Bisphosphonates: Efficacy (Controversies/safety later) Dennis M. Black, PhD Dept. of Epidemiology and Biostatistics UC San Francisco Financial Disclosures - Consulting or advisory boards: Radius, Asahi-Kasei - Research agreements: Alexion 2 * Page 1
Bisphosphonates Efficacy: Outline • A bit of background • A quick summary of a very large literature of RCTs Structure of Bisphosphonates Structure of Bisphosphonates Structure of Bisphosphonates When R 1 is an OH group binding to R 1 OH OH hydroxyapatite is enhanced O P O C P 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 2
Bisphosphonates: Overview • Bind to hydroxyapatite crystals in bone • Inhibit bone resorption – Impact on osteoclasts • Results in increased bone density • Some can reduce fracture risk • Several approved for oral use, 2 for injection/IV • Quickly summarize a very extensive literature Bisphosphonates Available in U.S. Name Administration Year Etidronate Oral 1977 Alendronate Oral (1/wk) 1995 Risedronate Oral (1/wk or 1/mo) 2000 Ibandronate Oral (1/mo) 2004 Zoledronic acid IV (1/yr) 2007 Bisphosphonates (alendronate>80%) represent vast majority of osteoporosis treatment Page 3
Evidence base supporting bisphosphonates • - Large set of placebo-controlled clinical trials with fracture endpoints starting in 1996 - Trials also show BMD gains and reductions in bone turnover Summary of Bisphosphonate Fracture Reductions (up to 5 Years)* Also reductions ~25% in non-vertebral fractures *Khosla S, et al. J Clin Endocrinol Metab 97: 2272–2282, 2012 Page 4
Alendronate: Fracture Intervention Trial (FIT) • First large fracture trial (1992-97) – Designed/managed by UCSF – Details: ALN most used and FIT a model for later studies • 6,459 women aged 55-80 – Femoral neck BMD <0.68 g/cm 2 (T<-1.6) • 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 Alendronate: Fracture Intervention Trial (FIT) Two separate studies 1. Women with existing vertebral fracture* – Vertebral Fracture arm – Main endpoint: new vertebral fractures – Goal: n=2000 – 3 years of follow-up 2. Women without existing vertebral fracture** – Clinical Fracture Arm – Main endpoint: new clinical fracture – Goal: n=4000 – 4.2 years of follow-up * Black, et. al, Lancet, 1996; **Cummings, et. al. JAMA 1998 Page 5
Fracture Intervention Trial: Baseline characteristics Vert Fx Arm Clinical Fx Arm (w/ vert. fx) (w/o vert fx) n = 2027 n = 4436 Vert. Fx 100% 0% Age 71 68 BMD (FN) 0.57 0.59 Prior Clin. Fx 58% 36% Change in Bone Turnover Markers Over Three Years with Alendronate Years 0 1 2 3 0 1 2 3 0 J J 0 -10 -10 PBO -20 % Reduction -20 PBO % Reduction -30 -30 ALN ALN -40 -40 -50 -50 ALN ALN -60 -60 Formation -70 -70 Resorption (NTX) B (BSAP) J Black, et. al, Lancet, 1996 Page 6
Effect of Alendronate on Spine BMD (5 mg/day 2 yrs then 10mg/day)* ALN ALN 8 PA Spine 6 6.2% 4 2 PBO 0 -2 0 6 12 18 24 30 36 Months * ~ 8% increase with 3 years of 10 mg daily (70 mg/wk) Alendronate and Vertebral Fracture Risk (women w/ existing VFx) 15% 16 PBO Alendronate Incidence (%) 47% reduction 12 P<.001 8% 8 4 0 1 or more New Vertebral Fractures Black, et al, Lancet , 1996. Page 7
Alendronate and Vertebral Fracture Risk (women w/ existing VFx) 15% 16 PBO Alendronate Incidence (%) 47% reduction 12 P<.001 8% 8 5% 90% reduction 4 P<0.0001 0.5% 0 2 or more 1 or more New Vertebral Fractures Black, et al, Lancet , 1996. Hip Fractures: ( Women with existing vertebral fractures) 4 with any clinical fracture Placebo Alendronate Relative hazard: 0.49 (0.23, 0.99) % of women 2.2% 2 1.1% 0 0 12 24 36 Months of Follow-up Black, et. al, Lancet, 1996 Page 8
Fracture Reductions in in Women with Existing Vertebral Fractures • Results for primary outcomes - Vertebral fractures: 47% decrease (p<0.001) - All clinical fractures: 28% decrease (p<0.01) • Results for secondary fracture outcomes - Wrist fractures: 48% decrease (p<0.001) - Hip fractures: 51% decrease (p=0.047) Black, et. al, Lancet, 1996 What About the Women Without Existing Vertebral Fractures at Start? • 50% risk of vertebral fracture • Overall, reductions in clinical fractures were not significant – Relative hazard: 0.86 (0.73, 1.01) – Reduction in hip and nonspine fracture more evident in those with hip BMD T-score <-2.5 Cummings, JAMA, 1997 Page 9
Any Clinical Fracture Incidence (ALN v PBO) in Women without Existing Vertebral Fractures Baseline BMD T-score 1.14 (0.82, 1.60) ~1/3 -1.6 – -2.0 ~1/3 1.03 (0.77, 1.39 ) -2.0 – -2.5 ~1/3 0.64 (0.50, 0.82) < - 2.5 0.86 (0.73, 1.01) Overall 0.1 1 10 Relative Hazard (± 95% CI) Cummings, JAMA, 1997 Hip Fracture Reduction in Women without Existing Vertebral Fracture Baseline BMD T-score -1.6 – -2.5 1.84 (0.7, 5.4) 0.44 (0.18, 0.97) < - 2.5 0.79 (0.43, 1.44) Overall 0.1 1 10 Relative Hazard (± 95% CI) Page 10
Risedronate and Fracture Risk: The VERT Study • 2458 women mean age 68, • All with existing vertebral fracture • Daily 5 mg (n=813) vs PBO (n = 815); • Endpoints: new vertebral, nonvertebral fracture Harris, et al, JAMA , 1999. Risedronate and Fracture Risk 16.3% 16 RR = 0.59 PBO (0.43-0.82) 5 mg Incidence (%) 12 11.3% RR = 0.60 8.4% (0.39-0.94) 8 5.2% 4 0 New Vertebral Fractures New Nonvertebral Fractures* * Osteoporotic fractures, Harris, et al, JAMA , 1999. Page 11
Risedronate and Hip Fracture Risk (“HIP” study) • 9497 women age > 70y (Mean = 78y) • Primary endpoint: hip fractures • Women 70 - 79 had T-score < -3.0 and one or more risk factors • Women > 80 y had one or more risk factors (not necessarily low BMD) • Risedronate/PBO, plus 1 g Ca, daily for 3 yr – McClung, NEJM, 2001 Risedronate and Hip Fracture Risk: HIP Study Results Overall Subgroup analysis Study Group 1 Group 2 (age 70-79, (age >80, BMD T< -3) risk factor) % redux. 30% 40% 16% P 0.02 0.01 0.35 McClung, et. al. NEJM, 2001 Page 12
Effect of Alendronate and Risedronate on Non-vertebral Fractures: Conclusions • Alendronate and Risedronate – Spine fractures reduced in all women studied – Non-vertebral fracture reductions: » Largest in those with lowest BMD (<-2.5) or with existing fractures (especially vertebral fracture) - Suggests two groups with greatest clinical benefit: » Low BMD (T-score < –2.5) or » Existing vertebral fracture Oral Ibandronate Fracture Study • 2946 post-menopausal women for 3 years • Existing vertebral fracture and low BMD • 2.5 mg/day vs. placebo – Chesnut, et. al. JBMR 8/2004 Page 13
Oral Ibandronate Fracture Study: Results for Daily vs. PBO • Vertebral fractures: 50% reductions • Non-vertebral fractures: no overall reduction – In women with lowest BMD?? – Evidence of reduction among those with very low BMD at baseline (T < -3 at fn hip) Chesnut, et. al. JBMR 8/2004 Less Frequent Dosing of Bisphosphonates • All fracture studies of Alendronate, Risedronate and Ibandronate used daily dosing • Bisphosphonate dosing inconvenient • Less frequent dose is desirable Page 14
Less Frequent Dosing of Bisphosphonates via “Bridging Studies” • “Bridge” to less frequent dose via BMD and marker studies starting in 2000 • Weekly: Alendronate and Risedronate (7x daily dose) - Similar BMD, markers. – No increase in upper GI effects. • Monthly: Ibandronate (60 x daily), Risedronate (30 x daily) • No oral drugs tested for fracture effects for less frequent than daily dosing Example: Bridging from daily to weekly Alendronate: BMD Changes at Spine Mean Percent Change from Baseline SE 6 5 Mean Percent Change 4 3 2 ALN 10 mg Daily 1 ALN 70 mg Once Weekly 0 0 6 12 Month Page 15
IV Bisphosphonates • Oral BP’s effective daily, weekly or monthly – Compliance low: < 30% still using after 1 year!! • What about less frequent use via injection or IV? • Ibandronate (quarterly injections) and zoledronic acid (annual infusions) both available IV Zoledronic Acid Fracture Trial (HORIZON Pivotal Fracture Trial) • 5 mg given once per year, 3 years – 15 minute infusion • 7706 patients with osteoporosis • Primary Endpoints: Vertebral and hip fracture * Black, et. al, NEJM, 5/07 Page 16
Effect of Zoledronic acid on Morphom etric Effect of Zoledronic acid on Morphom etric Vertebral Fracture Vertebral Fracture Placebo ZOL 5 m g 1 5 % Patients W ith New 7 0 % Reduction Vertebral Fracture P< .0 0 0 1 1 0 .9 % 1 0 9 0 % reduction in those w ith > 2 new Vfx 5 3 .3 % ( 6 6 vs 7 ) P< .0 0 0 0 1 0 0 –3 Years Effect of Zoledronic Acid on Hip Fracture Effect of Zoledronic Acid on Hip Fracture Risk Risk 3 Placebo ( n = 3 8 6 1 ) Cum ulative I ncidence ( % ) ZOL 5 m g ( n = 3 8 7 5 ) RH= 0 .5 9 2 ( 0 .4 2 , 0 .8 3 ) P = .0 0 2 4 1 Also, 25% reduction in non- vertebral fractures (p<.01) 0 0 3 6 9 1 2 1 5 1 8 2 1 2 4 2 7 3 0 3 3 3 6 Tim e to First Hip Fracture ( m onths) * Relative risk reduction vs placebo Page 17
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