What to Do after Drug Holidays No Conflicts of Interest Clifford - - PDF document
What to Do after Drug Holidays No Conflicts of Interest Clifford Rosen MD rosenc@mmc.org 2 1 Bisphosphonate Scripts in the US What To Do After Drug Holidays Over the last 2 decades Overview of Drug Holidays Who to stop, who to
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Clifford Rosen MD rosenc@mmc.org
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Overview of Drug Holidays
– Who to stop, who to continue, who to send on vacation
How to Assess Risk after a ‘Holiday’
– Gestalt – DXA – Bone Markers – What the patient wants
What to do about treatment?
– Anti-resorptive – Anabolic
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alendronate AFF first reports
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Wikipedia- 2016
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Study Drug Design N Follow-up years Notes FIT Long- Term Extension (FLEX) Alendronate (5 & 10 mg/day) Randomized , blinded trial 1099 5+5=10 HORIZON- PFT Ext. Zoledronic acid (5 mg/year) Randomized blinded trial 1233 3+3=6 Risedronate Risedronate weekly Observation al study 164 3+3+3=9 Small, non- randomized, adherent
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FIT N = 6,459 Placebo N = 3,223 Alendronate N = 3,236 Randomized in FLEX N = 1,099 Alendronate, 5 mg N = 329 Placebo N = 437 Alendronate, 10 mg N = 333
FIT (3 to 4.5 yrs) Post-FIT (1-2 yrs) FLEX (5 yrs)
* Black, et al, JAMA 12/2006
40% 30% 30% Primary endpoint: Change in hip BMD
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= Placebo = ALN (Pooled 5 mg and 10 mg groups) 1 2 3 4 5 F 0 F 1 F 2 F 3 F 4 FL 0 FL 1 FL 2 FL 3 FL 4 FL 5
Mean Percent Change Year Start of FLEX
P<0.001 ALN vs PBO
FIT FLEX FIT 3 to 4.5 yrs FIT/FLEX Recess 1 to 2 yrs FLEX 5 yrs 2.8%
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ALN (N = 662) RR (95% CI) 3% 19% 21% 1.02 (0.5, 2.3) 1.00 (0.8, 1.4) 0.93 (0.7, 1.2) 3% Hip 20% Non-vertebral 22% Any PBO (N = 437) 9.8% 2% 0.86 (0.6, 1.2) 0.45 (0.2, 0.8) 11.3% Morphometric 5% Clinical
Vertebral Clinical
* Black, et al, JAMA 12/2006
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5 10 15 20 1 2 3 4 Cumulative Incidence, % 5 Time to First Fracture, years
Placebo ALN (pooled) RH=1.00 (0.76, 1.32)
F = FIT, FL = FLEX . Black DM et al. JAMA. 2006;296:1–12.
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Similar to FLEX extension 3 years of annual ZOL, then randomized to
– 3 more years of ZOL (6 years, Z6) – 3 years of PBO (Z3P3)
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Z6 (N = 617) RR (95% CI) 1.3% 8.2% 0.90 (0.3, 2.5) 0.99 (0.7, 1.5) 1.4% Hip 7.6% Non-vertebral Z3P3 (N = 616) 3% 1.2% 0.48 (0.3, 0.9) 1.8 (0.5, 6.2) 6% Morphometric 0.7% Clinical
Vertebral Non-vertebral
* Black, et al, JBMR 2012
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Relative Risk (Bis vs. PBO)
Bisphosphonate benefit
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Fracture results for both drugs
– Continuing lowers vertebral fractures risk vs discontinuing – Continuing vs. discontinuing no effect on non-vertebral
BMD results for both drugs (ALN and ZOL):
– Continuing long term retains BMD gains – Discontinuing BMD loses are modest
What about long term safety? Does AFF risk increase with
longer duration of treatment?
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17 FLEX vertebral fracture benefit: Who to continue?
Femoral Neck BMD T- Score (start FLEX) 5 Yr risk (%) Clinical Vert.
Number Needed to Treat
All women in study
All BMD values 5.5 34 ≤ -2.5 9.3 21
5.8 33 ≥ -2 2.3 81 No prevalent vert. fracture (start of FLEX) ≤ -2.5 8.0 24
3.0 63 ≥ -2 1.8 102 Prevalent vertebral fracture (start of FLEX) ≤ -2.5 11.1 17
11.1 17 ≥ -2 3.7 51 Black, et al. NEJM 2012 May 31;366(22):2051-3
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Primary benefit is in reduction of vertebral fractures Therefore, logical to continue those at highest risk of
– NEJM; 5/2012
– Consider femoral neck BMD and vertebral fracture status at the end of the initial treatment period
Black, et al. NEJM 2012 May 31;366(22):2051-3
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Other clinical factors to assess to decide on discontinuation?
* Cosman et al. ASBMR 2012.
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USPSTF: No Risk Reduction for Vitamin D and Hip Fracture- 2014
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Risk of Hip Fracture by Age Group in WHI: Age and Fall Interaction
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Nakumara, 2012
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Very Little Evidence