OsteoporosisWRAP SlideCAST Complexities and Challenges of Measuring Fracture End Points Interpreting the Results of Existing Trials Steven T Harris MD FACP Clinical Professor of Medicine University of California, San Francisco

Fracture Endpoints ► Regulatory approval of existing medications has been based on fracture reduction, rather than changes in surrogates such as bone mineral density (BMD) alone ► The most common fracture endpoint has been the reduction in vertebral fracture ● Vertebral fracture has most often been defined on the basis of morphometric changes, including both “new” and “worsening” fractures ● “Clinical” vertebral fracture—defined as fracture associated with back pain—has usually been identified as a secondary endpoint

Fracture Endpoints, con’t ► “Non-vertebral fracture” has most commonly been identified as a secondary endpoint as well ● Varying definitions of “non-vertebral fracture”: all fractures vs fragility fractures vs a particular composite endpoint ● Hip fracture has sometimes—but not always— been identified as a separate endpoint of particular interest

Fracture Endpoints, con’t ► Fracture reduction has most often been expressed — both clinically and commercially—as relative risk reduction, rather than absolute risk reduction ► The rapidity with which fracture protection occurs has been of clinical—and commercial—interest ► There are no head-to-head randomized trials with fracture as the primary endpoint ► The pivotal fracture trials recruited patients with a certain “sameness”—but there were notable differences in demographics, baseline fracture status and baseline BMDs nevertheless ● There were obvious differences in observed fracture rates—both vertebral and non-vertebral

% of Patients With New Vertebral Fractures Over 3-5 Years Vertebral Fracture Effects In Prospective Trials Direct Comparisons Among Trials Cannot Be Made Chesnut CH, et al. Am J Med. 2000;109:267 Ettinger B, et al. JAMA. 1999;282:637 Black DM, et al. Lancet. 1996;348:1535 Cummings SR, et al. JAMA. 1998;280:2077 Harris ST, et al. JAMA. 1999;282:1344 Reginster J, et al. Osteoporos Int. 2000;11:83 Chesnut CH, et al. J Bone Miner Res. 2004;19:1241 Black DM, et al. N Engl J Med 2007:356: PROOF MORE FIT-VFA VERT-NA VERT-MN BONE HORIZON MORE FIT-CFA PROOF MORE FIT-VFA VERT-NA VERT-MN BONE HORIZON MORE FIT-CFA With Prevalent Vertebral Fractures ± Vert Fx Without Vert Fx With Prevalent Vertebral Fractures ± Vert Fx Without Vert Fx 30% 47% 41% 49% 50% 40% 50% 52% 70% Calcium CTRISALNRLXIBN ZOL % = Relative Fracture Risk Reduction

% of Patients With New Nonvertebral Fractures Over 3-5 Years Nonvertebral Fracture Effects In Prospective Trials Direct Comparisons Among Trials Cannot Be Made * Chesnut CH, et al. Am J Med. 2000;109:267 Ettinger B, et al. JAMA. 1999;282:637 Black DM, et al. Lancet. 1996;348:1535 Cummings SR, et al. JAMA. 1998;280:2077 Harris ST, et al. JAMA. 1999;282:1344 Reginster J, et al. Osteoporos Int. 2000;11:83 Chesnut CH, et al. J Bone Miner Res. 2004;19:1241 Black DM, et al. N Engl J Med 2007:356: PROOF MORE FIT-VFA FIT-CFA VERT-NA VERT-MN BONE HORIZON PROOF MORE FIT-VFA FIT-CFA VERT-NA VERT-MN BONE HORIZON 20% p = % p = n.s. 25% p < % p = 0.06 Calcium CTRISALNRLXIBN ZOL % = Relative Fracture Risk Reduction 10% p = n.s. 12% 39% p < 0.05 p = n.s. * Patient demographics and the definition of nonvertebral fracture varied among studies

Fracture Endpoints ► If existing randomized clinical trials cannot reasonably address all issues of clinical relevance, then additional insights can be gleaned from: ● Additional—post hoc—analyses of existing trial data ● Meta analyses of existing trial data ● Observational data

Nonvertebral Fracture Reduction Post-hoc analyses % patients with nonvertebral fracture Control Risedronate 59% P=0.002 * * * * * * * * * * * Time (months) * * * 36% P=0.002 ControlAlendronate Time (months) Harrington Calcif Tissue Int 2004;74:129Black JCEM 2000;85:4118 n= 3658; Patients with a baseline vertebral fracture or femoral neck T score of -2.5 or less. Nonvertebral osteoporotic fractures measured as a composite endpoint (sites are not defined). n=1172; Patients with lumbar spine BMD T-score <-2.5. Nonvertebral fractures based on a composite endpoint of the following: clavicle, hip, humerus, leg, pelvis and wrist.

Ibandronate and the risk of non-vertebral and clinical fractures in women with postmenopausal osteoporosis (PMO): results of a meta-analysis of Phase III studies Harris ST, Blumentals WA and Miller PD. Curr Med Res Opin. 2008;24:237-45

To evaluate the nonvertebral and clinical fracture efficacy of different doses of ibandronate using a pooled analysis of data from 4 pivotal phase III clinical trials: BONE, 1 IV Dose Fracture, 2 MOBILE, 3 and DIVA 4 To evaluate the nonvertebral and clinical fracture efficacy of different doses of ibandronate using a pooled analysis of data from 4 pivotal phase III clinical trials: BONE, 1 IV Dose Fracture, 2 MOBILE, 3 and DIVA 4 To estimate the fracture rate over time using the Kaplan-Meier method To estimate the fracture rate over time using the Kaplan-Meier method Study Objectives 1 oral iBandronate Osteoporosis vertebral fracture trial in North America and Europe. Chesnut CH, et al. Curr Med Res Opin. 2005;21: Recker R, et al. Bone. 2004;34: Monthly Oral iBandronate In LadiEs. Reginster JY, et al. Ann Rheum Dis. 2006;65: Dosing IntraVenous Administration. Delmas PD, et al. Arthritis Rheum. 2006;54:

Pooled Fracture Analysis Methods ► Cox regression analyses were adjusted for variables to allow for meaningful comparisons among trials ● Age ● Previous clinical fracture ● Baseline BMD Lumbar spine BMD for models with all clinical fractures Lumbar spine BMD for models with all clinical fractures Hip BMD for models with nonvertebral fractures (NVFs) or key NVFs Hip BMD for models with nonvertebral fractures (NVFs) or key NVFs ► Kaplan-Meier methods were used to: ● Plot survival curves for time to fracture ● Compare rates using a log-rank test Harris ST, Blumentals WA and Miller PD. Curr Med Res Opin. 2008;24:237-45

Pooled Fracture Analysis Methods (cont.) ► Fracture rates were determined by tabulating the proportion of all ITT patients with at least 1 fracture ► Doses were pooled based on annual cumulative exposure (ACE) ● ACE was calculated by multiplying the drug strength by the number of annual doses and by an absorption factor (0.6% for oral dosing and 100% for IV dosing) ● For example, the ACE for oral BONIVA 150 mg once-monthly would be 10.8 mg = 150 x 12 x Harris ST, Blumentals WA and Miller PD. Curr Med Res Opin. 2008;24:237-45

IV and oral ibandronate annual cumulative exposure across studies 1. Recker R, et al. Bone. 2004;34: Chesnut CH, et al. J Bone Miner Res. 2004;19: Adami S, et al. Bone. 2004;34: Miller PD, et al. J Bone Miner Res. 2005;20: Data on file (Reference # ), Hoffman-La Roche Inc, Nutley, NJ mg 12 mg 10.8 mg 5.5 mg 4 mg Annual cumulative exposure (mg) Quarterly IV Oral daily Oral monthly Oral monthly MF IRIS 3 DIVA 5 BONE 2 MOBILE 4

Fracture risk reductions for high dose of ibandronate (≥10.8 mg/yr), by fracture type +/- 95% Confidence Intervals † Relative risk reduction adjusted for age, baseline BMD, and fracture history. *P<0.05 Key nonvertebral sites 28.8%*29.9%*34.4%* All clinical fractures Nonvertebral fractures Relative risk reduction, † %

Pooled Ibandronate Fracture Analysis † Cox regression analyses for difference in relative risk of fracture with ibandronate vs placebo. Kaplan-Meier plot (2-year data). Estimated Clinical Fracture Rate, % Days ACE ≥10.8 mg Placebo Relative Risk Reduction 28.8% P<0.05 † Harris ST, Blumentals WA and Miller PD. Curr Med Res Opin. 2008;24:237-45

Pooled Ibandronate Fracture Analysis, con’t Estimated Nonvertebral Fracture Rate, % Days Relative Risk Reduction 29.9% P<0.05 † Harris ST, Blumentals WA and Miller PD. Curr Med Res Opin. 2008;24: ACE ≥10.8 mg Placebo † Cox regression analyses for difference in relative risk of fracture with ibandronate vs placebo. Kaplan-Meier plot (2-year data).

Limitations ► Not all studies were placebo-controlled ► A limited number of baseline patient characteristics (age, previous fracture, baseline BMD) were available for use in multivariable models ► This was an exploratory, post hoc analysis with no adjustment for multiple comparisons Harris ST, Blumentals WA and Miller PD. Curr Med Res Opin. 2008;24:237-45

Conclusions ► In this pooled analysis, doses of ibandronate resulting in an ACE of ≥10.8 mg—which include the marketed doses of 150 mg monthly oral and 3 mg IV quarterly—significantly reduced the risk of clinical fractures and non-vertebral fractures compared to placebo ► The high ACE group (≥10.8 mg) had a longer time to fracture compared to placebo for all clinical fractures, non-vertebral fractures and key non- vertebral fractures Harris ST, Blumentals WA and Miller PD. Curr Med Res Opin. 2008;24:237-45

Observational Studies Strengths and Limitations of Claims Data ► Strengths ● Treatment patterns are those in “real world” clinical practice ● A large number of patients can be followed over time ► Limitations ● No chart review available to validate the ICD-9 codes ● Selection bias is possible—if not probable ● Cannot assess the use of samples or OTC products ● Extraneous variables are not controlled

*Adjusted for age, sex, HRT use, number of concomitant medications and fragility fractures in pre-treatment period 69% 75% RIS vs. CAL RR=0.31 (p<0.05) 26% 25% ALN vs. CAL RR=0.74 (p=NS) ALN vs. CAL RR=0.75 (p=NS) RIS vs. CAL RR=0.25 (p<0.01) Protocare Sciences Database Nonvertebral Fracture Incidence 54% 59% RIS vs. ALN RR=0.46 (p=0.067) RIS vs. ALN RR=0.41 (p<0.05) Watts N, et al. J Manag Care Pharm 2004;10: months12-months Fracture incidence (%) Nasal calcitoninAlendronateRisedronate

► Effectiveness of Bisphosphonates on Nonvertebral and Hip Fractures in the First Year of Therapy: The Risedronate and Alendronate (REAL) Cohort Study Silverman SL, Watts NB, Delmas PD, Lange JL, Lindsay R Silverman L et al. Osteoporos Int. 2007;18:25-34

Study Objective ► To evaluate the onset of fracture reduction by bisphosphonate therapies in clinical medical practice by measuring the incidence of hip and nonvertebral fractures among women 65+ in the year following initiation of either once-a-week doing of risedronate or alendronate

Fracture Outcomes Fracture Sites and Analysis Methods

Study Population Inclusion Criteria ► All women ► > 65 years of age ► Once-weekly bisphosphonate (BP) use between July 2002 and September 2004 Exclusion criteria ► < 6 months of health plan enrollment before first BP use ► < 3 months of health plan enrollment after first BP use ► Any BP use during 6-month history period ► Diagnosis of malignancy or Paget’s disease ► Discontinuation of BP therapy with first 3 months of exposure period

Baseline Characteristics Determinants of Fracture Risk

Cumulative Hip Fracture Incidence

Cumulative Incidence of Hip Fractures During Therapy

Cumulative Nonvertebral Fracture Incidence

Cumulative Incidence of Nonvertebral Fractures During Therapy

Conclusion ► In an observational study of medical practice, patients using risedronate had a lower incidence of nonvertebral and of hip fractures in the first year of therapy than those using alendronate

The VIBE Study: eValuation of IBandronate Efficacy ► A retrospective cohort study comparing fracture rates for women receiving monthly ibandronate versus weekly bisphosphonates

Objective Objective ► To investigate the efficacy of monthly ibandronate versus weekly BPs by comparing rates of incident clinical fractures over 12 months in a retrospective cohort study BP = bisphosphonate

Methodology ► Longitudinal patient data from health plans: eligibility, medical and pharmaceutical claims (anonymous, HIPAA-compliant) ● i3 Research database (single, large health plan with 14 million annual enrolment) ● i3 Innovus IMPACT database (multiple, unaffiliated health plans with over 70 million enrolled 1997–2007) ► Endpoints: new fractures ● hip ● non-vertebral (inclusive of hip) ● vertebral (clinical) ● any (inclusive of all the above) ► Analysis ● time to first incident fracture (Kaplan-Meier methods) ● relative risk (hazard ratio) from Cox regression, controlled for baseline covariates

Study population ► Women aged ≥45 years newly started on an oral BP ● received ≥1 prescription between 1 April and 31 December 2005 (index date) for ibandronate (Boniva/Bonviva) 150mg once monthly, alendronate (Fosamax) 35mg or 70mg weekly or risedronate (Actonel) 35mg weekly ● no BP in baseline period (6 months prior to index date) ► Continuous enrolment in health plan for ≥9 months ● 6 months before starting BP therapy ● ≥3 months after the first BP prescription ► Excluded women with Paget’s disease of bone or malignant neoplasm

Baseline characteristics ► Patient ● age at index date ● co-pay of index treatment ● GI diagnosis ► Osteoporosis ● fracture history ● bone densitometry procedure ● osteoporosis diagnosis ● osteopenia diagnosis ► Healthcare utilisation ● number of outpatient visits ● hospitalisation ► Medication use ● number of therapeutic classes ● Estrogen ● Non-estrogen anti- osteoporotics (calcitonin, SERMs) ● GI medication (PPI, H2B, CTP) ● corticosteroid GI = gastrointestinal; SERM = selective estrogen receptor modulator PPI = proton pump inhibitor; H2B = H 2 B=H 2 blocker; CTP = cytoprotective

Period of observation ► Each subject required to have a 6 month baseline period ● to examine medication use and medical history ► After starting BP therapy (index date) each subject was observed for fracture for up to 12 months, or until ● loss to follow-up (end of health plan enrolment) ● discontinue therapy (for primary analysis only) ● change in BP therapy switched to a different BP switched to a different BP switched dosing regimen (e.g. weekly to daily) switched dosing regimen (e.g. weekly to daily) ► Further observations were then stopped (censored)

Study design: retrospective cohort study Patient intake period: start BP therapy (index date) 1 April December 2005 Follow-up period: up to 12 months 1 April December 2006 Baseline period: 6 months 1 October June 2005

Overview of Analyses Primary analysis: adherent patients ► “Head-to-Head” comparison of drug efficacy ● patients received minimum of 90 days therapy ● observed for fracture after 90 days, only while remaining on therapy Secondary analysis: all patients starting BP therapy ► patients required to have received ‘≥1 BP prescription’ ► observed for fracture after index prescription Sensitivity analyses ► exclude patients with clinically important baseline differences: use of oestrogen or other anti-osteoporotics, corticosteroids, GI medications, etc. ► definitions of adherence: refill gap for ibandronate* (30 days vs 45 days), requiring 90-day minimum adherence *Gaps for monthly ibandronate (always 30 days for weekly BPs)

Statistical Analysis ► Time-to-event analysis of fracture incidence with Kaplan-Meier methods ► Cox regression used to estimate RR (hazard ratio) of fracture comparing monthly versus weekly cohorts, adjusted for covariates ● results shown are from stepwise regression models with all baseline characteristics entered as candidate variables, retaining statistically significant variables age, osteoporosis diagnosis, use of DXA, fracture history age, osteoporosis diagnosis, use of DXA, fracture history number of medication classes used, oestrogen use number of medication classes used, oestrogen use number of outpatient visits number of outpatient visits ► Conclusions were unchanged in models that included other clinically important variables ● use of other anti-osteoporotics (calcitonin, SERMs) ● use of glucocorticosteroids RR = relative risk; DXA = dual energy X-ray absorptiometry

Patient disposition: primary and secondary analyses Candidate patients ≥1 prescription for BP* (n=445,430) Females aged ≥45 years (n=338,872) Eligible patients First treatment, no cancer or Paget’s disease (n=91,630) Secondary analysis population: all patients starting BPs (n=91,598) Primary analysis population: adherent patients (n=64,182) Aged <45 years or male (n=13,217) >1 study drug (n=19) BP pre-index (n=237,480) Cancer pre-index (n=9,681) Paget’s disease (n=81) Invalid data: negative costs (n=32) Discontinue BP <90 days (n=27,416) *Alendronate, ibandronate or risedronate

Baseline Characteristics: Primary Analysis Weekly BP therapy (n=56,837) Monthly ibandronate (n=7,345) p value Duration of observation in days, mean (SD) 218 (98.3) 223 (94.1) Age, mean (SD) 60.5 (8.8) 60.1 (8.6) Osteoporosis diagnosis, % <0.001 Osteopenia diagnosis, % Bone densitometry procedure, % Fracture history, % GI diagnosis, % <0.001 GI medication use, % <0.001 Oestrogen use, % <0.001 Other anti-osteoporotic, % <0.001 Glucocorticosteroid use, % <0.001 Number of therapeutic classes, mean (SD) 5.0 (5.30) 6.1 (4.93) <0.001 Outpatient visits, mean (SD) 15.0 (17.2) 15.9 (16.8) <0.001 Hospitalisation, %

Primary analysis: monthly ibandronate vs weekly bisphosphonates at 12 months RR = adjusted RR (hazard ratio) using Cox regression controlling for potential confounding variables; Persistent patient cohort with no refill gap >45 days (monthly) or 30 days (weekly); Fx = absolute number of fractures RR=0.36 p<0.01 RR=1.06 p=0.84 RR=0.88 p=0.26 RR=0.82 p=0.052 Fx= Fractures Monthly oral ibandronate (n=7,345) Weekly oral BPs (n=56,837) Fx=103 Non-vertebral Hip Vertebral Any Fracture incidence (%) 1.30 Fx=858 Fx=8Fx=135 Fx=106Fx=95 Fx=

RR=0.34 p<0.01 RR=1.00 p=1.00 RR=0.88 p=0.26 RR=0.80 p<0.05 Primary analysis: monthly ibandronate versus weekly alendronate at 12 months Fx=103Fx=542 Fx=8Fx=86Fx=15Fx=68Fx=95Fx=464 Fractures Non-vertebralHipVertebralAny Monthly oral ibandronate (n=7,345) Weekly oral alendronate (n=35,865) RR = adjusted RR (hazard ratio) using Cox regression controlling for potential confounding variables; Persistent patient cohort with no refill gap >45 days (monthly) or 30 days (weekly); Fx = absolute number of fractures Fracture incidence (%)

RR=1.19 p=0.57 RR=0.39 p<0.01 RR=0.91 p=0.42 RR=0.85 p=0.14 Primary analysis: monthly ibandronate versus weekly risedronate at 12 months Fractures Non-vertebralHipVertebralAny Monthly oral ibandronate (n=7,345) Weekly oral risedronate (n=20,972) Fx= Fx=316 Fx=8 Fx=49Fx=15Fx=38Fx=95Fx= RR = adjusted RR (hazard ratio) using Cox regression controlling for potential confounding variables; Persistent patient cohort with no refill gap >45 days (monthly) or 30 days (weekly); Fx = absolute number of fractures Fracture incidence (%)

Sensitivity analyses: exclude patients with clinically important baseline differences ► In order to understand whether the results were due to baseline differences in the populations, sensitivity analyses were performed which excluded patients with the following during baseline 1.Estrogen or other anti-osteoporotic medication use (SERMS, calcitonin) 2.corticosteroid use 3.fracture 4.GI medication use 5.corticosteroid use and/or osteopenia ► The conclusions regarding fracture endpoints remained unchanged in the analyses

Limitations ► Observational studies are subject to potential confounding (not randomised) ● there may be residual confounding that was not adequately controlled for ● but this was also evaluated with multiple sensitivity analyses ► Diagnosis data was collected for billing purposes, not for research ● a diagnosis code on a medical claim is not necessarily confirmation of a fracture ● vertebral fracture may be coded on basis of patient symptoms, rather than X-ray ● it is unlikely that fracture misclassification is differential and clinical fractures are the most important ► There is no perfect measure of patient compliance ● a filled prescription does not mean the medication was taken, and medication samples are not recorded in prescription claims data ● the above would underestimate antifracture benefit (and unlikely to be differential) ► Duration of follow-up period was limited to 12 months by the available data ► P values were not adjusted for multiple comparisons

Strengths ► Large observational study in a real-world population ● findings more appropriate for generalisation and representative than clinical trials ● learnings from other observational studies considered in study design ► All potential confounders were entered into the Cox- regression model and results were unchanged ► Results consistent across a broad range of sensitivity analyses

Discussion ► Risk of hip and non-vertebral fractures was the same with monthly ibandronate and weekly bisphosphonates ► Suggests efficacy of ibandronate on non vertebral fractures, consistent with data obtained in a recent meta- analysis 1 ► The rates of vertebral fractures were significantly lower with monthly ibandronate versus weekly bisphosphonates in the primary analysis, but the number of patients with vertebral fracture with monthly ibandronate was limited (n=8) 1 Adachi R, et al. J Bone Miner Res 2007;S221:S210–11 (Abstract M428)