update: osteoporosis

1. Update: Osteoporosis Lisa L. Willett, MD February 9, 2010 General Medicine Noon Conference Today’s speaker has no conflict of interest to disclose. The University of Alabama School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. UAB School of Medicine designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit (s) Physicians should only claim credit commensurate with the extent of their participation in the activity.

3. Case 83 YO WF Labile HTN Severe AI Mild asthma Osteoporosis ARB Clonidine Beta blocker Diuretic MVI Calcium/Vit D Alendronate weekly

4. Case 83 YO WF Labile HTN Severe AI Mild asthma Osteoporosis DEXA T -2.7 2004 T12 compression fracture 12/2007 DEXA T -3.4 2008 ARB Clonidine Beta blocker Diuretic MVI Calcium/Vit D Alendronate weekly

5. Osteoporosis Clinic Calcium/Vit D increased to TID Continued Alendronate Vit D 25(OH) 36 (normal) Recommended Forteo (teriparatide) Pt intolerant, and discontinued

7. Osteoporosis “Porous Bones” Diminished bone mineral density 2.5 SD below mean for normal Disrupted bone microarchitecture Decrease in bone strength Increase in fracture risk 8 million women, 2 million men in US

8. Fractures Vertebral fractures – 700,000 annually Most asymptomatic Morbidity, slight mortality Predicts hip fractures Hip fractures - 300,000 annually Hospitalization, surgery, rehab, NHP DVT, PTE 20 – 50% Mortality 5 - 20% first year after surgery

9. Prevention Adequate calcium 1,200 mg daily Adequate Vitamin D 400-1,000 IU daily Exercise Minimize risk factors

10. Risk Factors Tobacco Excessive alcohol Medications – steroids, dilantin Hyperthyroidism Hyperparathyroidism Low body weight Family history

11. USPSTF Recommendations Routinely screen women aged 65 and older Begin age 60 if increased risk Rationale: Good evidence that risk of osteoporosis and fracture increases with age, that bone density measurements accurately predict fracture risk short-term, and treating asymptomatic women with osteoporosis reduces fracture risk (B recommendation)

12. USPSTF Number needed to screen To prevent one hip fracture women, over 5 years 55 – 59 >4,000 60 – 64 1,856 65 – 69 731 75 -79 143

13. Osteoporosis in Men 1 in 8 men will fracture Twice the mortality from hip fracture Limited data NOF, Society for Clinical Densitometry All men > 70 Age 50 if increased risk USPSTF – no recommendation for men ACP – assess for risk, screen high risk

14. Treatment Oral bisphosphonates Inhibit osteoclasts Alendronate (Fosamax) – vertebral and hip Risedronate (Actonel) – vertebral and hip Ibandronate (Boniva) – vertebral only Adherence poor Half patients not taking after 1 year

15. Update 2010 Roadmap IV bisphosphonate (zolendronic acid) PTH analogue (teriparatide) Osteonecrosis of the jaw Vitamin D insufficiency Does it really matter?

16. Update 2010 Roadmap IV bisphosphonate (zolendronic acid) PTH analogue (teriparatide) Osteonecrosis of the jaw Vitamin D insufficiency Does it really matter?

17. Effect of Osteoporosis Treatment on Mortality: A Meta-Analysis Bolland et al J Clin Endocrin Metab Jan 15, 2010

18. Meta-Analysis Inclusion criteria: Randomized, double blind, PCT with ITT Agents with proven anti-fracture efficacy Mean age >50 at baseline Number of deaths >10 Trial duration >1 year

19. Included drugs Alendronate 10 mg daily Risedronate 5 mg daily Zoledronic acid 5 mg iv annually Teriparatide 20 ug subcut daily Stontium ranelate 2 g daily Denosumab 60 mg 6-mos Clodronate 800 mg daily Excluded trials of estrogen and SERM – might obscure mortality

20. Methods Initial search 5196 Screened 367 Included in analysis 8 108 duplicate publication 80 ineligible study population 53 study design 37 dose of agent 63 duration < 12 mos 16 number of deaths <10 or not reported

21. Results

22. Summary Osteoporosis treatment reduces mortality 11% RR 0.89 (0.80 – 0.99) p = 0.036 Mostly older, frailer, at high risk of fracture Unrelated to fracture site Benefit was similar across agents Most studies were bisphosphonates

23. Identifying high risk patients WHO Fracture Risk Assessment Tool FRAX Individual 10 year risk of fracture Clinical spine, forearm, hip, shoulder Hip Age, BMI, risk factors, DEXA, nationality

25. Identifying high risk patients Cost effective to treat Osteoporotic > 20% Hip > 3% By NOF, not clinical trials

26. Update 2010 Roadmap IV bisphosphonate (zolendronic acid) PTH analogue (teriparatide) Osteonecrosis of the jaw Vitamin D insufficiency Does it really matter?

27. Efficacy and Safety of Once-Yearly IV Zoledronic Acid 5 mg for Fracture Prevention in Elderly Postmenopausal Women with Osteoporosis Aged 75 and Older Boonen J Am Geriatric Jan 8, 2010

28. Background 50% of fractures occur in women >75 Increasing age ? decreasing likelihood of treatment Efficacy and safety of treatment Patient compliance Zoledronic acid (Reclast) 5 mg iv effective in preventing bone loss and fractures in prior studies

29. Methods Post-hoc subgroup analysis, HORIZON Trials Health Outcome and Reduced Incidence with Zoledronic Acid One Yearly Pivotal Fracture Trial* (n=7700) and Recurrent Fracture Trial (n=2100) Multicenter, DB, placebo RCT, 3 years Postmenopausal osteoporotic women > 75 Primary endpoint - clinical fracture

31. Adverse Events (AE) Within 3 days of infusion, higher AE with zoledronic acid than placebo for all ages Flu like illness Fever, chills Myalgias, bone pain Fatigue No increase in renal failure or atrial fibrillation 1.3% of HORIZON atrial fibrillation

32. Conclusions Once yearly infusion with zoledronic acid prevents clinical fractures (vertebral) in patients > 75 Hip fractures prevented in patients over 50 Safe Acceptable option for patients non compliant with oral bisphosphonates

33. Update 2010 Roadmap IV bisphosphonate (zolendronic acid) PTH analogue (teriparatide) Osteonecrosis of the jaw Vitamin D insufficiency Does it really matter?

34. Teriparatide (Forteo) Recombinant human parathyroid hormone Bone anabolic activity Induces differentiation of pro-osteoblasts into osteoblasts, stimulates new bone, decreases osteoblast and osteocyte apoptosis 20 ug subcutaneously daily, 2 years

35. Teriparatide (Forteo) Reduces vertebral and hip fractures Indications postmenopausal women severe bone loss no improvement on bisphosphonates men with high fracture risk

36. Teriparatide (Forteo) Better for GIOP compared to alendronate1 Timing with alendronate2 Not concurrent, should follow Increased risk of osteosarcoma in rats

37. Teriparatide (Forteo) Not first line option for postmenopausal osteoporosis May consider in GIOP Referral to osteoporosis clinic or rheumatology to monitor, time with alendronate

38. Update 2010 Roadmap IV bisphosphonate (zolendronic acid) PTH analogue (teriparatide) Osteonecrosis of the jaw Vitamin D insufficiency Does it really matter?

39. American Association of Oral and Maxillofacial Surgeons Position Paper on Bisphosphonate-Related Osteonecrosis of the Jaws - 2009 Update Journal of Oral and Maxillofacial Surgery May 2009;67(5):2-12

40. Bisphosphonate-Related Osteonecrosis of the Jaws First recognized as nonhealing exposed bone Patients treated with iv bisphosphonates for MM or metastatic cancer pamidronate (Aredia) zoledronic acid (Zometa) RR 2.7- 4.2 in cancer patients

41. Bisphosphonate-Related Osteonecrosis of the Jaws Definition: BRONJ Current or previous bisphosphonate Rx Exposed bone in maxillofacial region, 8 wks No history of radiation therapy to the jaws

43. Oral bisphosphonates for osteoporosis and BRONJ Case reports > 3 years treatment But much less than with IV monthly bisphosphonates in cancer patients 0.06% Kaiser-Permanente (PROBE, n=13,000) 0.01 – 0.04% Australian surveillance 0.004 German Central Registry

44. IV bisphosphonate for osteoporosis and BRONJ HORIZON Zolendronic acid (Reclast) annually Prospective PC study, 3 years (n>7,000) 2 cases of BRONJ one in each study group Suggests low risk

45. Risk Factors for BRONJ Drug related: IV route, cancer doses Duration: > 3 years for oral treatment Local risk factors Dentoalveolar surgery - ? risk 7-fold extractions, implants, periodontal surgery Concomitant oral disease Cancer + iv + dental procedure = 5 - 21-fold increased risk compared to cancer + iv without dental procedure

46. Prevention of BRONJ with bisphosphonates Before initiating monthly iv, thorough oral examination and remove unsalvageable teeth, complete dental procedures, optimize dental health If oral treatment, and risk of BRONJ, consider discontinuing after 3 yrs 3 months pre and 3 months post dental intervention

47. Asymptomatic Patient on Oral Bisphosphonate Reassure Less severe Respond to therapy Elective surgery not contraindicated Monitor clinically History and physical Not diagnosed by xrays

48. Update 2010 Roadmap IV bisphosphonate (zolendronic acid) PTH analogue (teriparatide) Osteonecrosis of the jaw Vitamin D insufficiency Does it really matter?

49. Vitamin D insufficiency Does vit D prevent fractures? What is the benefit of screening patients with osteoporosis for Vit D insufficiency? What is the benefit of high dose supplementation?

50. Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis Avenell, et al Cochrane Review 2009

51. Study Aim Does Vit D (with or without calcium) vs. placebo prevent Hip fractures Any other fracture, including vertebral What is the appropriate dosing? Bolus doses = daily dose (unknown)

52. Results: Vit D without calcium No protection against fractures from Annual injection of Vit D2 Oral intermittent bolus D2 or D3 Oral daily dose D3 May be benefit in very high risk NHPs with low sunlight, dose > 1100 IU daily

53. Results: Vit D with calcium Vitamin D (700-800 IU) with calcium (1,000 mg) reduces hip fractures in frail older women in institutions (n=3,853, RR 0.75) Not in community dwellers

54. Conclusions Need to establish Optimal serum 25(OH) Vit D level Supplemental dose to achieve it Whether it impacts fractures VITAL D study- Vitamin D and omega 3 trial NIH sponsored Men & women - cancer, heart disease, stroke prevention 500,000 IU annual Vit D dose Recruitment Jan 2010

55. Update 2010 Roadmap IV bisphosphonate (zolendronic acid) PTH analogue (teriparatide) Osteonecrosis of the jaw Vitamin D insufficiency Does it really matter?

56. Take Home Points Screen women at age 65 But don’t forget about it afterwards Target high risk patients Risk assessment tool (FRAX) History of fracture High risk elderly patients Institutionalized > community dwelling Don’t forget about men

57. Take Home Points Bisphosphonates first line (oral) Zoledronic acid iv annually is safe and effective if noncompliant or intolerant, even in elderly women Risk of fracture and death much higher than osteonecrosis of the jaw (BRONJ)

58. Take Home Points DEXA q 2 years to monitor response If no response and compliant PTH analogue (teriparatide) consideration 2 years Benefit for GIOP

59. Take Home Points Ensure adequate calcium/vit D (>1000 mg/800 IU) Consider checking vitamin D levels in high risk patients Low sunshine (NHP), frail Everyone with osteoporosis? Those you plan to treat No data supporting fracture prevention There is on bisphosphonates (fracture and mortality)!!

60. Future Directions VITAL D study – more to come Vit D Denosumab – investigational monoclonal antibody against RANKL Reduces osteoclastogenesis Concern about infections/malignancies Calcium receptor antagonists Other…

61. Final Take Home Point It matters!