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Prevention of Osteoporotic Fractures

Prevention of Osteoporotic Fractures. Douglas C. Bauer, MD University of California, San Francisco Research funding from NIH, Amgen, SKB, P and G, and Merck. What’s New in Osteoporosis. Under recognition Absolute risk Poor compliance Anabolic agents. Don’t Miss the Obvious….

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Prevention of Osteoporotic Fractures

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  1. Prevention of Osteoporotic Fractures Douglas C. Bauer, MD University of California, San Francisco Research funding from NIH, Amgen, SKB, P and G, and Merck

  2. What’s New in Osteoporosis • Under recognition • Absolute risk • Poor compliance • Anabolic agents

  3. Don’t Miss the Obvious…

  4. Under Recognition of Osteoporosis • Among women with fracture, <20% are evaluated and treated for osteoporosis! • Ask about fracture history, note vertebral fractures, use chart reminders. • Be aggressive about screening and treatment Soloman, Mayo Clin Proc, 2005

  5. Key Risk Factors • In addition to age, gender and race:- Previous fracture (especially spine) - Family history of fracture- Low body weight - Current cigarette smoking • Independent of BMD (additive)

  6. The W.H.O. Guidelines 1994The measurement defines a disease • Densitometry became widespread • How to apply the BMD numbers to the concept of “diagnosis” of osteoporosis? • T < -2.5 = “osteoporosis” • T between -1.0 and -2.5 = “osteopenia”

  7. Hip BMD and Fracture Risk at Age 70 Hip fracture risk T-score5 yearLifetime > -1 1% 4% -1 to -2 1% 8% -2 to -3 4% 16% < -3 9% 29%

  8. Hip BMD and Fracture Risk at Age 50 Hip fracture risk T-score5 yearLifetime > -1 <1% 10% -1 to -2 1% 16% -2 to -3 1% 27% < -3 2% 41%

  9. 100 T-score -4 -3 -2 -1 0 1 T-score -4 -3 -2 -1 0 1 10 WHO 10-Yr. Hip Fracture Risk in Women 1 0.1 Prior fracture No prior fracture 0.01 50 55 60 65 70 75 80 50 55 60 65 70 75 80 Age (years) Age (years)

  10. Who Should Be Tested and Treated*? • Hip BMD if >65, or >50 with risk factors • Treatment thresholds:- T-score < -2.0 without risk factors- T-score < -1.5 with risk factors • Treatment without BMD indicated:- Previous vertebral or hip fracture- Removed: >70 with multiple risk factors *Revised 2003 NOF Guidelines, Caucasian women not on therapy

  11. Medical Work-up • Very little data, lots of opinions • A reasonable start: • Vitamin D (25-OH, not 1,25-OH) • Calcium, Cr, TSH • Additional tests: • Sprue serology • SPEP, UEP

  12. Non-pharmacologic Interventions • Little new data • Smoking cessation, avoid alcohol abuse • Physical activity: modest transient effect on BMD; may reduce fracture risk • Conflicting data on hip protector pads (compliance is big issue)

  13. Calcium and Vitamin D • Chapuy, 1992 • Elderly women in long-term care • 30% decrease in hip fracture • Porthouse, 2005: • >70 with 1+ risk factor • No benefit on hip, nonspine (RR=1.01, CI: 0.71, 1,43) Chapuy, NEJM, 1992

  14. Bisphosphonates • Three approved agents: alendronate, risedronate, ibandronate (recently) • What we know: fracture risk reduced 30-50% if • Existing vertebral fracture OR • Low BMD (T-score < -2.5) …but no head-to-head fracture studies • What about those with higher BMD (“osteopenia”)? Multiple risk factors?

  15. Effect of Alendronate Depends on Baseline BMD Baseline hip BMD T -1.5 – -2.0 1.06 (0.77, 1.46) 0.97 (0.72, 1.29) T -2.0 – -2.5 T < -2.5 0.69 (0.53, 0.88) Overall 0.86 (0.73, 1.01) 0.1 1 10 Relative Hazard (± 95% CI) Cummings, Jama, 1998

  16. Risedronate HIP Study: Two Groups Group 1 • 5445 age <80; hip BMD T-score < -3.0 • 39% decreased hip fracture risk Group 2 • 3886 age >80; risk factors for hip fx • No significant effect on hip fracture risk McClung, NEJM, 2001

  17. Compliance with Bisphosphonates is Poor • Burdensome oral administration (fasting, remain upright for 30 minutes) • 50-60% persistence after one year (ask!) • Similar to other preventitive tx • Multiple practice settings • Less frequent administration improves compliance…

  18. Bisphosponates Once-a-week Alendronate: Daily vs. Weekly • Identical effects on BMD • Possibly fewer effects on esophagus • No fracture trials Schnitzer, Aging, 2000

  19. Zolendronate Once-a-year • Extremely potent bisphosphonate • One year, multicenter controlled trial • 360 women 45-80, T-score < -2.0 • IV zolendronate (4 mg once or 1 mg every 3 mo) vs. placebo • Outcome: bone turnover and BMD Reid, NEJM, 2002

  20. Yearly Zolendronate and Hip BMD 4 Placebo 3.5 4 mg x1 3 1 mg x4 2.5 2 1.5 BMD (% change) 1 0.5 0 9 0 3 6 12 -0.5 -1 Time (months) -1.5

  21. Osteonecrosis of the Jaw • Associated with potent bisphos use: • 94% treated with IV • 4% of cases have OP, most have cancer • 60% caused by tooth extraction • Risk factors unknown. Duration of tx? Over suppression of turnover? • Key: early identifcation, conservative tx Woo et al; Ann Intern Med, April 2006

  22. ONJ and Osteoporosis • How big a concern with oral treatments? • 30,000-40,000 subjects in RCTs • Duration of treatment 3-10 years • No confirmed cases of ONJ • Utilily of stopping bisphosphonates after prolonged use or before dental procedures unknown

  23. How Long to Use Bisphosphonates? • Long half-life also suggests that life-long treatment may not be necessary • Concerns about excessive suppression of bone resorption • FIT Long-term Extension (FLEX) study • 1099 ALN-treated FIT subjects • Randomized to ALN or PBO for 5 yr. Black, NEJM, 2004

  24. 6 5 4 Mean Percent Change 3 2 1 0 F 0 F 1 F 2 F 3 F 4 FL 0 FL 1 FL 2 FL 3 FL 4 FL 5 Year = Placebo = ALN (Pooled 5 mg and 10 mg groups) FLEX Change in Femoral Neck BMD: % Change from FIT Baseline Start of FLEX 2% FLEX FIT P<0.001 ALN vs PBO

  25. Cumulative Incidence of Fractures During FLEX ALN (N = 662) PBO (N = 437) RR (95% CI) Vertebral 11% 10% 0.9 (0.6, 1.2) Morphometric Other fractures Non-vertebral 20% 19% 1.0 (0.8, 1.4) Hip 3% 3% 1.1 (0.5, 2.3)

  26. Implications of Bisphosphonate Trials • Bisphosphonates reduce risk of spine, hip and non-spine fracture in women with spine fracture or low BMD (T-score < -2.5) • May not reduce risk of hip or non-spine fracture in women without osteoporosis • Intermittent dosing just as effective • After 4-5 years of treatment, some may stop. Duration? • Best data of any approved treatment

  27. The NOF Guidelines Revisited in 2005: Who Should Be Treated? • Hip BMD treatment thresholds:- T-score < -2.0 without risk factors. Use -2.5- T-score < -1.5 with risk factors. Probably not • Treatment without BMD indicated:- Existing vertebral or hip fracture. Yes!- >70 with multiple risk factors.No!

  28. Other Anti-resorptive Agents • Less effective than bisphosphonates • Calcitonin • Raloxifene • Hormone replacement

  29. The Future: Anabolic Agents • Most treatments for osteoporosis inhibit bone resorption (and formation) • Anabolic agents stimulate formation > resorption • Example: anabolic steroids, fluoride • Surprise finding: PTH is anabolic when administered intermittently in animals and humans • RCT of PTH (20 or 40 mcg) among 1637 older women with vertebral fracture

  30. Daily SQ PTH (1-34) for 18 months • Big effects on BMD • Spine increased 9-13% • Hip increased 3-6% • Wrist decreased 1-3% • Big effects on fracture • Vertebral decreased 65% • Non-spine decreased 54% • Well tolerated Neer, NEJM,2001

  31. Anabolic + Anti-resorptive? Sequential Treatment? • PTH and Alendronate (PaTH) Study • 238 postmenopausal osteoporotic women • 1st year randomize to: • PTH (1-84) alone, 100 ug/d (N=118) • Alendronate alone, 10 mg/d (N=60) • PTH + Alendronate (N=59) Change in spine BMD similar in all three groups • 2nd year re-randomize the PTH groups to: • ALN (10mg/d) or Placebo Black, NEJM 2005

  32. Change in DXA Spine BMD Over 24 Months of Treatment 20 24 month change 15 PTH Discontinued +12% ALN 10 Mean change (%) PTH 5 + 4% PLB 0 0 12 24 Month Black, NEJM, 2005

  33. Summary: PTH • Substantial BMD increase. Reduction in spine and non-spine fractures. Hip fracture? • Use with antiresorptive agents? Not during, after. • Lingering PTH safety issues: • Cortical bone BMD decreases during therapy? • Carcinogenesis? • Very expensive, daily self-administered injections... • Use with severe OP, when other agents have failed?

  34. Conclusions 1 • Aggressive screening and treatment = fewer fractures • Identify those who have already have the disease! • Bisphosphonates: treatment of choice • Use for spine fracture or low BMD. Intermittent dosing. • Duration of therapy? 5 years then off? • ERT: WHI confirms effectiveness but unacceptable side effects. Ultra low dose? • Data for other anti-resorptive agents (SERMs, calcitonin) less compelling

  35. Conclusions 2 • PTH: impressive effects on BMD and fracture • Indications not established • Long-term safety? Convenience? • Sequential treatment? • Many other potential treatments (tibolone, strontium, statins, RANKL AB). Stay tuned...

  36. Thanks For Listening. Questions Welcome!

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