drug holidays ver 7-10 7/12/2019 Financial Disclosures Long term Side Effects of Osteoporosis Treatment and Impact on Long Term Treatment - Consulting & talks: Zuellig pharma, -Advisory Board: Roche Diagnostics -DSMB (not bone): Eli Lilly Dennis M. Black, PhD Professor Epidemiology and Biostatistics, UCSF Decline in Treatment Wysowski DK, Greene P. Bone. 2013;57:423-428 1
drug holidays ver 7-10 7/12/2019 Bisphosphonates and ONJ: Summary Possible Harms of Osteoporosis Therapy • Very rare in osteoporosis patients (1 to 50 per 100,000 in BP users) Much higher in oncology use (higher doses, other factors) o Potential BP harms: Less impactful Also seen with non-BP therapies o - GI intolerance • Little evidence that doses used for osteoporosis increase risk of ONJ - Ophthalmologic, renal effects, acute phase reaction o If so, very low risk - Atrial fibrillation and esophageal cancer • Other RFs: periodontal disease, oral surgery (extractions/implants), diabetes, Ca, others Potential BP harms: More impactful - Osteonecrosis of the jaw (ONJ) • 2012 American Dental Association report (Hellstein et al) has helped - Atypical femur fractures (AFF) to decrease concerns in U.S. • Etiology/mechanism remains uncertain • Treatments increasingly effective 5 * Kahn, JBMR 2015; Hellstein, ADA 2012; Khan O.Int 2016 Summary of 2014 ASBMR Case Definition for Atypical Femur Fractures (AFF) Atypical Femur Fracture • Location along femoral diaphysis (between LT and DMF) and • Meets >4 of 5 Major Criteria o Minimal or no trauma o Fracture line from lateral cortex & transverse, may be oblique across femur o Complete fractures thru both cortices; incomplete fx lateral cortex o Non- or minimally comminuted o Localized reaction in lateral cortex • Minor Criteria (may be present) o Increased cortical thickness (generalized) o Prodromal symptoms (pain in thigh/groin) o Bilateral o Delayed healing Khosla 2012 (photo: Dr. M. Rosenwasser, Columbia U) Shane, et. al. JBMR, 2010/2014 2
drug holidays ver 7-10 7/12/2019 Atypical Femur Fracture Evidence Linking Osteoporosis Treatment to AFF* (~ASMBR criteria) 1) Case Reports and Case Series (from 2007) Fracture in (begins in) region 2) Observational/epidemiologic studies (Canada, Denmark, US, below lesser troch and distal Sweden, other countries) metaphyseal flare Case-control studies • Cohort studies • Has perpendicular fracture 3) A bit of data from RCT’s (too small for rare events) line in lateral cortex, can be oblique after that 2013: Meta-analysis of bisphosphonates and atypical fracture • (Gedmintas, JBMR, 2013) Endosteal or periosteal thickening at fracture site Note: Focus on bisphosphonates since most data. AFF seen • with other meds including denosumab, romosozumab, others Low trauma No or minimal comminution *Black, et al Endo Reviews 7/2018 Two Key AFF Cohort Study Examples for Incidence of AFF: Incidence and RR for BP/AFF Swedish Study of Bisphosphonates and Atypical Fracture (2011, 2014 update) 1) Swedish study (Schilcher) 2) Kaiser Northwest, U.S. (Feldstein) • Age > 55 y, F/M Both: • All hip/femur fractures in Sweden (Nat’l - Reviewed individual x-rays from fracture patients Reg) 2008-2010 - Large, population-based with good pharmacy records - Important limitation • Review X-rays for AFF: • Subtrochanteric or femoral shaft Helpful to assess: ICD-10 (S722 and S723) o - Incidence of AFF ASBMR 2014 criteria o - Relative risk of BP use and AFF • Link to pharmaceutical register Schilcher et al, NEJM 5/11; Schilcher et al, NEJM (ltr), 2014; Schilcher et al Acta Ortho, 2015 Feldstein, et al. JBMR 2012; Schilcher, NEJM 2014 3
drug holidays ver 7-10 7/12/2019 How Common are AFFs Among All Femur Fractures Incidence of AFF from Swedish Study in Swedish Data? • ~3 million Swedish men and women > age 55 • ~50,000 proximal femur fractures in 2008-10 3 million men and women 3 years 50,000 femur fractures 5,500 Subtrochanteric/femoral • ~5500 ICD-coded subtroch or femoral shaft (ST/FS) x-rays shaft reviewed using ASBMR 2014 criteria 172 AFF 1000 Hip/Femur Fractures • 172 confirmed atypical femur fractures 110 ICD-coded ST/FS* 172 AFF (out of 50,000 femur fractures) 3.4 AFF’s *ST/FS: subtroch or femoral shaft Schilcher et al, NEJM 5/11; Schilcher et al, NEJM (ltr), 2014; Schilcher et al Acta Ortho, 2015 Schilcher et al, NEJM 2014 Incidence of AFF’s: Number of AFF’s per 1000 Hip Fracture • Schilcher (Sweden) and Feldstein (KP NW) are only published population-based studies with x-ray confirmation (using ASBMR criteria) • Consistent with other population-based studies 15 16 Black, Rosen. NEJM 1/16 Feldstein, et al. JBMR 2012; Schilcher, NEJM 2014 Black et al. Endo Reviews 2018 4
drug holidays ver 7-10 7/12/2019 What is the Relative Risk for AFF with Any Bisphosphonate Use? What is the Relative Risk for AFF from BP - Relative risk in Schilcher (Swedish) and Feldstein studies. Use? - Both reviewed X-rays & both compare to “typical subtroch/fem shaft”. Relative risk: any Study 95% CI BP and AFF Schilcher 33.3 (18-38) Feldstein 2.1 (0.99-4.99) • Very different relative risks! Feldstein, et al. JBMR 2012; Schilcher, NEJM 2014 Meta-analysis of Any BP Use and ST/FS or AFF: Benefits vs. Risks for 3 Years of BP Therapy in 13 ‘Case-control’ and ‘Cohort’ Studies 1000 Osteoporotic Women All used ICD codes (no xrays) 4/100 1.70 (1.22 to 2.37) *Gedmintas L, et al J Bone Miner Res. 2013 Gedmintas L, J Bone Miner Res. 2013 Black DM, Rosen CJ. N Engl J Med 2016;374:254-262. 5
drug holidays ver 7-10 7/12/2019 Summary: If One Treats 1000 Osteoporotic Women for 3 Years Benefits and Risks for Treatment Beyond 5 Years Benefits: Prevent 100 fractures including 11 hip fx 1. Benefits/efficacy 2. Risks (AFF) Harms: ‘Cause’ 0.08 AFF Put another way, For every 1000 fractures prevented, 1 AFF caused 21 22 Black, Rosen. NEJM 1/16 Reductions (Relative Risks) for Fractures for Continuing vs. Discontinuing Benefits of BP Beyond 5 Years…. Bisphosphonates: Alendronate and ZOL Alendronate (FLEX: 5 yrs/5 yrs RCT – EXT1 2 RCT – EXT2 3 HORIZON Ext HORIZON-PFT 1 1.00 (0.8, 1.3) Z9 (n = 95) Zoledronic acid Z6 (n = 616) Non-vertebral Fracture ZOL (n = 3889) (Zoledronic acid) Z3P3 (n = 617) Z6P3 (n = 95) PBO (n = 3876) 0.45 (0.2, 0.85) Vertebral FX FLEX RCT – FLEX 6 FIT 4,5 Alendronate ALN 5 mg (n = 329) or 10 mg (n = ALN (n = 3236) (Alendronate) (clinical) 333) PBO (n = 3223) PBO (n = 437) Zoledronic acid: 0 2 4 6 8 10 VERT-MN 7 RCT – EXT 8 OL-EXT 9 HORIZON: 3yrs/3 yrs RIS 2.5 mg (n = 408) RIS 7 yrs (n = 83) Risedronate RIS (n=135) Years PBO 5 yrs/RIS 2yrs 5 mg (n = 407) PBO (n=130) (n = 81) PBO (n = 407) Time (Years) Non-vertebral Fracture 0.99 (0.7, 1.5) 0 2 4 6 8 10 Vertebral FX 3 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 (morphometric) 0.48 (0.3, 0.9) 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. 0.1 1 10 Black JAMA 2006; Black et al. JBMR 2012 Relative Hazard (± 95% CI) Favors Bisphosphonate Favors Placebo Black JAMA 2006; Black et al. JBMR 2012 Black JAMA 2006; Black et al. JBMR 2012 6
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