Bisphosphonates: Background, Efficacy and Recent Controversies Disclosures D. Black Research Funding: Novartis, Merck Dennis M. Black, PhD Consulting: Amgen, Lilly, Zosano, Nycomed Dept. of Epidemiology and Biostatistics University of California, San Francisco Atypical subtrochanteric hip fractures are: Bisphosphonates: Outline 1. An inevitable consequence of long term bisphosphonate use 2. Have been shown to be significantly increased in randomized trials extending beyond 4 years 3. Are quite common in bisphosphonate users 4. Are very rare, even in long term bisphosphonate users 5. None of the above A n i n e v i t a b l e c o n s e q u e... % H a v e b e e n s h o w n t o b e... 1% A r e q u i t e c o m m o n i n b... 4% A r e v e r y r a r e, e v e n i n l o.. 86% N o n e o f t h e a b o v e % A bit of background A quick summary of a very large literature of RCTs Optimal duration of use Recent safety concerns Osteonecrosis of the jaw Atypical femur fractures Page 1
Structure of Bisphosphonates Oral Bisphosphonates Available in U.S. When R 1 is an OH group binding to hydroxyapatite is enhanced The R 2 side chain determines potency O OH R 1 OH P OH C R 2 P OH 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 O P-C-P is essential for binding to hydroxyapatite Russell, R., et al.,oi I999;Suppl 2:S68-8 13 Name Type Year FDA indications (Partial list) Etidronate Nonnitrogen 1977 Paget s disease Alendronate Nitrogen 1995 Paget s Osteoporosis (P/T) Risedronate Nitrogen 2 Paget s Osteoporosis (P/T) Ibandronate Nitrogen 24 Osteoporosis Bisphosphonates (especially generic ALN) represent vast majority of osteoporosis treatment Alendronate: Fracture Intervention Trial (FIT) What is the evidence base supporting bisphosphonates for reducing fracture risk? First large fracture trial (1992-97) Designed/managed by UCSF Details: model for later studies 6,459 women aged 55-8 Femoral neck BMD <.68 g/cm 2 (T<-1.6) Randomized to daily alendronate vs. placebo 5 mg for 2 years 1 mg for 3rd & 4th year Black, et. al, Lancet, 1996; Cummings, et. al. JAMA 1998 Page 2
Alendronate: Fracture Intervention Trial (FIT) Two separate studies 1. Women with existing vertebral fracture Vertebral Fracture arm Main endpoint: new vertebral fractures Goal: n=2 3 years of follow-up 2. Women without existing vertebral fracture Clinical Fracture Arm Main endpoint: new clinical fracture Goal: n=4 4.2 years of follow-up Black, et. al, Lancet, 1996; Cummings, et. al. JAMA 1998 Fracture Intervention Trial: Baseline characteristics Vert Fx Arm Clinical Fx Arm n = 227 n = 4436 Vert. Fx 1% % Age 71 68 BMD (FN).57.59 Prior Clin. Fx 58% 36% Change in Bone Turnover Markers Over Three Years with Alendronate % Reduction J 1 2 3 Years J 1 2 3-1 -1 PBO -2 PBO -2-3 -3-4 -4 ALN -5-6 -7 ALN Resorption (NTX) Black, et. al, Lancet, 1996 B J % Reduction -5-6 -7 Formation (BSAP) Effect of Alendronate on Spine BMD 8 6 4 2 PA Spine 6.2% -2 6 12 18 24 3 36 Months ALN PBO * 5 mg 2 years/1 mg 3rd year/ ~ 8% increase with 3 years of 1 mg daily Page 3
Fracture Reductions in in Women with Existing Vertebral Fractures Results for main outcomes - Vertebral fractures: 5% decrease (p<.1) - All clinical fractures: 25% decrease (p<.1) Results for secondary fracture outcomes - Wrist fractures: 5% decrease (p<.1) - Hip fractures: 5% decrease (p=.47) Black, et. al, Lancet, 1996 All Clinical Fractures in Women with Existing Vertebral fractures % of women with any clinical fracture 2 1 Black, et. al, Lancet, 1996 Placebo Alendronate Months of Follow-up 18.2% 13.6% Relative hazard:.72 (.58,.9) 12 24 36 Hip Fractures: Women with Existing Vertebral fractures % of women with any clinical fracture 4 2 Black, et. al, Lancet, 1996 Placebo Alendronate Months of Follow-up Relative hazard:.49 (.23,.99) 12 24 36 2.2% 1.1% What About the Women Without Existing Vertebral Fractures? 5% risk of vertebral fracture Overall, reductions in non-spine fractures were not significant Relative hazard:.86 (.73, 1.1) Prevention of hip and of nonspine fracture depended on initial hip BMD Cummings, JAMA, 1997 Page 4
Non-spine Fracture in Women without Existing Vertebral Fractures Hip Fracture in Women without Existing Vertebral Fracture Baseline BMD T-score Baseline BMD T-score -1.6-2. -2. -2.5 1.14 (.82, 1.6) 1.3 (.77, 1.39) -1.6-2.5 1.84 (.7, 5.4) < - 2.5.64 (.5,.82) < - 2.5.44 (.18,.97) Overall.86 (.73, 1.1).1 1 1 Cummings, JAMA, 1997 Relative Hazard (± 95% CI) Overall.79 (.43, 1.44).1 1 1 Relative Hazard (± 95% CI) Risedronate and Fracture Risk: The VERT Study Risedronate and Fracture Risk 2458 women mean age 68, All with existing vertebral fracture PBO (n = 815); 5 mg (n=813) Endpoints: new vertebral, nonvertebral fracture Incidence (%) 16 12 8 16.3% RR =.59 (.43-.82) 11.3% 8.4% RR =.6 (.39-.94) 5.2% PBO 5 mg 4 New Vertebral Fractures New Nonvertebral Fractures* Harris, et al, JAMA, 1999. * Osteoporotic fractures only, Harris, et al, JAMA, 1999. Page 5
Risedronate and Hip Fracture Risk ( HIP study) 9497 women age > 7y (Mean = 78y) Primary endpoint: hip fractures Women 7-79 had T-score < -3. and one or more risk factors Women > 8 y had one or more risk factors (not necessarily low BMD) Risedronate/PBO, plus 1 g Ca, daily for 3 yr McClung, NEJM, 21 Risedronate and Hip Fracture Risk: HIP Study Results Overall Subgroup analysis Study Group 1 Group 2 (age 7-79, (age >8, BMD T< -3) risk factor) % redux. 3% 4% 16% P.2.1.35 McClung, et. al. NEJM, 21 Effect of Alendronate and Risedronate on Non-vertebral Fractures: Conclusions Alendronate and risedronate Vertebral fracture reductions-all women studied Non-vertebral fracture reductions:» 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)» Existing vertebral fracture» (More recently: High fracture risk from FRAX) Oral Ibandronate Fracture Study 2946 post-menopausal women for 3 years Existing vertebral fracture and low BMD 3 treatment regimens 2.5 mg/day vs. placebo Also intermittant oral dose Chesnut, et. Al. JBMR 8/24 Page 6
Oral Ibandronate Fracture Study: Results for Daily vs. PBO Spine BMD: 5.5% increase vs. placebo Vertebral fractures: 5% 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) Less Frequent Dosing of Bisphosphonates All fracture studies of Alendronate, Risedronate and Ibandronate used daily dosing Bisphosphonate dosing inconvenient: Less frequent dose is desirable Chesnut, et. Al. JBMR 8/24 Less Frequent Dosing of Bisphosphonates via Bridging Studies BMD Changes at Spine: Alendronate 1 mg/day vs. 7 mg/wk Bridge to less frequent dose via BMD and marker studies Weekly: Alendronate and Risedronate (7x daily dose) - Similar BMD, markers. No increase in upper GI effects. Monthly: Ibandronate (6 x daily), Risedronate (3 x daily) No oral drugs tested for fracture effects for less frequent than daily dosing Mean Percent Change Mean Percent Change from Baseline ± SE 6 5 4 3 2 ALN 1 mg Daily 1 ALN 7 mg Once Weekly 6 12 Month Page 7
IV Bisphosphonates Oral bisphosphonates given weekly or even monthly can increase BMD and probably reduce fracture risk 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 776 patients with osteoporosis Primary Endpoints: Vertebral and hip fracture * Black, et. al, NEJM, 5/7 Effect of Zoledronic acid on Morphometric Vertebral Fracture Effect of Zoledronic Acid on Hip Fracture Risk % Patients With New Vertebral Fracture 15 1 5 1.9% Placebo 3 Years 3.3% ZOL 5 mg RR=.3 (.24,.38) P<.1 Cumulative Incidence (%) 3 2 1 Placebo (n = 3861) ZOL 5 mg (n = 3875) P =.24 3 6 9 12 15 18 21 24 27 3 33 36 RH=.59 (.42,.83) Also, 25% reduction in nonvertebral fractures (p<.1) Time to First Hip Fracture (months) *Relative risk reduction vs placebo Page 8
Zoledronic Acid after a Hip Fracture: HORIZON-Recurrent Fracture Trial Patients within 12 weeks of hip fracture (first posthip fxture study) 2127 men/women, 23 countries, 1-3 years of FU ZOL 5 mg annual infusion or placebo Primary Endpoint: new clinical fractures Results: New clinical fractures reduced 35% (RR=.65, p=.1) Also reduction in total mortality 22% (RR=.78, p=.1) Current Controversies In Bisphosphonate Use What is the optimal duration of use Efficacy: Do bisphosphonates work beyond 3-5 years? Safety of bisphosphonates? Do they cause bad things to happen? Particularly after longer term use? Lyles KW, et al. N Engl J Med. 27. Optimal Duration of Use for Bisphosphonates Bisphosphonates effective in reducing fractures for up to 4.5 years (trials) What is optimal duration of treatment? Longer treatment may further decrease fracture risk Or longer term treatment may compromise bone quality Long term placebo-controlled fracture trials not feasible so must rely on extensions of shorter studies FIT Long Term Extension (FLEX) Study Design Women taking alendronate in FIT could continue 5 years average previous use at baseline Randomized for 5 more years to: Placebo (PBO) (4%) ALN 5 mg/day (ALN) (3%) ALN 1 mg/day (ALN) (3%) Endpoints 1 years total ALN 1 o : Total hip BMD Other: BMD other sites, bone markers, fractures * Black, et. al. JAMA, 12/6 Page 9
FLEX Baseline Characteristics (n=199) Age (y) Taking ALN at baseline Prior years ALN * Black, et. al. JAMA, 12/6 73 8% 5. Total Hip BMD: Mean % Change from FIT Baseline Mean Percent Change 5 4 3 2 1 FIT 3 to 4.5 yrs FLEX FIT/FLEX Recess 5 yrs 1 to 2 yrs Start of FLEX 2.8% F F 1 F 2 F 3 F 4 FL FL 1 FL 2 FL 3 FL 4 FL 5 Year FIT FLEX P<.1 ALN vs PBO = Placebo = ALN (Pooled 5 mg and 1 mg groups) * Black, et. al. JAMA, 12/6 Cumulative Incidence of Fractures During FLEX Long Term (6 year) Continuation Study of Zoledronic Acid Vertebral Clinical Clinical Morphometric Any Non-vertebral Hip PBO (N = 437) 5% 11% 22% 2% 3% * Black, et. al. JAMA, 12/6 ALN (N = 662) RR (95% CI) 2% 1% 21% 19% 3%.5 (.2,.8).9 (.6, 1.2).9 (.7, 1.2) 1. (.8, 1.4) 1.1 (.5, 2.3) 3 years of ZOL then randomized to: - 3 more years of ZOL (6 years total) - 3 years of placebo (3 years of ZOL then discontinuation) Results: - 3 more years of ZOL maintained BMD but discontinuation only small drop - Residual effect on bone turnover - Reductions in vertebral fractures but not non-vert fractures Morphometric vert but not clinical vert reduced Black, et. al JBMR 212 Page 1
Long-term Treatment with Bisphosphonates: Efficacy Summary Long term continuation: - Maintenance of BMD if continue but losses are small if discontinue (5 years ALN, 3 years ZOL) - No clinical evidence for compromise in bone quality with long-term treatment (any bisphosphonates) - Reductions in vertebral fractures suggest that those at high risk of vertebral fracture benefit by continuation, others might take a drug holiday (limited period) - Best information for ALN and ZOL: Little guidance for other bisphosphonates. More on safety later Safety of Bisphosphonates Potential safety issues with bisphosphonates Increased risk of esophageal cancer? Osteonecrosis of the jaw Subtrochanteric fractures Oral Bisphosphonates and Esophageal Cancer Oral bisphosphonates can cause esophageal irritation, especially if taken incorrectly Esophageal Cancer? Two large epidemiologic analyses from primary care database in UK: GPRD Results disagree if increased risk FDA website notice posted 7/21/11: FDA has not concluded that taking an oral bisphosphonate drug increases the risk of esophageal cancer and there are conflicting data on this risk Osteonecrosis of the Jaw and Bisphosphonates: Summary from ASBMR report, 27* Very rare (1 in 1, to 1,) Vast majority of cases in oncology patients who: Have cancer On chemotherapy Very high doses of IV bisphosphonates Little evidence that doses used for osteoporosis increase risk of ONJ If so, VERY low risk But some concerns remain in dental community *Khosla, et al, JBMR, 27 Page 11
Atypical subtrochanteric fractures: Case Reports and Case Studies Typical Morphologic Characteristics of Atypical Fractures from Case Reports First identified in case reports and case series NY and Singapore Associated with bisphosphonates? Compilation of 141 case reports (Giusti, Bone, 21) Transverse Cortical beaking Cortical thickening Lenart et al NEJM 28/ Goh J Bone Joint Sur. 27 Neviaser et al J. Ortho trauma 28 Atypical Subtrochanteric fractures: Characteristics from Initial Case Reports Location: Below lesser trochanter Specific morphologic characteristics from radiograph Transverse fracture (not spiral or oblique) Cortical thickening (focal or generalized) Beaking or medial spike Atraumatic-- Some cases - fx occurs before fall rather than the opposite Often delayed repair or healing Often a prodrome of wks - mos of pain, before fx occurs ASBMR Task Force Case Definition for Atypical Femur Fracture (21*) Major Criteria (must all be present) Location: Below lesser trochanter above distal metaphyseal flare No or minimal trauma Transverse or short-oblique (from x-ray) Non-comminuted, extend through both cortices Minor Criteria (may be present) Localized reaction in lateral cortex Increased cortical thickness (generalized) Prodromal symptoms (pain in thigh/groin) Bilateral Delayed healing *Shane, et. al. JBMR, 21 Page 12
Compilation of 141 case reports* Not unbiased set of patients from case reports Epidemiologic/observational studies Characteristics % of cases Age 68 years (mean) Bilateral 44-7% Prodromal pain 64% PPI s 39% Oral GC s 26% Bisphosphonates 75% *Giusti, Bone, 21 Several recent very large epidemiologic studies Several major studies in 29-211 Requires large studies, population-based studies Population registry studies without radiographs: Denmark (679, per years, ~7 hip fractures) 1 Ontario, Canada (795, women, ~97 hip fractures) 2 Population registry study with radiograph Sweden (1.5M women, all 12,8 hip fractures in 28) 3 Examine relation to drug use from linked prescription data bases Epidemiologic Studies: What are the Consistent Results? Subtrochanteric/diasphyseal fractures are very rare 1 to 5 in 1, (even with bisphosphonate use) Fractures meeting x-ray criteria even rarer 4 per 1,* Other (interacting?) risk factors include PPI and oral glucocorticoid use 1 Abrahamsen et al, JCEM, 21; 2 Park-Wylie, JAMA, 211; 3 Schilcher, et al. NEJM, 211 *Schilcher NEJM 211 Page 13
Epidemiologic Studies: What are the Inconsistent Results? Relationship to bisphosphonate Positive and negative studies Canadian and Swedish suggest some association but causation not certain Relationship to duration is puzzling Not clear that risk increases with duration of use or that very long term use confers very high risk Epidemiologic studies: Generally suggests some association but picture not fully clear (yet) Results from Randomized Trials 58 Analysis from 3 RCT s Secondary analysis of 14,195 patients from the FIT, FLEX and HORIZON-PFT trials Fracture records from all 284 hip and femoral fractures reviewed to: Identify fractures in subtrochanteric or diaphyseal region No radiographs to assess atypical features For each trial, relative hazard of fracture for patients receiving BPs vs placebo were calculated Black DM, et al. N Engl J Med 21;362:1761 1771 59 Femur Fractures in 14,195 women from 3 RCT s with > 5, person-years of observation Overall incidence: 2.3 per 1, person yrs 12 ST or diphy. fractures in 1 patients Relative hazard of subtrochanteric or diaphyseal fracture vs placebo: FIT (ALN) = 1.3 (95% CI,.6, 16.46) FLEX (ALN) = 1.33 (95% CI,.12, 14.67) HORIZON-PFT (ZOL) = 1.5 (95% CI,.25, 9.) No significant increase Important limitation: confidence intervals wide due to the small number of events Number of events would be fewer if we could exclude typical Black DM, et al. N Engl J Med 21 61 Page 14
Prevention of fractures with bisphosphonates (3 years treatment) Type of fracture NNT Events prevented per 1 pts Any non-vertebral fracture 35 29 (Hip 9 11) Vertebral fx 14 71 Any fracture 1 Benefits vs. Risk for 3 years treatment Type of fracture NNT Events prevented per 1 pts Any non-vertebral fracture 35 29 (Hip only 9 11) Vertebral fx 14 71 Any fracture 1 Subtrochanteric/diaphyseal fractures Black, et al NEJM 3/21 Black, et al NEJM 5/21 Hypothetical RR for subtroch NNH Events associated with 1 pts treated 1.5 33.3 3 758 1.3 Many fractures reported in case series are long-term bisphosphonate users Very rare Subtrochanteric Fractures: Summary of what we know.4 to 4 per 1, years Other risk factors: GC, PPI use, other comorbid conditions Recent epidemiologic studies point toward an association with bisphosphonate use but many inconsistencies Duration of use? Event too rare for meaningful results in randomized studies Very favorable benefit/risk ratio in people with osteoporosis Page 15
FDA Hearing on Bisphosphonate Safety Concerns about some side effects Atypical fractures very rare But could impact on risk/benefit for long term use Should patients take a drug holiday? FDA hearing on 9/11/11 (NEJM 5/12): Benefits and risks of long-term bisphosphonate use for.. osteoporosis in light of the emergence of the safety concerns of ONJ and atypical femur fractures FDA: Duration of Use Conclusions Bisphosphonates are highly efficacious in reducing the risk for fracture The available data suggest that therapy can be safely discontinued in patients at low risk of fracture Additional data are needed to further define the appropriate duration of drug cessation and to determine interim monitoring FDA (Kehoe): NEJM 5/12 67 Summary of Clinical Vertebral Fracture Results in FLEX (NEJM 5/12) Femoral Neck BMD T- Score (start FLEX) 5 Yr risk (%) Clinical Vert. Fx.in PBO All women in study Number Needed to Treat All BMD values 5.5 34-2.5 9.3 21-2.5 to -2 5.8 33 Summary of Clinical Vertebral Fracture Results in FLEX Femoral Neck BMD T- Score (start FLEX) 5 Yr risk (%) Clinical Vert. Fx. In PBO All women in study Number Needed to Treat All BMD values 5.5 34-2.5 9.3 21-2.5 to -2 5.8 33-2 2.3 81 No prevalent vert. fracture (start of FLEX) -2 2.3 81-2.5 8. 24-2.5 to -2 3. 63-2 1.8 12 Prevalent vertebral fracture (start of FLEX) * Black, et al. NEJM: 5/9/12 68 * Black, et al. NEJM: 5/9/12-2.5 11.1 17-2.5 to -2 11.1 17 69-2 3.7 51 Page 16
FLEX Recommendations about LT Use - After 5 years of alendronate: - Those at higher risk of vertebral fracture may benefit by continuation - Women with FN BMD T-score below -2.5 - Women with existing vertebral fractures and somewhat higher FN BMD (up to -2.) - Many can discontinue with little loss of efficacy (many of those started without osteoporosis) - Cannot generalize to risedronate or ibandronate - Need more info for efficacy (and risks) Key Limitations in FLEX Recommendations - Studies are too small for definitive fracture outcomes (best available) - Subgroups are even smaller - Looked only at efficacy (for vertebral fractures), no balance of benefits vs. risks - More knowledge about long-term negative effects could change recommendations * Black, et al. NEJM: 5/9/12 7 71 Limitations (cont d) Results cannot be generalized to risedronate and ibandronate Risedronate: faster offset Ibandronate: no data 72 Bisphosphonates: Summary BP s shown to prevent vertebral, non-vertebral and hip fractures in those with osteoporosis Vast majority of treatment for osteoporosis Trends toward increasing convenience: monthly oral dosing and annual IV dosing Generally very safe. Possible adverse effects but very rare. More evaluation on-going Optimal duration currently controversial Very favorable benefit to risk ratio in patients with osteoporosis Page 17