7/11/2019 Bisphosphonate Therapy for Fracture Financial Disclosures Risk Reduction: Efficacy (Short and Long Term) -Consulting & talks: Zuellig pharma, -Advisory Board: Roche Diagnostics (Risks etc. tomorrow) -DSMB (not bone): Eli Lilly Dennis M. Black, PhD Professor Epidemiology and Biostatistics, UCSF 1 Nitrogen-containing Bisphosphonates: Bisphosphonates: Differences in R 2 Side Chain Structure We’ve come a LONG way Zoledronic Acid Risedronate • 1990: No approved medications for osteoporosis O OH O OH N (U.S.) N P P C O – No real randomized fracture trial of any drug C OH O OH N OH P OH P OH OH OH • 1997-98: First amino-bisphosphonate approved HO (alendronate) Ibandronate Alendronate Accounts for about 85% of CH 3 osteoporosis treatment O OH O OH worldwide • 2018: > 10 approved medications H 2 N N P P – Bisphosphonates (~6) C O C O OH OH (+ other antiresorptives + PTHs) OH P OH P OH – Large evidence base supporting efficacy OH OH OH 4 1
7/11/2019 Summary of Design of Results: Effect of Alendronate on Lumbar Fracture Intervention Trial (FIT) spine BMD* • First large fracture trial (1991–97) (alendronate vs. 8 placebo) PA Spine 6 ~ 8% with 3 – Designed/managed by UCSF 6.2% years of 10 mg • 6,459 women aged 55–80 4 – Low femoral neck BMD T-score < –1.6 2 – Two sub-studies: 0 1. Women with vertebral fx (‘Vertebral Fracture arm’ aka FIT I) -2 0 6 12 18 24 30 36 2. Women without vertebral fx (‘Clinical Frx arm’ aka FIT II) Months • Alendronate 5 mg daily (2 years) then 10 mg daily (years 3-4) Morphometric Vertebral Fractures in FIT I & II Number of Women with Two or More New Vertebral Fractures: ALN vs. Placebo 48% p < 15% FIT Vertebral Fracture Arm 2 0.001 Placebo Alendronate 15 10mg/daily % Patients With New Vertebral Fracture 10 % of patients with fracture 90% 10 51% * p < 7.5% reduction 0.001 at Year 3 5 p 0.001 4% 5 2% 0 0 PBO ALN No existing vertebral Existing vertebral n=965 n=981 fractures (FIT II) fractures (FIT I) Black, Lancet 1996: Cummings JAMA 1998 1. Liberman UA, et al. NEJM . 1995;333(22):1437–1443. 2. Black DM, et al. Lancet . 1996;348(9041):1535–1541. 2
7/11/2019 Fracture Reductions in What About the Women Without in Women with Existing Vertebral Existing Vertebral Fractures at Start? Fractures • 50% risk of vertebral fracture • Results for primary outcomes - Vertebral fractures: 47% decrease (p<0.001) • Overall, reductions in clinical fractures were not significant - All clinical fractures: 28% decrease (p<0.01) – Relative hazard: 0.86 (0.73, 1.01) • Results for secondary fracture outcomes – Reduction in hip and nonspine fracture more evident in those with - Wrist fractures: 48% decrease (p<0.001) hip BMD T-score <-2.5 - Hip fractures: 51% decrease (p=0.047) Black, et. al, Lancet, 1996 Cummings, JAMA, 1997 Any Clinical Fracture Incidence (ALN v PBO) Hip Fracture Reduction in Women without Existing Vertebral Fractures in Women without Existing Vertebral Fracture Baseline BMD T-score Baseline BMD T-score 1.14 (0.82, 1.60) -1.6 – -2.0 ~1/3 -1.6 – -2.5 1.84 (0.7, 5.4) ~1/3 -2.0 – -2.5 1.03 (0.77, 1.39 ) < - 2.5 ~1/3 < - 2.5 0.44 (0.18, 0.97) 0.64 (0.50, 0.82) Overall 0.86 (0.73, 1.01) Overall 0.79 (0.43, 1.44) 0.1 1 10 0.1 1 10 Relative Hazard (± 95% CI) Relative Hazard (± 95% CI) Cummings, JAMA, 1997 3
7/11/2019 Risedronate and Fracture Risk: Alendronate Effect on Hip Fractures in FIT The VERT Study Clinical Fracture Arm 2,3 Vertebral fracture arm 1 • 2458 women mean age 68, With Prior VFx=0% All With Prior VFx=100% Subgroup with Hip T-score –1.6 Hip T-score –2.5 • All with existing vertebral fracture • Daily 5 mg (n=813) vs PBO (n = 815); 5 5 % of patients with fracture 51% 56% % of patients with fracture 4 4 • Endpoints: new vertebral, nonvertebral fracture reduction reduction 3 3 at Year 3 at Year 4 p =0.047 p =0.044 2 2 1 1 0 0 PBO ALN PBO ALN n=1,005 n=1,022 n=812 n=819 1. Black DM, et al. Lancet . 1996;348(9041):1535–1541. Harris, et al, JAMA , 1999. 2. Cummings SR, et al. JAMA. 1998;280(24):2077–2082. Risedronate and Hip Fracture Risk Risedronate and (“HIP” study) Fracture Risk 16.3% • 9497 women age > 70y (Mean = 78y) 16 RR = 0.59 PBO (0.43-0.82) 5 mg • Primary endpoint: hip fractures Incidence (%) 12 11.3% RR = 0.60 8.4% • Women 70 – 79: T-score < -3.0 and >= 1 risk (0.39-0.94) 8 factor 5.2% 4 • Women > 80 y had >= 1 risk factor (not necessarily low BMD) 0 New Vertebral Fractures New Nonvertebral Fractures* • Risedronate (2.5 and 5 mg)/PBO, plus 1 g Ca, daily for 3 yr * Osteoporotic fractures, Harris, et al, JAMA , 1999. 4
7/11/2019 Effect of Alendronate and Risedronate Risedronate and Hip Fracture Risk: on Non-vertebral Fractures: HIP Study Results Conclusions • Alendronate and Risedronate Overall Subgroup analysis – Spine fractures reduced in all women studied Study Group 1 Group 2 – Non-vertebral fracture reductions: (age 70-79, (age >80, » Largest in those with lowest BMD (<-2.5) or with BMD T< -3) risk factor) existing fractures (especially vertebral fracture) Why no % redux. 30% 40% 16% - Suggests two groups with greatest clinical redux > 80? benefit: P 0.02 0.01 0.35 » Low BMD (T-score < –2.5) or Possible reasons 1. BMD not low enough » Existing vertebral fracture 2. Older women don’t respond 3. Adherence low McClung, et. al. NEJM, 2001 Less Frequent Dosing of Oral Ibandronate Trial Bisphosphonates via “Bridging Studies” • All large phase III oral BPs tested in • Reduction in vertebral fractures fracture trials with daily dosing • No significant reductions in non-vertebral or hip • More convenient weekly and monthly fractures in overall population doses tested in “bridging studies” – (BMD T-score < -3…???) – Equivalent effects of daily/weekly/monthly on • Dose too low?? (currently monthly dose twice BMD and bone markers equivalent of daily dose used in study) Chesnut, 2003 5
7/11/2019 IV Zoledronic Acid Fracture Trial IV Bisphosphonates (HORIZON Pivotal Fracture Trial) • Oral BP’s effective daily, weekly or • 5 mg given once per year, 3 years monthly – 15 minute infusion – Compliance low: < 30% still using after 1 year!! • 7706 patients with osteoporosis • What about less frequent use via injection • Primary Endpoints: Vertebral and hip fracture or IV? • Zoledronic acid (annual infusions) – Also Ibandronate (quarterly injections) * Black, et. al, NEJM, 5/07 Effect of Zoledronic Acid on Hip Fracture Effect of Zoledronic Acid on Hip Fracture Effect of Zoledronic acid on Morphometric Effect of Zoledronic acid on Morphometric Risk Risk Vertebral Fracture Vertebral Fracture 3 Placebo ZOL 5 mg Placebo (n = 3861) 15 Cumulative Incidence (%) ZOL 5 mg (n = 3875) % Patients With New 70% Reduction Vertebral Fracture RH=0.59 P<.0001 10.9% 2 (0.42, 0.83) 10 P = .0024 90% reduction in those with > 2 new Vfx 1 5 Also, 25% reduction in non- 3.3% (66 vs 7) vertebral fractures (p<.01) P<.00001 0 0 – 3 0 Years 0 3 6 9 12 15 18 21 24 27 30 33 36 Time to First Hip Fracture (months) * Black, et. al, NEJM, 5/07 *Relative risk reduction vs placebo * Black, et. al, NEJM, 5/07 6
7/11/2019 Are BP’s effective after a fracture? Are BP’s effective after a fracture? ZoledronicAcid on Fractures in Elderly with Zoledronic Acid after a Hip Fracture: Zoledronic Acid after a Hip Fracture: Osteopenia (i.e. BMD T >=-2.5) - Recurrent Fracture Trial ( unique post hip- - Recurrent Fracture Trial ( unique post hip- fracture trial) fracture trial) • Test effect of ZOL in elderly without osteoporosis by BMD • 2 unique aspects ZOL given <12 wks after hip fracture ZOL given <12 wks after hip fracture o Treatment with ZOL every 18 months (not annually) 2127 men/women, 23 countries, 1-3 years of FU 2127 men/women, 23 countries, 1-3 years of FU o 6 year RCT (longer than any other osteoporosis RCT) ZOL or PBO ZOL or PBO • 2000 women (1000 each to Pbo and ZOL) Primary Endpoint: new clinical fractures Primary Endpoint: new clinical fractures • Primary endpoint: “fragility fractures” Results: Results: o Morphometric vertebral + any non-vertebral • BMD > -2.5 at the hip ▬ New clinical fractures reduced 35% (RR=0.65, p=.001) ▬ New clinical fractures reduced 35% (RR=0.65, p=.001) o Median FRAX 10 year risk: 12% for Osteo. Fx, 2.3% Hip Fx. ▬ Also reduction in total mortality 22% (RR=0.78, p=0.01) ▬ Also reduction in total mortality 22% (RR=0.78, p=0.01) Lyles KW, et al. N Engl J Med . 2007. Reid NEJM, 2018 Reduction in Fracture of 6 Years of Zol Long Term Efficacy of Bisphosphonates (@ 18 mo intervals) in Elderly without Osteoporosis by Hip BMD • Trials are 3-6 years but what about the longer term effects? • Remain effective? Safe? • What is optimal duration of therapy? Also, significant reductions in vertebral fractures 7
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