1. Osteoporosis Pharmacology Krishna Prasad Khanal, MD R1 CRMEF April 2, 2010

2. Objectives To describe pharmacological management of Osteoporosis. To compare efficacy of various pharmacotherapeutic agents vs. placebo in fracture reduction. To monitor response to therapy.

3. Osteoporosis: Gross pathology

4. Osteoporosis: Femur neck

5. Normal Bony Spicules

6. Decreased Bony Spicules

7. Osteoporosis: loss of bone density

8. Bisphosphonates DosePrevention?Treatment? Alendronate (Fosamax) PO Daily PO Weekly Yes Risedronate (Actonel) PO daily PO weekly PO monthly Yes Ibandronate (Boniva) PO daily PO monthly IV q3months Yes Zoledronic acidIV annuallyNoYes

9. Fracture Benefit BisphosphonateSpine NonvertebralHipCost/mon Alendronate x x x $33 Risedronate x x x $105 Ibandronate x - - $102 Zoledronic acid x x x $94 Raloxifene x - - $108 Calcitonin x - - $123 Estrogen(HRT) x x x $55 Teriparatide x x - $900

11. Cochrane Review: Alendronate 11 RCTs for at least 1 year in 12,068 women with post menopausal osteoporosis. Alendronate 10 mg PO daily vs. placebo Cochrane reference

12. Indications Following a hip or vertebral fracture. T score less than -2.5 at femoral neck, total hip or spine by DXA. T score -1 to -2.5 and secondary causes associated with high risk of fracture. Postmenopausal women or men more than 50 with: osteopenia and WHO absolute fracture risk model (FRAX): 10 yr hip fracture probability more than 3% or 10 yr all major osteoporosis-related fracture probability of more than 20%. National Osteoporosis Foundation Guidelines

13. Cochrane Review: Results AlendronatePlacebonNNT Primary vertebral fractures 1.9%3.4%457667 Secondary vertebral fractures 7.3%12.2%278521 Secondary non vertebral fractures 7.29.3504948 Secondary hip fracture 0.6% 1.3%5376143

15. FIT trials Level 1 evidence, FIT included women aged 55-80 yrs who were post-menopausal for at least 2 yrs and had femoral neck T score<- 1.6). FIT I trial: 2,027 women with at least 1 previous vertebral fracture, mean follow up 2.9 yrs. FIT II trial: 4,432 women with no vertebral fracture, mean follow up 4.3 yrs. J Am Geriatr Soc 2002 Mar; 50(3):409

16. FIT Trials Cont’d…… Reduced the risk of multiple symptomatic fractures in women with osteoporosis (vertebral fracture or T score<-2.5). FIT II: analysis of 1,631 women without vertebral fractures but with T score < - 2.5. Risk for multiple symptomatic fractures was 2.8% in alendronate group vs. 4.7% in placebo group (NNT 53).

17. FIT I Trial Reduced rate of clinically apparent non vertebral fracture by 50% in trial of 2,027 post- menopausal women with osteoporosis and at least one previous vertebral fracture. FIT randomized such women to alendronate 5- 10 mg orally once daily vs. placebo X 3 yrs, all clinical fractures reduced by 28%, hip fractures by 51%, wrist fractures by 48% and any non- vertebral fractures by 20%, clinical vertebral fractures reduced 55%; no increase in adverse GI effects. Lancet 1996 Dec 7;348(9041):1535

18. FIT II Results FIT II trial AlendronateARRNNTBMD<-2.5 Femoral neck fracture 36%6.5%15Not significant Vertebral fracture 44%1.7%60Not significant JAMA 1998 Dec 23/30;280(24):2077

19. FIT II Trial Recommends treatment with bisphosphonates for women with BMD>2.5 SD below mean, h/o any fracture after age 40 yrs, corticosteroid therapy, impending prolonged immobilization, or maternal h/o hip fracture Recommends weight bearing exercises, Calcium at least 1,500 mg/day and Vitamin D upto 1,000 units/day. JAMA 1998 Dec 23/30;280(24):2077 Am Fam Physician 1999 April 1;59(07):1977

21. Problem based learning…… After seeing advertisement on TV a 69 yr old F in your clinic to discuss her osteoporosis management. She has been on Fosamax for 7 yrs but now wants to try something new and also wants to know how much Fosamax has helped her bones in last 7 yrs. Vitals: Stable Ht: 5 ft 5 inch Wt: 200 Lbs Diet; Tries to take as much CA & Vit D from Diet & supplements. PMH: CHD, DM & Vertebral Stress fracture due to osteoporosis 7 yrs back.

22. Alendronate: Long term use 1,099 postmenopausal women in FIT trial who had taken alendronate for at least 3 yrs (mean 5 yrs) were then randomized to continue 5 mg/day vs. 10 mg/day vs. placebo for 5 yrs. 2.4% vs. 5.3% had clinical vertebral fracture (NNT 35). Level II evidence FLEX trial (JAMA 2006 Dec 27;296(24):2927)

23. FIT Trial: Secondary Analysis Routine bone-density monitoring may not be necessary within first 3 yrs of Bisphosphonate therapy. Mean hip bone density increased by 0.030 g/square cm after Alendronate treatment for 3 yrs. BMJ 2009 Jun 23;338:b2266

24. Dose Strength and Duration Alendronate 20 mg QD = 10 mg QD < 5 mg QD 10 mg vs. 5 mg RESULTS Less vertebral fractures (3% vs. 6%) and deformities, less loss of height and no major side effects. Continued alendronate for 10 yrs was well tolerated with sustained benefit in terms of BMD, based on 247 women from this trial who continued treatment. JAMA. 2006; 296:2927-38.

25. Alendronate vs. Risedronate FACT Study (N=1,053) Alendronate increased BMD> Risedronate(2.1% vs. 3.4%) at all sites after 12 months. Results persisted in year two of the study. No differences in the incidence of fractures, which were only reported as adverse events. Rojen CJ. et al Bone Miner Res2004: 10.1359

26. Alendronate: Male Osteoporosis Double blind trial of 241 men randomized to alendronate plus calcium and vitamin D vs. calcium and vitamin D alone for 2 yrs, 2.7% vs. 7.4% had vertebral fracture at 2 yrs (NNT22). N Engl J Med 2000 Aug 31;343(9): 604

28. Risedronate In a study of 2,458 North American post- menopausal women with at least one vertebral fracture at baseline. The risk of vertebral and non-vertebral fracture was reduced by 41 and 39% respectively. NNT 30. JAMA 1999 0ct 13;282(14):1344

29. Risedronate Cont’d….. Analysis of 1,392 osteoporotic women>80 yo, after one year, rate of new vertebral fracture was 2.5% with Risedronate vs. 10.9% with placebo (NNT 12). J Am Geriatr Soc 2004 Nov, 52(11):1832 Risedronate with male osteoporosis is less well studied.

30. Risedronate: Non vertebral fracture VERT Study Group. JAMA. 1999 Oct 13;282(14):1344-52.

31. Risedronate cont’d…. Assoc. with less GI side effects than Alendronate. Gastroenterology 2000 Sep; 119(3):63 It reduces the risk of hip fractures among elderly women with confirmed osteoporosis, but not among elderly women selected primarily on the basis of risk factors. N Engl J Med 2001 Feb 1; 344(5):333

33. Ibandronate Can be given intravenous. No consistent clinical trial data on hip fracture reduction. Monthly regimen improve BMD better than daily regimen. Ann Rheum Dis 2006 May; 65(5):654

34. Horizon study: Zoledronic acid N Engl J Med. 2007;1809-22.

35. Zoledronic Acid n=77655 mg ivPlacebo Vertebral fracture 3.3%10.9% Hip fracture 1.4%2.5%

36. Horizon trial cont’d….. Incidence of hip fracture was 2.5 and 1.4% in the placebo and ZA groups respectively, a 41% reduction (hazard ratio 0.59, 95% CI 0.42-0.83). Reduction of vertebral fracture by 70% over 3yrs. Reduction of all non-vertebral fractures of 25% over 3yrs yearly infusion of Zoledronic acid.

37. Zoledronic acid cont’d…… When given in men and women who suffered recent hip fracture (within three months), there is a reduction in future clinical fractures of 33% and increase in survival of 28%. N Engl J Med. 2007 Nov 1;357(18):1799-809.

39. Role and efficacy of PTH BMD changes with PTH begin level off after 18 months. In 1637 ambulatory post-menopausal women, 20 mcg subq once daily prevented non- vertebral fractures (NNT 30) and vertebral fractures (NNT 10-11) in women with pre- existing vertebral fractures in one RCT. CMAJ 2006 Jul 4; 175(1):52

40. Calcitonin Prevention: 52 post-menopausal women were randomly assigned to treatment with nasal calcitonin or placebo and all subjects received calcium supplement. Over two yrs, mean BMD increased to 2.5% in the calcitonin group and decreased by 5.7% in the placebo group. Treatment of osteoporosis: 208 elderly osteopenic women were treated with BMJ 1989; 299:477

41. Calcitonin Cont’d……. Calcium and either intranasal placebo, 50, 100 or 200 IU of Salmon Calcitonin daily for two years, mean spine BMD was increased in a dose dependent fashion with max. effect at 200 IU daily. No studies on clinical or non-vertebral fractures. Less effective than Bisphosphonates. BMJ 1992 Sep 5;305(6853):556-61.

43. HRT vs. Osteoporosis Acceptable only after all other treatments have been considered and when all the risks and benefits have been carefully explained to the patient. WHI with 16,608 patients showed: 1. Reduction in hip fracture (NNT 2,000/yr). 2. Osteoporotic fracture (NNT 228/yr). 3. Venous thromboembolism NNH 143

44. Raloxifene n=682860 mg120 mgPlacebo Vertebral fracture 6.6% NNT 29 5.4% NNT 21 10.1% Non- vertebral fracture No difference JAMA 1999 Aug 18; 282(7):637

46. Response to therapy Serial BMD measurements in every 1-2 yrs. Finding of a clinically significant BMD decrease in a treated patient should need additional evaluation. Decline in BMD>5% switch to iv bisphosphonates. Another alternative is switching rPTH (if severe osteoporosis.

47. Response to therapy Cont’d…. Indication for restart bisphosphonates: 1. Decrease in BMD (approx 5%) on at least two DEXA scan one year apart. 2. Increase in markers of bone turnover. Compliance with medications: Sharing results of BTMs with patients.

49. Compliance to therapy Meta-analysis of 24 studies of drug therapy for osteoporosis. 1. 52% for treatment lasting 1-6 months. 2. 42% for treatment lasting 13-24 months. Ref: Mayo Clin Proc 2007 Dec; 82(12):1493

50. Patient Education Administration: 1. Empty stomach 2. Take with 8 ounces of water only. 3. Away from other medications 4. Maintain upright for 30-60 min following administration. Missed doses: 1. Daily-skip dose 2. Weekly-take next morning (minimum 5 days between doses) 3. Monthly-take when remember (minimum of 7 days between)

52. Post-test Questions 1. Which of the following statements best describes the action of bisphosphonate drugs on bone? a. Bisphosphonates increase bone formation and have a short-term secondary effect on bone resorption, resulting in reduced fracture risk b. Bisphosphonates inhibit bone resorption and have a short-term secondary effect on bone formation resulting in reduced fracture risk c. Bisphosphonates reduce bone formation and have a short-term secondary effect on bone resorption resulting in reduced fracture risk d. All of the above

53. 2. Which of the following scenarios represents a situation in which it would be advisable to consider a “drug holiday” from bisphosphonate therapy? a. Postmenopausal patient on bisphosphonates for five years with stable BMD b. Postmenopausal patient on bisphosphonates for five years with prevalent wrist fracture c. Postmenopausal patient on bisphosphonates for five years with multiple vertebral fractures d. Postmenopausal woman on bisphophonates for five years with significantly declining BMD

54. 3. Which of the following statements best describes the factors that come into play when designing a treatment plan for a patient with osteoporosis? a. Patient’s compliance with prescribed medication schedule and response to treatment b. Patient’s access to care, functioning in activities of daily life and psychosocial status c. Patient’s age, disease severity, risk factors for fracture and past antiresorptive treatment d. Patient’s past response to bisphosphonate therapy and tolerance of treatment side effects

55. 4. Is the following statement true or false? Response to bisphosphonate treatment is considered favorable when bone mineral density either remains stable or improves and no fractures occur. a. True b. False

56. Summary Bisphosphonates are the drug of choice for osteoporosis. Oral bisphosphonates first choice and alternatives are iv bisphosphonates and other medications. Adequate Calcium and vitamin D crucial for therapy. Adherence and patient education is critical.