Osteoporosis Treatment

1. Osteoporosis Treatment Mahmoud Khattab, Ph.D.

2. Osteoporosis • In osteoporosis there is decreased bone mineral density (BMD) & disrupted bone architecture • This would increase fracture liability • Three hormones are responsible for Calcium homeostasis • Calcitonin • Parathyroid hormone • 1,25-OH-D3 production Mahmoud Khattab

3. Calcitonin • Nature: A 32-amino acid-polypeptide secreted by parafollicular(C-) cells of the thyroid gland • Calcitonin acts to decrease calcium concentration via calcitonin receptors in osteoclasts, GIT, kidney & brain • Inhibits Ca2+ absorption by the intestines • Inhibits osteoclast activity in bones • Inhibits Ca2+/phosphate reabsorption by the kidney tubules • Post-menopausal women tend to possess lower levels of plasma calcitonin levels • Pharmaceutical formulations include: • Nasal spray • Parenteral formulation for IM or S.C. injection Mahmoud Khattab

4. Calcitonin • Pharamcological Actions: • Osteoclasts size & motility are decreased leading to inhibition of bone desorption • It inhibits the parathyroid hormone-induced acceleration of bone turnover • GIT gastrin & pancreozymin or increased serum Ca2+ stimulate calcitonin secretion • It increases renal excretion of Na+, K+, Ca2+, Mg2+, and phosphate Mahmoud Khattab

5. Calcitonin Pharmacokinetics • Rapid absorption from injection sites (slow with addition of gelatin) • Half-life is short of about 20 minutes • Weak protein binding • Renal and hepatic metabolism • Nasal spray calcitonin has 5-50% availability when compared to IM route Mahmoud Khattab

6. Calcitonin adverse effects • Adverse effects are dose-dependent and more frequent with parenteral use but rarely observed after nasal spray administration • They include: • Anorexia, nausea, & facial flushing • Urticaria or anaphylaxis is rare • Long-term use may lead to formation of antibodies that possibly ineffective • Uncommon drug-drug interacions except for K+ depletion when calcitonin combined with thiazide diuretics Mahmoud Khattab

7. Calcium and Vitamin D Vitamin D–Ca2+ absorption activation • PTH up-regulates 25-OH-vitaminD3-1-alpha-hydroxylase in the kidney • This enzyme activates hyroxylation of 25-OH-vitamin D, to its active form 1,25-dihydroxy vitamin D • This activated form of vitamin D increases the absorption of Ca2+ ions by the intestine via calbindin Mahmoud Khattab

8. Calcium and Vitamin D Preparations • Ca chloride, Ca citrate, Ca lactate, Ca glucnate, and Ca carbonate (richest Ca source) • Insoluble Ca carbonate contains 40% elemental Ca2+, after conversion to Ca salts in the body • Vitamin D Used forms include: • Vitamin D2 (ergocalciferol) • Vitamin D3 (adequate amounts of vitamin D3 can be made in the skin after 10-15 min of sun exposure 2 times/week • 1,25-dihydroxyvitamin-D (calcitriol), the active form Mahmoud Khattab

9. Calcium and Vitamin D • 1500 mg of Calcium and 800 IU of vitamin D per day are recommended for postmenopausal women • 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 • Parathyroid hormone and calcitonin play a role Mahmoud Khattab

10. Calcium and Vitamin DAdverse Effects • Oral calcium may cause • Gastric irritation, nausea & constipation • Excessive Ca→ hypercalcemic toxicity especially in presence of high vitamin D intake • Decreased tetracycline absorption • Vitamin D • Overdose → hypercalcemia & hyperphosphatemia • Renal dysfunction (nephro-lithisis & -calcinosis) • Localised/generalised lowered bone density • GIT complaints Mahmoud Khattab

11. Hormone Replacement Therapy (HRT) • Esterogen deficiency causes bone loss via increased bone desorption over bone formation • Loss of esterogen→ ↑IL-1, IL-6 & TNF-α → enhance osteoclast replication & differentiation • HRT Beneficial Effects: • HRT increases BMD → beneficial in vertebral & non-vertebral fractures • Control of menopausal/urogenital symptoms • Reduced risk of colon cancer • HRT Risk: ↑CV & CerebroV diseases, gall bladder disease, DVT, pulmonary emboli, & breast cancer Mahmoud Khattab

12. Selective Esterogen Receptor Modulators (SERMs)Raloxifene • Non-hormonal agents that bind to esterogen receptors with an affinity equivalent to estradiol • They induce esterogen-like effects in some but not all tissues • Raloxifene (60 mg/day) is the only approved member for prevention & treatment of osteoporosis • Pharmacokinetics: • It is rapidly absorbed by 60% from oral route • It has low bioavailability (2%) because of extensive first-pass metabolism and glucuronide conjugation • It has high plasma protein binding • Cholestyramine reduces absorption & enterohepatic cycling Mahmoud Khattab

13. RaloxifeneEffects on BMD and Bone Turnover • Clinical evidence (MORE) of 30-50% reduction of vertebral fractions • Non-vertebral fractions are either non-significantl affected or reduced in women with severe vertebral factures • Significant increase of BMD in the lumbar spine and femoral neck • Reduction of bone turnover markers Mahmoud Khattab

14. RaloxifeneExtra-Skeletal and Adverse Effects • Reduction of total lipids and LDL-cholesterol • Reduction of CVD risk ONLY in women at high risk or with established CVD • Reduction of incidence of the esterogen receptor-dependent invasive breast cancer in low-risk osteoporotic post-menopausal women • Adverse Effects It is safe and well-tolerated • Increased hot flashes & leg cramps • Infrequent venous thromboembolism (VTE), not related to leg cramps • Contraindicated in patients with VTE history Mahmoud Khattab

15. Bisphosphonates • They are used for many bone diseases including: osteoporosis, Paget’s disease, malignacy hypercalcemia and bone metastases • They have a very high affinity for bone tissue, • 50% of administered dose is excreted unchanged by the kidney, the remainder is rapidly taken up by the osteoclasts • Pharmacokinetics: • Poor absorption (2% during fasting) • Food reduces absorption • T1/2: 1 hour • Administered 1 hour before meals with water only Mahmoud Khattab

16. Pyrophosphate-like Etidronate Metabolised in the cell to forming a nonfunctional cytotoxic ATP molecules Apoptosis/cell death of osteoclast occurs leading to a decrease in the breakdown of bone Nitrogen-containing Alendronate & Risedronate 1000-times more potent Blocking the enzyme farnesyl diphosphate synthase (FPPS) in the HMG-CoA reductase (the mevalonate) pathway This prevents the formation of two metabolites essential for connecting some small proteins to the cell membrane (prenylation) Proper sub-cellular protein trafficking is impaired as well BisphosphonatesMechanism of Action J Bone Miner Res. 1997, 12(9): 1358-67 Bone 2003; 33 (5): 805–11 Mahmoud Khattab

17. BisphosphonatesAdverse Effects • Oral N-containing bisphosphonates may cause upset 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 bisphosphonates contraindicted with esophageal pathology • Intravenous bisphosphonates 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 Mahmoud Khattab

18. Parathyroid Hormone (PTH)Teriparatide {rhPTH(1-34)} • Recombinant hPTH(1-34) showed good efficacy against 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 osteoporsis postmenopausal women • Adverse effects: • Nausea, headache, dizziness • Infrequently leg cramps • Occasional hypercalcemia &/or hypercalciuria Mahmoud Khattab

19. Parathyroid Hormone (PTH)Reminder of Activity • PTH acts to increase the concentration of calcium in the blood by acting upon PTHR in three organs • Bone: It enhances the release of calcium from the large reservoir contained in the bones • Kidney: It enhances active re-absorption of calcium and magnesium from distal tubules and the thick ascending limb and increases the excretion of phosphate • Intestine: It enhances the absorption of calcium in the intestine by increasing the production of activated vitamin D in the kidney Mahmoud Khattab