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July 2017 CME (25 minutes) 7/11/2019 Financial Disclosures Financial Disclosures Epidemiology and Consequences of Fractures I have nothing to disclose Ann V. Schwartz, PhD Department of Epidemiology and Biostatistics UCSF Outline Outline Fracture Incidence in Older Adults Fracture Incidence in Older Adults • Fracture incidence • The total number of fractures in adults • Determinants of fracture incidence 50+ estimated at 2.05 million (2005). – Age – Gender – Race – Geography – History of fracture • Consequences of fracture • Treatment trends • Projected increases in fracture Burge et al JBMR 2007

July 2017 CME (25 minutes) 7/11/2019 Incidence and Economic Burden of Osteoporosis ‐ Related Fractures in the United States, 2005–2025 Lifetime risks of clinical fractures Lifetime risks of clinical fractures Common sites of fracture in older adults Common sites of fracture in older adults 50 year old white women (U.S.) 50 year old white women (U.S.) Lifetime risk* • Hip fracture 17% • Wrist fracture 16% • Vertebral fracture 16% • Any fracture > 50% Breast cancer 15% Incident fracture distribution by type, 2005, U.S. ≥50 Burge et al JBMR 2007 *Refs: Melton; Black; Kanis Prevalence of Osteoporosis in US: Prevalence of Osteoporosis in US: Osteoporotic fractures: At high risk of fracture At high risk of fracture Incidence rate compared with others Postmenopausal Women Men 80 80 Hospitalizations 70 70 60 60 50 50+ 50 50+ 30% 40 40 16% 30 30 20 20 10 10 0 0 50-59 60-69 70-79 80+ 50-59 60-69 70-79 80+ 2005-08 NHANES Osteoporosis: BMD T-score <-2.5 OR qualifying U.S. women 55+ low trauma fx OR FRAX score >3% for hip fx or Wright et al Osteo Int 2017 Singer A et al Mayo Clinic Proceedings , 2015 >20% for MOF

July 2017 CME (25 minutes) 7/11/2019 Age and gender are important determinants Major determinants of fracture Major determinants of fracture of fracture incidence incidence incidence Demographic: Age Gender Race Geography Previous fracture: vertebral & non-vertebral More on risk factors for fracture and fracture prediction: Talk by Dr. Harris coming up next. Harvey N et al ASBMR Primer Ch 40 2013 Lifetime risks of fracture: Lifetime risks of fracture: Age is Independent of BMD as Risk Factor for Age is Independent of BMD as Risk Factor for Hip Fracture Hip Fracture Impact of gender Impact of gender Age (yrs) Lifetime Risk at Age 50* 20 80 Fracture Men (%) Women (%)  5-fold increase in fracture Hip 6 17 70 probability from Wrist 3 16 age 50 to 80 at 10 Clinical Vert Fx 5 16 same BMD 60 Any 16% > 50% 50 0 -3 1 -2 -1 0 * Among Caucasians Hip BMD T-score (SD) Kanis et al, 2004

July 2017 CME (25 minutes) 7/11/2019 Hip fracture incidence by race Hip fracture incidence by race Osteoporosis in Men Osteoporosis in Men (California) (California) • 1 in 5 to 6 men over age 50 will suffer osteoporotic fracture • 30% of hip fractures worldwide are in men • Mortality rates after fracture higher in men than women • Treatment rates following fracture are abysmal Sullivan et al 2016 Vertebral Fracture Incidence Vertebral Fracture Incidence Hip fracture rates vary dramatically by region and country Worldwide Worldwide Clinical fractures. Age standardized. Cauley et al. (2014) Nat. Rev. Endocrinol. Ballane et al Osteo Intl 2017

July 2017 CME (25 minutes) 7/11/2019 History of fracture: History of fracture: Vertebral fractures dramatically Vertebral fractures dramatically Increased risk of another fracture Increased risk of another fracture increase risk of future fracture increase risk of future fracture • History of any fracture: 1.5-3.0 fold • 4x risk of more vert fxs greater risk of fracture • 2x risk of other fractures True for • Clinical diagnosis of • any fracture type vertebral fracture -> 5 yr hip fracture risk of 13% in • even traumatic fractures women and 7% in men! • especially strong for men • mostly independent of BMD Not in FRAX vanStaa, Osteop Int 2002;13:624-9 Klotzbuecher JBMR 2000; Van Meta-analysis: Klotzbuecher, JBMR 2000;15:721; Kanis Osteop Int 2004 Staa Osteoporos Int 2002 Existing Vertebral Fracture Predictive of Existing Vertebral Fracture Predictive of Existing Vertebral Fracture Predictive of Existing Vertebral Fracture Predictive of Any Future Fracture Independent of BMD Any Future Fracture Independent of BMD Future Vertebral Fracture Independent of BMD Future Vertebral Fracture Independent of BMD No vert fx Absolute fracture risk (%) >1 vert fx 6 5.8 Previous 3.4 5 Vert Frx Low BMD 2.3 4 Mid BMD 3 High BMD 1.7 2 No Vert Frx 1.0 1 0.2 0 -2 -3 -4 0 1 2 3 4 5 6 Femoral neck T-score Risk of New Vertebral Fractures (% / yr) Ross 1991 Siris et al, Osteo Int 2007

July 2017 CME (25 minutes) 7/11/2019 Prevalence of vertebral fracture: Prevalence of vertebral fracture: Prevalence of vertebral fracture: Prevalence of vertebral fracture: NHANES 2013-14 NHANES 2013-14 NHANES 2013-14 NHANES 2013-14 Age Vert Fracture (%) Age Vert Fracture (%) >90% were not Women Men Women Men aware of 50-59 3.3 5.2 50-59 3.3 5.2 vertebral 60-69 4.6 6.3 60-69 4.6 6.3 fracture 70-79 10.6 10.3 70-79 10.6 10.3 80+ 16.3 20.7 80+ 16.3 20.7 DXA Vertebral Fracture Assessment (VFA) DXA Vertebral Fracture Assessment (VFA) Cosman et al Osteoporos Int 2017 Cosman et al Osteoporos Int 2017 Hip fractures are associated with increased morbidity and mortality Consequences of fracture Consequences of fracture No longer able to live independently No longer able 50% to walk independently No longer able to 40% get in/out of bath 30% 17% Death within Among those independent prefracture one year Magaziner J. J. Gerontol A Biol Sci Med Sci 2000

July 2017 CME (25 minutes) 7/11/2019 Impact of Vertebral Impact of Vertebral Mortality elevated after hip fracture Mortality elevated after hip fracture Fractures Fractures • 20% excess mortality in 5 yrs Women after fracture • Deformity & height loss • Acute & chronic pain • Pulmonary dysfunction • Diminished quality of life: loss of self-esteem, sleep Men disorder, depression, loss of independence Haentjens et al JAMA 2010 High medical costs for hip and for other Limited Activity Days Post Fracture: fractures Postmenopausal Women in FIT Hip $25,519 Consequences of fracture Consequences of fracture Excess direct costs for Medicare patients with nonvertebral fractures Costs for year after fracture (1999-2006) Fink et al. Osteo Intl 2003 Pike et al PharmacoEconomics 2012 Expressed in 2006 dollars

July 2017 CME (25 minutes) 7/11/2019 Length of stay and hospitalization costs: Fractures, MI, stroke, breast cancer Trends in Use of Osteoporosis Trends in Use of Osteoporosis Therapy Therapy HIP MI Singer et al Mayo Clinic Proceedings 2015, NYT (6/2/16): Osteoporosis drugs NYT (6/2/16): Osteoporosis drugs Osteoporosis medication use to Osteoporosis medication use to shunned for fear of rare side effects shunned for fear of rare side effects 2004 2004 Brauer et al JAMA 2009

July 2017 CME (25 minutes) 7/11/2019 Oral Bisphosphonate Use in the U.S. Oral Bisphosphonate Use in the U.S. U.S. Google search activity for “Fosamax” U.S. Google search activity for “Fosamax” Declines after 2008 Declines after 2008 A = Lawsuit filed against Merck for Fosamax causing osteonecrosis of the jaw. B = Study published associating Fosamax with atrial fibrillation. C = Jury deliberations start for first Fosamax trial. D = ABC World News runs feature segment on Fosamax and atypical femoral fractures. % of 55+ y.o. with ≥1 prescription in annual federal survey Jha et al JBMR 2015 Jha et al JBMR 2015 FDA safety announcements and use of Osteoporosis Medication Use After Hip Fracture Osteoporosis Medication Use After Hip Fracture osteoporosis medications 5/05 3/10 ONJ AFF 10/07 A fib U.S., men & women, 50+, 2002-11 Solomon et al JBMR 2014 Kim et al JBMR 2015

July 2017 CME (25 minutes) 7/11/2019 Osteoporosis ‐ Related Health Services Utilization After Osteoporosis ‐ Related Health Services Utilization After Osteoporosis Therapy after Fracture Osteoporosis Therapy after Fracture First Hip Fracture First Hip Fracture (Medicare, 2008-13) (Medicare, 2008-13) Women in the United States, 2008–2014 Women in the United States, 2008–2014 Within 1 yr Gillespie & Morin JBMR 2017 Weaver…Harris et al J Manag Care Spec Pharm. 2017 Decline in DXA testing utilization… Decline in DXA testing utilization… Osteoporosis Therapy after Fracture, by Sex Osteoporosis Therapy after Fracture, by Sex (Medicare, 2008-13) (Medicare, 2008-13) Within 1 yr Medicare, women, 65+ Weaver…Harris et al J Manag Care Spec Pharm. 2017 Leweicki et al Osteoporos Int 2018

July 2017 CME (25 minutes) 7/11/2019 Poor Compliance with Osteoporosis Therapy: Poor Compliance with Osteoporosis Therapy: Poor Compliance with Osteoporosis Therapy: Poor Compliance with Osteoporosis Therapy: 12 months after initial prescription 12 months after initial prescription 24 months after initial prescription 24 months after initial prescription U.S., women, 50+ U.S., women, 50+ Durden et al Arch Osteoporos 2017 Durden et al Arch Osteoporos 2017 Prospects for the Future… Prospects for the Future… Hip fracture incidence declined in U.S. Hip fracture incidence declined in U.S. after 1995 after 1995 Prospects for the Future Prospects for the Future U.S., 55+ Jha et al JBMR 2015