OsteoporosisWRAP SlideCAST

OsteoporosisWRAP SlideCASTOsteoporosisWRAP SlideCAST

Complexities and Challenges ofComplexities and Challenges ofMeasuring Fracture End Points Measuring Fracture End Points

Interpreting the Results of Existing Trials Interpreting the Results of Existing Trials

Steven T Harris MD FACPSteven T Harris MD FACPClinical Professor of MedicineClinical Professor of Medicine

University of California, San FranciscoUniversity of California, San Francisco

Fracture EndpointsFracture Endpoints

► Regulatory approval of existing medications has Regulatory approval of existing medications has been based on fracture reduction, rather than been based on fracture reduction, rather than changes in surrogates such as bone mineral changes in surrogates such as bone mineral density (BMD) alonedensity (BMD) alone

► The most common fracture endpoint has been the The most common fracture endpoint has been the reduction in vertebral fracturereduction in vertebral fracture● Vertebral fracture has most often been defined on the Vertebral fracture has most often been defined on the

basis of morphometric changes, including both “new” and basis of morphometric changes, including both “new” and “worsening” fractures“worsening” fractures

● ““Clinical” vertebral fracture—defined as fracture Clinical” vertebral fracture—defined as fracture associated with back pain—has usually been identified as associated with back pain—has usually been identified as a secondary endpointa secondary endpoint

Fracture Endpoints, con’tFracture Endpoints, con’t

► ““Non-vertebral fracture” has most commonly been Non-vertebral fracture” has most commonly been identified as a secondary endpoint as wellidentified as a secondary endpoint as well● Varying definitions of “non-vertebral fracture”: all Varying definitions of “non-vertebral fracture”: all

fractures vs fragility fractures vs a particular fractures vs fragility fractures vs a particular composite endpointcomposite endpoint

● Hip fracture has sometimes—but not always—Hip fracture has sometimes—but not always—been identified as a separate endpoint of been identified as a separate endpoint of particular interestparticular interest

Fracture Endpoints, con’tFracture Endpoints, con’t

► Fracture reduction has most often been expressed —Fracture reduction has most often been expressed —both clinically and commercially—as relative risk both clinically and commercially—as relative risk reduction, rather than absolute risk reductionreduction, rather than absolute risk reduction

► The rapidity with which fracture protection occurs has The rapidity with which fracture protection occurs has been of clinical—and commercial—interestbeen of clinical—and commercial—interest

► There are no head-to-head randomized trials with There are no head-to-head randomized trials with fracture as the primary endpointfracture as the primary endpoint

► The pivotal fracture trials recruited patients with a The pivotal fracture trials recruited patients with a certain “sameness”—but there were notable differences certain “sameness”—but there were notable differences in demographics, baseline fracture status and baseline in demographics, baseline fracture status and baseline BMDs neverthelessBMDs nevertheless● There were obvious differences in observed fracture ratesThere were obvious differences in observed fracture rates

—both vertebral and non-vertebral—both vertebral and non-vertebral

% of % of Patients Patients With New With New Vertebral Vertebral FracturesFracturesOver 3-5 Over 3-5

YearsYears

Vertebral Fracture Effects In Prospective TrialsVertebral Fracture Effects In Prospective Trials

Direct Comparisons Among Trials Cannot Be Made Direct Comparisons Among Trials Cannot Be Made

Chesnut CH, et al. Chesnut CH, et al. Am J MedAm J Med. 2000;109:267 . 2000;109:267 Ettinger B, et al. Ettinger B, et al. JAMA.JAMA. 1999;282:637 1999;282:637Black DM, et al. Black DM, et al. Lancet.Lancet. 1996;348:1535 1996;348:1535 Cummings SR, et al. Cummings SR, et al. JAMA.JAMA. 1998;280:2077 1998;280:2077Harris ST, et al. Harris ST, et al. JAMA.JAMA. 1999;282:1344 1999;282:1344 Reginster J, et al. Reginster J, et al. Osteoporos Int.Osteoporos Int. 2000;11:83 2000;11:83Chesnut CH, et al. Chesnut CH, et al. J Bone Miner Res.J Bone Miner Res. 2004;19:1241 2004;19:1241 Black DM, et al. Black DM, et al. N Engl J MedN Engl J Med 2007:356:1809 2007:356:1809

00

55

1010

1515

2020

2525

3030

PROOF MORE FIT-VFA VERT-NA VERT-MN BONE HORIZON MORE FIT-CFAPROOF MORE FIT-VFA VERT-NA VERT-MN BONE HORIZON MORE FIT-CFA

With Prevalent Vertebral Fractures ± Vert Fx Without Vert FxWith Prevalent Vertebral Fractures ± Vert Fx Without Vert Fx

30%30%

47%47% 41%41%

49%49%

50%50%

40%40%

50%50%

52%52% 70%70%

CalciumCalcium CTCT RISRISALNALNRLXRLX IBNIBN ZOLZOL

% = Relative Fracture Risk % = Relative Fracture Risk ReductionReduction

% of Patients % of Patients With New With New

Nonvertebral Nonvertebral FracturesFracturesOver 3-5 Over 3-5

YearsYears

Nonvertebral Fracture Effects Nonvertebral Fracture Effects In Prospective TrialsIn Prospective Trials

Direct Comparisons Among Trials Cannot Be Made *

Chesnut CH, et al. Chesnut CH, et al. Am J MedAm J Med. 2000;109:267 . 2000;109:267 Ettinger B, et al. Ettinger B, et al. JAMA.JAMA. 1999;282:637 1999;282:637Black DM, et al. Black DM, et al. Lancet.Lancet. 1996;348:1535 1996;348:1535 Cummings SR, et al. Cummings SR, et al. JAMA.JAMA. 1998;280:2077 1998;280:2077Harris ST, et al. Harris ST, et al. JAMA.JAMA. 1999;282:1344 1999;282:1344 Reginster J, et al. Reginster J, et al. Osteoporos Int.Osteoporos Int. 2000;11:83 2000;11:83Chesnut CH, et al. Chesnut CH, et al. J Bone Miner Res.J Bone Miner Res. 2004;19:1241 2004;19:1241 Black DM, et al. Black DM, et al. N Engl J MedN Engl J Med 2007:356:18092007:356:1809

00

55

1010

1515

2020

2525

3030

PROOF MORE FIT-VFA FIT-CFA VERT-NA VERT-MN BONE HORIZONPROOF MORE FIT-VFA FIT-CFA VERT-NA VERT-MN BONE HORIZON

20%20%p = 0.06p = 0.06

12%12%p = n.s.p = n.s.

25%25%p < 0.001p < 0.001

33%33%p = 0.06p = 0.06

CalciumCalcium CTCT RISRISALNALNRLXRLX IBNIBN ZOLZOL

% = Relative Fracture Risk Reduction% = Relative Fracture Risk Reduction

10%10%p = n.s.p = n.s.

12%12%p = n.s.p = n.s.

39%39%p < 0.05p < 0.05 p = n.s.p = n.s.

* Patient demographics and the definition of nonvertebral fracture varied among studies* Patient demographics and the definition of nonvertebral fracture varied among studies

Fracture EndpointsFracture Endpoints

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

datadata● Meta analyses of existing trial dataMeta analyses of existing trial data● Observational dataObservational data

Nonvertebral Fracture ReductionNonvertebral Fracture ReductionPost-hoc analysesPost-hoc analyses

0

2

4

6

8

10

12

14

6 12 18 24 30 36% p

atie

nts

with

non

vert

ebra

l fra

ctur

e

Control Risedronate

59%P=0.002

* * * * * **

**

* *

Time (months)

0

2

4

6

8

10

12

14

0 6 12 18 24 30 36

**

*

36%P=0.002

Control Alendronate

Time (months)

Harrington Calcif Tissue Int 2004;74:129 Black 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 Ibandronate and the risk of non-vertebral and clinical fractures in women with and clinical fractures in women with

postmenopausal osteoporosis (PMO): postmenopausal osteoporosis (PMO): results of a meta-analysis of results of a meta-analysis of

Phase III studiesPhase III studies

Harris ST, Blumentals WA and Miller PD. Harris ST, Blumentals WA and Miller PD. Curr Med Res Opin. Curr Med Res Opin. 2008;24:237-452008;24:237-45

To evaluate the nonvertebral and clinical To evaluate the nonvertebral and clinical fracture efficacy of different doses of fracture efficacy of different doses of ibandronate using a pooled analysis of data ibandronate using a pooled analysis of data from 4 pivotal phase III clinical trials: BONE,from 4 pivotal phase III clinical trials: BONE,11 IV Dose Fracture,IV Dose Fracture,22 MOBILE, MOBILE,33 and DIVA and DIVA44

To estimate the fracture rate over time using To estimate the fracture rate over time using the Kaplan-Meier methodthe Kaplan-Meier method

Study ObjectivesStudy Objectives

11oral iBandronate Osteoporosis vertebral fracture trial in North America and Europe. Chesnut CH, et al. oral iBandronate Osteoporosis vertebral fracture trial in North America and Europe. Chesnut CH, et al. Curr Med Res Opin.Curr Med Res Opin. 2005;21:11-18. 2005;21:11-18.

22Recker R, et al. Recker R, et al. Bone.Bone. 2004;34:890-899. 2004;34:890-899.

33Monthly Oral iBandronate In LadiEs. Reginster JY, et al. Monthly Oral iBandronate In LadiEs. Reginster JY, et al. Ann Rheum DisAnn Rheum Dis. 2006;65:654-661.. 2006;65:654-661.

44Dosing IntraVenous Administration. Delmas PD, et al. Dosing IntraVenous Administration. Delmas PD, et al. Arthritis Rheum.Arthritis Rheum. 2006;54:1838-1846. 2006;54:1838-1846.

Pooled Fracture AnalysisPooled Fracture AnalysisMethodsMethods

► Cox regression analyses were adjusted for variables Cox regression analyses were adjusted for variables to allow for meaningful comparisons among trialsto allow for meaningful comparisons among trials● AgeAge● Previous clinical fracturePrevious clinical fracture● Baseline BMDBaseline BMD• Lumbar spine BMD for models with all clinical Lumbar spine BMD for models with all clinical

fractures fractures • Hip BMD for models with nonvertebral fractures Hip BMD for models with nonvertebral fractures

(NVFs) or key NVFs(NVFs) or key NVFs► Kaplan-Meier methods were used to: Kaplan-Meier methods were used to:

● Plot survival curves for time to fracturePlot survival curves for time to fracture● Compare rates using a log-rank testCompare rates using a log-rank test

Harris ST, Blumentals WA and Miller PD. Harris ST, Blumentals WA and Miller PD. Curr Med Res Opin. Curr Med Res Opin. 2008;24:237-452008;24:237-45

Pooled Fracture Analysis Pooled Fracture Analysis Methods (cont.)Methods (cont.)

► Fracture rates were determined by tabulating the Fracture rates were determined by tabulating the proportion of all ITT patients with at least 1 fractureproportion of all ITT patients with at least 1 fracture

► Doses were pooled based on annual cumulative Doses were pooled based on annual cumulative exposure (ACE) exposure (ACE) ● ACE was calculated by multiplying the drug ACE was calculated by multiplying the drug

strength by the number of annual doses and by an strength by the number of annual doses and by an absorption factor (0.6% for oral dosing and 100% absorption factor (0.6% for oral dosing and 100% for IV dosing)for IV dosing)

● For example, the ACE for oral BONIVA 150 mg For example, the ACE for oral BONIVA 150 mg once-monthly would be 10.8 mg = 150 x 12 x 0.006once-monthly would be 10.8 mg = 150 x 12 x 0.006

Harris ST, Blumentals WA and Miller PD. Curr Med Res Opin. 2008;24:237-45

IV and oral ibandronate annual cumulative IV and oral ibandronate annual cumulative exposure across studiesexposure across studies

1. Recker R, et al. 1. Recker R, et al. BoneBone. 2004;34:890-899. 2. Chesnut CH, et al. . 2004;34:890-899. 2. Chesnut CH, et al. J Bone Miner Res.J Bone Miner Res. 2004;19:1241-1249. 3. Adami S, 2004;19:1241-1249. 3. Adami S, et al. et al. Bone.Bone. 2004;34:881 2004;34:881--889. 4. Miller PD, et al. 889. 4. Miller PD, et al. J Bone Miner ResJ Bone Miner Res. 2005;. 2005;20:1315-1322. 5. Data on file (Reference 20:1315-1322. 5. Data on file (Reference #161-153), Hoffman-La Roche Inc, Nutley, NJ 07110#161-153), Hoffman-La Roche Inc, Nutley, NJ 07110

8 mg8 mg

12 mg12 mg10.8 mg10.8 mg

5.5 mg5.5 mg

4 mg4 mg

00

44

88

1212

An

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l cum

ula

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exp

osu

re (

mg

)A

nnu

al c

umu

lativ

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xpo

sure

(m

g)

Quarterly IVQuarterly IV Quarterly IVQuarterly IV Quarterly IVQuarterly IVOral dailyOral daily Oral monthlyOral monthly

MF4380MF438011 IRISIRIS33 DIVADIVA55BONEBONE22 MOBILEMOBILE44

Fracture risk reductions for high dose of Fracture risk reductions for high dose of ibandronate (≥10.8 mg/yr), by fracture typeibandronate (≥10.8 mg/yr), by fracture type

+/- 95% Confidence Intervals+/- 95% Confidence Intervals

††Relative risk reduction adjusted for age, baseline BMD, and fracture history. Relative risk reduction adjusted for age, baseline BMD, and fracture history.

*P<0.05*P<0.05

Key nonvertebral sitesKey nonvertebral sites

28.8%*28.8%* 29.9%*29.9%* 34.4%*34.4%*

All clinical fracturesAll clinical fractures Nonvertebral fracturesNonvertebral fractures

-60-60

-50-50

-40-40

-30-30

-20-20

-10-10

00

Rel

ativ

e ri

sk r

educ

tion,

Rel

ativ

e ri

sk r

educ

tion,

†† %%

Pooled Ibandronate Fracture Analysis Pooled Ibandronate Fracture Analysis

†Cox regression analyses for difference in relative risk of fracture with ibandronate vs placebo.Kaplan-Meier plot (2-year data).

Est

ima

ted

Clin

ica

l F

ract

ure

Ra

te, %

Days

ACE ≥10.8 mg

Placebo

0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 750

10

8

6

4

2

0

Relative Risk Reduction

28.8%P<0.05†


Pooled Ibandronate Fracture Analysis, con’tPooled Ibandronate Fracture Analysis, con’tE

stim

ate

d N

on

vert

ebra

l F

ract

ure

Ra

te, %

Days0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 750

Relative Risk Reduction

29.9%P<0.05†


ACE ≥10.8 mg

Placebo

10

8

6

4

2

0†Cox regression analyses for difference in relative risk of fracture with ibandronate vs placebo.Kaplan-Meier plot (2-year data).

LimitationsLimitations

► Not all studies were placebo-controlledNot all studies were placebo-controlled

► A limited number of baseline patient characteristics A limited number of baseline patient characteristics (age, previous fracture, baseline BMD) were (age, previous fracture, baseline BMD) were available for use in multivariable modelsavailable for use in multivariable models

► This was an exploratory, post hoc analysis with no This was an exploratory, post hoc analysis with no adjustment for multiple comparisons adjustment for multiple comparisons


ConclusionsConclusions

► In this pooled analysis, doses of ibandronate In this pooled analysis, doses of ibandronate resulting in an ACE of resulting in an ACE of ≥≥10.8 mg—which include the 10.8 mg—which include the marketed doses of 150 mg monthly oral and 3 mg marketed doses of 150 mg monthly oral and 3 mg IV quarterly—significantly reduced the risk of clinical IV quarterly—significantly reduced the risk of clinical fractures and non-vertebral fractures compared to fractures and non-vertebral fractures compared to placeboplacebo

► The high ACE group (≥10.8 mg) had a longer time The high ACE group (≥10.8 mg) had a longer time to fracture compared to placebo for all clinical to fracture compared to placebo for all clinical fractures, non-vertebral fractures and key non-fractures, non-vertebral fractures and key non-vertebral fractures vertebral fractures


Observational StudiesObservational StudiesStrengths and Limitations of Claims DataStrengths and Limitations of Claims Data

► StrengthsStrengths● Treatment patterns are those in “real world” clinical practice Treatment patterns are those in “real world” clinical practice ● A large number of patients can be followed over timeA large number of patients can be followed over time

► LimitationsLimitations● No chart review available to validate the ICD-9 codesNo chart review available to validate the ICD-9 codes● Selection bias is possible—if not probableSelection bias is possible—if not probable● Cannot assess the use of samples or OTC productsCannot assess the use of samples or OTC products● Extraneous variables are not controlledExtraneous 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. CALRR=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. CALRR=0.25 (p<0.01)

Protocare Sciences DatabaseProtocare Sciences DatabaseNonvertebral Fracture IncidenceNonvertebral Fracture Incidence

54%

59%

RIS vs. ALNRR=0.46(p=0.067)

RIS vs. ALNRR=0.41(p<0.05)

Watts N, et al. J Manag Care Pharm 2004;10:142-151

0.0

1.0

2.0

3.0

4.0

6-months 12-months

Fra

ctur

e in

cide

nce

(%)

Nasal calcitonin Alendronate Risedronate

► Effectiveness of Bisphosphonates Effectiveness of Bisphosphonates on Nonvertebral and Hip Fractures on Nonvertebral and Hip Fractures in the First Year of Therapy: The in the First Year of Therapy: The Risedronate and Alendronate Risedronate and Alendronate (REAL) Cohort Study(REAL) Cohort Study

Silverman SL, Watts NB, Delmas PD, Lange JL, Lindsay RSilverman SL, Watts NB, Delmas PD, Lange JL, Lindsay R

Silverman L et al. Osteoporos Int. 2007;18:25-34Silverman L et al. Osteoporos Int. 2007;18:25-34

Study ObjectiveStudy Objective

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

Fracture OutcomesFracture OutcomesFracture Sites and Analysis MethodsFracture Sites and Analysis Methods

Study PopulationStudy Population

Inclusion CriteriaInclusion Criteria► All womenAll women

► >> 65 years of age 65 years of age

► Once-weekly bisphosphonate (BP) use between July 2002 Once-weekly bisphosphonate (BP) use between July 2002 and September 2004and September 2004

Exclusion criteriaExclusion criteria► < 6 months of health plan enrollment before first BP use< 6 months of health plan enrollment before first BP use

► < 3 months of health plan enrollment after first BP use< 3 months of health plan enrollment after first BP use

► Any BP use during 6-month history periodAny BP use during 6-month history period

► Diagnosis of malignancy or Paget’s diseaseDiagnosis of malignancy or Paget’s disease

► Discontinuation of BP therapy with first 3 months of Discontinuation of BP therapy with first 3 months of exposure periodexposure period

Baseline CharacteristicsBaseline CharacteristicsDeterminants of Fracture RiskDeterminants of Fracture Risk

Cumulative Hip Fracture IncidenceCumulative Hip Fracture Incidence

Cumulative Incidence of Hip Fractures During TherapyCumulative Incidence of Hip Fractures During Therapy

Cumulative Nonvertebral Fracture Incidence Cumulative Nonvertebral Fracture Incidence

Cumulative Incidence of Nonvertebral Cumulative Incidence of Nonvertebral Fractures During TherapyFractures During Therapy

ConclusionConclusion

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

TheThe VIBEVIBE Study:Study: eeVValuation of aluation of IBIBandronateandronate EEfficacyfficacy

► A retrospective cohort study A retrospective cohort study comparing fracture rates for women comparing fracture rates for women receiving monthly ibandronate receiving monthly ibandronate versus weekly bisphosphonatesversus weekly bisphosphonates

ObjectiveObjective

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

BP = bisphosphonate

MethodologyMethodology

► Longitudinal patient data from health plans: eligibility, medical and Longitudinal patient data from health plans: eligibility, medical and pharmaceutical claims (anonymous, HIPAA-compliant) pharmaceutical claims (anonymous, HIPAA-compliant)

● i3 Research database (single, large health plan with 14 million annual i3 Research database (single, large health plan with 14 million annual enrolment)enrolment)

● i3 Innovus IMPACT database (multiple, unaffiliated health plans with i3 Innovus IMPACT database (multiple, unaffiliated health plans with over 70 million enrolled 1997–2007)over 70 million enrolled 1997–2007)

► Endpoints: new fractures Endpoints: new fractures ● hiphip● non-vertebral (inclusive of hip)non-vertebral (inclusive of hip)● vertebral (clinical)vertebral (clinical)● any (inclusive of all the above)any (inclusive of all the above)

► AnalysisAnalysis● time to first incident fracture (Kaplan-Meier methods)time to first incident fracture (Kaplan-Meier methods)● relative risk (hazard ratio) from Cox regression, controlled for relative risk (hazard ratio) from Cox regression, controlled for

baseline covariatesbaseline covariates

Study populationStudy population

► Women aged ≥45 years newly started on an oral BP Women aged ≥45 years newly started on an oral BP ● received ≥1 prescription between 1 April and 31 December received ≥1 prescription between 1 April and 31 December

2005 (index date) for ibandronate (Boniva/Bonviva) 150mg 2005 (index date) for ibandronate (Boniva/Bonviva) 150mg once monthly, alendronate (Fosamax) 35mg or 70mg once monthly, alendronate (Fosamax) 35mg or 70mg weekly or risedronate (Actonel) 35mg weeklyweekly or risedronate (Actonel) 35mg weekly

● no BP in baseline period (6 months prior to index date)no BP in baseline period (6 months prior to index date)

► Continuous enrolment in health plan for ≥9 monthsContinuous enrolment in health plan for ≥9 months● 6 months before starting BP therapy 6 months before starting BP therapy ● ≥≥3 months after the first BP prescription3 months after the first BP prescription

► Excluded women with Paget’s disease of bone or Excluded women with Paget’s disease of bone or malignant neoplasmmalignant neoplasm

Baseline characteristicsBaseline characteristics

► PatientPatient● age at index dateage at index date● co-pay of index treatmentco-pay of index treatment● GI diagnosisGI diagnosis

► OsteoporosisOsteoporosis● fracture historyfracture history● bone densitometry bone densitometry

procedureprocedure● osteoporosis diagnosisosteoporosis diagnosis● osteopenia diagnosisosteopenia diagnosis

► Healthcare utilisationHealthcare utilisation● number of outpatient visitsnumber of outpatient visits● hospitalisationhospitalisation

► Medication useMedication use● number of therapeutic classesnumber of therapeutic classes● EstrogenEstrogen● Non-estrogen anti-Non-estrogen anti-

osteoporotics (calcitonin, osteoporotics (calcitonin, SERMs)SERMs)

● GI medication (PPI, H2B, CTP)GI medication (PPI, H2B, CTP)● corticosteroidcorticosteroid

GI = gastrointestinal; SERM = selective estrogen receptor modulatorPPI = proton pump inhibitor; H2B = H2B=H2 blocker; CTP = cytoprotective

Period of observationPeriod of observation

► Each subject required to have a 6 month baseline periodEach subject required to have a 6 month baseline period● to examine medication use and medical historyto examine medication use and medical history

► After starting BP therapy (index date) each subject was observed for After starting BP therapy (index date) each subject was observed for fracture for up to 12 months, or untilfracture for up to 12 months, or until

● loss to follow-up (end of health plan enrolment)loss to follow-up (end of health plan enrolment)● discontinue therapy (for primary analysis only)discontinue therapy (for primary analysis only)● change in BP therapychange 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)Further observations were then stopped (censored)

Study design: retrospective cohort studyStudy design: retrospective cohort study

Patient intake period: start BP therapy (index date)1 April 2005 31 December 2005

Follow-up period: up to 12 months1 April 2005 31 December 2006

Baseline period: 6 months1 October 2004 30 June 2005

Overview of AnalysesOverview of Analyses

Primary analysis: adherent patients Primary analysis: adherent patients

► ““Head-to-Head” comparison of drug efficacyHead-to-Head” comparison of drug efficacy● patients received minimum of 90 days therapypatients received minimum of 90 days therapy● observed for fracture after 90 days, only while remaining on therapyobserved for fracture after 90 days, only while remaining on therapy

Secondary analysis: all patients starting BP therapySecondary analysis: all patients starting BP therapy

► patients required to have received ‘patients required to have received ‘≥≥1 BP prescription’1 BP prescription’

► observed for fracture after index prescriptionobserved for fracture after index prescription

Sensitivity analysesSensitivity analyses

► exclude patients with clinically important baseline differences: use of exclude patients with clinically important baseline differences: use of oestrogen or other anti-osteoporotics, corticosteroids, GI medications, etc.oestrogen or other anti-osteoporotics, corticosteroids, GI medications, etc.

► definitions of adherence: refill gap for ibandronate* (30 days vs 45 days), definitions of adherence: refill gap for ibandronate* (30 days vs 45 days), requiring 90-day minimum adherencerequiring 90-day minimum adherence

*Gaps for monthly ibandronate (always 30 days for weekly BPs)

Statistical AnalysisStatistical Analysis

► Time-to-event analysis of fracture incidence with Kaplan-Meier methodsTime-to-event analysis of fracture incidence with Kaplan-Meier methods

► Cox regression used to estimate RR (hazard ratio) of fracture comparing monthly Cox regression used to estimate RR (hazard ratio) of fracture comparing monthly versus weekly cohorts, adjusted for covariatesversus weekly cohorts, adjusted for covariates● results shown are from stepwise regression models with all baseline results shown are from stepwise regression models with all baseline

characteristics entered as candidate variables, retaining statistically significant characteristics entered as candidate variables, retaining statistically significant variablesvariables• age, osteoporosis diagnosis, use of DXA, fracture historyage, osteoporosis diagnosis, use of DXA, fracture history• number of medication classes used, oestrogen usenumber of medication classes used, oestrogen use• number of outpatient visitsnumber of outpatient visits

► Conclusions were unchanged in models that included other clinically important Conclusions were unchanged in models that included other clinically important variablesvariables● use of other anti-osteoporotics (calcitonin, SERMs)use of other anti-osteoporotics (calcitonin, SERMs)● use of glucocorticosteroidsuse of glucocorticosteroids

RR = relative risk; DXA = dual energy X-ray absorptiometry

Patient disposition:Patient disposition:primaryprimary andand secondary secondary analysesanalyses

Candidate patients≥1 prescription for BP*

(n=445,430)

Females aged ≥45 years(n=338,872)

Eligible patientsFirst 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)

1

2

3

4

*Alendronate, ibandronate or risedronate

Baseline Characteristics: Primary AnalysisBaseline Characteristics: Primary Analysis

WeeklyWeekly

BP therapyBP therapy(n=56,837)(n=56,837)

Monthly Monthly ibandronateibandronate(n=7,345) (n=7,345)

p value p value

Duration of observation in days, mean (SD)Duration of observation in days, mean (SD) 218 (98.3)218 (98.3) 223 (94.1)223 (94.1) 0.002 0.002

Age, mean (SD)Age, mean (SD) 60.5 (8.8) 60.5 (8.8) 60.1 (8.6)60.1 (8.6) 0.002 0.002

Osteoporosis diagnosis, % Osteoporosis diagnosis, % 35.5 35.5 40.2 40.2 <0.001 <0.001

Osteopenia diagnosis, % Osteopenia diagnosis, % 0.3 0.3 0.4 0.4 0.076 0.076

Bone densitometry procedure, % Bone densitometry procedure, % 55.3 55.3 56.2 56.2 0.116 0.116

Fracture history, % Fracture history, % 3.7 3.7 3.6 3.6 0.520 0.520

GI diagnosis, % GI diagnosis, % 16.6 16.6 21.9 21.9 <0.001<0.001

GI medication use, % GI medication use, % 16.5 16.5 23.623.6 <0.001 <0.001

Oestrogen use, % Oestrogen use, % 19.2 19.2 24.924.9 <0.001 <0.001

Other anti-osteoporotic, %Other anti-osteoporotic, % 5.95.9 10.810.8 <0.001<0.001

Glucocorticosteroid use, % Glucocorticosteroid use, % 9.89.8 12.412.4 <0.001 <0.001

Number of therapeutic classes, mean (SD)Number of therapeutic classes, mean (SD) 5.0 (5.30)5.0 (5.30) 6.1 (4.93) 6.1 (4.93) <0.001 <0.001

Outpatient visits, mean (SD) Outpatient visits, mean (SD) 15.0 (17.2)15.0 (17.2) 15.9 (16.8)15.9 (16.8) <0.001<0.001

Hospitalisation, % Hospitalisation, % 5.55.5 5.45.4 0.559 0.559

Primary analysis: Primary analysis: monthlymonthly ibandronateibandronatevs vs weekly bisphosphonatesweekly bisphosphonates at 12 months at 12 months

RR = adjusted RR (hazard ratio) using Cox regression controlling for potentialconfounding variables; Persistent patient cohort with no refill gap >45 days(monthly) or 30 days (weekly); Fx = absolute number of fractures

RR=0.36p<0.01

RR=1.06p=0.84

RR=0.88p=0.26

RR=0.82p=0.052

Fx=15

0.20

FracturesFractures

Monthly oral ibandronateMonthly oral ibandronate(n=7,345)(n=7,345)

Weekly oral BPsWeekly oral BPs(n=56,837)(n=56,837)

Fx=103

Non-vertebral Hip Vertebral Any

Fra

ctur

e in

cide

nce

(%)

Fra

ctur

e in

cide

nce

(%)

1.30

Fx=858Fx=8Fx=135

Fx=106Fx=95Fx=738

1.29

0.190.24

0.11

1.511.40

1.6

1.2

0.8

0.4

0

RR=0.34p<0.01

RR=1.00p=1.00

RR=0.88p=0.26

RR=0.80p<0.05

Primary analysis: Primary analysis: monthlymonthly ibandronateibandronateversus versus weekly alendronateweekly alendronate at 12 months at 12 months

0.20

1.29 1.29

0.190.24

0.11

1.511.40

Fx=103Fx=542Fx=8Fx=86Fx=15Fx=68Fx=95Fx=464

FracturesFractures Non-vertebral Hip Vertebral Any

1.6

1.2

0.8

0.4

0

Monthly oral ibandronateMonthly oral ibandronate(n=7,345)(n=7,345)

Weekly oral alendronateWeekly oral alendronate(n=35,865)(n=35,865)


Fra

ctur

e in

cide

nce

(%)

Fra

ctur

e in

cide

nce

(%)

RR=1.19p=0.57

RR=0.39p<0.01

RR=0.91p=0.42

RR=0.85p=0.14

Primary analysis: Primary analysis: monthlymonthly ibandronateibandronateversus versus weekly risedronateweekly risedronate at 12 months at 12 months

FracturesNon-vertebral Hip Vertebral Any

1.6

1.2

0.8

0.4

0

Monthly oral ibandronate(n=7,345)

Weekly oral risedronate(n=20,972)

Fx=103

1.29

Fx=316Fx=8Fx=49Fx=15Fx=38Fx=95Fx=274

1.31

0.200.18 0.230.11

1.511.40


Fra

ctur

e in

cide

nce

(%)

Sensitivity analyses: exclude patients with Sensitivity analyses: exclude patients with clinically important baseline differencesclinically important baseline differences

► In order to understand whether the results were due In order to understand whether the results were due to baseline differences in the populations, sensitivity to baseline differences in the populations, sensitivity analyses were performed which excluded patients analyses were performed which excluded patients with the following during baselinewith the following during baseline1.1. Estrogen or other anti-osteoporotic medication use (SERMS, Estrogen or other anti-osteoporotic medication use (SERMS,

calcitonin)calcitonin)

2.2. corticosteroid usecorticosteroid use

3.3. fracturefracture

4.4. GI medication useGI medication use

5.5. corticosteroid use and/or osteopeniacorticosteroid use and/or osteopenia

► The conclusions regarding fracture endpoints The conclusions regarding fracture endpoints remained unchanged in the analysesremained unchanged in the analyses

LimitationsLimitations

► Observational studies are subject to potential confounding (not randomised)Observational studies are subject to potential confounding (not randomised)● there may be residual confounding that was not adequately controlled forthere may be residual confounding that was not adequately controlled for● but this was also evaluated with multiple sensitivity analysesbut this was also evaluated with multiple sensitivity analyses

► Diagnosis data was collected for billing purposes, not for researchDiagnosis data was collected for billing purposes, not for research● a diagnosis code on a medical claim is not necessarily confirmation of a fracturea 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-rayvertebral 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 it is unlikely that fracture misclassification is differential and clinical fractures are the

most important most important

► There is no perfect measure of patient complianceThere is no perfect measure of patient compliance● a filled prescription does not mean the medication was taken, and medication a filled prescription does not mean the medication was taken, and medication

samples are not recorded in prescription claims datasamples are not recorded in prescription claims data● the above would underestimate antifracture benefit (and unlikely to be differential)the above would underestimate antifracture benefit (and unlikely to be differential)

► Duration of follow-up period was limited to 12 months by the available dataDuration of follow-up period was limited to 12 months by the available data

► P values were not adjusted for multiple comparisonsP values were not adjusted for multiple comparisons

StrengthsStrengths

► Large observational study in a real-world populationLarge observational study in a real-world population● findings more appropriate for generalisation and findings more appropriate for generalisation and

representative than clinical trialsrepresentative than clinical trials● learnings from other observational studies considered learnings from other observational studies considered

in study designin study design

► All potential confounders were entered into the Cox-All potential confounders were entered into the Cox-regression model and results were unchangedregression model and results were unchanged

► Results consistent across a broad range of sensitivity Results consistent across a broad range of sensitivity analysesanalyses

DiscussionDiscussion

► Risk of hip and non-vertebral fractures was the same Risk of hip and non-vertebral fractures was the same with monthly ibandronate and weekly bisphosphonateswith monthly ibandronate and weekly bisphosphonates

► Suggests efficacy of ibandronate on non vertebral Suggests efficacy of ibandronate on non vertebral fractures, consistent with data obtained in a recent meta-fractures, consistent with data obtained in a recent meta-analysisanalysis11

► The rates of vertebral fractures were significantly lower The rates of vertebral fractures were significantly lower with monthly ibandronate versus weekly with monthly ibandronate versus weekly bisphosphonates in the primary analysis, but the number bisphosphonates in the primary analysis, but the number of patients with vertebral fracture with monthly of patients with vertebral fracture with monthly ibandronate was limited (n=8) ibandronate was limited (n=8)

1Adachi R, et al. J Bone Miner Res 2007;S221:S210–11 (Abstract M428)

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OsteoporosisWRAP SlideCAST