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7/12/2019 Conflict of Interest Statement Editorship Treatment Gaps and Patient New England Journal Concerns: Where Do We Go from Here? eLife UpToDate Clifford J Rosen MD rosenc@mmc.org MMCRI Scarborough, Maine Outline

  1. 7/12/2019 Conflict of Interest Statement • Editorship Treatment Gaps and Patient – New England Journal Concerns: Where Do We Go from Here? – eLife – UpToDate Clifford J Rosen MD rosenc@mmc.org MMCRI –Scarborough, Maine Outline • Brief Overview of Osteoporosis Treatments 1-trauma; 2- prediction of subsequent fractures • State of Prescribing- 2019 • Treatment Gaps and What to Do About those? • What do Patients Worry About? • What can we do? 1

  2. 7/12/2019 BMD: SOF Very Long-Term Prediction (no models): We Knew This 25 Years Ago!!! But have we made advances? a Single Hip BMD* is Remarkably Predictive for 25 years ! 35 5.8 Lowest BMD 29.6% 30 Cumulative incidence (%) Quartile Previous 3.4 25 Vert Frx Quartile 2 Low BMD 2.3 20 20.1% >2 VFx  Mid BMD Quartile 3 15 14.1% High BMD 1.7 10 times risk of 10 Highest Quartile 7.6% 1.0 future VFx** No Vert Frx 5 0.2 0 0 5 10 15 20 25 0 1 2 3 4 5 6 Years since baseline Risk of New Vertebral Fractures (% / yr) * Age-adjusted *Ross 1991 ** Black, JBMR 1999 Black, et al. JBMR 2017; Napoli, ASBMR, 2016 Estrogen Prevents Fractures: the WHI Currently Available Treatments 2

  3. 7/12/2019 Fracture Risk Reduction with the Denosumab Treatment Reduces Vert Bisphosphonates Fractures Cummings, NEJM 2009 Effect of Teriparatide on Incidence of Vertebral and Non-Vertebral Fractures in Postmenopausal Women with Osteoporosis New vertebral fracture Non-vertebral fractures 20 20 P< 0.01 P< 0.01 Patients (%) with fracture 18 18 Patients (%) with fracture 16 16 14 14 12 12 10 10 8 8 65% 53% 6 6 4 4 2 2 0 0 20  g PTH 20  g PTH Placebo Placebo Neer RM, et al. N Engl J Med. 2001;344:1434-41 3

  4. 7/12/2019 Abaloparatide Reduces Fractures vs PTH 1-34 Romozsozumab Reduces Vert Fractures Romosozumab Reduces Spine but not non-spine Frx 2019 Treatment Summary • Treat the most affected individuals • Fracture Prediction is Straightforward- – Age – Previous Fracture – Low BMD – FRAX • Anti-Resorptives reduce fractures consistently if there is adherence to treatment regiments • Anabolic therapies can also reduce fracture and boost BMD more than the anti-resorptives 4

  5. 7/12/2019 Algorithm for the Management of Postmenopausal Osteoporosis Meta-Analysis of Osteoporosis Treatments; Endocrine Society Guidelines Relative Risk and 95% CI Effect of treatment compared to placebo Direct calculation Eastell, et al JCEM March 2019 Eastell R, Rosen CJ, Black DM, Cheung AM, Murad H, Shoback D. JCEM, 2019; 104(5) OSTEOPOROSIS TREATMENT: REMARKABLE PROGRESS YET PROFOUND CHALLENGES In assessing both existing and potential treatments and optimizing duration, “Millions of Americans researchers should make use of innovative designs and approaches are missing out on a Future clinical trials should evaluate new agents or multicomponent chance to avoid interventions (e.g., oral care, FLS) that potentially lack the side effects of current debilitating fractures anti-resorptive treatments and may have greater efficacy from weakened bones, researchers say, More evidence and research are needed to determine which patients are optimal because they are candidates for drug holidays and sequential therapies, and possible strategies for terrified of exceedingly mitigating serious adverse events associated with long-term bisphosphonate or rare side effects from denosumab use (i.e., AFF and ONJ). drugs that can help More research is needed to prevent and characterize AFF and ONJ as rare serious them.” adverse events are associated with long-term bisphosphonate or denosumab use. More research on barriers to osteoporotic drug therapy is needed. 5

  6. 7/12/2019 Gaps In Treatment- What Are The Mind the Gap!!!! Current Issues? • What to Do After a Drug Holiday is Over? PREVALENCE OF BISPHOSPHONATE USE FROM 1996 TO 2012 • How long is long enough in treatment? • Can we predict serious adverse events ? • Can anabolic treatments be repeated and if not what do we do? • How Do We Monitor Efficacy Most Efficiently CHANGING HIP FRACTURE RATES: PROBABILITY OF OSTEOPOROSIS MEDICATION USE FOLLOWING A CAUSE FOR CONCERN? HIP FRACTURE WITHIN 12 MONTHS AFTER DISCHARGE Solomon et al. JBMR 29:1929, 2014 Lewiecki, et al. ASBMR 2016, 1077 6

  7. 7/12/2019 What Are Patient Concerns About Atypical Femoral Fractures Treatment Regimens- Meta-Analysis • 1- Efficacy • 2-Cost • 3-Fear of Fractures !!!!! • 4-Other Adverse Events Eastell, 2019 THE PROBLEM FOR THE FIELD OF THE CHALLENGE OSTEOPOROSIS: AFFs • Patient/physician attitudes shaped by • Urgent need to demonstrate to patients  Media attention to AFFs that we have heard their concerns and are  Concern that they may be vastly under- addressing them in the short-, reported intermediate- and long-terms  Osteoporosis is not that serious a problem • Clear that simply quoting statistics to • Key is to diagnose AFFs before they occur patients without carefully listening and and over the longer term, better identify addressing their concerns is not going to those patients at increased risk even before work starting osteoporosis medications 7

  8. 7/12/2019 SHORT TERM FOR AFFs What Can We Do? Education • Patient education regarding prodromal • Promote the value of DXA to help screen and symptoms, e.g., groin and hip pain treat high risk individuals • Physician education regarding taking these • Recognize that a fracture in a postmenopausal symptoms seriously and defining an woman is a sentinel event requiring treatment appropriate, cost-effective evaluation plan to exclude incipient AFF • Re-educate the public on the value of osteoporosis medications • Brief, standardized and simple-to administer • Innovate and encourage newer safer questionnaires for common prodromal symptoms of AFF that could be linked to treatments or better technology to predict prescription renewals by physicians adverse events SHORT TERM Monitoring • Agreement from bone density manufacturers to modify existing DXA scanners to obtain a femur “monitoring scan” that includes the region of the femur where AFFs occur • Ideally covered by Medicare/insurance – could be done with or independent of standard BMD testing • Consider this a part of the cost of therapy, and not to be confused with BMD monitoring for efficacy – as such, cost of this safety monitoring test should be very low 8

  9. 7/12/2019 INTERMEDIATE TERM LONG TERM Pharmacogenomics Identification of higher risk patients • Compared femur geometrical data in 56 AFF patients vs 112 controls with • Mutations in geranylgeranyl diphosphate synthase traumatic or fragility fractures ( GGPS1 ) identified by whole-exome sequencing in 3 sisters who sustained atypical femoral fractures during treatment with bisphosphonates  Mutations impaired GGPPS function; GGPPS also inhibited by bisphosphonates  Identified other susceptibility variants • Larger, collaborative pharmacogenomics studies needed Majoub, 2016 JBMR Roca-Ayats et al. NEJM 376:1794, 2017 Benefits of Therapy: Take Home Messages Fractures prevented in 1,000 osteoporotic women treated for 3 years* • Listen to the Patient !!!! What are the concerns? Fractures prevented Based on results • Initiate Patient Education in a timely manner from from large without constraints Spine 71 RCTS: FIT, HORIZON, VERT Non- 29 • Be up to date on the recent literature to better NA, others vertebral inform with shared decision making (hip) (11) • If all else fails, don ’ t be afraid to call ` a Spine/non 100 * Like women in FIT, Consultant!!!!! Another opinion always helps HORIZON trials spine Black, Rosen. NEJM 1/16 36 9

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