Presentation on theme: "New Developments in Osteoporosis"— Presentation transcript:
1 New Developments in Osteoporosis Douglas C. Bauer, MDUniversity of California, San FranciscoResearch funding from NIH, Amgen, SKB, P and G, and Merck
2 What’s New in Osteoporosis Absolute riskUnder recognitionPoor complianceWhen to stop bisphosphonatesNew treatments
3 What Would You Do? Mrs. P…66 grandmother and prominent politician without previous fracture or other risk factors. Sister with breast cancer, otherwise healthy. No medsHip BMD T-score –2.2No contraindication to treatmentWill follow your advice…
4 What Would You Do? Start calcium 1000 mg + vitamin D 800 iu per day Start alendronate 70 mg or risedronate 35 mg per weekStart raloxifene 60 mg/dBoth 1) and 2)Both 1) and 3)
5 Key Risk FactorsIn addition to age, gender and race: - Previous fracture (especially spine) - Family history of fracture - Low body weight - Current cigarette smokingIndependent of BMD (additive)
6 Cummings et al., NEJM 332(12):767-773, 1995 BMD and Risk FactorsCummings et al., NEJM 332(12): , 1995
7 The W.H.O. Guidelines 1994 The measurement defines a disease Densitometry became widespreadHow to apply the BMD numbers to the concept of “diagnosis” of osteoporosis?T < -2.5 = “osteoporosis”T between -1.0 and -2.5 = “osteopenia”
8 Hip BMD and Fracture Risk at Age 70 Hip fracture riskT-score 5 year Lifetime> % 4%-1 to % 8%-2 to % %< % %
9 Hip BMD and Fracture Risk at Age 50 Hip fracture riskT-score 5 year Lifetime> -1 <1% 10%-1 to % %-2 to % %< % %
10 Treatment Threshold Concept AGECurrent treatment threshold based on T-score8070Treatment threshold concept based on WHO Absolute Fracture Risk10-Year Fracture Probability (%)6050Adapted from JA Kanis et al, Osteoporos Int. 2001;12:
12 Who Should Be Tested and Treated*? Preventive measures for everyone: calcium, vitamin D, exercise, clean livingHip BMD: women >65, men >70, and after fractureTreatment thresholds:Anyone with hip or spine fractureT-score < -2.5“Osteopenia” and 10 year hip fracture risk >3% or OP-related fracture risk >20%*Revised 2008 NOF Guidelines
13 Under Recognition of Osteoporosis Among women with fracture or BMD<-2.5 , only 20-30% are evaluated and treated!Ask about fracture history, note vertebral fractures, use chart reminders.Be aggressive about screening and, when indicated, appropriate treatmentSoloman, Mayo Clin Proc, 2005
14 Medical Work-up Very little data, lots of opinions A reasonable start: Vitamin D (25-OH, not 1,25-OH)serum calcium, Cr, TSHAdditional tests that may be helpful:Sprue serology, SPEP, UEPUnlikely to be helpful:PTH, urine calciumJamal et al, Osteo Inter, 2005
16 Non-pharmacologic Interventions Little new dataSmoking cessation, avoid alcohol abusePhysical activity: modest transient effect on BMD; may reduce fracture riskConflicting data on hip protector pads (compliance is big issue)
17 Calcium and Vitamin D Elderly women in long-term care Chapuy, 1992Elderly women in long-term care30% decrease in hip fracturePorthouse, 2005:Women >70 with 1+ risk factorNo benefit on hip, nonspine (RR=1.01, CI: 0.71, 1,43)Chapuy, NEJM, 1992
18 BisphosphonatesFour approved agents: alendronate, risedronate, ibandronate, and zolendronic acid (recently)No head-to-head fracture studiesWhat we know: fracture risk reduced 30-50% ifExisting vertebral fracture ORLow BMD (T-score < -2.5)What about those with higher BMD (“osteopenia”)? Multiple risk factors?
19 Effect of Alendronate on Non-spine Fracture Depends on Baseline BMD Baseline hip BMDT -1.5 – -2.01.06 (0.77, 1.46)T -2.0 – -2.50.97 (0.72, 1.29)T < -2.50.69 (0.53, 0.88)Overall0.86 (0.73, 1.01)0.1110Relative Hazard (± 95% CI)Cummings, Jama, 1998
20 Risedronate HIP Study: Two Groups 5445 age <80; hip BMD T-score < -3.039% decreased hip fracture riskGroup 23886 age >80; risk factors for hip fxNo significant effect on hip fracture riskMcClung, NEJM, 2001
21 Compliance with Bisphosphonates is Poor Burdensome oral administration (fasting, remain upright for 30 minutes). Weekly dosing50-60% persistence after one year (ask!)Similar to other preventative txMultiple practice settingsLess frequent administration improves compliance…
22 Bisphosponates Once-a-week Alendronate: Daily vs. WeeklyIdentical effects on BMDPossibly fewer effects on esophagusNo fracture trialsSchnitzer, Aging, 2000
23 Zolendronate Once-a-year: Horizon Extremely potent bisphosphonate3 year, multicenter controlled trial7741 women 55-89, T-score < -2.5 or < -1 + vertebral fractureIV zolendronate (5mg IV once/yr) vs. placeboOutcome: BMD, turnover, fractureBlack et al, NEJM, 2007
24 Horizon: Percentage Change in Total Hip BMD –2.0–1.00.01.02.03.04.0–3.05.0[6.00*][4.70*][2.83*][1.93*]ZOL 5 mg% Change From BaselinePlacebo61218243036MonthsZOL n =PBO n =3516322423503544354332412408Bracketed values are least square mean difference*P < .0001Black et al, NEJM, 2007
25 Horizon: Risk of New Vertebral Fracture RRR 70% (CI: 62, 76)PlaceboZOL 5 mg1512.8%RRR 71% (CI: 61, 78)10% Patients With NewVertebral Fracture7.7%RRR 60% (CI: 43, 72)53.8%3.7%2.2%1.5%0–10–20–3YearsRRR = relative risk reduction;95% confidence intervalBlack et al, NEJM, 2007
28 Osteonecrosis of the Jaw Associated with potent bisphos use:94% treated with IV bisphosphonates4% of cases have OP, most have cancer60% caused by tooth extractionRisk factors unknown. Duration of tx? Over suppression of turnover?Key: early identification, conservative txWoo et al; Ann Intern Med, April 2006
29 ONJ and Osteoporosis How big a concern with oral treatments? 30,000-40,000 subjects in RCTsDuration of treatment 3-10 yearsNo confirmed cases of ONJDental exam before initiating bisphosphonates recommended but unlikely to helpUtility of stopping bisphosphonates before dental procedures unknown (not advised)
31 What Would You Do?Mrs. P has now been on an oral bisphosphonate for 5 yearsNo new fracturesRepeat hip BMD: T-score –2.3How would you advise her?
32 What Would You Do?Assess compliance and continue current an oral bisphosphonateSwitch to IV bisphosphonateSwitch to raloxifene 60 mg/dayStop bisphosphonate, continue calcium/D, repeat BMD in 3-5 years
33 How Long to Use Bisphosphonates? Long half-life also suggests that life-long treatment may not be necessaryConcerns about excessive suppression of bone resorptionFIT Long-term Extension (FLEX) study1099 ALN-treated FIT subjectsRandomized to ALN or PBO for 5 yr.Black Jama, 2006
34 FLEX Change in Femoral Neck BMD: % Change from FIT Baseline Start of FLEX123456F 0F 1F 2F 3F 4FL 0FL 1FL 2FL 3FL 4FL 5Mean Percent ChangeYear2%FLEXFIT= Placebo= ALN (Pooled 5 mg and 10 mg groups)P<0.001 ALN vs PBO
36 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 osteoporosisIntermittent dosing, even yearly, effectiveAfter 5 years of treatment, some may stop.Who? For how long? How to monitor?Best data of any approved treatment
37 The NOF Guidelines Revisited in 2008: Who Should Be Treated? Treatment thresholds:Existing hip or vertebral fracture. YesT-score < Yes“Osteopenia” with risk factors. Probably not
38 Other Anti-resorptive Agents Less effective than bisphosphonatesCalcitoninRaloxifeneHormone replacement
39 Multiple Outcomes of Raloxifene Evaluation (MORE) Design:7705 women >55 with low BMD or fractureRaloxifene (60 or 120 mg) vs. placebo for 3 yr.Primary Endpoints:New spine fracture: RR = 0.65 (0.53, 0.79)Non-spine fracture: RR = 0.94 (0.79, 1.12)Other Endpoints:Breast cancer: RR = 0.24 (0.13, 0.44)
40 Women’s Health Initiative RCT of ERT, PERT or PBO among women age 50-79, 10,739 with hysterectomy. Primary preventionPERT, ERT arms stopped after 5-7 yearsFollow-up 93% completeEndpoints: ERT vs. PBOHip RR = 0.61 (0.41, 0.91)Non-spine RR = 0.70 (0.63, 0.79)CVD RR = 1.12 (1.01, 1.24WHI Writing Group, Jama, 2004
41 The Future: Anabolic Agents Most treatments for osteoporosis inhibit bone resorption (and formation)Anabolic agents stimulate formation > resorptionExample: anabolic steroids, fluorideSurprise finding: PTH is anabolic when administered intermittently in animals and humansRCT of PTH (20 or 40 mcg) among 1637 older women with vertebral fracture
42 Daily SQ PTH (1-34) for 18 months Big effects on BMDSpine increased 9-13%Hip increased 3-6%Wrist decreased 1-3%Big effects on fractureVertebral decreased 65%Non-spine decreased 54%Well toleratedNeer, NEJM, 2001
43 Anabolic + Anti-resorptive? Sequential Treatment? PTH and Alendronate (PaTH) Study238 postmenopausal osteoporotic women1st 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 groups2nd year re-randomize the PTH groups to:ALN (10mg/d) or PlaceboTo answer these questions, we conducted a randomized, double blind trial , the Path Study. Dr. Dennis Black presented overall 1 yr results on Sat. during the plenary session, but I will summarize the key design features here.Path is a two year study of 238 postmenopausal womenBlack, NEJM 2005
44 One Year Change in BMD with PTH alone, ALN alone, or PTH + ALN 1086****4Mean Change (%)2-2-4-6Total SpineTotal HipRadius 1/3* p<.05*** p<.0001PTHPTH/ALNALNBlack, NEJM 2003
45 Change in DXA Spine BMD Over 24 Months of Treatment 2024 month change15PTH Discontinued+12%ALN10Mean change (%)PTH5+ 4%PLB1224MonthBlack, NEJM, 2005
46 Summary: PTHSubstantial 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?
47 Conclusions 1 Aggressive screening and treatment = fewer fractures Identify those who have already have the disease!Bisphosphonates: treatment of choiceUse for spine fracture or low BMD. Intermittent dosing.Duration of therapy? 5 years then off?Data for other anti-resorptive agents (SERMs, calcitonin) less compelling
48 Conclusions 2 PTH: impressive effects on BMD and fracture Indications not established: severe cases?Long-term safety? Convenience?Sequential treatment?Many other potential treatments (tibolone, strontium, statins, RANKL AB). Stay tuned...
49 What Would You Do? Mrs. P…68 WF without previous fracture or other risk factors. Sister with breast cancer, otherwise healthy. No medsHip BMD T-score –2.2No contraindication to treatmentWill follow your advice…
50 What Would You Do?Mrs. P. has now been on an oral bisphosphonate for 5 yearsNo new fracturesRepeat BMD: T-score –2.3How would you advise her?
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