drug holidays ver 7-10 7/13/2018 Long-term Treatment and Drug Financial Disclosures Holidays Include some interesting/surprisingly -Consulting or advisory boards: hot-off-the-press results Radius, Asahi-Kasei Dennis M. Black, PhD Professor Epidemiology and Biostatistics, UCSF 1 Drug Holiday Depends on Treatment Denosumab, Teriparatide and Abaloparatide (2 years only), HRT, Raloxifene: Drug Holiday??? DON’T STOP without follow up Cannot consider drug holiday Depends on Treatment… Benefits lost soon after stopping - Quick BMD loss after anabolic - Denosumab: may be rebound, multiple Vfx after stopping in some patients If patient wants to discontinue, other therapy to solidify gains (mostly likely bisphosphonate or denosumab) - 1
drug holidays ver 7-10 7/13/2018 ASBMR Task Force Guidelines on Long Term Treatment Drug Holiday For Bisphosphonates (Adler et al 2015-16) Alendronate or Zoledronic acid (RCT evidence) - Residual benefit after stopping - Can consider drug holiday (I’ll tell you why) Risedronate or ibandronate -Less evidence about residual benefit - More cautious about drug holidays Benefits of BP Beyond 5 Years…. Benefits and Risks for Treatment Beyond 5 Years RCT – EXT2 3 RCT – EXT1 2 HORIZON Ext HORIZON-PFT 1 Z9 (n = 95) Zoledronic acid Z6 (n = 616) ZOL (n = 3889) Z3P3 (n = 617) Z6P3 (n = 95) (Zoledronic acid) PBO (n = 3876) 1. Benefits/efficacy FLEX RCT – FLEX 6 2. Risks (AFF) FIT 4,5 Alendronate ALN 5 mg (n = 329) or 10 mg (n = ALN (n = 3236) (Alendronate) 333) PBO (n = 3223) PBO (n = 437) 0 2 4 6 8 10 VERT-MN 7 OL-EXT 9 RCT – EXT 8 RIS 7 yrs (n = 83) Risedronate RIS 2.5 mg (n = 408) RIS (n=135) Years PBO 5 yrs/RIS 2yrs 5 mg (n = 407) PBO (n=130) (n = 81) PBO (n = 407) Time (Years) 0 2 4 6 8 10 ALN = alendronate; DB = double-blind; EXT 1= extension 1; EXT 2= extension 2; FIT = Fracture Intervention Trial; FLEX = FIT Long-term EXtension; HORIZON-PFT = Health Outcomes and Reduced Incidence with Zoledronic acid Once Yearly Pivotal Fracture Trial; OL, Open-label; PBO = placebo; RCT = randomized controlled trial; RIS = risedronate; VERT-MN = Vertebral Efficacy with Risedronate Therapy MultiNational; Z3P3 = zoledronic acid treatment for 3 years followed by placebo for 3 years; Z6 = zoledronic acid treatment for 6 years; ZOL = zoledronic acid. 1. Black DM, et al. N Engl J Med . 2007;356:1809-1822. 2. Black DM, et al. J Bone Miner Res . 2012; 27:243-254. 3. The Effect of 6 versus 9 Years of Zoledronic Acid Treatment in Osteoporosis: A Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT).Presented at ASBMR 2013 (abstract no. SA0389). 4. Black DM, et al. Lancet . 1996;348:1535-1541. 5. Cummings SR, et al. JAMA . 1998;280:2077–2082. 6. Black DM, et al. JAMA . 2006;296:2927-2938. 7. Reginster J-Y, et al. Osteoporos Int . 2000;11:83–91. 8. Sorensen OH, et al. Bone . 2003;32:120-126. 9. Mellström DD, et al. Calif Tissue Int . 2004;75:462-468. 7 Black JAMA 2006; Black et al. JBMR 2012 Black JAMA 2006; Black et al. JBMR 2012 2
drug holidays ver 7-10 7/13/2018 Total Hip BMD Change in FLEX: Reductions (Relative Risks) for Fractures for Continuing vs. Discontinuing Residual Benefit After Stopping Bisphosphonates: Alendronate and ZOL FLEX Alendronate FIT/FLEX Recess 5 yrs (FLEX: 5 yrs/5 yrs 1 to 2 yrs FIT 1.00 (0.8, 1.3) Mean Percent Change Non-vertebral Fracture Start of FLEX 3 to 4.5 yrs 5 0.45 (0.2, 0.85) Vertebral FX 4 (clinical) 3 Zoledronic acid: 2 HORIZON: 3yrs/3 yrs 2.8% 1 Non-vertebral Fracture 0.99 (0.7, 1.5) 0 Vertebral FX 3 F 0 F 1 F 2 F 3 F 4 FL 0 FL 1 FL 2 FL 3 FL 4 FL 5 (morphometric) 0.48 (0.3, 0.9) Year FLEX 0.1 1 10 FIT P <0.001 ALN vs PBO Relative Hazard (± 95% CI) = Placebo Favors Bisphosphonate Favors Placebo = ALN (Pooled 5 mg and 10 mg groups) * Black, et. al. JAMA, 12/06 Black JAMA 2006; Black et al. JBMR 2012 Number 5 Yr risk (%) Fracture reductions with long-term continuation Femoral Neck BMD T- Needed to Clinical Vert. of bisphosphonates (2 RCTs*) Score (start FLEX) Fx. In PBO Treat All women in study FLEX vertebral fracture All BMD values 5.5 34 benefit: Who to continue? • Consistent fracture results for Alendronate and ZOL ≤ -2.5 9.3 21 -2.5 to -2 5.8 33 • Continuing for an additional 5 years ... ≥ -2 2.3 81 o Lowers vertebral fractures risk No prevalent vert. fracture (start of FLEX ) o No evidence for a reduction in non-vertebral − Confidence intervals are wide and allow for possible benefit ≤ -2.5 8.0 24 -2.5 to -2 3.0 63 ≥ -2 1.8 102 • There are benefits to continuing > 5 years, but fewer than initiating Prevalent vertebral fracture (start of FLEX) • Continue those at highest risk of vertebral fracture 11.1 ≤ -2.5 17 *Black JAMA 2006; Black et al. JBMR 2012 11.1 -2.5 to -2 17 12 3.7 ≥ -2 51 Black, et al. NEJM. 2012 May 31;366(22):2051-3 Black JAMA 2006; Black et al. JBMR 2012 3
drug holidays ver 7-10 7/13/2018 What about long term safety? Does AFF risk Incidence of AFF by Duration of BP Exposure in increase with longer duration of BP treatment? 142 cases from KP So. Calif (2007-10)* Note: these results are adjusted for age only…what about other confounders? No ASBMR criteria Several studies treatment duration and AFF risk. 2 examples: (100,000 person yrs) Incidence of AFF 1. 2012 Kaiser Southern Calif. case series of AFF* o X-rays evaluations: 142 cases o Influential (but some methodologic limitations) 2. Swedish study (2008-2010) Duration of Bisphosphonate Use 14 High risk may be explained by higher fx risk (lower BMD, higher Similar results in Swedish study previous fx) *Dell et. al. JBMR 2012 *Dell JBMR 2012; **Schilcher et al 2014 Thinking too much about AFF…. ( obsessed? ) Kaiser Permanente Southern California (KPSC) Osteoporosis Cohort Study (SOCS) 2018 Study (D. Black, Annette Adams, Co-PIs) • Population 4.5 million, ~990,000 women > age 50 studied • Racially diverse cohort • Evaluate all x-rays from subtrochanteric and femoral shaft fractures (ASBMR criteria) from 2007 to 2015 (being extended thru 2017) • Adjust in a prospective analysis (time-dependent covars) Endocrine Reviews: Review of AFF o Adjust for duration of BP use and many other clinical risk factors - 6 months of my life (with 4 colleagues*) o Novel: Adjust for pre-treatment BMD - 20,000 words, on line this week o Goal: prediction tool for AFF risk - Identify important evidence gaps and suggestions for improved/perfect studies o Also look at decrease in AFF risk following discontinuation of BP 15 * Kaiser S. Cal new study (first results at ASBMR 2018) PRELIMINARY RESULTS to be presented at ASBMR 2018 (Sept) *Black, Abrahamsen, Bouxsein, Einhorn, Napoli . Endo Reviews. Epub 7/2018 4
drug holidays ver 7-10 7/13/2018 Kaiser Permanent Southern California Osteoporosis Cohort (SOCS): AFF Risk Factors In 990k women> age 50, 233 AFFs - 25 (10%) in women with no BP use - 206 (90%) in women with some BP use Limited this analysis to 175,000 women >50 who with BP use >=3 months (2007-2017) Hypotheses: - Adjustment for clinical risk factors will attenuate relationship of BP duration to AFF - Adjustment for BMD will further attenuate BP relationships 18 Black, Rosen. NEJM 1/16 - Several clinical variables will be predictive of AFF risk Black et al. Endo Reviews In Press Kaiser Permanent Southern California Osteoporosis Cohort (SOCS) Predictors of AFF (preliminary) Risk factor Unadjusted RR (p) Multivariable Adjusted Digression…BMD and AFF: Some really interesting RR (p) BP duration but preliminary results! (vs < 1 year) 1-4 years 6 (<0.001) 4 (0.003) 4-8 years 19 (<0.001) 37 (<.001) > 8 years 80 (<0.001) 42 (<0.001) • Analysis using women with BMD and some BP use (about 150,000) Adjust for age, Asian race, GC use > 1 year, any fx history, height Surprise! Adjustment for hip BMD (pretreatment) in a subset (150k) made no difference Relative risks are attenuated after adjustment but still a strong 20 association with longer duration beyond 5 years ABSOLUTE RISKS ARE STILL LOW! *Dell et. al. JBMR 2012 Black, Adams, Geiger, Dell ASBMR 2018 5
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