DISCLOSURES SUNDEEP KHOSLA, M.D.

Transcription

1 ADDRESSING PATIENT CONCERNS REGARDING COMPLICATIONS OF ANTIRESORPTIVE THERAPY Sundeep Khosla, M.D. Mayo Clinic, Rochester, MN DISCLOSURES SUNDEEP KHOSLA, M.D. NONE 1

2 OVERALL CONCLUSIONS There has been remarkable progress in our understanding of the pathogenesis of osteoporosis and new drugs available to treat the disease However, despite this remarkable progress in drug development, there are major challenges to implementing appropriate treatment APPROVED (US FDA) AND PENDING THERAPIES FOR OSTEOPOROSIS Anti-resorptive Estrogen: Oral, transdermal SERM: Raloxifene Calcitonin: Salmon, human Bisphosphonates: Alendronate, risedronate, ibandronate, zoledronic acid RANKL Ab: Denosumab Anabolic PTH: Teriparatide, Abaloparatide Mixed Sclerostin Ab: Romosozumab Cathepsin K inhibitor: Odanacatib 2

3 OSTEOPOROSIS TREATMENT: REMARKABLE PROGRESS YET PROFOUND CHALLENGES Millions of Americans are missing out on a chance to avoid debilitating fractures from weakened bones, researchers say, because they are terrified of exceedingly rare side effects from drugs that can help them. US GOOGLE SEARCH ACTIVITY FOR FOSAMAX Lawsuit for ONJ ABC News story on Fosamax and AFF Study on AF link Jha et al. JBMR 30:2179,

4 PREVALENCE OF BISPHOSPHONATE USE FROM 1996 TO 2012 Jha et al. JBMR 30:2179, 2015 THE PROBLEM FOR THE FIELD OF OSTEOPOROSIS Increasingly, patients who clearly need osteoporosis therapy are either not being offered or choosing not to take bisphosphonates (or other osteoporosis drugs) due to the fear of Atypical Femur Fractures (AFFs) Incidence estimates for AFFs with prolonged bisphosphonate use vary widely (3.2 to in 100,000 person-years) (Shane et al. JBMR 29:1, 2014) Nonetheless, best estimates are that with bisphosphonate therapy, 80 to 5,000 fragility fractures would be prevented for every AFF possibly induced by treatment (Black and Rosen, NEJM 374:254, 2016) 4

5 THE PROBLEM FOR THE FIELD OF OSTEOPOROSIS (Cont d) Patient/physician attitudes shaped by Media attention to AFFs Concern that they may be vastly under-reported Clear that simply quoting statistics to patients without carefully listening and addressing their concerns is not going to work THE CHALLENGE Urgent need to demonstrate to patients that we have heard their concerns and are addressing them in the short-, intermediate- and long-terms Key is to diagnose AFFs before they occur and over the longer term, better identify those patients at increased risk even before starting osteoporosis medications 5

6 SHORT TERM Education Patient education regarding prodromal symptoms, e.g., groin and hip pain Physician education regarding taking these symptoms seriously and defining an appropriate, cost-effective evaluation plan to exclude incipient AFF Brief, standardized and simple-to administer questionnaires for common prodromal symptoms of AFF that could be linked to prescription renewals by physicians 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 6

7 SHORT TERM Monitoring (Cont d) Hologic currently offers this option now FDA approved but only on its new scanner 7

8 SHORT TERM Monitoring (Cont d) Needs to be made available as a low cost update to all existing scanners Monitoring scan analogous to monitoring LFTs for patients on a statin, renal function on patients started on ACE inhibitors SHORT TERM Monitoring (Cont d) GE Lunar now offering a similar option as an update to existing software Just approved by FDA Quantify focal thickening Visualization Single scan Can retrospectively analyze patient database 8

9 GE LUNAR SOFTWARE FOR AFF DETECTION ANY EVIDENCE THAT THIS APPROACH WILL WORK? McKenna et al. J Clin Densitometry 16:579,

10 ANY EVIDENCE THAT THIS APPROACH WILL WORK? McKenna et al. J Clin Densitometry 16:579, 2013 ANY EVIDENCE THAT THIS APPROACH WILL WORK? 257 patients > age 50 yr, on bisphosphonate therapy for > 5 yr Extended femur scan at the time of routine DXA Abnormal DXA images (e.g., flaring, beaking ) suggested in 19 (7.4%) On x-ray, 7 showed no abnormality, 5 showed an unrelated radiographic abnormality, and 7 (2.7%) showed evidence of incomplete AFF 5 with periosteal flare and 2 with a visible fracture line (also had thigh pain) McKenna et al. J Clin Densitometry 16:579,

11 ANY EVIDENCE THAT THIS APPROACH WILL WORK? 257 patients > age 50 yr, on bisphosphonate therapy for > 5 yr Extended femur scan at the time of routine DXA Abnormal DXA images (e.g., flaring, beaking ) suggested in 19 (7.4%) On x-ray, 7 showed no abnormality, 5 showed an unrelated radiographic abnormality, and 7 (2.7%) showed evidence of incomplete AFF 5 with periosteal flare and 2 with a visible fracture line (also had thigh pain) McKenna et al. J Clin Densitometry 16:579, 2013 CAVEATS Convenience sample of patients, whereas population data on clinical AFFs indicate a far lower prevalence, at worst in the range of 0.13% to 0.22% (Park-Wyllie et al. JAMA 305:783, 2011) In addition, the majority of patients with radiographic changes consistent with partial or incomplete AFF may not, in fact, progress to clinical AFFs (Min et al. JCEM 102:545, 2016) Nonetheless, monitoring patients for such radiographic changes would clearly identify a potentially high risk sub-group for more extensive imaging and consideration of drug discontinuation as appropriate 11

12 FOLLOW UP STUDY May 2013 Sep 2014: 173 patients on bisphosphonate therapy for > 5 years 0/173 patients had any DXA features of AFF Associated with a clear decrease in bisphosphonate prescriptions in Ireland McKenna et al. J Endo Soc 1:211, 2017 BISPHOSPHONATE USE IN IRELAND McKenna et al. J Endo Soc 1:211,

13 SHORT TERM Monitoring Can be instituted fairly rapidly Proactive, makes sense clinically, something we can do today to begin to address patient concerns Guard against false reassurance: Does not imply that patients or physician ignore symptoms, even if they occur soon after a negative monitoring scan INTERMEDIATE TERM Identification of higher risk patients Compared femur geometrical data in 56 AFF patients vs 112 controls with traumatic or fragility fractures Mahjoub et al. JBMR 31:767,

14 INTERMEDIATE TERM Identification of higher risk patients (Cont d) Mahjoub et al. JBMR 31:767, 2016 LONG TERM Pharmacogenomics Mutations in geranylgeranyl diphosphate synthase (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 Roca-Ayats et al. NEJM 376:1794,

15 ADDITIONAL LONG TERM APPROACHES New drug development Better coordination of recommendations and guidelines regarding screening and treatment of osteoporosis Enhanced patient engagement strategies ONGOING AND PLANNED INITIATIVES 2 recent perspectives: - Khosla & Shane, A Crisis in the Treatment of Osteoporosis, JBMR 31:1485, Khosla, Cauley, Compston, Kiel, Rosen, Saag, Shane, Addressing the Crisis in the Treatment of Osteoporosis: A Path Forward, JBMR 32:424, 2017 Special session at the 2016 ASBMR Meeting Individual meetings with Hologic and Lunar regarding availability of femur monitoring software 15

16 ASBMR Call to Action to Address the Crisis in the Treatment of Osteoporosis The 30-year downward trend in hip fractures in the U.S. a case study for medical success - has hit a plateau in the last few years. Worldwide osteoporosis causes more than 8.9 million fractures/year. By 2050, the worldwide incidence of hip fracture is projected to increase by 310% in men and 240% in women compared to rates from Allowing these patients to go untested and untreated frequently leads to debilitating fractures that cause disability, loss of independence and even death. Thirty-seven organizations have come together to sign this call to action pledging to intensify their current efforts to increase the screening, diagnosis and treatment of high-risk individuals to prevent fractures. 37 Organizations Have Pledged to Increase Efforts for the Call to Action American Society for Bone and Mineral Research American Academy of Orthopaedic Surgeons American Academy of Physician Assistants American Association of Clinical Endocrinologists American Bone Health American College of Rheumatology American Medical Society for Sports Medicine American Orthopaedic Association American Osteopathic Academy of Orthopedics American Society for Surgery of the Hand Australia New Zealand Bone and Mineral Society Bulgarian Society of Osteoporosis and Osteoarthritis Czech Society for Metabolic Bone Diseases Dutch Society of Cancer and Bone Metabolism European Calcified Tissue Society European Union Geriatric Medicine Society Finnish Osteoporosis Association Georgian Association of Skeletal Metabolism Diseases Hellenic Osteoporosis Foundation International Geriatric Fracture Society, Inc. International Osteoporosis Foundation International Society for Clinical Densitometry Michigan Consortium for Osteoporosis National Bone Health Alliance (US) National Osteoporosis Foundation (US) National Osteoporosis Society (UK) Northern California Institute for Bone Health, Inc. Orthopaedic Research and Education Foundation Orthopedic Research Society Orthopedic Trauma Association (US) Osteoporosis Australia Osteoporosis Canada Osteoporosis New Zealand Syrian National Osteoporosis Society University of Rochester Department of Orthopaedics and Rehabilitation U.S. Bone and Joint Initiative 4BoneHealth 16

17 MULTI-STAKEHOLDER INITIATIVE BY ASBMR AND CENTER FOR MEDICAL TECHNOLOGY POLICY (CMTP) Identify and prioritize key barriers to appropriate rates of osteoporosis screening, diagnosis, and treatment to prevent fractures, incorporating the attitudes, values, and preferences of key stakeholders Collaborate with ASBMR and key stakeholders to develop strategic options for addressing identified barriers Develop a plan for disseminating and implementing the strategy NIH OFFICE OF DISEASE PREVENTION (ODP): FRACTURES Objective, external review of current state-of-the-science related to fracture prevention and important gaps in knowledge Effort involving multiple NIH Institutes (led by NIAMS and NIA, partnering with NIDDK, NCATS, NCCIH, NIDCR, Office of Research on Women s Health) ODP will work with AHRQ to solicit proposals from Evidence-Based Practice Centers to prepare an evidence report addressing the key questions being posed Followed in ~2 years from now by a conference (similar to previous NIH Consensus Conferences) 17

18 QUESTIONS/DISCUSSION 18