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Pharmacotherapy of Osteoporosis.

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  2. 2. OSTEOPOROSIS Reduction in strength of bone that leads to an increased risk of fracture  Bone mass – reduced,  Internal bone architecture – degrades  Decreased bone formation  Increased bone resorption 
  3. 3. ANTIRESORPTIVE BONE ANABOLIC AGENT Bisphosphonates  SERM  HRT  RANKL antagonist  Calcitonin  Cathepsin K Inhibitor (Odanacatib )  r Osteoprotegerin   Parathyroid hormone  Strontium Ranelate  Endogenous PTH stimulation – calcium sensing receptor antagonist (calcilytic)  Sclerostin inhibitor PHARMACOLOGICAL AGENT
  4. 4. BISPHOSPHONATES 1st Generation Etidronate Tiludronate 2nd Generation Pamidronate Alendronate Ibandronate 3rd Generation Risedronate Zoledronate
  5. 5. BISPHOSPHONATES Pyrophosphate analouge : carbon atom replacing oxygen in the P-O-P skeleton  The most effective antiresorptive drug  1st generetion compound have simple side chain  2nd & 3rd generation have an amino or nitrogenous ring substitution in the side chain 
  6. 6. Mechanism of Action Strong affinity for calcium phosphate ↓ Concentrate in mineralized tissue ↓ Remain unmetabolized and biologically active ↓ Acids secreted by osteoclast dissociates it from mineral ↓ Within osteoclast blocks mevalonate pathway ↓ Osteoclast apoptosis
  7. 7. Alendronate Alendronate treatment (5 mg/d for 2 years and 10 mg/d for 9 months afterwards) reduces vertebral fracture risk by about 50%, multiple vertebral fractures by up to 90%, and hip fractures by up to 50%.  Trials comparing once-weekly alendronate, 70 mg, with daily 10-mg dosing have shown equivalence with regard to bone mass and bone turnover responses.  once-weekly therapy generally is preferred because of the low incidence of gastrointestinal side effects and ease of administration. 
  8. 8. Alendronate  Approved for: ◦ Treatment and prevention of osteoporosis in post – menopausal women ◦ Treatment of osteoporosis in men ◦ Treatment of steroid induced osteoporosis Dose : 10mg /d or 70 mg/ week  Route : oral 
  9. 9. Alendronate  Empty stomach, full glass of water, before breakfast  Remain upright for at least 30 min after taking the medication  To prevent esophageal irritation, oesophagitis  Contraindicated in patients who have stricture or inadequate emptying of the esophagus
  10. 10. Risedronate  Controlled clinical trials have demonstrated 40–50% reduction in vertebral fracture risk over 3 years, accompanied by a 40% reduction in clinical nonspine fractures.  The only clinical trial specifically designed to evaluate hip fracture outcome (HIP) indicated that risedronate reduced hip fracture risk in women in their seventies with confirmed osteoporosis by 40%.
  11. 11. Risedronate  Osteoporosis in Postmenopausal Women: ◦ ◦ ◦ ◦  5 mg daily 35 mg once a week 75 mg taken on two consecutive days each month 150 mg once a month Prevention of Osteoporosis in Postmenopausal Women: ◦ 5 mg daily, 35 mg once a week  Men with Osteoporosis: ◦ 35 mg once a week  Treatment and Prevention of GlucocorticoidInduced Osteoporosis ◦ 5 mg daily
  12. 12. Ibandronate  Reduce vertebral fracture risk by 40% but with no overall effect on nonvertebral fractures  Approved for ◦ Treatment and prevention of postmenopausal osteoporosis  Dose: ◦ One 150 mg tablet taken once monthly ◦ one 2.5 mg tablet taken once daily
  13. 13. Zoledronate  Highly effective in fracture risk reduction  Zoledronic acid (5 mg as a single IV infusion annually) reduced the risk of vertebral fractures by 70%, nonvertebral fractures by 25%, and
  14. 14. Zoledronate  Approved For: ◦ Treatment of osteoporosis in postmenopausal women ◦ Treatment to increase bone mass in men with osteoporosis ◦ Treatment and prevention of glucocorticoid-induced osteoporosis in patients expected to be on glucocorticoids for at least 12 months
  15. 15. Zoledronate  Dose ◦a 5 mg infusion once a year given intravenously over no less than 15 minutes  Administer through a separate vented infusion line and do not allow to come in contact with any calcium or divalent cation-containing solutions
  16. 16. BISPHOSPHONATES – ADVERSE EFFECTS Oral bisphosphonates can cause heartburn, esophageal irritation, or esophagitis.  Other GI side effects include abdominal pain and diarrhea  Osteonecrosis of the jaw  Hypocalcemia  Musculo-skeletal pain 
  17. 17. SERMs  Group of compound – binds to estrogen receptor (ER)  Tissue selective effects on target organ  Estrogen agonist or antagonist  Retain the beneficial effects on estrogen in one or more tissues  Eliminates the undesirable effects of estrogen in other tissue
  18. 18. RALOXIFENE  Estrogen agonist in bone , antagonist in breast and endometrium  Approved for the treatment and prevention of osteoporosis in post – menopausal women  Dose: 60 mg/d, orally  Increases bone mass density  Reduce the risk of breast cancer  No risk of endometrial carcinoma
  19. 19. RALOXIFENE  Reduces serum total and low-density lipoprotein cholesterol, lipoprotein(a), and fibrinogen. Reduce vertebral fracture  No effect on incidence of heart disease  Increase risk of venous thromboses and pulmonary embolism  Increases the occurrence of hot flashes
  20. 20. LASOFOXIFENE  Investigational SERM  Not approved by FDA, US.  Approved by the European Commission for the treatment of osteoporosis fractures in post-menopausal women.
  21. 21. LASOFOXIFENE  Phase II or phase III clinical trials demonstrated efficacy and safety in the suppression of bone loss and the prevention of vertebral and nonvertebral fractures.  Reduce breast cancer risk and the occurrence of vaginal atrophy.
  22. 22. OTHER SERMs under Clinical Trials: Bazedoxifene  Ospemifene  Arzoxifene 
  23. 23. Hormone Replacement Therapy       HRT restores the Ca 2+ balance Bone loss is prevented Administered orally or transdermally Doses: oral estrogens esterified estrogens - 0.3 mg/d  conjugated equine estrogens - 0.625 mg/d  ethinyl estradiol – 5 mcg/d . Transdermal estrogen, ◦ 50 mcg estradiol per day.
  24. 24. Hormone Replacement Therapy  WHI (Womens Health Initiative) data:  Hip and vertebral fractures reduced by 34%  All osteoporotic fractures reduced by 24%  Increased risk of fatal and nonfatal myocardial infarction by 29%   Risk of invasive breast cancer increased by 25% The FDA now recommends that estrogen be reserved for women at significant risk of osteoporosis who cannot take other medications.
  25. 25. RANKL antagonist - Denosumab  Human monoclonal antibody  Target - RANKL (RANK ligand)  Approved by the FDA in 2010 ◦ Treatment of postmenopausal women who have a high risk for osteoporotic fractures, including those with a history of fracture or multiple risk factors for fracture ◦ Who have failed or are intolerant to other osteoporosis therapy.
  26. 26. Denosumab Dose : 60 mg every 6 month  Route : S.C.  Increase BMD in the spine, hip, and forearm and reduce vertebral, hip, and nonvertebral fractures  Adverse reactions  ◦ hypocalcemia, infections, and dermatologic reactions such as dermatitis, rashes, and eczema ◦ Osteonecrosis of jow
  27. 27. CALCITONIN  Polypeptide hormone produced by the thyroid gland  Suppresses osteoclast activity by direct action on the osteoclast calcitonin receptor  Approved by the FDA for osteoporosis in women >5 years past menopause.
  28. 28. CALCITONIN  Preparation : ◦ Nasal spray : 200 IU/d ◦ Parentral : S.C. or I.M. 50 to 100 IU/alternative day  Difficulty of administration and frequent reactions, including nausea and facial flushing, make general use limited.
  29. 29. ODANACATIB  Cathepsin K- plays a key role in degradation of the matrix  Cathepsin K Inhibitor  Investigational Drug  Under Clinical Trial
  30. 30. Gene therapy ( r Osteoprotegerin  Osteoprotegerin (OPG) is a naturally occuring protein that prevents bone resorption by inhibiting osteoclast formation, function and survival  Binds to RANKL and prevents its binding to RANK on Osteoclast precursor and osteolclast  Gene therapy has the potential to deliver protein-based antiresorptive agents without the need for repeated administration.
  31. 31. Gene therapy ( r Osteoprotegerin)  Adeno-associated virus (AAV) could deliver OPG at levels that are sufficient to reverse established osteopenia in ovariectomized (OVX) mice without causing liver toxicity  AAV delivery appears to be a safe and effective method for producing sustained systemic exposure to OPG.
  32. 32. PARATHYROID HORMONE TERIPARATIDE     Exogenous PTH analogue Recombinant human parathyroid hormone (1-34), [rhPTH(1-34)] Direct actions on osteoblast activity Stimulates IGF-I and collagen production and appears to increase osteoblast number by stimulating replication, enhancing osteoblast recruitment, and inhibiting apoptosis
  33. 33. TERIPARATIDE     Reduced vertebral fractures by 65% and nonvertebral fractures by 45% Increases in bone mass and mediates architectural improvements in skeletal structure. These effects are lower when patients have been exposed previously to bisphosphonates When 1–34hPTH is being considered for treatment-naive patients, it is best administered as monotherapy and followed by an antiresorptive agent such as a bisphosphonate.
  34. 34. TERIPARATIDE  Approved for : ◦ Osteoporosis in postmenopausal women ◦ Idiopathic and hypogonadal osteoporosis in men ◦ Glucocorticoid induced osteoprorosis    DOSE : 20 mcg / day ROUTE : SC Side effects : ◦ muscle pain, weakness, dizziness, headache, and nausea  In Rodents – caused osteogenic
  35. 35. STRONTIUM RANELATE    A new antiosteoporotic treatment with a dual mode of action, both increasing bone formation and decreasing bone resorption Stimulates the calcium sensing receptors and leads to the differentiation of preosteoblast to osteoblast which increases the bone formation. Stimulates osteoblasts to secrete osteoprotegerin in inhibiting osteoclasts formed from pre-osteoclasts in relation to the RANKL system, which leads to the decrease of bone resorption.
  36. 36. STRONTIUM RANELATE  Not approved by US FDA  Approved in European Country  Indicated for post- menopausal osteoporosis  Dose : 2 g / day  Route : oral
  37. 37. CALCIUM SENSING RECEPTOR ANTAGONIST (CALCILYTIC) Calcium-sensing receptor (CaSR) is a G protein-coupled receptor which was identified as a molecule that medicates the suppression of parathyroid hormone (PTH) secretion by extracellular Ca.  Oral antagonists of the calciumsensing receptor (calcilytics) stimulate PTH secretion  Investigational drug 
  38. 38. SCLEROSTIN INHIBITOR  Sclerostin is a potent inhibitor of osteoblastogenesis is a glycoprotein secreted by osteocytes  Monoclonal antibody  can be administered subcutaneously  Investigational Drug
  39. 39. References: 1. 2. 3. 4. Robert Lindsay, Felicia Cosman. Osteoporosis. In: Fauci S, editor : Harrison’s Principles of Internal Medicine, 18th ed. . New York: Mcgraw Hill; 2012.p.3120- 35. Peter A Friedman.Agents Affecting Mineral Ion Homeostasis and Bone Turnover In: Brunton L, editor.Goodman & Gillman’s The Pharmacological Basis of Therapeutics, 12th ed. New York: Mcgraw Hill; 2011.p.1275- 1306. Robert M. Neer, Ehrin J. Armstrong, Armen H. Tashjian, Jr. Pharmacology of Bone Mineral Homeostasis. In: David Golan, editor. Principles of Pharmacology, The rd Pathophysiological Basis of Drug Therapy, 3 ed. Philadelphia: Lippincott Williams and Wilkins Publications; 2012.p.541-61. Lewiecki EM. Odanacatib, a cathepsin K inhibitor for the treatment of osteoporosis and other skeletal disorders associated with excessive bone remodeling. IDrugs. 2009 Dec;12(12):799-809.
  40. 40. References:   John MR et al. ATF936, a novel oral calcilytic, increases bone mineral density in rats and transiently releases parathyroid hormone in humans. Bone. Aug 2011;49(2):233-41. Epub 2011 Apr 14. Luigi Gennari, Daniela Merlotti, Vincenzo De Paola, and Ranuccio Nuti. Lasofoxifene: Evidence of its therapeutic value in osteoporosis. Core Evid. 2009; 4: 113–129.