Osteoporosis Treatment

1. Osteoporosis Treatment Dr. SAEED AHMED

2. osteoporosis • Bone undergoes a continuous remodeling process involving bone resorption and formation. • Increase resorption more than formation  osteoporosis

3. Characteristics • Abnormal loss of bone & skeletal fragility predisposing to fractures. • In osteoporosis:bone mineral density(BMD) is reduced & bone microarchitecture is disrupted.

4. Causes and risk factors • Age > 65 years • Occurs in elderly, most pronounced in postmenopausal women • Malabsorption syndrome • As a manifestation of endocrine disease (thyrotoxicosis or hyperparathyroidism) • Alcohol abuse & cigarette smoking • Long-term use of glucocorticoids or other drugs • Idiopathic

5. Long-term use of Glucocorticoidsmight induce osteoporosis by the following mechanisms: • 1- Decreasing Calcium intestinal absorption • 2- Increasing Calcium renal excretion • 3- Decreasing bone formation Antagonizing vit.D

6. Osteoporosis • In osteoporosis there is decreased bone mineral density (BMD) & disrupted bone architecture • This would increase fractures liability (common in hip bone and vertebrae) • Three hormones are responsible for Calcium homeostasis: • Calcitonin • Parathyroid hormone • 1,25-OH-D3 production

7. Drugs used in osteoporosis Hormones: • Calcium • Vit D • Hormone replacement therapy (estrogen) • Raloxifene (Selective Estorgen Receptor Modulator) • Calcitonin • Teriparatide ( r-PTH) Nonhormones: • bisphosphonates All drugs inhibit bone resorption except teriparatide

8. Calcitonin • A 32-amino-acid peptide secreted by parafollicular C cells of the thyroid gland • Calcitonin acts to decrease calcium concentration via calcitonin receptors in osteoclasts, GIT, kidney & brain • Inhibits osteoclastic activity in bones • Inhibits Ca2+/phosphate reabsorption by the renal tubules • Inhibits Ca2+ absorption by the intestine • Postmenopausal women tend to possess lower levels of plasma calcitonin levels Gastrin, pancreozymin (CCK), and increased serum Ca++ ↑secretion of calcitonin

9. Calcitonin • Pharamcological Actions: • Osteoclasts size & motility are decreased leading to inhibition of bone resorption • It inhibits the parathyroid hormone-induced acceleration of bone-turnover • It increases renal excretion of Na+, K+, Ca2+, Mg2+, and phosphate • Pharmaceutical formulations include: • Nasal spray • Parenteral formulation for IM or S.C. injection

10. Calcitonin Pharmacokinetics • Rapid absorption from injection sites (slow with the addition of gelatin) • T1/2 = 20 minutes • Weak protein binding • Hepatic (mainly) and renal metabolism • Nasal spray calcitonin has 5-50% bioavailability when compared to IM route

11. Calcitonin’s adverse effects • Dose dependent. • Increased with parenteral route. • They include: • Anorexia, nausea, and facial flushing • Urticaria or anaphylaxis are rare • Long-term use may lead to the formation of antibodies that are possibly ineffective • Drug-drug interaction: calcitonin + thiazide = K+ depletion Long term use  ↓Ca and phosphate  impaired bone formation

12. Vitamin D Vitamin D–Ca2+ absorption activation • PTH stimulates 25-OH-vitaminD3 1-α-hydroxylase in the kidney • This enzyme catalyzes hyroxylation of 25-OH-vitamin D3, to its active form 1,25-dihydroxy vitamin D3 (calcitriol) • This activated form of vitamin D increases the absorption of Ca2+ by the intestine via calbindin(calcium binding protein)

13. Preperations of Vit.D • 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 per week) • 1,25-dihydroxyvitamin-D (calcitriol), the active form Usually D2 or D3 are given with Ca++ If there was impaired activation of vit.D you can give calcitriol as a supplement

14. uses • Can be used in hypo and hyperparathyroidism Recommendation • 800 IU per day is recommended for postmenopausal women Vitamin D receptors (VDR) activation in the intestine, bone, kidney,& parathyroid gland cells leads to the maintenance of calcium and phosphate levels in the blood & for the maintenance of bone content

15. Low levels of vit.D ↑mineralization of bone High levels  potentiates the action of PTH In toxicity only

16. Calcium • Ca2+ chloride, Ca2+ citrate, Ca2+lactate, Ca2+gluconate(IV because has least vascular irritation), and Ca2+carbonate (taken orally) • Ca+2 carbonate converts to Ca+2 in the body which contains 40% elemental Ca Pharmaceutical forms Recommendation 1500 mg per day for post menopausal women

17. Calcium Adverse Effects • Oral calcium may cause: • Gastric irritation, nausea & constipation • Excessive Ca2+→ hypercalcemic toxicity especially in the presence of high vitamin D intake • Decrease tetracycline absorption

18. Hormone Replacement Therapy (HRT) • Estrogen deficiency causes bone loss via increased bone resorption. • Loss of estrogen→ ↑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 &Cerebrovasculardiseases, gallbladder disease, DVT, pulmonary thromboembolism,&breast cancer

19. Selective Estrogen Receptor Modulators (SERMs)Raloxifene • A non-hormonal agent that binds to estrogen receptors • They induce estrogen-like effects in some but not all tissues (specific) • Raloxifene(60 mg/day) is the only approved member for prevention & treatment of osteoporosis Pharmacokinetics: • 60% absorption from oral route • Bioavailability= 2% because of 1st pass metabolism and conjugation • high plasma protein binding. • Cholestyramine reduces absorption &enterohepatic cycling.

20. RaloxifeneEffects on BMD and Bone Turnover • 30-50% reduction of vertebral fractures • Non-vertebral fractures are either non-significantly 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

21. RaloxifeneExtra-Skeletal Benefits 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 in the incidences of estrogen receptor-dependent invasive breast cancer in low-risk osteoporotic postmenopausal women • Adverse Effects: Are safe and well-tolerated • Hot flashes & leg cramps • Infrequent venous thromboembolism (VTE), unrelated to leg cramps • Contraindicated in patients with VTE history

22. Bisphosphonates • Used for: osteoporosis, Paget’s disease, malignacyhypercalcemia and bone metastases • They have high affinity for bone tissue. • 50% is excreted by the kidney. The rest taken up by osteoclast Pharmacokinetics: • 2% absorption during fasting • Food reduces absorption • T1/2: 1 hour • Administered 1 hour before meals with water only. The patient is advised to take it in an upright position and remain so for 30 to 60 minutes in order to prevent esophagitis and esophageal ulcers.

23. Pyrophosphate-like Etidronate Mechanism: Metabolized in cells forming non-functional cytotoxic ATP molecules Cell death of osteoclast ↓bone resorption Nitrogen-containing Alendronate&Risedronate Mechanism: 1000-times more potent Blocking the enzyme farnesyldiphosphatesynthase (FPPS) in the HMG-CoAreductase (the mevalonic acid) pathway This prevents the formation of two metabolites essential for connecting small proteins to the cell membrane of osteoclast (prenylation) Proper sub-cellular protein trafficking is impaired BisphosphonatesMechanism of Action

24. BisphosphonatesAdverse Effects • N-containing bisphosphonates are contraindicted with esophageal pathology. (they may cause gastroesophageal reflux) • IV  fever and flu like symptoms (after 1st infusion) • ↑risk for electrolyte disturbances • In chronic renal failure, the drugs are excreted much more slowly, thus dose adjustment is required. • At high doses, etidronate may cause osteomalacia.

25. Parathyroid Hormone (PTH) • PTH acts to increase the concentration of calcium in the blood by acting upon PTH receptors in three organs • Bone: Release of calcium from the large reservoir contained in the bones • Kidney:Reabsorption of calcium and magnesium from distal tubules and the thick ascending limb and increases the excretion of phosphate • Intestine: Absorption of calcium in the intestine indirectly by increasing the production of activated vitamin D in the kidney.

26. Bone physiologic effects of PTH • In high amounts of PTH (physiologic PTH)  induction of bone resorption(stimulate osteoclasts) • In small quantity or intermittent amounts of PTH bone formation (stimulates osteoblasts)

27. Parathyroid Hormone (PTH)Teriparatide {rh-PTH(1-34)} • Recombinant hPTH(1-34) shows good efficacy against vertebral & non-vertebral fractures in postmenopausal 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 and/or hypercalciuria

28. A 58-year old postmenopausal woman waas sent for dual-energy x-ray absorptiometry to evaluate her BMD of her lumbar spine, femoral neck and total hip. The test results revealed significantly low BMD in all sites.

29. Chronic use of which of the following drugs is MOST likely to have contributed to this woman's osteoporosis? • Lovastatin • Metformin • Prednisone • Propranalol • Thiazide diuretic prednisone

30. If this patient began oral therapy with alendronate, she would be advised to drink large quantities of water with the tablets and remain in the upright position for at least 30 min and until eating the first meal of the day. These instructions would be given to decrease the risk of • Cholelithiasis • Diarrhea • Constipation • Erosive esophagitis • Pernicious anemia • Erosive esophagitis

31. The patients condition was not sufficiently controlled with alendronate, so she began therapy with a nasal spray containing a protein that inhibit bone resorption. The drug contained in the nasal spray was • Calcitonin • Calcitriol • Cinacalcet • Cortisol • Teriparatide • Calcitonin