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New Developments in Osteoporosis Douglas C. Bauer, MD University of California, San Francisco Research funding from NIH, Amgen, SKB, P and G, and Merck.

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Presentation on theme: "New Developments in Osteoporosis Douglas C. Bauer, MD University of California, San Francisco Research funding from NIH, Amgen, SKB, P and G, and Merck."— Presentation transcript:

1 New Developments in Osteoporosis Douglas C. Bauer, MD University of California, San Francisco Research funding from NIH, Amgen, SKB, P and G, and Merck

2 Whats New in Osteoporosis Absolute riskAbsolute risk Under recognitionUnder recognition Poor compliancePoor compliance When to stop bisphosphonatesWhen to stop bisphosphonates New treatmentsNew 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 meds66 grandmother and prominent politician without previous fracture or other risk factors. Sister with breast cancer, otherwise healthy. No meds Hip BMD T-score –2.2Hip BMD T-score –2.2 No contraindication to treatmentNo contraindication to treatment Will follow your advice…Will follow your advice…

4 What Would You Do? 1)Start calcium 1000 mg + vitamin D 800 iu per day 2)Start alendronate 70 mg or risedronate 35 mg per week 3)Start raloxifene 60 mg/d 4)Both 1) and 2) 5)Both 1) and 3)

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

6 BMD and Risk Factors Cummings et al., NEJM 332(12):767-773, 1995

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

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

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

10 Treatment Threshold Concept 80 AGE 70 60 50 10-Year Fracture Probability (%) Current treatment threshold based on T-score Treatment threshold concept based on WHO Absolute Fracture Risk Adapted from JA Kanis et al, Osteoporos Int. 2001;12:989-995

11 http://www.shef.ac.uk/FRAX/tool.jsp Calculating Absolute Fracture Risk: FRAX

12 Who Should Be Tested and Treated*? Preventive measures for everyone: calcium, vitamin D, exercise, clean livingPreventive measures for everyone: calcium, vitamin D, exercise, clean living Hip BMD: women >65, men >70, and after fractureHip BMD: women >65, men >70, and after fracture Treatment thresholds:Treatment thresholds: –Anyone with hip or spine fracture –T-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!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.Ask about fracture history, note vertebral fractures, use chart reminders. Be aggressive about screening and, when indicated, appropriate treatmentBe aggressive about screening and, when indicated, appropriate treatment Soloman, Mayo Clin Proc, 2005

14 Medical Work-up Very little data, lots of opinionsVery little data, lots of opinions A reasonable start:A reasonable start: –Vitamin D (25-OH, not 1,25-OH) –serum calcium, Cr, TSH Additional tests that may be helpful:Additional tests that may be helpful: –Sprue serology, SPEP, UEP Unlikely to be helpful:Unlikely to be helpful: –PTH, urine calcium Jamal et al, Osteo Inter, 2005

15 What Else Can Be Done To Prevent Osteoporosis?

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

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

18 Bisphosphonates Four approved agents: alendronate, risedronate, ibandronate, and zolendronic acid (recently)Four approved agents: alendronate, risedronate, ibandronate, and zolendronic acid (recently) – No head-to-head fracture studies What we know: fracture risk reduced 30-50% ifWhat we know: fracture risk reduced 30-50% if – Existing vertebral fracture OR – Low BMD (T-score < -2.5) What about those with higher BMD (osteopenia)? Multiple risk factors?What about those with higher BMD (osteopenia)? Multiple risk factors?

19 Effect of Alendronate on Non-spine Fracture Depends on Baseline BMD Baseline hip BMD Overall T < -2.5 T -2.0 – -2.5 T -1.5 – -2.0 0.1110 Relative Hazard (± 95% CI) 0.86 (0.73, 1.01) 0.69 (0.53, 0.88) 0.97 (0.72, 1.29) 1.06 (0.77, 1.46) Cummings, Jama, 1998

20 Risedronate HIP Study: Two Groups Group 1 5445 age <80; hip BMD T-score < -3.05445 age <80; hip BMD T-score < -3.0 39% decreased hip fracture risk39% decreased hip fracture risk Group 2 3886 age >80; risk factors for hip fx3886 age >80; risk factors for hip fx No significant effect on hip fracture riskNo significant effect on hip fracture risk McClung, NEJM, 2001

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

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

23 Zolendronate Once-a-year: Horizon Extremely potent bisphosphonateExtremely potent bisphosphonate 3 year, multicenter controlled trial3 year, multicenter controlled trial 7741 women 55-89, T-score < -2.5 or < -1 + vertebral fracture7741 women 55-89, T-score < -2.5 or < -1 + vertebral fracture IV zolendronate (5mg IV once/yr) vs. placeboIV zolendronate (5mg IV once/yr) vs. placebo Outcome: BMD, turnover, fractureOutcome: BMD, turnover, fracture Black et al, NEJM, 2007

24 Bracketed values are least square mean difference *P <.0001 Horizon: Percentage Change in Total Hip BMD % Change From Baseline 061218243036 –2.0 –1.0 0.0 1.0 2.0 3.0 4.0 –3.0 5.0 Months [2.83*] [1.93*] [4.70*] [6.00*] ZOL 5 mg Placebo 3516351632242350 3544354332412408 ZOL n = PBO n = Black et al, NEJM, 2007

25 Horizon: Risk of New Vertebral Fracture RRR = relative risk reduction; 95% confidence interval ZOL 5 mg Placebo % Patients With New Vertebral Fracture RRR 60% (CI: 43, 72) RRR 71% (CI: 61, 78) 0 10 0–10–10–20–20–30–3 Years 5 15 1.5% 3.7% 2.2% 7.7% 3.8% 12.8% RRR 70% (CI: 62, 76) Black et al, NEJM, 2007

26 Horizon: Risk of Clinical Fractures (Hip, Vert, Non-Vert) RRR = relative risk reduction; 95% confidence interval RRR 40% (CI: 15, 57) RRR 75% (CI: 60, 85) RRR 25% (CI: 13, 36) Clinical Vertebral Fracture Hip Fracture Clinical Non- vertebral Fracture 1.5% 0.6% 2.5% 2.6% 7.9% 10.6% ZOL 5 mg (n = 3875) Placebo (n = 3861) % Patients With New Fracture 0 10 5 15 Black et al, NEJM, 2007

27 A New Side Effect of Potent Bisphosphonates?

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

29 ONJ and Osteoporosis How big a concern with oral treatments?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 Dental exam before initiating bisphosphonates recommended but unlikely to helpDental exam before initiating bisphosphonates recommended but unlikely to help Utility of stopping bisphosphonates before dental procedures unknown (not advised)Utility of stopping bisphosphonates before dental procedures unknown (not advised)

30 Another Worry with Bisphosphonates?

31 What Would You Do? Mrs. P has now been on an oral bisphosphonate for 5 yearsMrs. P has now been on an oral bisphosphonate for 5 years No new fracturesNo new fractures Repeat hip BMD: T-score –2.3Repeat hip BMD: T-score –2.3 How would you advise her?How would you advise her?

32 What Would You Do? 1)Assess compliance and continue current an oral bisphosphonate 2)Switch to IV bisphosphonate 3)Switch to raloxifene 60 mg/day 4)Stop 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 necessaryLong half-life also suggests that life- long treatment may not be necessary Concerns about excessive suppression of bone resorptionConcerns about excessive suppression of bone resorption FIT Long-term Extension (FLEX) studyFIT Long-term Extension (FLEX) study – 1099 ALN-treated FIT subjects – Randomized to ALN or PBO for 5 yr. Black Jama, 2006

34 FLEX Change in Femoral Neck BMD: % Change from FIT Baseline = Placebo = ALN (Pooled 5 mg and 10 mg groups) 2% Start of FLEX P<0.001 ALN vs PBO FIT FLEX

35 Cumulative Incidence of Fractures During FLEX ALN (N = 662) RR (95% CI) 3% 19% 2% 1.1 (0.5, 2.3) 1.0 (0.8, 1.4) 0.5 (0.2, 0.8) 3% Hip 20% Non-vertebral 5% PBO (N = 437) 10% 0.9 (0.6, 1.2) 11% Morphometric Vertebral Other fractures Clinical

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)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 osteoporosisMay not reduce risk of hip or non-spine fracture in women without osteoporosis Intermittent dosing, even yearly, effectiveIntermittent dosing, even yearly, effective After 5 years of treatment, some may stop.After 5 years of treatment, some may stop. –Who? For how long? How to monitor? Best data of any approved treatmentBest data of any approved treatment

37 The NOF Guidelines Revisited in 2008: Who Should Be Treated? Treatment thresholds:Treatment thresholds: –Existing hip or vertebral fracture. Yes –T-score < -2.5. Yes –Osteopenia with risk factors. Probably not

38 Other Anti-resorptive Agents Less effective than bisphosphonatesLess effective than bisphosphonates –Calcitonin –Raloxifene Hormone replacementHormone replacement

39 Design: 7705 women >55 with low BMD or fracture Raloxifene (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) Multiple Outcomes of Raloxifene Evaluation (MORE)

40 Womens Health Initiative RCT of ERT, PERT or PBO among women age 50- 79, 10,739 with hysterectomy. Primary preventionRCT of ERT, PERT or PBO among women age 50- 79, 10,739 with hysterectomy. Primary prevention PERT, ERT arms stopped after 5-7 yearsPERT, ERT arms stopped after 5-7 years – Follow-up 93% complete Endpoints: ERT vs. PBOEndpoints: ERT vs. PBO – Hip RR = 0.61 (0.41, 0.91) – Non-spine RR = 0.70 (0.63, 0.79) – CVD RR = 1.12 (1.01, 1.24 WHI Writing Group, Jama, 2004

41 The Future: Anabolic Agents Most treatments for osteoporosis inhibit bone resorption (and formation)Most treatments for osteoporosis inhibit bone resorption (and formation) Anabolic agents stimulate formation > resorptionAnabolic agents stimulate formation > resorption Example: anabolic steroids, fluorideExample: anabolic steroids, fluoride Surprise finding: PTH is anabolic when administered intermittently in animals and humansSurprise finding: PTH is anabolic when administered intermittently in animals and humans RCT of PTH (20 or 40 mcg) among 1637 older women with vertebral fractureRCT 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 BMDBig effects on BMD –Spine increased 9-13% –Hip increased 3-6% –Wrist decreased 1-3% Big effects on fractureBig effects on fracture –Vertebral decreased 65% –Non-spine decreased 54% Well toleratedWell tolerated Neer, NEJM, 2001

43 PTH and Alendronate (PaTH) StudyPTH and Alendronate (PaTH) Study 238 postmenopausal osteoporotic women238 postmenopausal osteoporotic women 1 st year randomize to:1 st 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 2 nd year re-randomize the PTH groups to:2 nd year re-randomize the PTH groups to: –ALN (10mg/d) or Placebo Anabolic + Anti-resorptive? Sequential Treatment? Black, NEJM 2005

44 One Year Change in BMD with PTH alone, ALN alone, or PTH + ALN Total Spine Total Hip Radius 1/3 -6 -4 -2 0 2 4 6 8 10 PTHPTH/ALNALN * Mean Change (%) *** * p<.05 *** p<.0001 Black, NEJM 2003

45 Change in DXA Spine BMD Over 24 Months of Treatment Mean change (%) 0 5 10 15 20 01224 Month PLB ALN PTH Discontinued PTH 24 month change +12% + 4% Black, NEJM, 2005

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

47 Conclusions 1 Aggressive screening and treatment = fewer fracturesAggressive screening and treatment = fewer fractures – Identify those who have already have the disease! Bisphosphonates: treatment of choiceBisphosphonates: treatment of choice – Use for spine fracture or low BMD. Intermittent dosing. – Duration of therapy? 5 years then off? Data for other anti-resorptive agents (SERMs, calcitonin) less compellingData for other anti-resorptive agents (SERMs, calcitonin) less compelling

48 Conclusions 2 PTH: impressive effects on BMD and fracturePTH: 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...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 meds68 WF without previous fracture or other risk factors. Sister with breast cancer, otherwise healthy. No meds Hip BMD T-score –2.2Hip BMD T-score –2.2 No contraindication to treatmentNo contraindication to treatment Will follow your advice…Will follow your advice…

50 What Would You Do? Mrs. P. has now been on an oral bisphosphonate for 5 yearsMrs. P. has now been on an oral bisphosphonate for 5 years No new fracturesNo new fractures Repeat BMD: T-score –2.3Repeat BMD: T-score –2.3 How would you advise her?How would you advise her?

51 Thanks For Listening. Questions Welcome!


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