reclast zoledronic acid once in year Appearance of rickets (phosphate is critical to normal bone mineralization )and hypophosphatemia in children, although they may first present in adults By mutations in PHEX (endopeptidase) By mutations in FGF23 FGF23 blocks the renal uptake of phosphate and blocks 1,25(OH)2D3 production Oral phosphate (1-3 g daily) and calcitriol (0.25-2 mcg daily) These diseases are rare Type I vitamin D-dependent rickets ◦ deficiency of 1,25(OH)2D production ◦ mutations in 25(OH)D-1a-hydroxylase ◦ treated with vitamin D (4000 units daily) or calcitriol (0.25-0.5 mcg daily) Type II vitamin D-dependent rickets ◦ ◦ ◦ ◦ mutations in the gene for the vitamin D receptor The serum levels of 1,25(OH)2D are very high large doses of calcitriol has been claimed to be effective One recent report indicates a reversal of resistance to calcitriol when 24,25(OH)2D was given loss of the vitamin D-binding protein lose vitamin D metabolites in the urine (25(OH)D) Some of them develop bone disease Hypercalciuria and nephrolithiasis with normal serum calcium and PTH levels ◦ (1) hyperabsorbers, high-normal serum calcium, lownormal PTH ◦ (2) renal calcium leakers, low-normal serum calcium and high-normal serum PTH ◦ (3) renal phosphate leakers, leading to stimulation of 1,25(OH)2D Hydrochlorothiazide, up to 50 mg twice daily Allopurinol (altrnative) ◦ hyperuricosuria is associated with idiopathic hypercalcemia ◦ a small nidus of urate crystals could lead to the calcium oxalate stone formation A localized bone disease Uncontrolled osteoclastic bone resorption with secondary increases in bone formation This new bone is poorly organized Elevation of ALP & urinary hydroxyproline (diagnostic & treatment response aids) Treatment: ◦ To reduce bone pain, progressive deformity, hearing loss, high-output cardiac failure, and immobilization hypercalcemia ◦ Calcitonin and bisphosphonates are the first-line agents ◦ Plicamycin ◦ Sodium etidronate, alendronate, risedronate, pamidronate, and tiludronate are the bisphosphonates currently used ◦ Etidronate, 5 mg/kg/d; alendronate, 40 mg/d; risedronate, 30 mg/d; and tiludronate, 400 mg/d ◦ Long-term (months to years) remission may be expected in patients who respond to these agents ◦ Treatment should not exceed 6 months per course but can be repeated after 6 months if necessary ◦ The principal toxicity of etidronate is the development of osteomalacia (bone pain) and an increased incidence of fractures when the dosage is raised substantially above 5 mg/kg/d ◦ The principal side effect of alendronate and the newer bisphosphonates is gastric irritation Short bowel syndromes fat malabsorption oxaluria calcium oxalate stones 1. in the intestinal lumen, calcium (which is now bound to fat) fails to bind oxalate and no longer prevents its absorption 2. enteric flora, acting on the increased supply of nutrients reaching the colon, produce larger amounts of oxalate One to 2 g of calcium carbonate can be given daily in divided doses