Osteoporosis Treatment Dr SAEED AHMED osteoporosis n Bone
Osteoporosis Treatment Dr. SAEED AHMED
osteoporosis n Bone undergoes a continuous remodeling, process involving bone resorption and formation. n Any process that disrupt this balance by increasing resorption relative to formation results in osteoporosis 2009 Mahmoud Khattab
Drugs used in osteoporosis n Calcium n Vit D n HRT(estrogen( n Raloxifene (SERM( n BISPHOPHONATES n Calcitonin n Teriparatide ( PTH, recombinant( 2009 Mahmoud Khattab
n Abnormal loss of bone & skeletal fragility predisposing to fractures. n In osteoporosis ! bone mineral density (BMD) is reduced & n bone microarchitecture is disrupted. 2009 Mahmoud Khattab
n Causes/ Risk factors: n Long-term use of glucocorticoides/ other drugs n As a manifestation of endocrine disease n n n 2009 (thyrotoxicosis/ hyperparathyroidism) Malabs syndrome Alcohol abuse & cigarette smoking Age > 65 yrs Idiopathic. Occur in elderly in both sexes, is most pronounced in postmenopausal women. Mahmoud Khattab
Osteoporosis q In osteoporosis there is decreased bone mineral density (BMD) & disrupted bone architecture q This would increase fracture liability q Three hormones are responsible for Calcium homeostasis ü Calcitonin ü Parathyroid hormone ü 1, 25 -OH-D 3 production 2009 Mahmoud Khattab
Calcitonin q Nature: A 32 -amino acid-polypeptide secreted by parafollicular(C-) cells of the thyroid gland q Calcitonin acts to decrease calcium concentration via calcitonin receptors in osteoclasts, GIT, kidney & brain ü Inhibits Ca 2+ absorption by the intestines ü Inhibits osteoclast activity in bones ü Inhibits Ca 2+/phosphate reabsorption by the kidney tubules q Post-menopausal women tend to possess lower levels of plasma calcitonin levels q Pharmaceutical formulations include: ü Nasal spray Mahmoud Khattab ü 2009 Parenteral formulation for IM or S. C. injection
Calcitonin q Pharamcological Actions: ü Osteoclasts size & motility are decreased leading to inhibition of bone resorption ü It inhibits the parathyroid hormone-induced acceleration of bone turnover ü GIT gastrin & pancreozymin or increased serum Ca 2+ stimulate calcitonin secretion ü It increases renal excretion of Na+, K+, Ca 2+, Mg 2+, and phosphate 2009 Mahmoud Khattab
Calcitonin Pharmacokinetics n Rapid absorption from injection sites (slow with addition of gelatin( n Half-life is short of about 20 minutes n Weak protein binding n Renal and hepatic metabolism n Nasal spray calcitonin has 5 -50% availability when compared to IM route 2009 Mahmoud Khattab
Calcitonin adverse effects n Adverse effects are dose-dependent and more frequent n Ø Ø with parenteral use but rarely observed after nasal spray administration They include: Anorexia, nausea, & fascial flushing Urticaria or anaphylaxis is rare Long-term use may lead to formation of antibodies that possibly are ineffective Uncommon drug-drug interacions except for K+ depletion when calcitonin combined with thiazide diuretics 2009 Mahmoud Khattab
Calcium and Vitamin D–Ca 2+ absorption activation n PTH up-regulates 25 -OH-vitamin. D 3 -1 -alphahydroxylase in the kidney n This enzyme activates hyroxylation of 25 -OHvitamin D, to its active form 1, 25 -dihydroxy vitamin D n This activated form of vitamin D increases the absorption of Ca 2+ ions by the intestine via calbindin 2009 Mahmoud Khattab
Calcium and Vitamin D Preparations q Ca chloride, Ca citrate, Ca lactate, Ca gluconate, and Ca q q ü ü ü carbonate (richest Ca source) Insoluble Ca carbonate contains 40% elemental Ca 2+, after conversion to Ca salts in the body Vitamin D Used forms include: Vitamin D 2 (ergocalciferol) Vitamin D 3 (adequate amounts of vitamin D 3 can be made in the skin after 10 -15 min of sun exposure 2 times/week 1, 25 -dihydroxyvitamin-D (calcitriol), the active form 2009 Mahmoud Khattab
Calcium and Vitamin D n 1500 mg of Calcium and 800 IU of vitamin D per day are recommended for postmenopausal women n Vitamin D receptors (VDR) activation in the intestine, bone, kidney, & parathyroid gland cells leads to the maintenance of calcium and phosphorus levels in the blood & to the maintenance of bone content n Parathyroid hormone and calcitonin play a role 2009 Mahmoud Khattab
Calcium and Vitamin D Adverse Effects q Oral calcium may cause ü Gastric irritation, nausea & constipation ü Excessive Ca→ hypercalcemic toxicity especially in presence of high vitamin D intake ü Decreased tetracycline absorption q Vitamin D ü Overdose → hypercalcemia & hyperphosphatemia ü Renal dysfunction (nephro-lithisis & -calcinosis) ü Localised/generalised lowered bone density ü GIT complaints 2009 Mahmoud Khattab
Hormone Replacement Therapy (HRT) q Estrogen deficiency causes bone loss via increased bone resorption over bone formation q Loss of estrogen→ ↑IL-1, IL-6 & TNF-α → enhance osteoclast replication & differentiation q HRT Beneficial Effects: ü HRT increases BMD → beneficial in vertebral & non-vertebral fractures ü Control of menopausal/urogenital symptoms ü Reduced risk of colon cancer q HRT Risk: ↑CV & Cerebro. V diseases, gall bladder disease, DVT, pulmonary emboli, & breast cancer 2009 Mahmoud Khattab
Selective Estrogen Receptor Modulators (SERMs) Raloxifene q Non-hormonal agents that bind to estrogen receptors with an affinity equivalent to estradiol q They induce estrogen-like effects in some but not all tissues q Raloxifene (60 mg/day) is the only approved member for prevention & treatment of osteoporosis q Pharmacokinetics: Ø It is rapidly absorbed by 60% from oral route Ø It has low bioavailability (2%) because of extensive firstpass metabolism and glucuronide conjugation Ø It has high plasma protein binding Ø Cholestyramine reduces absorption & enterohepatic cycling 2009 Mahmoud Khattab
Raloxifene Effects on BMD and Bone Turnover n Clinical evidence (MORE) of 30 -50% reduction of vertebral fractures n Non-vertebral fractures are either non-significantly affected or reduced in women with severe vertebral factures n Significant increase of BMD in the lumbar spine and femoral neck n Reduction of bone turnover markers 2009 Mahmoud Khattab
Raloxifene Extra-Skeletal and Adverse Effects n Reduction of total lipids and LDL-cholesterol n Reduction of CVD risk ONLY in women at high risk or with established CVD n Reduction of incidence of the estrogen receptordependent invasive breast cancer in low-risk osteoporotic post-menopausal women n Adverse Effects It is safe and well-tolerated Ø Increased hot flashes & leg cramps Ø Infrequent venous thromboembolism (VTE), not related to leg cramps Ø Contraindicated in patients with VTE history 2009 Mahmoud Khattab
Bisphonates q They are used for many bone diseases including: osteoporosis, Paget’s disease, malignacy hypercalcemia and bone metastases q They have a very high affinity for bone tissue, ü 50% of administered dose is excreted unchanged by the kidney, the remainder is rapidly taken up by the osteoclasts q Pharmacokinetics: ü Poor absorption (2% during fasting) ü Food reduces absorption ü T 1/2: 1 hour ü Administered 1 hour before meals with water only 2009 Mahmoud Khattab
Bisphonates Mechanism of Action Pyrophosphate-like q Etidronate q Metabolised in the cell to forming a nonfunctional cytotoxic ATP molecules q Apoptosis/cell death of osteoclast occurs leading to a decrease in the breakdown of bone J Bone Miner Res. 1997, 12(9): 1358 -67 Bone 2003; 33 (5): 805– 11 2009 Nitrogen-containing q Alendronate & Risedronate q 1000 -times more potent q Blocking the enzyme farnesyl diphosphate synthase (FPPS) in the HMG-Co. A reductase (the mevalonate) pathway Ø This prevents the formation of two metabolites essential for connecting some small proteins to the cell membrane (prenylation) Ø Proper sub-cellular protein trafficking is impaired as well Mahmoud Khattab
Bisphonates Adverse Effects n Oral N-containing bisphonates may cause upset n n n stomach and inflammation & erosions of the esophagus, can be prevented by remaining seated upright for 30 to 60 minutes after taking the medication N-containing bisphonates contraindicted with esophageal pathology Intravenous bisphonates can give fever and flu-like symptoms after the first infusion only A slightly increased risk for electrolyte disturbances In chronic renal failure, the drugs are excreted much more slowly, and dose adjustment is required At high doses, etidronate may cause osteomalcia 2009 Mahmoud Khattab
Parathyroid Hormone (PTH) Teriparatide {rh. PTH(1 -34)} q Recombinant h. PTH(1 -34) showed good efficacy against q q q ü ü ü vertebral & non-vertebral fractures in post-menopausal women It increases BMD at skeleton sites except radius It increases BMD at the spine in severe osteoporotic men & glucocorticoid-induced osteoporosis postmenopausal women Adverse effects: Nausea, headache, dizziness Infrequently leg cramps Occasional hypercalcemia &/or hypercalciuria 2009 Mahmoud Khattab
Parathyroid Hormone (PTH) Reminder of Activity q PTH acts to increase the concentration of calcium in the blood by acting upon PTHR in three organs ü Bone: It enhances the release of calcium from the large reservoir contained in the bones ü Kidney: It enhances active re-absorption of calcium and magnesium from distal tubules and the thick ascending limb and increases the excretion of phosphate ü Intestine: It enhances the absorption of calcium in the intestine by increasing the production of activated vitamin D in the kidney 2009 Mahmoud Khattab
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