7/5/2017 ADDRESSING PATIENT CONCERNS REGARDING COMPLICATIONS OF ANTIRESORPTIVE THERAPY Sundeep Khosla, M.D. Mayo Clinic, Rochester, MN DISCLOSURES SUNDEEP KHOSLA, M.D. NONE 1
7/5/2017 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
7/5/2017 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 ABC News story on Fosamax Lawsuit for ONJ and AFF Study on AF link Jha et al. JBMR 30:2179, 2015 3
7/5/2017 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 50-100 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
7/5/2017 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
7/5/2017 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
7/5/2017 SHORT TERM Monitoring (Cont’d) • Hologic currently offers this option – now FDA approved – but only on its new scanner 7
7/5/2017 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
7/5/2017 GE LUNAR SOFTWARE FOR AFF DETECTION ANY EVIDENCE THAT THIS APPROACH WILL WORK? McKenna et al. J Clin Densitometry 16:579, 2013 9
7/5/2017 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, 2013 10
7/5/2017 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
7/5/2017 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, 2017 12
7/5/2017 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, 2016 13
7/5/2017 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, 2017 14
7/5/2017 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, 2016 - 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
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