Drugs Affecting Calcium Metabolism and Bone Turnover PDF

Drugs That Affect Calcium Metabolism And Bone Turnover Hussein Hallak, Ph.D. Al-Quds University Hormones That Regulate Calcium Metabolism Calcium Homeostasis Diseases Of Calcium Metabolism: Osteoporosis Low bone mass and disruption of bone architecture which result in frequent...

Drugs That Affect Calcium Metabolism And Bone Turnover Hussein Hallak, Ph.D. Al-Quds University Hormones That Regulate Calcium Metabolism Calcium Homeostasis Diseases Of Calcium Metabolism: Osteoporosis Low bone mass and disruption of bone architecture which result in frequent fractions caused by minimal trauma. Classification. Primary. Secondary.  Definition of Osteoporosis Pathology: Absolute decrease in both bone mineral and matrix, reduced mechanical strength Radiology: Bone density measurements > 2.5 S.D. below young normal mean (> 30% loss of bone mass) Clinical: Predisposition to fracture after minimal trauma World Health Organization (WHO) guidelines for osteoporosis Peak Bone Mass Normal Osteopenia T-Score -2.5 -2 1 0  Change in Bone Mass for Men and Women 1400 Males 1200 Females 1000 Total Body 800 Calcium (g) 600 400 Menopause 200 0 0 1 5 10 15 20 30 40 50 60 70 80 Age in Years  Estimated Skeletal Status of US White Women, 1990 15 Normal Osteopenia 10 Osteoporosis Population 5 Osteoporosis & millions fractures 0 5 10 30 40 50 60 70 80 From Melton, 1995 Age group (yrs) Vitamin D Main effect = increased absorption of calcium. Net effect = hypercalcemia Available for oral or IM administration Alfacalcidol is an active metabolite of Vitamin D, formed by the enzyme 25-hydroxylase in the liver for systemic and in osteoblasts for local D-hormone actions. Alfacalcidol 0.25 & 1mcg Capsules Alfacalcidol 0.25 mcg/Drops Figure above from Isr Med Assoc J., 12(12), Oren Y, Shapira Y, Agmon-Levin N, Kivity S, Zafrir Y, Altman A, Lerner A, Shoenfeld Y., Vitamin D insufficiency in a sunny environment: a demographic and seasonal analysis, 751-6  CALCITONIN Main effect = inhibition of bone resorption. Net effect = hypocalcemia. Preparations available. Salmon calcitonin. Synthetic human calcitonin. Available for subcutaneous or intramuscular injections and as a nasal spray.  Effects of Intranasal Calcitonin on New Vertebral Fractures P.R.O.O.F. Study New Vertebral Fractures after 4 Years 100 IU 200 IU 400 IU Placebo Number with at least one 53/272 47/286 54/278 67/269 new fracture/ number at risk Relative risk.815.643.776 to placebo (% reduction) (18%) (36%) (23%) P Value.265.020.165 From Chesnut, 1998  BISPHOSPHONATES Inhibit bone resorption. Net effect = hypocalcemia. Preparations available. Alendronate, tiludronate and risedronate Etidronate, pamidronate Zoledronic Acid Problems: poorly absorbed when taken orally and they may induce esophagitis. FOSAMAX® (ALENDRONATE SODIUM) TABLETS AND ORAL SOLUTION ACTONEL® (Risedronate sodium tablets)  Bisphosphonates: Long term Inhibitors of Bone Resorption R1 Alendronate (oral) Risedronate (oral) P C P Etidronate (oral or parenteral) Pamidronate (parenteral) R2 Bind to hydroxyapatite For patients with multiple myeloma & Inhibit osteoclast action metastatic bone lesions of solid tumors for patients with creatinine clearance Long skeletal retention (CrCl) greater than 60 mL/min the dose is 4 mg infused over 15 minutes every 4 weeks. Poor GI absorption Potency depends on side chains  Bisphosphonates Post-marketing Osteonecrosis of the Jaw Bone under the teeth is exposed, often painfully Swelling and loosening of teeth may be seen Attempts at surgical correction make lesions worse Most cases follow dental procedure such as tooth extraction Many cases are complicated by infection Occurs mainly in patients with cancer after prolonged IV therapy at high dose levels Subtrochanteric or Femoral Shaft Fractures Controversial finding Under FDA review Risk Benefit: Use for osteoporosis not osteopenia  Hormone Replacement Therapy (HRT): Estrogen and Derivatives WHI study halted when risk of HRT exceeded benefits Hip and vertebral fractures reduced by 34% All osteoporotic fractures reduced by 24% Slight increases in risk of heart attacks, strokes, and blood clots Risk of invasive breast cancer increased by 25% No increase in all-cause mortality Number of Prescriptions of Menopausal Hormone Therapy in U.S. by Year  Selective estrogen receptor modulators (SERMs) Raloxifene is the first SERM approved for osteoporosis Produces estrogen-agonist effects on bone and estrogen- antagonist effects on endometrial and breast tissue Minimizes undesirable effects of estrogen Meta-analysis shows positive effects on bone density; these increased over time and were independent of dose Significant increases in BMD for total body, lumbar spine, combined forearm, and combined hip BMDs (p< 0.01) Forms of Human PTH Preparations hPTH (1-84) – intact human PTH hPTH (1-34) – teriparatide Synthetic hPTH (1-34) or Recombinant hPTH (1-34) Effect of Teriparatide on Lumbar Spine BMD in Postmenopausal Women with Osteoporosis 16 14 * * * % change ± SE 12 10 * * 8 * * 6 4 * * 2 * 0 0 3 6 12 18 24 Months End Placebo TPTD20 TPTD40 *P 1 fracture Neer et al. N Engl J Med 2001; 344:1434-41 Effect of Teriparatide on the Risk of Nonvertebral Fragility1 Fractures RR 0.46 (95% CI, 0.25 to 0.86)** 7 RR 0.47 (95% CI, 0.25 to 0.88)* 6 % of Women 5 4 53% 54% 3 2 1 30 14 14 0 Placebo TPTD20 TPTD40 (n=544) (n=541) (n=552) No. of women who had > 1 fragility fracture  Denosumab: Prolia®/Xgeva® Denosumab At menopose, drop in estrogen results in increase RANKL release. This activates osteoclasts, triggered by receptor activator of nuclear factor kappa B (RANK). Denosumab binds RANK ligand (RANKL) with high specificity/affinity preventing RANK activation and osteoclasts Results: Decreased bone loss, increased cortical/ trabecular bone growth, and bone mineralization density (BMD).  Denosumab: Prolia®/Xgeva® Indication & Treatment regimen Prolia-Osteoporosis 1x every 6 months 60mg/1ml sc. inj. o Postmenopausal women and in men at increased risk of fractures. o Bone loss associated with hormone ablation in men with prostate cancer at increased risk of fractures. Xgeva-Bone metastases in cancer 1x every 4 weeks 120mg/1.7ml sc. inj. o Prevents skeletal related events (pathological fracture, radiation to bone, spinal cord compression or surgery to bone) in adults w/ bone metastases from solid tumors. o Adults and skeletally mature adolescents with giant cell tumor of bone that is unrespectable or where surgical resection is likely to result in severe morbidity. |  Prevention and Treatment To increase calcium absorption: Calcium supplementation Vitamin D To prevent calcium mobilization from bone: Calcitonin Bisphosphonates Estrogen + Progestins Selective estrogen receptor modulators (Raloxifene) Teriparatide (PTH 1-34) Denosumab (Prolia®/Xgeva®) Diseases Of Calcium Metabolism: HYPOCALCEMIA Causes Dietary calcium deficiency Vitamin D deficiency (nutritional rickets) Other forms of vitamin D deficiency or resistance (metabolic rickets osteomalacia) Hormonal imbalances (hypoparathyroidism, pseudohypoparathyroidism) Treatments Calcium salts (increase calcium uptake) Vitamin D (increase calcium absorption)  Diseases Of Calcium Metabolism: HYPERCALCEMIA Causes Hyperparathyroidism Ectopic PTH production Vitamin D excess Body immobilization Treatments Calcitonin (prevents bone resorption) Bisphosphonates (prevent bone resorption) Glucocorticoides (prevent intestinal calcium absorption)