Structure of Bisphosphonates Structure of Bisphosphonates - PowerPoint PPT Presentation

Financial Disclosures Bisphosphonates: Efficacy (Controversies/safety later) Research grants, speaking or consulting: Amgen, Lilly, Merck, Novartis, Radius Dennis M. Black, PhD Dept. of Epidemiology and Biostatistics University of California, San Francisco 2 * Structure of Bisphosphonates Structure of Bisphosphonates Bisphosphonates Efficacy: Outline Structure of Bisphosphonates When R 1 is an OH group binding to R 1 • A bit of background OH OH hydroxyapatite is enhanced • A quick summary of a very large O O P P C literature of RCTs P-C-P is essential for OH OH binding to The R 2 side chain hydroxyapatite determines potency R 2 R 2 = -CH 2 -3-pyridine = Risedronate R 2 = -CH 2 CH 2 CH 2 NH 2 = Alendronate R 2 = -CH 2 CH 2 NH 2 = Pamidronate R 2 = -CH 3 = Etidronate 13 Russell, R., et al., OI I999 ; Suppl 2:S68-80 Page 1

Bisphosphonates Available in U.S. Bisphosphonates • Bind to hydroxyapatite crystals in bone Name Administration Year • Inhibit bone resorption Etidronate Oral 1977 – Impact on osteoclasts Alendronate Oral 1995 • Results in increased bone density Risedronate Oral 2000 Ibandronate Oral 2004 • Some can reduce fracture risk Zoledronic acid IV 2007 • Several approved for oral use, 2 for injection/IV • Quickly summarize a very extensive Bisphosphonates (especially generic ALN) represent vast literature majority of osteoporosis treatment Evidence base supporting bisphosphonates Alendronate: Fracture Intervention Trial (FIT) • • First large fracture trial (1992-97) - Large set of placebo-controlled clinical trials – Designed/managed by UCSF with fracture endpoints starting in 1996 – Details: model for later studies • 6,459 women aged 55-80 - Trials also show BMD gains and reductions – Femoral neck BMD <0.68 g/cm 2 (T<-1.6) in bone turnover • Randomized to daily alendronate vs. placebo – 5 mg for 2 years – 10 mg for 3rd & 4th year Black, et. al, Lancet, 1996; Cummings, et. al. JAMA 1998 Page 2

Alendronate: Fracture Intervention Trial: Fracture Intervention Trial (FIT) Baseline characteristics Two separate studies Vert Fx Arm Clinical Fx Arm 1. Women with existing vertebral fracture (w/ vert. fx) (w/o vert fx) – Vertebral Fracture arm n = 2027 n = 4436 – Main endpoint: new vertebral fractures – Goal: n=2000 Vert. Fx 100% 0% – 3 years of follow-up Age 71 68 2. Women without existing vertebral fracture BMD (FN) 0.57 0.59 – Clinical Fracture Arm Prior Clin. Fx 58% 36% – Main endpoint: new clinical fracture – Goal: n=4000 – 4.2 years of follow-up Black, et. al, Lancet, 1996; Cummings, et. al. JAMA 1998 Change in Bone Turnover Markers Over Effect of Alendronate on Spine BMD Three Years with Alendronate Years 0 1 2 3 0 1 2 3 0 J ALN ALN J 8 0 PA Spine -10 6 -10 PBO 6.2% 4 -20 % Reduction -20 PBO % Reduction 2 PBO -30 -30 ALN ALN 0 -40 -40 -2 -50 0 6 -50 12 18 24 30 36 ALN ALN Months -60 -60 -70 Formation * 5 mg 2 years/10 mg 3rd year/ -70 B Resorption (NTX) (BSAP) ~ 8% increase with 3 years of 10 mg daily J Black, et. al, Lancet, 1996 Page 3

Alendronate and Vertebral Fracture Fracture Reductions in in Women with Existing Vertebral Risk (women w/ existing VFx) Fractures 15% 16 • Results for primary outcomes PBO - Vertebral fractures: 47% decrease (p<0.001) Alendronate Incidence (%) 47% reduction 12 P<.001 - All clinical fractures: 28% decrease (p<0.01) 8% 8 • Results for secondary fracture outcomes 5% - Wrist fractures: 48% decrease (p<0.001) 90% reduction 4 P<0.0001 - Hip fractures: 51% decrease (p=0.047) 0.5% 0 2 or more 1 or more Black, et. al, Lancet, 1996 New Vertebral Fractures Black, et al, Lancet , 1996. Hip Fractures: What About the Women Without Women with Existing Vertebral Existing Vertebral Fractures? fractures 4 • 50% risk of vertebral fracture with any clinical fracture Placebo Alendronate Relative hazard: • Overall, reductions in non-spine 0.49 (0.23, 0.99) % of women fractures were not significant 2.2% 2 – Relative hazard: 0.86 (0.73, 1.01) – Prevention of hip and of nonspine 1.1% fracture depended on initial hip BMD 0 0 12 24 36 Months of Follow-up Cummings, JAMA, 1997 Black, et. al, Lancet, 1996 Page 4

Non-spine Fracture in Women without Hip Fracture in Women Existing Vertebral Fractures without Existing Vertebral Fracture Baseline BMD T-score Baseline BMD T-score -1.6 – -2.0 1.14 (0.82, 1.60) -1.6 – -2.5 1.84 (0.7, 5.4) -2.0 – -2.5 1.03 (0.77, 1.39 ) < - 2.5 < - 2.5 0.44 (0.18, 0.97) 0.64 (0.50, 0.82) Overall Overall 0.86 (0.73, 1.01) 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 Risedronate and Fracture Risk: Risedronate and The VERT Study Fracture Risk 16.3% • 2458 women mean age 68, 16 RR = 0.59 PBO (0.43-0.82) • All with existing vertebral fracture 5 mg Incidence (%) 12 11.3% • Daily 5 mg (n=813) vs PBO (n = 815); RR = 0.60 8.4% (0.39-0.94) • Endpoints: new vertebral, nonvertebral fracture 8 5.2% 4 0 New Vertebral Fractures New Nonvertebral Fractures* Harris, et al, JAMA , 1999. * Osteoporotic fractures, Harris, et al, JAMA , 1999. Page 5

Risedronate and Hip Fracture Risk Risedronate and Hip Fracture Risk: (“HIP” study) HIP Study Results • 9497 women age > 70y (Mean = 78y) Overall Subgroup analysis • Primary endpoint: hip fractures Study Group 1 Group 2 (age 70-79, (age >80, • Women 70 - 79 had T-score < -3.0 and one or BMD T< -3) risk factor) more risk factors % redux. 30% 40% 16% • Women > 80 y had one or more risk factors P 0.02 0.01 0.35 (not necessarily low BMD) • Risedronate/PBO, plus 1 g Ca, daily for 3 yr McClung, et. al. NEJM, 2001 – McClung, NEJM, 2001 Effect of Alendronate and Risedronate Oral Ibandronate Fracture Study on Non-vertebral Fractures: Conclusions • Alendronate and Risedronate • 2946 post-menopausal women for 3 years – Vertebral fracture reductions-all women studied • Existing vertebral fracture and low BMD – Non-vertebral fracture reductions: • 2.5 mg/day vs. placebo » Largest in those with lowest BMD (<-2 to -2.5) or with existing fractures (especially vertebral fracture) - Suggests two groups with greatest clinical benefit: » Low BMD (T-score < –2.5) or – Chesnut, et. al. JBMR 8/2004 » Existing vertebral fracture Page 6

Oral Ibandronate Fracture Study: Less Frequent Dosing of Results for Daily vs. PBO Bisphosphonates • Vertebral fractures: 50% reductions • All fracture studies of Alendronate, • Non-vertebral fractures: no overall Risedronate and Ibandronate used daily dosing reduction • Bisphosphonate dosing inconvenient – In women with lowest BMD?? • Less frequent dose is desirable – Evidence of reduction among those with very low BMD at baseline (T < -3 at fn hip) Chesnut, et. al. JBMR 8/2004 Example: Less Frequent Dosing of Bridging from daily to weekly Alendronate: Bisphosphonates via “Bridging Studies” BMD Changes at Spine Mean Percent Change from Baseline ± SE 6 • “Bridge” to less frequent dose via BMD and marker studies 5 Mean Percent Change • Weekly: Alendronate and Risedronate (7x 4 daily dose) 3 - Similar BMD, markers. 2 ALN 10 mg Daily – No increase in upper GI effects. ALN 70 mg Once Weekly 1 • Monthly: Ibandronate (60 x daily), 0 Risedronate (30 x daily) 0 6 12 • No oral drugs tested for fracture effects Month for less frequent than daily dosing Page 7

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? • Ibandronate (quarterly injections) and zoledronic acid (annual infusions) both available * 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) Cumulative Incidence (%) 15 % Patients With New ZOL 5 mg (n = 3875) Vertebral Fracture 70% Reduction RH=0.59 P<.0001 10.9% 2 (0.42, 0.83) 10 P = .0024 1 Also, 25% reduction in non- 5 3.3% vertebral fractures (p<.01) 0 0 – 3 0 Years 0 3 6 9 12 15 18 21 24 27 30 33 36 Time to First Hip Fracture (months) *Relative risk reduction vs placebo Page 8