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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 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
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
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)
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”
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%
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%
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)
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
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
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)
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
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?
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
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
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…
Bisphosponates Once-a-week Alendronate: Daily vs. Weekly • Identical effects on BMD • Possibly fewer effects on esophagus • No fracture trials Schnitzer, Aging, 2000
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
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
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
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
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
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
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)
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
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!
Other Anti-resorptive Agents • Less effective than bisphosphonates • Calcitonin • Raloxifene • Hormone replacement
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
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
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
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
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?
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
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...