bp 7-2 18 version 7/13/2018 Financial Disclosures Addressing Patient and Provider Concerns About Osteoporosis Treatments None Douglas C. Bauer, MD Professor Medicine and Epidemiology & Biostatistics, UCSF 1 A Clear Example of a Therapeutic Gap: Trends in US Bisphosphonate Prescription Post-Hip Fracture Treatment • 40% of US Medicare enrollees, 80,000 hip fractures 2007-11 • OP medication use in 4 months before and after surgery • Discouraging results: 19% use before and 21% use after… • Post-op zoledronic acid reduces fractures and mortality Jha S et al. J Bone Miner Res. 2015 Munson, Jama Internal Med. 2016; Lyles, NEJM. 2007 1
bp 7-2 18 version 7/13/2018 Another Therapeutic Gap and Memorable Case Another Therapeutic Gap and Memorable Case • 65 yr. old white female followed for decades with HTN • Sudden onset severe thoracic back pain while picking up (Hctz), eczema (topical steroids) and glucose intolerance grandchild • Osteoporotic BMD (fnBMD -2.6, spineBMD -2.8) • X-rays: severe T8 wedge fracture. • Uneventful menopause age 52, no other risk factors. • When asked about medication compliance: Adequate dietary calcium intake. No previous fracture. • Labs and vitamin D level normal “I had some stomach upset and read that Fosamax had • Discussed treatment options, agreed to weekly ALN bad side effects, so I stopped it after a month or so. …” • Briefly discussed both common (GI) and uncommon (ONJ, AFF) side effects “I did not want to disappoint you so I did not tell you…” • Seen regularly over next two years, medications refilled Quantitative Assessment of Benefits and Risks of Osteoporosis Treatment Who is Responsible for the Therapeutic Gap? Short-term treatment (3-5 years) • Providers, patients and health system (payers) all contribute - Benefits (fracture reductions) • Key factors for primary care providers: - Risks (ONJ, AFF) o Lack of awareness and competing priorities - Benefits vs. risk o Complex and conflicting guidelines Focus on Anti-resorptives (esp. BP’s) • Key factors for patients: o Under estimation of personal risk and consequences o Uncertainty about drug efficacy o Media-fueled fears about drug side effects National Osteoporosis Foundation Survey, 2017 2
bp 7-2 18 version 7/13/2018 Summary of Bisphosphonate Fracture Reductions NNT and Fractures Prevented for (up to 5 Years) 3 Years of BP (or Dmab) Treatment Zoledronic acid Among older women with prevalent VF or T-score<-2.5 Zoledronic acid g Compare to 3 years of statin to prevent one major cardiovascular event: NNT= 95 Black, Rosen. NEJM 1/16; **Khosla, JBMR 9/16 Also reductions ~25% in non-vertebral fractures Khosla S, et al. JCEM, 2012; Black NEJM 2016; Khosla JCEM 2012 Possible Harms of Osteoporosis Therapy “Bisphosphonates might lead to jawbone death in patients who have dental surgery” New York Times, 2009 Potential BP harms: Less impactful - GI intolerance - Ophthalmologic, renal effects, acute phase reaction - Atrial fibrillation and esophageal cancer Potential BP harms: More impactful - Osteonecrosis of the jaw (ONJ) - Atypical femur fractures (AFF) 12 * 3
bp 7-2 18 version 7/13/2018 Bisphosphonates and ONJ: Summary • Very rare in osteoporosis patients (about 4-6 per 10,000 py in BP users) Higher in oncology use (higher doses, other factors) o • Little evidence that doses used for osteoporosis increase risk of ONJ o If so, very low risk • 2012 American Dental Association report (Hellstein et al) has helped to decrease concerns in U.S. • Etiology/mechanism remains uncertain Kahn, JBMR 2015; Hellstein, ADA 2012 Summary of 2014 ASBMR Case Definition for Morphologic Characteristics of Atypical Femur Fracture Atypical Femur Fracture (AFF) • Location along femoral diaphysis (between LT and DMF) and • Meets >4 of 5 Major Criteria Minimal or no trauma o Fracture line from lateral cortex & transverse, may be oblique across o femur Complete fractures thru both cortices; incomplete fx lateral cortex o Non- or minimally comminuted o Localized reaction in lateral cortex o • Minor Criteria (may be present) Increased cortical thickness (generalized) o Prodromal symptoms (pain in thigh/groin) o Bilateral o Khosla 2012 (photo: Dr. M. Rosenwasser, Columbia U) Delayed healing o Shane, et. al. JBMR, 2010/2014 Khosla 2012 (photo: Dr. M. Rosenwasser, Columbia U) 4
bp 7-2 18 version 7/13/2018 Two Important Cohort Studies for Evidence Linking Osteoporosis Treatment to AFF Risks vs. Benefits over 3-5 Years BP Treatment 1) Case Reports and Case Series (from 2007) 1) Swedish study (Schilcher) 2) Observational/epidemiologic studies (Canada, Denmark, US, Sweden, other countries) 2) Kaiser Northwest, U.S. (Feldstein) Case-control studies • Cohort studies • Both: • Most use ICD codes, did not have x-rays - Reviewed individual x-rays from fracture patients • Problematic comparitors - Large, population-based with good pharmacy records 3) A bit of data from RCT’s (too small for rare events) Helpful to assess: 2013: Meta-analysis of bisphosphonates and atypical • fracture (Gedmintas, JBMR, 2013) - Incidence of AFF - Relative risk of BP use and AFF *Black, et al Endo Reviews e pub 7/2018 Feldstein, et al. JBMR 2012; Schilcher, NEJM 2014 Incidence of AFF from Swedish Study Swedish Study of Bisphosphonates and Atypical Fracture (2011, 2014 update) • ~3 million Swedish men and women > age 55 • ~50,000 proximal femur fractures in 2008-10 • All hip/femur fractures in Sweden (Nat’l Reg) 2008-2010 • ~5500 subtroch or femoral shaft (ST/FS) x-rays reviewed using ASBMR 2014 criteria • Review X-rays for AFF: • Subtrochanteric or femoral shaft ICD-10 (S722 and S723) o • 172 confirmed atypical femur fractures ASBMR 2014 criteria o • Link to pharmaceutical register (start 2005, 3-5 yrs only) 172 AFF (out of 50,000 femur fractures) Schilcher et al, NEJM 5/11; Schilcher et al, NEJM (ltr), 2014; Schilcher et al Acta Ortho, 2015 Schilcher et al, NEJM 5/11; Schilcher et al, NEJM (ltr), 2014; Schilcher et al Acta Ortho, 2015 5
bp 7-2 18 version 7/13/2018 How Common are AFFs Among All Femur Fractures in Swedish Data? 1000 Hip/Femur Fractures 110 ICD-coded ST/FS* 3.4 AFF’s 24 Black, Rosen. NEJM 1/16 *ST/FS: subtroch or femoral shaft Taken from Schilcher, NEJM 2014 Black et al. Endo Reviews In Press Meta-analysis of BP Use and ST/FS or AFF: Incidence of AFF’s: 13 ‘Case-control’ and ‘Cohort’ Studies Number of AFF’s per 1000 Hip Fracture • Swedish and Kaiser Northwest are the only published population-based studies with x-ray confirmation (using ASBMR criteria) • Incidence in both studies is about 4 AFF per 1000 hip fractures • Consistent with other population-based studies 1.70 (1.22 to 2.37) 25 *Gedmintas L, et al J Bone Miner Res. 2013 Feldstein, et al. JBMR 2012; Schilcher, NEJM 2014 Gedmintas L, J Bone Miner Res. 2013 6
bp 7-2 18 version 7/13/2018 Benefits vs. Risks for 3 Years of BP Therapy in Summary: If One Treats 1000 Osteoporotic 1000 Osteoporotic Women Women for 3 Years Benefits: Prevent 100 fractures including 11 hip fx Harms: ‘Cause’ 0.08 AFF Put another way, For every 1000 fractures prevented, 1 AFF caused 30 Black, Rosen. NEJM 1/16 Black DM, Rosen CJ. N Engl J Med 2016;374:254-262. What Else Can Be Done to Osteoporosis Treatment 3-5 years: Reassure Patients? the Bottom Line Can we predict AFF risk and avoid BPs in - certain populations? Benefits for osteoporosis treatment far outweigh any risks, even Geometry: neck-shaft angle, - allowing for some risk of AFF cortical thickness differ in some studies. Asian populations? BUT Weak associations … Genetic: geranylgeranyl - Simply quoting statistics to patients diphosphate synthase without carefully listening and ( GGPS1 ) mutations in 3 addressing their concerns is not sisters with AFF. going to work… Rare variants… 31 32 Unlikely to be clinically useful - Mahjoub, JBMR 2016; Roca-Ayats et al. NEJM 2017 7
bp 7-2 18 version 7/13/2018 What Else Can Be Done to Reassure Patients? Likely that AFF begin as stress fractures. - Can we find potential AFF before they occur? - Prodromal pain: Common but no good data - yet on prevalence or utility of systematic assessments. - - Monitoring for preclinical abnornalities: - No reliable serum biomarkers to date - X-ray surveillance impractical 33 - DXA? GE LUNAR SOFTWARE FOR AFF DETECTION Early Reports of Femur Imaging in BP Users • 257 Irish patients, BP therapy > 5 yr • Extended femur scan at the time of routine DXA • Abnormal DXA images (e.g., “flaring”, “beaking”) suggested in 19 (7.4%) • Radiographic evaluation: 7 had no abnormality 5 with unrelated radiographic abnormality 7 (2.7%) incomplete AFF (2 with thigh pain) McKenna, J Clin Densitometry 2013 8
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