1

Clifford J. Rosen, MDClifford J. Rosen, MDProgram ChairmanProgram Chairman

Past President, ASBMRPast President, ASBMRClinical Professor of NutritionClinical Professor of Nutrition

University of MaineUniversity of MaineDirector of the Maine Center for OsteoporosisDirector of the Maine Center for Osteoporosis

Research and EducationResearch and EducationSt. Joseph HospitalSt. Joseph Hospital

Bangor, MaineBangor, Maine

Critical Challenges and LandmarkCritical Challenges and LandmarkAdvances in OsteoporosisAdvances in Osteoporosis

Translating Science, Guidelines, and Clinical Trials Translating Science, Guidelines, and Clinical Trials to Specialty Practice for Bone Diseaseto Specialty Practice for Bone Disease

A Year 2007 ScienceA Year 2007 Science--toto--Strategy UpdateStrategy Update

2

CMECME--accredited symposiumaccredited symposium jointly sponsored by the University of jointly sponsored by the University of Massachusetts Medical School and Massachusetts Medical School and CMEducationCMEducation Resources, LLCResources, LLC

Commercial Support:Commercial Support: Sponsored by an independent educational Sponsored by an independent educational grant from Roche Laboratoriesgrant from Roche Laboratories

Mission statement:Mission statement: Improve patient care through evidenceImprove patient care through evidence--based based education, expert analysis, and case studyeducation, expert analysis, and case study--based managementbased management

Processes:Processes: Strives for fair balance, clinical relevance, onStrives for fair balance, clinical relevance, on--label label indications for agents discussed, and emerging evidence and indications for agents discussed, and emerging evidence and information from recent studiesinformation from recent studies

COI:COI: Full faculty disclosures provided in syllabus and at the Full faculty disclosures provided in syllabus and at the beginning of the programbeginning of the program

Welcome and Program OverviewWelcome and Program Overview

Program Educational ObjectivesProgram Educational Objectives

As a result of this session, physicians will be able to:

► Learn how recent advances in basic and clinical research have helped to advance strategies for osteoporosis management.

► Learn how to evaluate recent clinical trials in osteoporosis and how to apply the results of these trials to optimize management of patients with postmenopausal osteoporosis.

► Learn to analyze concepts, strategies, and findings emanating from basic research studies in osteoporosis—at the cellular level involving ligands, osteoclastic activation, cell-cell interactions—and determine directions for future research and trial design.

► Learn to analyze concepts, strategies, and findings emanating from clinical research studies in osteoporosis—at the level of BMD, regimen adherence and persistence, dose and dosing frequency—and determine directions for future research and trial design, and possible implications for clinical practice.

As a result of this session, physicians will be able to:As a result of this session, physicians will be able to:

►► Learn how recent advances in basic and clinical research have heLearn how recent advances in basic and clinical research have helped lped to advance strategies for osteoporosis management.to advance strategies for osteoporosis management.

►► Learn how to evaluate recent clinical trials in osteoporosis andLearn how to evaluate recent clinical trials in osteoporosis and how to how to apply the results of these trials to optimize management of patiapply the results of these trials to optimize management of patients ents with postmenopausal osteoporosis.with postmenopausal osteoporosis.

►► Learn to analyze concepts, strategies, and findings emanating frLearn to analyze concepts, strategies, and findings emanating from om basic research studies in osteoporosisbasic research studies in osteoporosis——at the cellular level involving at the cellular level involving ligandsligands, , osteoclasticosteoclastic activation, cellactivation, cell--cell interactionscell interactions——and determine and determine directions for future research and trial design.directions for future research and trial design.

►► Learn to analyze concepts, strategies, and findings emanating frLearn to analyze concepts, strategies, and findings emanating from om clinical research studies in osteoporosisclinical research studies in osteoporosis——at the level of BMD, regimen at the level of BMD, regimen adherence and persistence, dose and dosing frequencyadherence and persistence, dose and dosing frequency——and and determine directions for future research and trial design, and pdetermine directions for future research and trial design, and possible ossible implications for clinical practice.implications for clinical practice.

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Program Educational ObjectivesProgram Educational Objectives

As a result of this session, physicians will be able to:

► Learn evidence-based approaches for reducing progression of osteoporosis, and reducing risk of fracture complications based on finding reported in the latest clinical research.

► Learn how, based on research and evidence, to select safe and effective pharmacotherapy for prevention and treatment of postmenopausal osteoporosis.

► Learn how landmark trials and analyses focusing on BMD, bisphosphonate therapy, predictive risk, and fracture reduction should guide clinical management of patients with osteoporosis.

As a result of this session, physicians will be able to:As a result of this session, physicians will be able to:

►► Learn evidenceLearn evidence--based approaches for reducing progression of based approaches for reducing progression of osteoporosis, and reducing risk of fracture complications based osteoporosis, and reducing risk of fracture complications based on on finding reported in the latest clinical research.finding reported in the latest clinical research.

►► Learn how, based on research and evidence, to select safe and efLearn how, based on research and evidence, to select safe and effective fective pharmacotherapy for prevention and treatment of postmenopausal pharmacotherapy for prevention and treatment of postmenopausal osteoporosis.osteoporosis.

►► Learn how landmark trials and analyses focusing on BMD, Learn how landmark trials and analyses focusing on BMD, bisphosphonatebisphosphonate therapy, predictive risk, and fracture reduction should therapy, predictive risk, and fracture reduction should guide clinical management of patients with osteoporosis.guide clinical management of patients with osteoporosis.

Program FacultyProgram Faculty

Program ChairmanProgram ChairmanClifford J. Rosen, MDClifford J. Rosen, MDPast President, ASBMRPast President, ASBMRClinical Professor of NutritionClinical Professor of NutritionUniversity of MaineUniversity of MaineDirector of the Maine Center for Director of the Maine Center for OsteoporosisOsteoporosisResearch and EducationResearch and EducationSt. Joseph HospitalSt. Joseph HospitalBangor, MEBangor, ME

Distinguished FacultyDistinguished FacultyJonathan D. Adachi, MD,Jonathan D. Adachi, MD,Professor, Department of MedicineProfessor, Department of MedicineSt. JosephSt. Joseph’’s Hospitals HospitalMcMaster UniversityMcMaster UniversityHamilton, OntarioHamilton, OntarioOntario, CanadaOntario, Canada

Roberto Roberto CivitelliCivitelli, MD, MDProfessor of Medicine, Orthopedic Professor of Medicine, Orthopedic Surgery, and Cell Biology and Surgery, and Cell Biology and PhysiologyPhysiologyDirector, Clinical Research UnitDirector, Clinical Research UnitWashington University School of Washington University School of MedicineMedicineSt. Louis, MissouriSt. Louis, Missouri

Sol Epstein, MDSol Epstein, MDProfessor of Medicine and Geriatrics Professor of Medicine and Geriatrics Mount Sinai School of MedicineMount Sinai School of MedicineDirector of Osteoporosis Research Director of Osteoporosis Research

and Centerand CenterDoylestown HospitalDoylestown HospitalDoylestown, PennsylvaniaDoylestown, Pennsylvania

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Program FacultyProgram Faculty

Stuart Silverman, MDStuart Silverman, MDProfessor of MedicineProfessor of MedicineUCLA David Geffen School of MedicineUCLA David Geffen School of MedicineDepartment of RheumatologyDepartment of RheumatologyLos Angeles, CaliforniaLos Angeles, California

MoneMone ZaidiZaidi, MD, PhD, FRCP, MD, PhD, FRCPProfessor of Medicine and PhysiologyProfessor of Medicine and PhysiologyDirector, Mount Sinai Bone ProgramDirector, Mount Sinai Bone ProgramMount Sinai School of MedicineMount Sinai School of MedicineNew York, New YorkNew York, New York

Faculty DisclosuresFaculty Disclosures

Clifford J. Rosen, MDClifford J. Rosen, MDNothing to discloseNothing to disclose

Roberto Roberto CivitelliCivitelli, MD, MDGrant/Research Support: HoffmanGrant/Research Support: Hoffman--La Roche, La Roche, Procter & Gamble, EliProcter & Gamble, Eli--Lilly, AmgenLilly, AmgenConsultant: Roche, GSK, Merck, Amgen, Consultant: Roche, GSK, Merck, Amgen, Wyeth, NovartisWyeth, NovartisSpeakers Bureau: Roche, Merck, Amgen, Speakers Bureau: Roche, Merck, Amgen, NovartisNovartis

Jonathan D. Adachi, MD, FRCP(C)Jonathan D. Adachi, MD, FRCP(C)Grant/research support: Aventis, Eli Lilly and Co., GlaxoSmithKline, Merck & Co., Procter & Gamble, Novartis, NPS Allelix Corp., Roche Diagnostics, and Wyeth Pharmaceuticals; Consultant: Amgen, AstraZeneca, Aventis, Eli Lilly and Co., GlaxoSmithKline, Merck & Co., Procter & Gamble, Novartis, and Roche Diagnostics.

Sol Epstein, MDSol Epstein, MDGrant/Research Support: Roche, Merck, Grant/Research Support: Roche, Merck, NPS, Amgen NPS, Amgen Consultant: Roche, Merck, NPS Consultant: Roche, Merck, NPS Speakers Bureau: Roche, MerckSpeakers Bureau: Roche, Merck

Stuart Silverman, MDStuart Silverman, MDGrant/Research Support: Lilly, Merck, Grant/Research Support: Lilly, Merck, Novartis, Wyeth, P&G, Roche Novartis, Wyeth, P&G, Roche Consultant: Amgen, Roche/GSK, Merck, Consultant: Amgen, Roche/GSK, Merck, Wyeth, Lilly, Novartis Wyeth, Lilly, Novartis Advisory Board: Amgen, Lilly, Merck, Advisory Board: Amgen, Lilly, Merck, Novartis, P&G, Wyeth Novartis, P&G, Wyeth Speakers Bureau: Lilly, Roche/GSK, Speakers Bureau: Lilly, Roche/GSK, KyphonKyphon, , Merck, Novartis, P&GMerck, Novartis, P&G

MoneMone ZaidiZaidi, MD, PhD, FRCP, MD, PhD, FRCPGrants/research support : Procter and Grants/research support : Procter and Gamble Pharmaceuticals, IRIS (Paris) and Gamble Pharmaceuticals, IRIS (Paris) and GenzymeGenzyme CorporationCorporationSpeaker's Bureau: Alliance for Better Bone Speaker's Bureau: Alliance for Better Bone Health, Procter and Gamble and Health, Procter and Gamble and SanofiSanofi--Aventis Aventis Pharmaceuticals,NovartisPharmaceuticals,Novartis, Merck, , Merck, Roche, GlaxoSmithKlineRoche, GlaxoSmithKline

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Online CME Focused on Online CME Focused on Osteoporosis and Bone DiseaseOsteoporosis and Bone Disease

Online CME and Clinical UpdatesOsteoporosis WebCASTs, HealthWRAPs, Guidelines and Resources:

ClinicalWebcasts.com

MedicineCAST.net

OsteoporosisCAST.com

Online CME and Clinical UpdatesOnline CME and Clinical UpdatesOsteoporosis Osteoporosis WebCASTsWebCASTs, , HealthWRAPsHealthWRAPs, , Guidelines and Resources:Guidelines and Resources:

ClinicalWebcasts.comClinicalWebcasts.com

MedicineCAST.netMedicineCAST.net

OsteoporosisCAST.comOsteoporosisCAST.com

Additional Online CMEAdditional Online CME

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Critical Challenges and LandmarkCritical Challenges and LandmarkAdvances in OsteoporosisAdvances in Osteoporosis

Translating Science, Guidelines, and Clinical Trials Translating Science, Guidelines, and Clinical Trials to Specialty Practice for Bone Diseaseto Specialty Practice for Bone Disease

Clifford J. Rosen, MDClifford J. Rosen, MDProgram ChairmanProgram Chairman

Past President, ASBMRPast President, ASBMRClinical Professor of NutritionClinical Professor of Nutrition

University of MaineUniversity of MaineDirector of the Maine Center for OsteoporosisDirector of the Maine Center for Osteoporosis

Research and EducationResearch and EducationSt. Joseph HospitalSt. Joseph Hospital

Bangor, MaineBangor, Maine

Introduction and ChairmanIntroduction and Chairman’’s Overviews Overview

Remodeling: CellRemodeling: Cell--Cell Interactions in theCell Interactions in theBone Marrow MicroenvironmentBone Marrow Microenvironment

HSC NICHE

SSC NICHE

N-CADHERIN CADHERIN-11 β-CATENIN

ADIPOCYTES HEMATOPOIETIC CELLS

CADHERIN-6 RANK-RANKL

OSTEOBLAST COMMITMENT

DIFFERENTIATED OSTEOBLASTS

OSTEOCLASTOGENESIS

OSTEOCLAST

Mbalaviele et al. Mbalaviele et al. J Bone Miner ResJ Bone Miner Res 20062006

7

Osteoblast DifferentiationOsteoblast Differentiation

StromalStem Cell

Commitment

Proliferation and

Differentiation

Adipocyte

Runx2

Matrix ProductionMineralization

Runx2c-FosΔfos-D

Runx2Dlx5Osx

HoxaMsx2

PPARγ

Osteocyte

Lining cell

Apoptosis

Leptin/β-AR

Leptin

B6 – 4 months B6- 12 months

Marrow Fat Increases With AgeWhile BMD Declines

1 month 3months 6 months 20 months

PPARγ2

Cho B

Adult Old

8

The Wnt/The Wnt/ββ--catenin Signaling Systemcatenin Signaling System

Krishnan et al., Krishnan et al., J J ClinClin InvestInvest 116116--1202; 20061202; 2006

Bone Remodeling Bone Remodeling A Central Control MechanismA Central Control Mechanism

HSC NICHE

SSC NICHE

N-CADHERIN CADHERIN-11 β-CATENIN

ADIPOCYTES HEMATOPOIETIC CELLS

CADHERIN-6 RANK-RANKL

OSTEOBLAST COMMITMENT

DIFFERENTIATED OSTEOBLASTS

OSTEOCLASTOGENESIS

OSTEOCLAST

Mbalaviele et al. Mbalaviele et al. J Bone Miner ResJ Bone Miner Res 20062006

9

Central Control of Bone FormationCentral Control of Bone Formation

Fat Osteoblast

Leptin

=Thyroid Axis=HPA Axis=Reproductive Axis

Hypothalamusβ-adrenergic

neurons

Blood-brain barrier

+

+

-β2-AR

Y2NPY

?

KhoslaKhosla, , EndocrinolEndocrinol. 149:4161, 2002. 149:4161, 2002Balanced Bone Formation

High caloric intake / Increased fat stores

pinealretinaSCN-Hypothalamus

SCGSympatheticCervicalganglia

Retinal-hypothalamic

tract

melatonin

Neuro-endocrine

Neuro

circadianPhoto period

circannual

Pituitary/Pars Tuberalis

Target Clock GenesPer1,2; Cry1,2, others

?

Light

Master oscillator

Rhythms

PeripheralCalender cells

Rhythm generator

Bone marrowStromal cells, OBs

?Prolactin

Leptin

Time Keeping: Circadian and Circannual

The PNS

10

Therapeutic StrategiesTherapeutic Strategies

Bone marrow precursorsBone marrow precursors

OsteoblastsOsteoblastsOsteoclastOsteoclast

Lining cellsLining cells

Stimulators of Stimulators of Bone FormationBone Formation

FluorideFluoridePTH analogsPTH analogsSrSr RanelateRanelate (?)(?)

Inhibitors ofInhibitors ofBone ResorptionBone Resorption

Estrogen, Estrogen, SERMsSERMs,,BisphosphonatesBisphosphonatesCalcitoninCalcitonin

Inhibitors ofRANKL

Cathepsin K

BisphosphonatesBisphosphonatesMechanisms of ActionMechanisms of Action

apoptosisApoptosis

loss of resorptivefunction

Loss of resorptivefunction

intracellular uptake ofbisphosphonate by osteoclasts

during resorption

Intracellular uptake ofbisphosphonate by osteoclasts

during resorption

BonePCP PCPPCP PCP

PCP

PCP

Hughes et al 1995Selander et al 1996Hughes et al 1995

Selander et al 1996

Flanagan et al 1991Sato et al 1991

Flanagan et al 1991Sato et al 1991

PCP PCP

PCPBone

PCP PCPPCP PCP

PCP

PCP

BonePCP PCPPCP PCP

PCPPCP

PCP

11

Sol Epstein, MDSol Epstein, MDProfessor of Medicine and Geriatrics Mount Sinai School of MedicProfessor of Medicine and Geriatrics Mount Sinai School of Medicineine

Director of Osteoporosis Research and CenterDirector of Osteoporosis Research and CenterDoylestown HospitalDoylestown Hospital

Doylestown, PennsylvaniaDoylestown, Pennsylvania

Critical Challenges and Landmark Critical Challenges and Landmark Developments in OsteoporosisDevelopments in Osteoporosis

Advancing Research, Science and Clinical Advancing Research, Science and Clinical Strategies for Osteoporosis: The Evolving Strategies for Osteoporosis: The Evolving Landscape of Basic and Clinical Research Landscape of Basic and Clinical Research

A Year 2007 ScienceA Year 2007 Science--toto--Strategy UpdateStrategy Update

Two Giant Leaps for OsteoporosisTwo Giant Leaps for Osteoporosis

DXA in the 1980DXA in the 1980’’ssand and

NN--BisphosphonatesBisphosphonates in the 1990in the 1990’’ss

12

BMDBMD Bone Bone QualityQuality

TurnoverTurnover

Bone Bone strengthstrength

BMD = bone mineral density

Determinants of Bone StrengthDeterminants of Bone Strength

What Can We Learn From DXA? What Can We Learn From DXA?

►►DXA StrengthsDXA StrengthsBone sizeBone sizeBone volume per tissue volumeBone volume per tissue volumeAmount of mineralization in bone and surrounding Amount of mineralization in bone and surrounding tissuestissues

►►DXA LimitationsDXA LimitationsTrabecularTrabecular connectivity and numberconnectivity and numberCollagen qualityCollagen qualityRepair of microscopic damage (e.g. Repair of microscopic damage (e.g. microcracksmicrocracks))Bone shapeBone shape

13

Antifracture Efficacy Was Associated Antifracture Efficacy Was Associated with Increases in BMDwith Increases in BMD

►► In a metaIn a meta--analysis of 18 trials in women with postmenopausal osteoporosisanalysis of 18 trials in women with postmenopausal osteoporosisLarger increases in BMD at both the lumbar spine and hip were asLarger increases in BMD at both the lumbar spine and hip were associated with sociated with significantly greater risk reductions in nonvertebral fracturessignificantly greater risk reductions in nonvertebral fracturesAgents that produced large increases in BMD were the most effectAgents that produced large increases in BMD were the most effective in ive in reducing the risk of nonvertebral and vertebral fracturesreducing the risk of nonvertebral and vertebral fractures

Change in Spine BMDat 1 Year (vs Placebo), %

Change in Hip BMDat 1 Year (vs Placebo), %

Rel

ativ

e R

isk

of

Non

vert

ebra

l Fra

ctur

e

Rel

ativ

e R

isk

of

Non

vert

ebra

l Fra

ctur

e

39%Risk

Reduction

46%Risk

Reduction

Dashed line = no effect Dashed line = no effect

Patients were treated with bisphosphonates or bisphosphonates and hormone therapy.Ibandronate was not included in this analysis.

Adapted from Hochberg MC et al. Adapted from Hochberg MC et al. J J ClinClin EndocrinolEndocrinol MetabMetab. 2002;87:1586. 2002;87:1586--15921592

0

0.4

0.8

1.2

1.6

-1 0 1 2 3 4 5 6 7 8 90

0.4

0.8

1.2

1.6

-1 0 1 2 3 4 5 6 7 8 9

Relationship Between Relationship Between IbandronateIbandronate--induced induced Change in BMD and Fracture Risk*Change in BMD and Fracture Risk*

PlaceboOral daily and intermittent ibandronate

17

15

13

11

9

7

5

3

Frac

ture

rate

per

100

pat

ient

s(v

erte

bral

frac

ture

s)

–4 –3 –2 –1 0 1 2 3 4 5 6 7 8 9BMD change (%)

*Results from individual patients in a single study

WasnichWasnich R, et al. R, et al. OsteoporosOsteoporos IntInt 2003;14(Suppl. 7):S76 (Abstract P272)2003;14(Suppl. 7):S76 (Abstract P272)

14

Other Methods of Bone ImagingOther Methods of Bone Imaging

►► Quantitative computed tomography Quantitative computed tomography —— Extreme Extreme uCTuCT

►► Qualitative ultrasoundQualitative ultrasound

►► Hip Structure AnalysisHip Structure Analysis

►► Magnetic resonance imagingMagnetic resonance imaging

BMD Bone Quality

Turnover

Bone strength

BMD = bone mineral density

Determinants of Bone StrengthDeterminants of Bone Strength

15

Consequences of Increased Consequences of Increased Bone RemodelingBone Remodeling

Consequences include decreased BMD, cortical bone thinning, and increased cortical porosity

and trabecular thinning, which may lead to increased bone fragility.

Relationship Between 1Relationship Between 1--Year Reduction in BSAP During Year Reduction in BSAP During Alendronate Treatment and Fracture Incidence: Alendronate Treatment and Fracture Incidence:

Fracture Intervention TrialFracture Intervention Trial

-100 -50 0 50 100

0.0

0.05

0.10

0.15

-100 -50 0 50 100-100 -50 0 50 100

0.0

0.05

0.02

0.03

0.0

0.05

0.10

0.15

1-Year Change in BSAP, % 1-Year Change in BSAP, % 1-Year Change in BSAP, %

Prob

abilit

y of

Ver

tebr

al F

ract

ure

Prob

abilit

y of

Non

verte

bral

Fra

ctur

e

Prob

abilit

y of

Hip

Fra

ctur

e

Vertebral Fracture Risk Nonvertebral Fracture Risk Hip Fracture Risk

Reprinted from Reprinted from CurrCurr Med Res Med Res OpinOpin, Vol. 21, , Vol. 21, Miller PD et al, How useful are measures Miller PD et al, How useful are measures of BMD and bone turnover? 545of BMD and bone turnover? 545––553, 2005, with permission from 553, 2005, with permission from LibraPharmLibraPharm

BSAP = bone-specific alkaline phosphatase

16

Relationship Between Change In Urinary CTX Relationship Between Change In Urinary CTX After After IbandronateIbandronate Treatment And Fracture RateTreatment And Fracture Rate

18

16

14

12

10

8

6

4

2

0

Frac

ture

rate

(pat

ient

s)

–90 –80 –70 –60 –50 –40 –30 –20 –10 0 10 20Urinary CTX change (%)

Placebo 2.5mg

EULAR Congress Barcelona, June 14th 2007

Predicting Fracture Risk:Predicting Fracture Risk:Combining Bone Turnover And BMD Combining Bone Turnover And BMD

>mean + 2 SD of premenopausal range†Defined according to WHO criteria (T-score ≤–2.5)

High rate ofbone resorption*

Low hip BMD†

High rate ofbone resorption +

low hip BMD

0 1 2 3 4 5Risk of hip fracture (odds ratio)

GarneroGarnero P, et al. J Bone Miner Res 1996;11:1531P, et al. J Bone Miner Res 1996;11:1531––88

17

Desired Effects of Desired Effects of BisphosphonateBisphosphonateTreatment Treatment —— ObjectivesObjectives

Desired Effects of Desired Effects of BisphosphonateBisphosphonate TreatmentTreatmentDecreased bone turnover rateDecreased bone turnover rateImprovements in structural Improvements in structural properties of the hip that reflect properties of the hip that reflect bone strengthbone strength•• Decreased cortical porosityDecreased cortical porosity•• Increased cortical thicknessIncreased cortical thickness•• Maintain /increase Maintain /increase periostealperiosteal cellscells

Decreased risk of hip fractureDecreased risk of hip fracture

SzulcSzulc P et al. P et al. OsteoporosOsteoporos Int.Int. 20052005

Evolution of NEvolution of N--BisphosphonateBisphosphonate DosingDosing

►► Daily Daily alendronatealendronate and and risedronaterisedronate mid to mid to late 1990s (FIT and VERT,HIP trials)late 1990s (FIT and VERT,HIP trials)

►► Weekly Weekly alendronatealendronate and and risedronaterisedronate early early 20002000’’ss

►► Monthly Monthly ibandronateibandronate late 2005 (proposed late 2005 (proposed Oct 2000)Oct 2000)-- BONE trialBONE trial

►► Annual Annual zoledroniczoledronic acid August 2007 acid August 2007 (HORIZON(HORIZON--PFT trial)PFT trial)

18

Bisphosphonates: Potency to Inhibit Bisphosphonates: Potency to Inhibit Bone ResorptionBone Resorption

Bisphosphonate R1 R2 Potency

Etidronate OH CH3 ~1 Clodronate Cl Cl ~10 Tiludronate H CH2-S-phenyl-Cl ~10 Pamidronate OH CH2CH2 NH2 ~100 Neridronate OH (CH2)5 NH 2 ~100 Alendronate OH (CH2)3 NH 2 >100-<1000 EB-1053 OH CH2-1-pyrrolidinyl >100-<1000 Incadronate H N-(cyclo-heptyl) >100-<1000 Olpadronate OH CH2CH2 N(CH3)2 >100-<1000 Risedronate OH CH2-3-pyridine >1000-<10 000 Ibandronate OH CH2CH2 N(CH3) (pentyl) >1000-<10 000 Minodronate OH CH2-2-imidazo-pyridinyl >10 000 Zoledronate OH CH2-imidazole >10 000

Bauss (2001), modified after Bauss (2001), modified after FleischFleisch (2000) and Russell & Rogers (1999)(2000) and Russell & Rogers (1999)

R1

R2

CO O

OH

P

O

HO

P

O

Ibandronate: Summary of Ibandronate: Summary of Total Dose ConceptTotal Dose Concept

ugug/kg/day /kg/day BaussBauss & Russell, Osteoporosis Int. 15:423& Russell, Osteoporosis Int. 15:423--433 (2004) 433 (2004)

a: OVX Rata: OVX Rat

b: OVX Ratb: OVX Rat

c: OHX Dogc: OHX Dog0

5

10

15

20

25

30

Sham OVX OVXSolvent 1 2.75 4.4 5.5

ug/kg/day

Tibia, proximal Tibia, proximal metaphysesmetaphysesaa

0

5

10

15

20

0

5

10

15

20

25

30

Sham OVX OVX Sham OVX OVXSolvent 1 25 Solvent 14 65

Cont Cont intint intint intint1/2 1/4 1/61/2 1/4 1/6wks wks wkswks wks wks

Cont Cont intint1/251/25daysdays

Cont Cont intint2/112/11

weeksweeks

Tibia, proximal Tibia, proximal metaphysesmetaphyses IllacIllac CrestCrestbb

cc

19

Ibandronate: Summary of TotalIbandronate: Summary of TotalDose Concept Dose Concept

In all doses, the concentration in vertebrae is significantly higher than those in tibiae (p≤0.001, Mann-Whitney rank sum test, one-tailed)

0 20 40 60 80 100 120 140 160

8

7

6

5

4

3

2

1

0

pg/kg i.v

ng/m

g dr

y w

eigh

tConcentration (ng/mg dry weight) of BM 21.0955 in Bones from OVX Cynomologus Monkeys treated i.v. with BM 21.0955 (once

every 30 days x 16) (ClinTrials BioRes project No. 87248)

Total Left Tibia Total Lumbar Vertebrae L6

Mode Of Mode Of BisphosphonateBisphosphonate Administration Administration And Suppression Of Bone And Suppression Of Bone ResorptionResorption

dailyweekly

intermittent

intermittent

20

FACT StudyFACT StudyAlendronateAlendronate Provided Greater Increases in BMD thanProvided Greater Increases in BMD than

RisedronateRisedronate at 12 Monthsat 12 Months

0

1

2

3

4

Hip trochanter Lumbar spine Total hip Femoral neck

Cha

nge

from

bas

elin

e in

BM

D (%

) Alendronate 70mg once-weeklyRisedronate 35mg once-weekly

1.4%*1.2%*

1.1%*

0.7%*

*P < 0.001

Sebba AI et al. Sebba AI et al. Curr Med Res OpinCurr Med Res Opin. 2004;20:2031. 2004;20:2031––20412041

0

2

4

6

8

Lumbar Spine Total Hip Trochanter Femoral Neck*

Ibandronate 150 mg Once-Monthly

Alendronate 70 mg Once-Weekly

5.1

5.8

2.9 3.0

2.1 2.3

4.2 4.2

MOTION TrialMOTION Trial——IbandronateIbandronate Proven as Clinically Proven as Clinically Effective as Effective as AlendronateAlendronate to Increase BMDto Increase BMD

Clinical effectiveness was defined by a noninferiority margin, which was predefined as 1.41% for lumbar spine and 0.87% for total hip

*Post-hoc analysis

Mea

n R

elat

ive

Cha

nge

in B

MD

Fro

m

Bas

elin

e, %

[95%

Con

fiden

ce In

terv

al]

Data on file (Reference #161-205), Hoffmann-La Roche Inc., Nutley, NJ 07110

21

HORIZON TrialHORIZON Trial——Relative Risk of Fracture IncidenceRelative Risk of Fracture Incidence

Black DM, et al. Black DM, et al. NEJMNEJM 356;18: 1809356;18: 1809--2222

Relative RiskRelative RiskZoledronicZoledronic or Hazard Ratioor Hazard Ratio PP

Type of Fracture Type of Fracture PlaceboPlacebo AcidAcid (95% CI)(95% CI)†† ValueValueno. of patients (%)no. of patients (%)

Primary end pointsPrimary end pointsMorphometricMorphometric vertebralvertebral

fracture (stratum 1) fracture (stratum 1) 310 (10.9) 310 (10.9) 92 (3.3) 92 (3.3) 0.30 (0.240.30 (0.24––0.38) 0.38) <0.001<0.001Hip fracture Hip fracture 88 (2.5) 88 (2.5) 52 (1.4) 52 (1.4) 0.59 (0.420.59 (0.42––0.83) 0.83) 0.0020.002

Secondary end pointsSecondary end pointsNonvertebralNonvertebral fracture fracture 388 (10.7) 388 (10.7) 292 (8.0) 292 (8.0) 0.75 (0.640.75 (0.64––0.87) 0.87) <0.001<0.001Any clinical fracture Any clinical fracture 456 (12.8) 456 (12.8) 308 (8.4) 308 (8.4) 0.67 (0.580.67 (0.58––0.77) 0.77) <0.001<0.001

Clinical vertebral Clinical vertebral fracture fracture 84 (2.6) 84 (2.6) 19 (0.5) 19 (0.5) 0.23 (0.140.23 (0.14––0.37) 0.37) <0.001<0.001

Multiple (Multiple (≥≥2) 2) morphometricmorphometric vertebral vertebral fractures (stratum 1)fractures (stratum 1) 66 (2.3) 66 (2.3) 7 (0.2) 7 (0.2) 0.11 (0.050.11 (0.05––0.23) 0.23) <0.001<0.001

BMD Bone Quality

Turnover

Bone strength

BMD = bone mineral density

Determinants of Bone StrengthDeterminants of Bone Strength

22

The Long Term Effects of The Long Term Effects of BisphosphonatesBisphosphonates

Bone Quality and Sustained Bone Quality and Sustained Fracture ReductionFracture Reduction

Duration of Effect

FLEX FLEX —— Lumbar Spine BMD Lumbar Spine BMD Changes From FIT Baseline (Changes From FIT Baseline (mITTmITT))

0

2

4

6

8

10

12

14

16

0 12 24 36 48 60 72 84 96 108 120

Mean Percent Change (± SE) in Lumbar Spine BMDFrom Original FIT Baseline

P<0.001 ALN/ALN vs ALN/PBO

Mea

n Pe

rcen

t Cha

nge

Mea

n Pe

rcen

t Cha

nge

MonthMonth

= ALN/Placebo= ALN/Placebo= ALN/ALN (Pooled 5 mg and 10 mg groups)= ALN/ALN (Pooled 5 mg and 10 mg groups)

Black DM, et al. NEJM 356;18:1809-22

23

FLEX FLEX —— Total Hip BMD Total Hip BMD Changes From FIT Baseline (Changes From FIT Baseline (mITTmITT))

–1

0

1

2

3

4

5

0 12 24 36 48 60 72 84 96 108 120

Mea

n Pe

rcen

t Cha

nge

Mea

n Pe

rcen

t Cha

nge

MonthMonthP<0.001 ALN/ALN vs ALN/PBO

= ALN/Placebo= ALN/Placebo= ALN/ALN (Pooled 5 mg and 10 mg groups)= ALN/ALN (Pooled 5 mg and 10 mg groups)

Mean Percent Change (± SE) in Total Spine BMDFrom Original FIT Baseline

Black DM, et al. NEJM 356;18:1809-22

Bone Microarchitecture AfterBone Microarchitecture After10 Years of Alendronate Treatment 10 Years of Alendronate Treatment ——

The FLEX StudyThe FLEX Study

11Creighton University; Creighton University; 22University of Minnesota; University of Minnesota; 33Merck & Co., Inc.;Merck & Co., Inc.;44Ludwig Boltzmann Institute of Ludwig Boltzmann Institute of OsteologyOsteology; ; 55Max Planck Institute of Colloids and InterfacesMax Planck Institute of Colloids and Interfaces

Long Term Effects of Long Term Effects of BisphosphonateBisphosphonate TherapyTherapy

24

En FaceEn Face ObliqueOblique On Edge On Edge

ALN/10 mg ALN (group average BV/TV 16.6%)ALN/10 mg ALN (group average BV/TV 16.6%)

ALN/Placebo (group average BV/TV 16.5%)ALN/Placebo (group average BV/TV 16.5%)

Representative 3D Samples from Placebo and ALN Biopsy Specimens

General ResultsGeneral Results

►► Normal Bone QualityNormal Bone Quality

No quantitative differencesNo quantitative differencesbetween groupsbetween groups

Dual labeling in all specimensDual labeling in all specimens

Normal trabecular and corticalNormal trabecular and corticalbone histologybone histology

Normal bone mineralizationNormal bone mineralization

25

Fig. 4. The 3D Synchrotron images provide visual illustrations of changes in low-mineralized bone fractions (green areas) as an indicator of the remodeling at trabecular surfaces in a paired biopsy of one patient at baseline and after 5 years of risedronate treatment. Also shown for comparison is an image of a biopsy from a premenopausal woman. The image volume is 8.6 mm3 in all cases.

Borah et al, Bone (2006) 39:345Borah et al, Bone (2006) 39:345--5252

Age Is An Independent Age Is An Independent Risk Factor For FractureRisk Factor For Fracture

Aging bone demonstrates . . .Aging bone demonstrates . . .

Increasing levels of Increasing levels of osteoclastogenesisosteoclastogenesisIncreasing bone marrow Increasing bone marrow adipogenesisadipogenesisDecreasing Decreasing osteoblastogenesisosteoblastogenesisDecreased Decreased osteocyteosteocyte densitydensityPremature Premature osteocyteosteocyte apoptosisapoptosis

26

OsteocyteOsteocyte FunctionFunction

►► Produces Produces SclerostinSclerostin —— A product of the A product of the SOST geneSOST gene

►► Produces FG 23 Produces FG 23 —— regulates Phosphate regulates Phosphate metabolism metabolism

►► Dentin Matrix Protein stimulates FGDentin Matrix Protein stimulates FG--23 23

Age, Age, OsteocyteOsteocyte Viability, and Viability, and Increased Fracture RiskIncreased Fracture Risk

Age can be more critical in determining fracture Age can be more critical in determining fracture risk than bone mineral density (BMD)risk than bone mineral density (BMD)

MicrodamageMicrodamage in aged bones results fromin aged bones results from•• Decline in Decline in osteocyteosteocyte densitydensity•• Osteocyte decrease in lacunaeOsteocyte decrease in lacunae•• Premature Premature osteocyteosteocyte deathdeath

Osteocyte death is also linked with Osteocyte death is also linked with •• Hip fractures in the elderly Hip fractures in the elderly •• GlucocorticoidGlucocorticoid--induced hip induced hip osteonecrosisosteonecrosis•• Low Low OsteocyteOsteocyte density promotes increased remodelingdensity promotes increased remodeling•• African Americans have higher African Americans have higher osteocyteosteocyte density and density and

increased BMD and lower rates of stress fracturesincreased BMD and lower rates of stress fractures

Manolagas SC. BoneKEY-Osteovision. 2006;3:5-14.; Frank JD, et al. Bone. 2002;30:201-206; Vashishth D, et al.Bone. 2000;26:375-380; Qiu S, et al. Bone. 2002;31:313-318; Qiu S, et al. J Bone Miner Res. 2003;18:1657-1663; Dunstan CR, et al. Calcif Tissue Int. 1990;47:270-275

27

Cortical Porosity IncreasesCortical Porosity IncreasesSignificantly With AgeSignificantly With Age

0

2

4

6

8

10

12

14

16

18

10 to 1920 to 2930 to 3940 to 4950 to 5960 to 6970 to 7980 to 99

Cor

tical

Por

osity

(%)

Age (Years)

Females

Relationship between age and increasing porosity, P<0.001

BoussonBousson V et al. V et al. Radiology.Radiology. 2000;217:1792000;217:179––187187

AGING And Diversion From AGING And Diversion From OsteoblastogenesisOsteoblastogenesis To To AdipogenesisAdipogenesis

Duque G. Duque G. BoneKEyBoneKEy--OsteovisionOsteovision 2007;4:1292007;4:129––4040

IGF-1PDGFEGFTGF-αHGFFGF-2Thrombin

OsteoblastsStromal cells

Cbfa-1

PPARγ2CEBPα

Lamin A/C

Oxidative stressAGING

MSCs

28

Hip Cortical Bone PropertiesHip Cortical Bone Properties

Examining the HipKey Determinants of Fracture

Why Does Cortical Bone Respond to Treatment Why Does Cortical Bone Respond to Treatment Differently From Differently From CancellousCancellous Bone? Bone?

►► Size and depth of BMU in cortical versus Size and depth of BMU in cortical versus trabeculartrabecular bonebone►► Remodeling by periosteal apposition to maintain strengthRemodeling by periosteal apposition to maintain strength►► Genetically linked site specificity, (e.g. vitamin D, Genetically linked site specificity, (e.g. vitamin D,

ProcollagenProcollagen type 1 polymorphism)type 1 polymorphism)►► Sex steroid actions very different from trabecular boneSex steroid actions very different from trabecular bone►► Muscle strain, mechanical loads, vascular and nerve supply, Muscle strain, mechanical loads, vascular and nerve supply,

local factors (e.g. IGFlocal factors (e.g. IGF--1)1)►► LeptinLeptin deficiency causes cortical but not deficiency causes cortical but not trabeculartrabecular

bone lossbone loss►► AccumalationAccumalation of of glycosalatedglycosalated end productsend products

disturbing collagendisturbing collagen►► Does this impact drug pharmacology?Does this impact drug pharmacology?

BMU = basic multicellular units

29

AnabolicsAnabolics and Cortical Boneand Cortical Bone

The Role of Anabolics in Osteoporosis Therapy

B3D-MC-GHACUCSF - Jiang

Patient 1124

Baseline Follow-up

Female, age 65Duration of therapy: 637 days (approx 21 mos)

BMD Change⇒Lumbar Spine: +7.4% (group mean = 9.7 ± 7.4%)⇒Total Hip: +5.2% (group mean = 2.6 ± 4.9%)

Effect of Effect of TeriparatideTeriparatide 20mcg20mcg

Jiang Y et al. Jiang Y et al. J Bone Miner ResJ Bone Miner Res. 2003;18:1932. 2003;18:1932––19411941

30

Ma L, et al. Ma L, et al. J Bone Miner ResJ Bone Miner Res. 2006;21:855. 2006;21:855--864864

CancellousCancellous Bone and Bone and PeriosteumPeriosteum

Placebon = 17

0

5

10

15

20

25

30

Teriparatiden = 25

P = 0.012

Jiang Y et al. Jiang Y et al. J Bone Miner ResJ Bone Miner Res. 2003;18:1932. 2003;18:1932––19411941

% c

hang

e fro

m b

asel

ine

med

ian

(±S

D b

oots

trap)

3D3D--CT Scans of Iliac Crest BiopsiesCT Scans of Iliac Crest Biopsies% Change in Cortical Bone Thickness% Change in Cortical Bone Thickness

31

Strontium MetalStrontium Metal

Mimics calcium

Cortical Bone Effects Cortical Bone Effects of RANKL Inhibitionof RANKL Inhibition

Evolving StrategiesEvolving Strategies

32

15

20

25

30

Veh

*

Kostenuik et al. Kostenuik et al. Osteoporosis InternationalOsteoporosis International. 2005;16(suppl 3):S68. 2005;16(suppl 3):S68Reviewed in Kostenuik. Reviewed in Kostenuik. Curr Opin Pharmacol. Curr Opin Pharmacol. 2005;5:12005;5:1

RANKL Inhibition Increases Cortical ThicknessRANKL Inhibition Increases Cortical Thicknessin the Radius of Female Monkeysin the Radius of Female Monkeys

Periosteal Circumference Expansion

0

5

10

15

20

Veh OPG0

0.51.01.52.02.53.03.5

Veh OPG

Cor

tical

th

ickn

ess

(mm

)

Perio

stea

lci

rcum

fere

nce

(mm

)

Endo

stea

lci

rcum

fere

nce

(mm

)*

*

*Significantly different from vehicle, P<0.05

OPG

Effect of SixEffect of Six--Month Regimen Month Regimen of of DenosumabDenosumab on BMDon BMD

McClung MR, et al. McClung MR, et al. NEJMNEJM 354;8:821354;8:821--3131

Total Hip BMD

-2

-1

0

1

2

3

4

Placebo 6 mg 14 mg 30 mg 70 mg

Cha

nge

from

bas

elin

e (%

)

0 1 2 3 4 5 6 7 8 9 10 11 12

Months

33

Future Needs and OpportunitiesFuture Needs and Opportunities

►► Identifying patients at risk Identifying patients at risk ►► Clarifying criteria for treatment (e.g. Clarifying criteria for treatment (e.g.

osteopenicosteopenic women)women)►► Gene polymorphism and markers for early Gene polymorphism and markers for early

detectiondetection►► Reproducible and precise Reproducible and precise BTMBTM’’ss reflecting reflecting

stages of bone metabolismstages of bone metabolism►► Imaging techniques to reveal bone quality Imaging techniques to reveal bone quality

propertiesproperties►► Enhancing long term usage of drugsEnhancing long term usage of drugs►► Be aware of associated public health Be aware of associated public health

diseases and fracture (e.g. diabetes and diseases and fracture (e.g. diabetes and cardiovascular disease)cardiovascular disease)

Drug Development (Have To Target Drug Development (Have To Target Cortical And Cortical And PeriostealPeriosteal Sites)Sites)

►► Genes involved in the Genes involved in the WntWnt signallingsignalling pathwaypathway(e.g. Lrp5, (e.g. Lrp5, SclerostinSclerostin))

►► BMPBMP’’ss and HIF factorsand HIF factors►► RanklRankl ––RankRank--OPG pathway (e.g. anti OPG pathway (e.g. anti RanklRankl vaccines)vaccines)►► CalcilyticsCalcilytics►► New PTH or New PTH or PTHrPPTHrP analogsanalogs►► Vitamin D analogsVitamin D analogs►► ProstaglandinsProstaglandins►► IGFIGF’’ss►► StatinsStatins►► Cat K inhibitorsCat K inhibitors►► SermsSerms and and SarmsSarms►► Neuroendocrine,GITNeuroendocrine,GIT, hypothalamic and Pituitary hormones, hypothalamic and Pituitary hormones►► VaccinesVaccines

34

Scientific Advances in Bone Cell Regulation

Roberto Civitelli, M.D.Roberto Civitelli, M.D.Division of Bone and Mineral DiseasesDivision of Bone and Mineral Diseases

Washington University School of MedicineWashington University School of MedicineSt. Louis, Missouri, USASt. Louis, Missouri, USA

Systemic and Local Signals Regulating Systemic and Local Signals Regulating Skeletal HomeostasisSkeletal Homeostasis——Implications for Implications for Therapy in OsteoporosisTherapy in Osteoporosis

Outline

•• Current therapeutic strategiesCurrent therapeutic strategies•• NeuroendocrineNeuroendocrine regulation of bone regulation of bone

formation formation –– leptinleptin and and ββ2 receptors2 receptors•• High bone mass syndromesHigh bone mass syndromes•• Wnt signaling as an anabolic targetWnt signaling as an anabolic target•• CellCell--cell interactions in the bone cell interactions in the bone

microenvironmentmicroenvironment•• ConclusionsConclusions

35

Therapeutic Strategies

Bone marrow precursorsBone marrow precursors

OsteoblastsOsteoblastsOsteoclastOsteoclast

Lining cellsLining cells

Stimulators of Stimulators of Bone FormationBone Formation

FluorideFluoridePTH analogsPTH analogsSrSr RanelateRanelate (?)(?)

Inhibitors ofInhibitors ofBone Bone ResorptionResorption

Estrogen, Estrogen, SERMsSERMsBisphosphonatesBisphosphonatesCalcitoninCalcitonin

Inhibitors ofRANKL

Cathepsin K

Osteoblast Differentiation

StromalStem Cell

Commitment

Proliferation and

Differentiation

Adipocyte

Runx2

Matrix ProductionMineralization

Runx2c-FosΔfos-D

Runx2Dlx5Osx

HoxaMsx2

PPARγ

Osteocyte

Lining cell

Apoptosis

BoneMorphogenetic

Proteins

Insulin-LikeGrowth Factors

36

Anabolic Action of PTH

StromalStem Cell

Commitment

Proliferation and

Differentiation

Adipocyte

Runx2

Matrix ProductionMineralization

Runx2c-FosΔfos-D

Runx2Dlx5Osx

HoxaMsx2

PPARγ

Osteocyte

Lining cell

Apoptosis

X

PTH

Limitations of PTH as Anabolic Agent

•• Daily subcutaneous injectionsDaily subcutaneous injections•• Lifetime limit of 2 years of therapyLifetime limit of 2 years of therapy•• Unclear effect on cortical boneUnclear effect on cortical bone•• CostCost

•• Orally active PTH analogsOrally active PTH analogs•• Calcium sensing receptor antagonistsCalcium sensing receptor antagonists•• PTHrPPTHrP analogsanalogs

Ongoing Research

37

Osteoblast Differentiation

StromalStem Cell

Commitment

Proliferation and

Differentiation

Adipocyte

Runx2

Matrix ProductionMineralization

Runx2c-FosΔfos-D

Runx2Dlx5Osx

HoxaMsx2

PPARγ

Osteocyte

Lining cell

Apoptosis

Leptin/β-AR

Leptin

Leptin in Bone Remodeling

•• Positive (but weak) correlation between Positive (but weak) correlation between serum serum leptinleptin and bone densityand bone density

•• LeptinLeptin administration to ratsadministration to ratsreduces ovariectomy induced bone lossreduces ovariectomy induced bone lossincreases bone mass and densityincreases bone mass and density

•• In human cell cultures, In human cell cultures, leptinleptininduces osteoblast differentiation from bone induces osteoblast differentiation from bone marrow precursors and inhibits adipogenesismarrow precursors and inhibits adipogenesisstimulates osteoblasts mineralizationstimulates osteoblasts mineralizationinhibits support of osteoclastogenesisinhibits support of osteoclastogenesis

38

High Bone Mass in LeptinDeficient or Resistant Mice

DucyDucy et al., Cell 100:197, 2000et al., Cell 100:197, 2000

Central Control of Bone Formation:The Leptin-β-adrenergic Axis

Takeda et al., Cell 111:305, 2002

Parabiosis

39

High Bone Mass in Leptin and Y2 Receptor Deficient Mice

Baldock et al., JBMR 21:1600, 2006

Central Control of Bone Formation

Fat Osteoblast

Leptin

Thyroid AxisHPA AxisReproductive Axis

Hypothalamusβ-adrenergic

neurons

Blood-brain barrier

+/-

+

-β2-AR

Y2NPY

?

40

Central Control of Bone Formation

Fat Osteoblast

Leptin

Thyroid AxisHPA AxisReproductive Axis

Hypothalamusβ-adrenergic

neurons

Blood-brain barrier

-

+

β2-AR

Y2NPY

?

KhoslaKhosla, , EndocrinolEndocrinol. 149:4161, 2002. 149:4161, 2002 Balanced Bone Formation

Caloric restriction / Reduced fat mass

Central Control of Bone Formation

Fat Osteoblast

Leptin

=Thyroid Axis=HPA Axis=Reproductive Axis

Hypothalamusβ-adrenergic

neurons

Blood-brain barrier

+

+

-β2-AR

Y2NPY

?

KhoslaKhosla, , EndocrinolEndocrinol. 149:4161, 2002. 149:4161, 2002 Balanced Bone Formation

High caloric intake / Increased fat stores

41

β-AR Antagonists for Osteoporosis?

•• Epidemiologic studies on Epidemiologic studies on ββ--blockers not blockers not consistent for fracture reductionconsistent for fracture reduction

•• Specific Specific ββ1 blockers ineffective 1 blockers ineffective (osteoblasts express (osteoblasts express ββ2 receptors)2 receptors)

•• Doses uncertainDoses uncertain•• Bone specific blockade difficultBone specific blockade difficult

New Targets for Bone Anabolism:Lessons Learned from Human Diseases

•• SclerosingSclerosing Bone DisordersBone DisordersEndosteal Hyperostosis (or Osteosclerosis) Worth typeEndosteal Hyperostosis (or Osteosclerosis) Worth typeAutosomalAutosomal Dominant Osteosclerosis, a.k.a. Dominant Osteosclerosis, a.k.a. AutosomalAutosomalDominant Dominant OsteopetrosisOsteopetrosis Type IType ISclerosteosisSclerosteosis and Van and Van BuchemBuchem DiseaseDiseaseHigh Bone Mass PhenotypeHigh Bone Mass Phenotype

•• Common phenotypic features Common phenotypic features Hyperostosis: cortical thickening of the long bones with no Hyperostosis: cortical thickening of the long bones with no alteration in external shapealteration in external shapeRemarkable resistance to fracturesRemarkable resistance to fracturesVarious degrees of thickening of the cranial vault, mandible, Various degrees of thickening of the cranial vault, mandible, maxillamaxilla

42

High Bone Mass Phenotype

Boyden et al., N. Eng. J. Med. 346:1315, 2002

High Bone Mass Linked to a LRP-5 Mutation

Little et al., Am. J. Hum. Gen. 70:11, 2002Little et al., Am. J. Hum. Gen. 70:11, 2002

43

Wnt Signaling Pathway

Wnt/β-catenin and Osteoblast Differentiation

StromalStem Cell

Commitment

Proliferation and

Differentiation

Adipocyte

Runx2

Function

Runx2c-FosΔfos-D

Runx2Dlx5Osx

HoxaMsx2

PPARγ

ββ--catenincatenin

Wnts

44

Other LRP-5 Mutations Linked to High Bone Mass Syndromes•• 6262--yearyear--old woman referred for possible old woman referred for possible ““PagetPaget’’s diseases disease””•• DEXA TDEXA T--score Lscore L--spine: +8.7; never fracturedspine: +8.7; never fractured•• XX--rays at age 20: very dense bonesrays at age 20: very dense bones•• Extensive oral Extensive oral exostosesexostoses•• Genotype: A154M mutation in LRP5Genotype: A154M mutation in LRP5

RickelsRickels et al. J Bone Miner Res 20:878: 2005et al. J Bone Miner Res 20:878: 2005

LRP-5 Mutations Linked to High Bone Mass Syndromes•• 3737--yearyear--old woman referred for old woman referred for ““osteopetrosisosteopetrosis””•• Cranial nerve symptoms throughout life (strabismus, Cranial nerve symptoms throughout life (strabismus,

trigeminal neuralgia, facial nerve palsy)trigeminal neuralgia, facial nerve palsy)•• Treated for Treated for pseudotumorpseudotumor cerebricerebri•• Generalized bone painGeneralized bone pain•• Genotype: G171V mutation in LRP5Genotype: G171V mutation in LRP5

Whyte et al., N. Eng. J. Med. 350:2096, 2004Whyte et al., N. Eng. J. Med. 350:2096, 2004

45

LRP5 Mutations in Other High Bone Mass Syndromes

Family OriginFamily Origin Original DiagnosisOriginal Diagnosis MutationMutationPortland (OR)Portland (OR) Endosteal hyperostosisEndosteal hyperostosis A242TA242TPortland (OR)Portland (OR) Endosteal hyperostosisEndosteal hyperostosis A242TA242TPortland (OR)Portland (OR) Endosteal hyperostosisEndosteal hyperostosis A214TA214TSardiniaSardinia Van Van BuchemBuchem disease (?)disease (?) A242TA242TEnglandEngland AutosomalAutosomal dominant osteosclerosisdominant osteosclerosis A214VA214VBelgiumBelgium OsteopetrosisOsteopetrosis G171RG171RFranceFrance OsteopetrosisOsteopetrosis A242TA242TArgentinaArgentina OsteopetrosisOsteopetrosis D111YD111YDenmarkDenmark Autos. Autos. domindomin. . osteopetrosisosteopetrosis type Itype I T253IT253IDenmarkDenmark Autos. Autos. domindomin. . osteopetrosisosteopetrosis type Itype I T253IT253I

Van Van WesenbeckWesenbeck et al., Am J Hum Gen 72:763; 2003et al., Am J Hum Gen 72:763; 2003

Other Sclerosing Bone Disorders

•• Van Van BuchemBuchem DiseaseDiseaseEnlarged mandible, Enlarged mandible, increased thickness increased thickness of the skull and the of the skull and the cortices of the long cortices of the long bones bones

•• SclerosteosisSclerosteosisIncreased thickness Increased thickness of the skull, squared of the skull, squared mandible, syndactylymandible, syndactyly

Balemans et al. Am J Hum Gen 39:91; 2001

46

Gardner et al. J Gardner et al. J ClinClin EndocrinolEndocrinol MetabMetab 90:6392; 200590:6392; 2005

High Bone Mass in Sclerosteosisand SOST Heterozygous Mutants

SclerosteosisCarriers

The Wnt/β-catenin Signaling System

Krishnan et al., J Clin Invest 116-1202; 2006

47

Challenges for Wnt Pathway Targeting•• Bone specificityBone specificity

No No ““bone specificbone specific”” component identifiedcomponent identifiedSclerostinSclerostin osteocyte specific?osteocyte specific?

•• Interference with cell proliferationInterference with cell proliferationββ--catenin and GSK3 inhibition implicated in some tumorscatenin and GSK3 inhibition implicated in some tumors

•• Craniofacial hyperostosisCraniofacial hyperostosisActivating mutations of LRP5 or SOST, perhaps because of Activating mutations of LRP5 or SOST, perhaps because of interaction with other genetic or environmental factors may interaction with other genetic or environmental factors may engender other skeletal abnormalities resulting in engender other skeletal abnormalities resulting in oropharyngealoropharyngeal or neurological complicationsor neurological complications

Wnt/β-catenin Signaling

Nelson and Nusse, Science 303-1483; 2004

sFRP

48

Severe Osteopenia in Ncad+/-;Cad11-/-

Mice

Ncad+/+;Cad11+/+ Ncad+/+;Cad11-/- Ncad+/-;Cad11-/-

Ncad+/+;Cad11+/+

Ncad+/+;Cad11-/-

Ncad+/-;Cad11-/-

MalesFemales

C. DonsanteC. Donsante

Low Bone Mass in Ncad+/-;Cad11-/-

Mice

AA

BV/TV = 15.7±3.7% 12.5±2.7% 6.4±1.9%*

Ncad+/+;Cad11+/+ Ncad+/–;Cad11–/–Ncad+/+;Cad11–/–

C. Donsante

49

Osteoblasts Maintain the Hematopoietic Stem Cell Niche

Zhang et al. Nature 425:836; 2003

Osteoblasts and Stem Cell Niches

Li and Li, TiBS 31:589; 2006

SSC?

50

Potential New Molecular Targets for Bone Anabolism

StromalStem Cell

Commitment

Proliferation and

Differentiation

Adipocyte

Runx2

Function

Runx2c-FosΔfos-D

Runx2Dlx5Osx

HoxaMsx2

PPARγ

Leptin/β-AR

ββ--catenincatenin

Wnts

Self Renewal

Cell-cell interactions

Leptin

LRP5

““Bone LossBone Loss”” or or ““Lost BoneLost Bone””When Should We TreatWhen Should We Treat

MoneMone ZaidiZaidiProfessor of MedicineProfessor of Medicine

Director, Mount Sinai Bone ProgramDirector, Mount Sinai Bone ProgramMount Sinai School of MedicineMount Sinai School of Medicine

New YorkNew York

51

Clinical ScenariosClinical Scenarios

A 65 yearA 65 year--old woman with a Told woman with a T--score score of of ––2.62.6

Traditional NOF CriteriaTraditional NOF Criteria

A 80 yearA 80 year--old woman with a Told woman with a T--score score of of --1.3 and a history of smoking1.3 and a history of smoking

New WHO Stratification ToolNew WHO Stratification Tool

Continuum of Bone LossContinuum of Bone Loss

OsteoclasticOsteoclastic ResorptionResorptionBone Remodeling MarkersBone Remodeling Markers

TrabecularTrabecular Perforation and LossPerforation and LossBone Imaging Bone Imaging –– CT and MRICT and MRI

““Lost BoneLost Bone””BMDBMD

FractureFractureClinicalClinicalXX--rayrayVFAVFA

Current Therapeutics Current Therapeutics ““Lost BoneLost Bone””

52

FDA Has Required that Drugs FDA Has Required that Drugs Demonstrate Demonstrate Fracture Fracture

Reduction atReduction at Vertebral SitesVertebral Sites

Primary End Point

Vertebral Fracture

Statistics Power

Analysis

Required Patient

Numbers

Secondary End Points

Non-Vertebral Fracture, BMD, Markers, Others

Pivotal clinical trials were not powered to examine non-vertebral fracture reduction, with the exception of zoledronic acid

FDA Registration TrialsFDA Registration Trials

53

Non-Vertebral Fracture

Incidence in the Placebo Group

Disease Severity in Placebo Group

Multiple SitesDefinition Varies

Different Types of Bone (CorticalVersus Trabecular)

Different PatientPopulations

Vertebral Fracture ReductionVertebral Fracture Reduction

30%

47%

41%

49%

50%

36%

50%

1Chesnut CH, et al. Am J Med. 2000;109:267-76 2Ettinger B, et al. JAMA. 1999;282:637-453Black DM, et al. Lancet 1996;348:1535-41 4Harris ST, et al. JAMA. 1999;282:1344-525Reginster J, et al. Osteoporos Int. 2000;11:83-91 6Chesnut CH, et al. J Bone Miner Res. 2004;19:1241-97Cummings SR, et al. JAMA. 1998;280:2077-82 * All reductions are statistically significant

IbandronateCalcium Calcitonin RisedronateAlendronateRaloxifene

52%

05

1015202530

PROOFPROOF11 MOREMORE22 FIT VFAFIT VFA33 VERT NAVERT NA44 VERT MNVERT MN55 BONEBONE66 MOREMORE22 FIT CFAFIT CFA77

OP with Prevalent Vertebral Fractures OP with Prevalent Vertebral Fractures ** OP without Vert Fx OP without Vert Fx **

% of Patients with New Vertebral Fracture

54

NonNon--Vertebral Fracture ReductionVertebral Fracture Reduction

05

1015202530

% of Patients with New

Non-vertebral Fracture

1Chesnut CH, et al. Am J Med. 2000;109:267-76 2Ettinger B, et al. JAMA. 1999;282:637-45 (pooled groups)3Black DM, et al. Lancet 1996;348:1535-41 4Harris ST, et al. JAMA. 1999;282:1344-525Reginster J, et al. Osteoporos Int. 2000;11:83-91 6Chesnut CH, et al. J Bone Miner Res. 2004;19:1241-97Cummings SR, et al. JAMA. 1998;280:2077-82 N/A = not available; NS = not statistically significant

PROOFPROOF11 MOREMORE22 FIT VFAFIT VFA33 VERT NAVERT NA44 VERT MNVERT MN55 BONEBONE66 MOREMORE22 FIT CFAFIT CFA77

OP with Prevalent Vertebral FracturesOP with Prevalent Vertebral Fractures OP without Vert FxOP without Vert Fx

Calcium Calcitonin RisedronateAlendronateRaloxifene Ibandronate

39%

N/A

NS NS NS p = .02 NS NS NS

Bridging TrialsBridging Trials

55

River Forth, ScotlandRiver Forth, Scotland

NonNon--InferiorityInferiorityBMD TrialsBMD Trials

NonNon--Inferiority BMD Inferiority BMD TrialsTrials

MOBILEDIVA

Bridging Trials

FRACTURE TrialsFRACTURE Trials

DAILYDAILY

AlendronateAlendronate (10)(10)

RisedronateRisedronate (5)(5)

DAILYDAILYIbandronateIbandronate (2.5)(2.5)

WEEKLYWEEKLY

AlendronateAlendronate (70)(70)

RisedronateRisedronate (35)(35)

Monthly/QuarterlyMonthly/QuarterlyIbandronateIbandronate (150)(150)

Extended IntervalExtended Interval

2.5 mg/day x 30 days 2.5 mg/day x 30 days ≠≠ 150 mg/month150 mg/month

1.1. Schnitzer T, et al. Schnitzer T, et al. Aging Clin Exp Res.Aging Clin Exp Res. 2000;12:12000;12:1--12.12.2.2. Rizzoli R, et al. Rizzoli R, et al. J Bone Miner Res.J Bone Miner Res. 2002;17:19882002;17:1988--1996.1996.

70 mg Once Weekly at Year 11

70 mg Once Weekly at Year 2210 mg Daily at Year 11

10 mg Daily at Year 22

6.8

4.13.3

5.9

7.4

4.33.5

6.1

5.1

2.9 2.33.9

5.4

3.1 2.94.4M

ean

% C

hang

ein

BM

D F

rom

Bas

elin

e

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

8.0

Lumbar Spine Total Hip Femoral Neck Trochanter

BMD Increases With BMD Increases With AlendronateAlendronate

56

BMD Changes With BMD Changes With RisedronateRisedronate

Mea

n %

Cha

nge

in B

MD

Fro

m B

asel

ine

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

8.0

Lumbar Spine Total Hip Femoral Neck Trochanter

3.92.4

4.02.5 2.1

4.7

3.0

1.9

4.2

5.2

3.42.5

4.7

35 mg Once Weekly at Year 11

35 mg Once Weekly at Year 225 mg Daily at Year 11

5 mg Daily at Year 22

1.93.03.3

1. Brown JP, et al. 1. Brown JP, et al. Calcif Tissue Int.Calcif Tissue Int. 2002;71:1032002;71:103--111. 111. 2. Harris ST, et al. 2. Harris ST, et al. Curr Med Res Opin.Curr Med Res Opin. 2004;20:7572004;20:757--764.764.

River Forth, ScotlandRiver Forth, Scotland

NonNon--Inferiority BMD Inferiority BMD TrialsTrials

MOBILEDIVA

Bridging Trials

FRACTURE TrialsFRACTURE Trials

DAILYDAILYIbandronateIbandronate (2.5)(2.5)

Monthly/QuarterlyMonthly/QuarterlyIbandronateIbandronate (150)(150)

Extended IntervalExtended Interval

2.5 mg/day x 30 days 2.5 mg/day x 30 days ≠≠ 150 mg/month150 mg/month

57

Annual Cumulative Exposure (ACE)Annual Cumulative Exposure (ACE)

0.0

2.5

5.0

7.5

10.0

12.5

Annual Skeletal Annual Skeletal Exposure (mg)Exposure (mg)

2.5 mg 2.5 mg DailyDailyOralOral

5.46 mg5.46 mg

150 mg 150 mg MonthlyMonthly

OralOral

10.9 mg10.9 mg

Annual Cumulative Exposure: Dose x %Absorbed (0.6%) x FrequencyAnnual Cumulative Exposure: Dose x %Absorbed (0.6%) x Frequency

Extending Interval Requires More DrugExtending Interval Requires More DrugHypothesisHypothesis: More Drug Per Year Will : More Drug Per Year Will

Produce A Greater BMD Benefit Than Less Produce A Greater BMD Benefit Than Less Drug Per YearDrug Per Year

2 mg 2 mg BimonthlyBimonthlyInjectionInjection

12 mg12 mg

3 mg 3 mg QuarterlyQuarterlyInjectionInjection

12 mg12 mg

5.0

(294)

6.6

(291)

2.5(292)

4.2

(289)

6.2

(289)4.0(292)3.1

(289)1.9(292)

MOBILE: Daily MOBILE: Daily Versus Versus Monthly Monthly IbandronateIbandronate

Mea

n %

Cha

nge

in B

MD

Fro

m B

asel

ine

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

8.0

Lumbar Spine Total Hip Femoral Neck Trochanter

3.7

(314)

4.8

(314)2.0(315)

3.0(316)

4.6

(316)

3.2(315)

2.2(316)

1.7(315)

2.5 mg Daily at Year 1 150 mg Monthly at Year 12.5 mg Daily at Year 2 150 mg Monthly at Year 2

Year 1 P=0.001 P<0.0001 P=0.09 P<0.0001Year 2 P<0.0001 P<0.0001 P=0.0002 P<0.0001vs 2.5 mg daily

Data on file (Reference # 161Data on file (Reference # 161--094, 161094, 161--098, 161098, 161--173) Hoffmann173) Hoffmann--La Roche Inc., Nutley, NJ 07110.La Roche Inc., Nutley, NJ 07110.

58

Understanding ACEUnderstanding ACE

ACE Levels In ACE Levels In IbandronateIbandronate TrialsTrials

0

2

4

6

8

10

12

AC

E (m

g)

0.25

mg

0.25

mg

qdqd

0.5

mg

0.5

mg

qdqd

0.25

mg

IV q

3mo

0.25

mg

IV q

3mo

0.5

mg

IV q

3mo

0.5

mg

IV q

3mo

1.0

mg

1.0

mg

qdqd

1 m

g IV

q3m

o1

mg

IV q

3mo

2.5

mg

2.5

mg

qdqd

20 m

g 20

mg

int

int

50+5

0 m

g q1

mo

50+5

0 m

g q1

mo

100

mg

q1m

o10

0 m

g q1

mo

2 m

g IV

q3m

o2

mg

IV q

3mo

150

mg

q1m

o15

0 m

g q1

mo

5 m

g 5

mg

qdqd

2 m

g IV

q2m

o2

mg

IV q

2mo

3 m

g IV

q3m

o3

mg

IV q

3mo

# Marketed# Marketed

5.55.5##

10.810.8##1212##

7.27.2

1212

59

NonNon--Vertebral Fracture Rates Vertebral Fracture Rates High ACE Versus Low ACEHigh ACE Versus Low ACE

0.7450.7450.6340.6340.6200.6200.5690.569

Adjusted Adjusted Hazard RatioHazard Ratio

0.140.140.500.50--1.101.1025.525.5292129215.55.5>>7.27.20.020.020.430.43--0.940.9436.636.629212921<7.2<7.2>>10.810.80.040.040.400.40--0.970.9738.038.0213721375.55.5>>10.810.80.050.050.320.32--1.001.0043.143.1135513555.55.51212

PP valuevalue95% CI95% CIRelative Risk Relative Risk Reduction Reduction

(%)(%)

NNLow ACE Low ACE (mg)(mg)

High ACE High ACE (mg)(mg)

Analysis performed by Rick Adachi, MDAnalysis performed by Rick Adachi, MD

ZaidiZaidi, M., et al. Ann. NY Acad. , M., et al. Ann. NY Acad. SciSci., 2007., 2007

versusversus

versusversus

versusversus

versusversus

The high ACE (>10 mg) includes 150 mg monthly oral and 3 mg quarterly IV as used in clinical practice

Clinical and NonClinical and Non--Vertebral Fracture Rates Vertebral Fracture Rates High ACE Versus PlaceboHigh ACE Versus Placebo

129012903585358519111911

129012903585358519111911

129012903585358519111911

NN

.334.3340.660.66––1.151.150.8710.871LowLow ((≤≤4.0)4.0)

.270.2700.900.90––1.461.461.151.15MidMid (5.5 to 7.2)(5.5 to 7.2).032.032**0.450.45––0.960.960.6560.656High (High (≥≥10.8) 10.8)

NonNon--Vertebral (clavicle, Vertebral (clavicle, humerus, wrist, pelvis, humerus, wrist, pelvis, hip, and leg)hip, and leg)

.383.3830.690.69––1.151.150.8930.893LowLow ((≤≤4.0)4.0)

.722.7220.830.83––1.301.301.041.04MidMid (5.5 to 7.2)(5.5 to 7.2).041.041**0.500.50––0.990.990.7010.701High (High (≥≥10.8) 10.8)

NonNon--Vertebral (all sites)Vertebral (all sites).211.2110.730.73––1.071.070.8870.887Low (Low (≤≤4.0)4.0).148.1480.740.74––1.051.050.8810.881MidMid (5.5 to 7.2)(5.5 to 7.2).010.010**0.550.55––0.920.920.7120.712High (High (≥≥10.8) 10.8)

All clinicalAll clinical

PP--valuevalue95% CI95% CIAdjusted HazardAdjusted HazardRatioRatio

Fracture Type Fracture Type (ACE in mg)(ACE in mg)

28.8% RRR

29.9% RRR

34.4% RRR

From Paul Miller and Steve HarrisFrom Paul Miller and Steve Harris

60

Time To Non-Vertebral Fracture At 2 YearsIbandronate ACE ≥10.8 mg

NonNon

-- Ver

tebr

al F

ract

ure

Rat

e (%

)Ve

rteb

ral F

ract

ure

Rat

e (%

)100100

9595

9090

85850 0

p = 0.025p = 0.025

Data included from BONE, MOBILE, MF4380 and DIVA TrialsData included from BONE, MOBILE, MF4380 and DIVA Trials

6 6 1212 1818 2424

IbandronateIbandronate (ACE (ACE ≥≥10.8 mg)10.8 mg)PlaceboPlacebo

From: From: ZaidiZaidi, M., et al. Ann. NY Acad. , M., et al. Ann. NY Acad. SciSci., 2007., 2007

MonthsMonths

LearningsLearnings From From ““ACEACE””

To separate two doses of a To separate two doses of a bisphosphonatebisphosphonate beyond two to three beyond two to three weeks, a higher ACE may be requiredweeks, a higher ACE may be required

While smaller While smaller ACEsACEs may provide may provide evidence for BMD increases, larger evidence for BMD increases, larger ACEsACEs may be required for differences in may be required for differences in fracture reduction to emerge, particularly fracture reduction to emerge, particularly at cortical sitesat cortical sites

61

The The ““ACEACE”” Concept May Not Concept May Not Apply to High Potency, High Apply to High Potency, High

Affinity Affinity BisphosphonatesBisphosphonates

HORIZON Trial HORIZON Trial –– ZoledronicZoledronic AcidAcidMorphometricMorphometric Vertebral FractureVertebral Fracture

Black DM, et al. NEJM 356; 18: 1809Black DM, et al. NEJM 356; 18: 1809--2222

3.7

7.7

10.9

1.52.2

3.3

0

2

4

6

8

10

12

0-1 0-2 •0-3

PlaceboZoledronic Acid

YearYear

Patie

nts

with

New

Pa

tient

s w

ith N

ew

Vert

ebra

l Fra

ctur

es (%

)Ve

rteb

ral F

ract

ures

(%)

Relative risk, 0.40Relative risk, 0.40P<0.001P<0.001

Relative risk, 0.29Relative risk, 0.29P<0.001P<0.001

Relative risk, 0.30Relative risk, 0.30P<0.001P<0.001

62

HORIZON Trial HORIZON Trial –– ZoledronicZoledronic AcidAcid

Black DM, et al. Black DM, et al. NEJMNEJM 356;18: 1809356;18: 1809--2222

MonthMonth

0 6 12 18 24 30 360 6 12 18 24 30 36

Cum

ulat

ive

Inci

denc

e (%

)C

umul

ativ

e In

cide

nce

(%) 33

Hazard ratio, 0.75 (95% CI, 0.64Hazard ratio, 0.75 (95% CI, 0.64--0.87)0.87)P=0.001P=0.001

PlaceboPlacebo

ZoledronicZoledronic AcidAcid

22

11

00

MonthMonthC

umul

ativ

e In

cide

nce

(%)

Cum

ulat

ive

Inci

denc

e (%

)

Hazard ratio, 0.59 (95% CI, 0.42Hazard ratio, 0.59 (95% CI, 0.42--0.83)0.83)P=0.002P=0.002

PlaceboPlacebo

ZoledronicZoledronic AcidAcid

33

22

11

000 6 12 18 24 30 360 6 12 18 24 30 36

NonNon--VertebralVertebral HipHip

PlaceboPlacebo--Controlled Fracture Controlled Fracture Trials Will No Longer Be Trials Will No Longer Be

Possible for Ethical ReasonsPossible for Ethical Reasons

HORIZON is likely the lastHORIZON is likely the last…………..

63

Comparator Studies For Comparator Studies For Fracture Reduction Will:Fracture Reduction Will:

Require Unrealistic Numbers of Require Unrealistic Numbers of PatientsPatients

ExpensiveExpensive

Hypothetical Comparator TrialsHypothetical Comparator TrialsAlendronateAlendronate Versus Versus IbandronateIbandronate

Non Vertebral Fracture TrialsNon Vertebral Fracture Trials23,682 patients per arm23,682 patients per arm

Hip Fracture TrialsHip Fracture Trials27,109 patients per arm27,109 patients per arm

64

Why Not Focus OnWhy Not Focus On………………??

A 53 yearA 53 year--old woman just entering the old woman just entering the menopause, with a Tmenopause, with a T--score of score of ––1.4 and a 1.4 and a urinary Nurinary N--telopeptidetelopeptide of 70 of 70 nmol/mmolnmol/mmolCrCr

PerimenopausalPerimenopausaland and

Early PostEarly Post--Menopausal Menopausal Bone LossBone Loss

65

Continuum of Bone LossContinuum of Bone Loss

OsteoclasticOsteoclastic ResorptionResorptionBone Remodeling MarkersBone Remodeling Markers

TrabecularTrabecular Perforation and LossPerforation and LossBone Imaging Bone Imaging –– CT and MRICT and MRI

““Lost BoneLost Bone””BMDBMD

FractureFractureClinicalClinicalXX--rayrayVFAVFA

Current Therapeutics Current Therapeutics ““Lost BoneLost Bone””

Identify and Treat Identify and Treat ““Bone LossBone Loss””

PerimenopausePerimenopause

8070605040

30

20

10

90

42 44 46 48 50 52 54

70

60

50

40

3042 44 46 48 50 52 54

80

Estr

adio

l(pg

/mL)

FSH

(IU

/L)

Age (years)

Age (years)

CaucasiansAfrican-Americans

ChineseHispanicsJapanese

Randolph et al, 2007Randolph et al, 2007

66

0.98

1

1.02

1.04

1.06

1.08

1.1

1 2 3 4 5

Annual Visit

Lum

bar S

pine

BM

D (g

m/c

m2 )

PremenopausalPremenopausalEarly Early PerimenopausalPerimenopausal

Late Late PerimenopausalPerimenopausal

PostPost--menopausalmenopausal

Study of Women Across Nations (SWAN)Study of Women Across Nations (SWAN)

2375 Women Aged 42 to 52 Years

Activation Frequency Accelerates Activation Frequency Accelerates Early PostEarly Post--MenopauseMenopause

Black DM, et al. NEJM 356; 18: 1809Black DM, et al. NEJM 356; 18: 1809--2222

0

5

10

15

20

25

30

0 0-2 •0-3

YearYear

Rel

ativ

e Fr

eque

ncy

Rel

ativ

e Fr

eque

ncy

35

0.1 0.1

67

PREPRE

PERIPERI

TrabecularTrabecular Perforations in Perforations in The The PerimenopausePerimenopause

From: From: ReckerRecker, R., et al (2007), R., et al (2007)

Bone Loss and Serum FSHSWAN

68

EARLY POSTEARLY POST--MENOPAUSAL WOMENMENOPAUSAL WOMENEffect of Effect of IbandronateIbandronate

+0.4+0.4+1.6+1.6--2.42.4--1.41.4

0.5 mg 0.5 mg qdqd

+2.6+2.6+1.5+1.5--1.01.0--1.0 to 1.0 to --2.52.5> 3 yr> 3 yr+3.4+3.4+1.9+1.9+0.4+0.4> > --1.01.0> 3 yr> 3 yr+1+1--1.51.5--1.81.8--1.0 to 1.0 to --2.52.51 1 –– 3 yr3 yr

+0.5+0.5--0.30.3--2.12.1> > --1.01.01 1 –– 3 yr3 yr

2.5 mg 2.5 mg qdqd1 mg 1 mg qdqdPlaceboPlaceboLumbar Spine Lumbar Spine TT--ScoreScore

Time Since Time Since MenopauseMenopause

McClung, M.R. et al. (2004) JBMR 19: 11McClung, M.R. et al. (2004) JBMR 19: 11--1818

Decline in placeboDecline in placebo: 1: 1--3 yrs versus > 3 yrs TSM; p = 0.00013 yrs versus > 3 yrs TSM; p = 0.0001Placebo Placebo versusversus 1 or 2.5 mg 1 or 2.5 mg qdqd ibandronateibandronate; p < 0.003 at 6 mo and thereafter; p < 0.003 at 6 mo and thereafter

% change in BMD% change in BMD

Age 57Age 57--58 yrs58 yrs

EARLY POSTEARLY POST--MENOPAUSAL WOMENMENOPAUSAL WOMENEFFECT OF ALENDRONATEEFFECT OF ALENDRONATE

McClung, M.R. et al. (2004) JCEM 89: 4879McClung, M.R. et al. (2004) JCEM 89: 4879--8585

THE THE EPIC EPIC STUDY STUDY

69

Adherence toAdherence toOsteoporosis TherapiesOsteoporosis Therapies

Stuart Silverman, MD, FACP, FACRStuart Silverman, MD, FACP, FACRClinical ProfessorClinical Professor

University of California at Los AngelesUniversity of California at Los AngelesCedars Sinai Medical CenterCedars Sinai Medical Center

Medical DirectorMedical DirectorOMC Clinical Research Center, Beverly Hills, CAOMC Clinical Research Center, Beverly Hills, CA

A Year 2007 ScienceA Year 2007 Science--toto--Strategy UpdateStrategy Update

Definitions Definitions —— Critical to Our Critical to Our Understanding of OutcomesUnderstanding of Outcomes

Compliance Compliance Taking the medication as directedTaking the medication as directedHow much medication is available How much medication is available

to the patient?to the patient?

PersistencePersistenceHow long do patientsHow long do patientstake the medication?take the medication?

Reginster JY, et al. In: Business briefing: long-term healthcare 2004. Available at: http://www.bbriefings.com/cdps/cditem.cfm?NID=886&CID=5&CFID=4535829&CFTOKEN=17213767 Accessed March 4, 2005.

70

Approaches to Collecting Approaches to Collecting Compliance DataCompliance Data

Farmer KC. Farmer KC. ClinClin TherTher. 1999;21:1074. 1999;21:1074--10901090

Knowledge of database required

Real-world, noninvasive, long-term data, large populations; control of other variables

Prescription records (databases)

Expensive, inconvenientExpensive, inconvenient

Potential for Potential for overestimationoverestimation

Impractical in outpatient Impractical in outpatient settingsetting

PatientPatient--specific kinetic specific kinetic variationsvariations

ConsCons

Precise dataPrecise dataElectronic monitoringElectronic monitoring

Verified useVerified useDirect patient Direct patient observationobservation

Easy to use, inexpensiveEasy to use, inexpensivePatient selfPatient self--reportreport

Recent use verifiedRecent use verifiedDrug levels in biologic Drug levels in biologic fluidsfluids

ProsProsApproachApproach

Half of Patients Discontinue Half of Patients Discontinue BisphosphonateBisphosphonateTreatment Within One YearTreatment Within One Year

0

10

20

30

40

50

Pers

iste

nt P

atie

nts

at 1

Yea

r (%

)

Daily Weekly(n = 2010) (n = 731)

31.7%

44.2%

Mean time to discontinuation: daily = 185 days; weekly = 227 days

Cramer JA, et al. J Bone Miner Res. 2004;19:S448

*P ≤ .0001 vs daily.Administrative claims data (1997–2002) from 30 health plans were used to assess treatment adherence in 2,741 postmenopausal osteoporotic women (≥45 years) newly prescribed either a once-daily or once-weekly bisphosphonate. Both groups were followed up for 12 months after filling the index prescription.

*

71

Significantly Better Persistence With Significantly Better Persistence With Weekly Than With Daily Bisphosphonate DosingWeekly Than With Daily Bisphosphonate Dosing

*Log-rank P < .0001 for weekly vs daily proportion persisting†Median time to discontinuation (P < .001)

100100

8080

6060

4040

2020

00

Pers

iste

nt P

atie

nts

(%)

00 139139†† daysdays 269269†† daysdays(once daily)(once daily) (once weekly)(once weekly)

Weekly Weekly DailyDaily

44.2%44.2%**

31.7%31.7%

365 days365 days

Cramer JA, et al. Cramer JA, et al. CurrCurr MedMed ResRes OpinOpin.. 2005;21:14532005;21:1453--14601460

180 180 daysdays

Over 12 MonthsOver 12 Months

What Are the Consequences of What Are the Consequences of Poor Adherence?Poor Adherence?

Clinical ImplicationsClinical Implications

72

Potential Consequences of Poor Potential Consequences of Poor AdherenceAdherenceto Osteoporosis Therapyto Osteoporosis Therapy

►► Poorer clinical outcomesPoorer clinical outcomesLess effective suppression in rate of Less effective suppression in rate of bone turnoverbone turnover11

Lower gains or greater losses in Lower gains or greater losses in bone mineral densitybone mineral density1,21,2

Greater risk of fracturesGreater risk of fractures3,43,4

►► Results in higher medical costs and Results in higher medical costs and greater health care utilizationgreater health care utilization55

1.1. EastellEastell R, et al. R, et al. CalcifCalcif Tissue IntTissue Int. 2003;72:408. Abstract P. 2003;72:408. Abstract P--297 297 2.2. FiniganFinigan J, et al. J, et al. OsteoporosOsteoporos IntInt. 2001;12:S48. 2001;12:S48--S49. Abstract P110S49. Abstract P1103.3. CaroCaro JJ, et al. JJ, et al. OsteoporosOsteoporos Int.Int. 2004;15:10032004;15:1003--100810084.4. SirisSiris ES ,et al. ES ,et al. Mayo Clin ProcMayo Clin Proc. 2006;81:1013. 2006;81:1013--102210225.5. McCombsMcCombs JS, et al. JS, et al. MaturitasMaturitas. 2004;48:271. 2004;48:271--287287

*P < .0001†Compliance defined as taking medication ≥80% of the time over a 24-month periodRetrospective cohort study that used longitudinal medical and pharmacy claims data from Medstat MarketScan®

Research Databases to assess adherence and fracture risk over 24 months (1999–2003)

Siris ES, et al. Siris ES, et al. Mayo Mayo ClinClin ProcProc. 2006;81:1013. 2006;81:1013--10221022

Better LongBetter Long--Term ComplianceTerm ComplianceReduces Fracture RiskReduces Fracture Risk

Compliance With Bisphosphonates and Fracture Risk Over 2 Years in Women ≥45 Years With Postmenopausal Osteoporosis (N = 6825)

Patie

nts

With

Fra

ctur

e (%

)

0

2

4

6

8

10

12

14

Compliant Noncompliant(n = 3400) (n = 3425)

*

†

9.4%

12.6%

73

What Are the Possible Causes What Are the Possible Causes of Poor Compliance?of Poor Compliance?

Addressing Underlying CausesAddressing Underlying Causes

What Are Some Possible CausesWhat Are Some Possible CausesOf Poor Of Poor ComplianceCompliance??

Disruption of daily routine?

(need for frequent dosing)

Concern about side effects?

Osteoporosis eclipsed by

other chronic conditions?

Lack of positive reinforcement?

Complex dosing

guidelines?

Cost?POORADHERENCE

Gold DT, et al. Gold DT, et al. CurrCurr OsteoporosOsteoporos RepRep. 2006;4:21. 2006;4:21--2727

74

Patient Beliefs MayPatient Beliefs MayInfluence ComplianceInfluence Compliance

►► Patients may not believe they have Patients may not believe they have osteoporosisosteoporosis

There is no risk for those with no family There is no risk for those with no family history of osteoporosishistory of osteoporosisHow can I have osteoporosis if I exercise How can I have osteoporosis if I exercise and take calciumand take calcium??

►► Patients may not understand the Patients may not understand the consequences of having osteoporosisconsequences of having osteoporosis

There is no need to treat a silent, There is no need to treat a silent, asymptomatic diseaseasymptomatic diseaseOsteoporosis is expected as you ageOsteoporosis is expected as you age

Gold DT, et al. Gold DT, et al. CurrCurr OsteoporosOsteoporos RepRep. 2006;4:21. 2006;4:21--2727

►► Patients may be concerned about the Patients may be concerned about the adverse effects of therapyadverse effects of therapy

It is preferable to risk fracturing a hip than to take more It is preferable to risk fracturing a hip than to take more medicationsmedicationsConcomitant use of multiple medications will Concomitant use of multiple medications will ““cancel cancel each other outeach other out””Treatment benefits do not outweigh adverse effectsTreatment benefits do not outweigh adverse effects

►► Patients may have barriers to taking Patients may have barriers to taking medicationmedication

I canI can’’t get started in the morning until I have my t get started in the morning until I have my morning coffeemorning coffeeI canI can’’t wait 30 to 60 minutes before I have breakfastt wait 30 to 60 minutes before I have breakfast

Gold DT, et al. Gold DT, et al. CurrCurr OsteoporosOsteoporos RepRep. 2006;4:21. 2006;4:21--2727

Patient Beliefs MayPatient Beliefs MayInfluence Compliance (continued)Influence Compliance (continued)

75

How Can WeHow Can WeImprove Improve ComplianceCompliance??

Addressing the ChallengesAddressing the Challenges

Improving Improving Compliance Compliance by by Reinforcing Treatment EfficacyReinforcing Treatment Efficacy

►► Osteoporosis is largely asymptomatic, so symptoms Osteoporosis is largely asymptomatic, so symptoms do not improve with therapydo not improve with therapy

►► Effective treatments are available to treat Effective treatments are available to treat postmenopausal osteoporosispostmenopausal osteoporosis

►► Patient monitoring may be helpful in demonstrating Patient monitoring may be helpful in demonstrating effects of treatmenteffects of treatment11--33

Bone mineral density (BMD)Bone mineral density (BMD)Biochemical markers of bone turnoverBiochemical markers of bone turnover

►► However, all studies have shown that continued However, all studies have shown that continued reinforcement by the physician is the simplest and reinforcement by the physician is the simplest and most effective interventionmost effective intervention33

1.1. DelmasDelmas PD, et al. PD, et al. OsteoporosOsteoporos Int.Int. 2000;6(suppl):22000;6(suppl):2--17172.2. Deal CL. Deal CL. CurrCurr RheumatolRheumatol Rep.Rep. 2001;3:2332001;3:233--2392393.3. Gold DT, et al. Gold DT, et al. CurrCurr OsteoporosOsteoporos RepRep. 2006;4:21. 2006;4:21--2727

76

We Can Improve We Can Improve Compliance Compliance by Improving by Improving Communication with PatientsCommunication with Patients

►► Patients make their own reasoned decisions Patients make their own reasoned decisions about whether to take treatment based onabout whether to take treatment based on1,21,2

Health beliefsHealth beliefsPersonal circumstancesPersonal circumstancesInformation available to themInformation available to them

►► Thus, we as Thus, we as prescribersprescribers shouldshould22

Provide information that is clear and tailoredProvide information that is clear and tailoredSpeak with patients to find the treatment best suited to Speak with patients to find the treatment best suited to their individual lifestylestheir individual lifestyles

1.1. Donovan JL. Donovan JL. IntInt J J TechnolTechnol Assess Health CareAssess Health Care. 1995;11:443. 1995;11:443--4554552.2. VermeireVermeire E, et al. E, et al. J J ClinClin PharmPharm TherTher. 2001;26:331. 2001;26:331--342342

Improving Improving Compliance Compliance Through Through Modifying Dosing Interval Modifying Dosing Interval ——Focus on Focus on BisphosphonatesBisphosphonates

The Critical Role of Dosing IntervalThe Critical Role of Dosing Interval

77

Women Preferred WeeklyWomen Preferred WeeklyOver Daily DosingOver Daily Dosing

►► 288 postmenopausal women with osteoporosis were randomized to 288 postmenopausal women with osteoporosis were randomized to crossover treatment withcrossover treatment with

70 mg once70 mg once--weekly alendronate weekly alendronate ×× 4 weeks4 weeks10 mg once10 mg once--daily alendronate daily alendronate ×× 4 weeks4 weeks

►► At the final visit, patients completed a preference study questiAt the final visit, patients completed a preference study questionnaireonnaire

Simon JA, et al. Simon JA, et al. ClinClin TherTher.. 2002;24:18712002;24:1871--18861886

No preferenceOnce weekly Once daily

86.4

9.24.4

0102030405060708090

100

Treatment Preference

Patie

nts

(%)

Treatment Convenience

89

7.7 3.30

102030405060708090

100

Patie

nts

(%)

Anticipated Treatment Compliance

87.5

8.54

0102030405060708090

100

Patie

nts

(%)

Women Reported Preference forWomen Reported Preference for OnceOnce--Monthly Monthly Regimens Over Weekly Dosing Regimens*Regimens Over Weekly Dosing Regimens*

30%63%

7%

*US market survey of 393 women with postmenopausal osteoporosis (≥50 years) asked their preference for their current weekly bisphosphonate treatment, a new proposed monthly bisphosphonate therapy that required a 60-minute fast, or no preference

Simon JA, et al. Simon JA, et al. Female Patient Female Patient ((OB/GYNOB/GYN)).. 2005;30:312005;30:31--3636

Once monthly (n = 247)

Once weekly (n = 120)

No preference (n = 26)

78

What Do Observational Studies Tell What Do Observational Studies Tell Us About Compliance to Monthly Us About Compliance to Monthly Versus Weekly Bisphosphonate?Versus Weekly Bisphosphonate?

Observational DatabasesObservational Databases

General Study DesignGeneral Study DesignDatabaseDatabase

Step 1Female members/patients

Step 1Female members/patients

Step 2Select members with ≥1 pharmacy claim for a bisphosphonate from

April 1, 2005 onwards

Step 2Select members with ≥1 pharmacy claim for a bisphosphonate from

April 1, 2005 onwards

Step 3Exclude members not continuously enrolled

6 or 12 months before and for required follow-up time after the

index date

Step 3Exclude members not continuously enrolled

6 or 12 months before and for required follow-up time after the

index date

Focus on women treated with bisphosphonate therapy

Focus on women treated with bisphosphonate therapy

Step 4Stratify based on index drug

and dosing schedule

Step 4Stratify based on index drug

and dosing schedule

Step 5Assess persistence and refill

compliance during follow-up period

Step 5Assess persistence and refill

compliance during follow-up period

Assign the date of first pharmacy

claim for a bisphosphonate

as index date

Assign the date of first pharmacy

claim for a bisphosphonate

as index date

Use run-in window to define

patient subgroups

Use run-in window to define

patient subgroups

Where possible, control for other

variables (comorbidities,

age, copay, other meds)

Where possible, control for other

variables (comorbidities,

age, copay, other meds)

Exclude Paget’s disease, cancer, and HIV patients

Exclude Paget’s disease, cancer, and HIV patients

Definition of persistence gap:

45 days for monthly dosing;

30 days for weekly dosing

Definition of persistence gap:

45 days for monthly dosing;

30 days for weekly dosing

79

Pt. takes meds

Pt. takes meds

Pt. takes meds

Pt. takes meds

Refill Gap Length Explanation: ExamplesRefill Gap Length Explanation: Examples

30-day gap

Patie

nt F

ills

BP

Rx

45-day gap

60-day gap

90-day gap

Not persistent

Not persistent

Not persistent

NP

July Aug Sept Oct Nov

Failure to refill Rx within “gap” = NOT persistent

Refill Gap LengthRefill Gap LengthIbandronateIbandronate Persistence StudiesPersistence Studies

July Aug Sept Oct Nov

Pt. takes weekly 30-day gap

Patie

nt F

ills

BP

Rx

45-day gapPt. takes Ibandronate

Not persistent

Not persistent

Rx package inserts define acceptable window for missed treatment:Weekly = 6 days; Monthly (Ibandronate) = 21 days

24-day extra grace period

24-day extra grace period

80

Outcome Measures: PersistenceOutcome Measures: Persistence

►►Primary analysis:Primary analysis: Patients are Patients are persistentpersistent if if the refill gap after previous prescription is:the refill gap after previous prescription is:

<45 days for monthly <45 days for monthly ibandronateibandronate<30 days for weekly <30 days for weekly bisphosphonatebisphosphonate

►►Results reported as:Results reported as:Percent of patients who are persistent at followPercent of patients who are persistent at follow--up up (primary endpoint)(primary endpoint)Length of persistence: number of days from the Length of persistence: number of days from the index prescription to the date at which patients are index prescription to the date at which patients are deemed to be nonpersistent deemed to be nonpersistent (time to next refill > allowed gap)(time to next refill > allowed gap)

Statistical AnalysisStatistical Analysis

►►Unadjusted resultsUnadjusted resultsPercent persistentPercent persistent

►►Controlled (adjusted) resultsControlled (adjusted) results(Relative likelihood, comparing monthly (Relative likelihood, comparing monthly vsvs weekly)weekly)

Multivariate analysis to control for observed factors Multivariate analysis to control for observed factors such as baseline variables (age, such as baseline variables (age, comorbiditiescomorbidities, , healthcare costs) and average healthcare costs) and average copaycopayCox regression for persistence (time to discontinuation)Cox regression for persistence (time to discontinuation)•• Relative risk or Relative risk or ““hazardhazard”” of discontinuing therapy of discontinuing therapy

within the study period, comparing monthly vs within the study period, comparing monthly vs weeklyweekly

•• Relative risk or likelihood of staying on therapy Relative risk or likelihood of staying on therapy

81

i3 Innovus: 1i3 Innovus: 1--Year ResultsYear Results

Monthly versus WeeklyMonthly versus Weekly

<.0001<.000128.628.637.437.4MPR MPR ≥≥80% (%)80% (%)

<.0001<.000146465252Mean MPR (%)Mean MPR (%)

<.0001<.000124.824.835.735.7Persistence (%)Persistence (%)

143143

WeeklyWeekly(n=13,967)(n=13,967)

208208

MonthlyMonthly(n=3,512)(n=3,512)

<.0001<.0001Mean number of Mean number of days to days to discontinuationdiscontinuation

PP--ValueValue

Overall Monthly vs Weekly Persistence and Compliance at 1 Year (Unadjusted Results) - i3 Innovus

Overall Monthly vs Weekly Persistence and Compliance Overall Monthly vs Weekly Persistence and Compliance at 1 Year (Unadjusted Results) at 1 Year (Unadjusted Results) -- i3 Innovusi3 Innovus

i3 Innovus, Poster 176, ISCD, March 14, 2007

82

Cox Proportional Hazard Regression Cox Proportional Hazard Regression Results for Persistence Results for Persistence -- i3 Innovusi3 Innovus

<<.0001.00010.600.60––0.670.670.640.64>>3030--day supplyday supply<<.0001.00011.001.00––1.011.011.001.00Average copayAverage copay<<.0001.00010.900.90––0.910.910.900.90Concomitant medicationsConcomitant medications<<.0001.00010.630.63––0.700.700.670.67Prior DXA scanPrior DXA scan.0975.09750.990.99––1.191.191.091.09Prior fracturePrior fracture<<.0001.00011.331.33––1.381.381.351.35DeyoDeyo--CCICCI<<.0001.00010.990.99––0.990.990.990.99Mean ageMean age.3054.30540.920.92––1.031.030.970.97Bisphosphonate naiveBisphosphonate naive

<<.0001.00010.700.70––0.800.800.750.75Cohort: monthly vs Cohort: monthly vs weeklyweekly

PP--ValueValue95% CI95% CIHazard Hazard Ratio Ratio

EstimateEstimate

25% less likelyto discontinue

i3 Innovus, Poster 176, ISCD, March 14, 2007

HealthCore: 1-Year Results HealthCore: 1HealthCore: 1--Year Results Year Results

Healthcore Managed Care Database, Poster 173, ISCD, March 14, 2007

Managed Care DatabaseManaged Care Database

83

<.0001<.000128.728.735.135.1MPR MPR ≥≥80% (%)80% (%)

<.0001<.000144445151Mean MPR (%)Mean MPR (%)

<.0001<.000126.926.936.336.3Persistence (%)Persistence (%)

175175

WeeklyWeekly(n =10,658)(n =10,658)

205205

MonthlyMonthly(n = 1,006)(n = 1,006)

<.0001<.0001Mean number of days Mean number of days to discontinuationto discontinuation

PP--ValueValue

Overall Monthly vs Weekly Persistence and Compliance at 1 Year (Unadjusted Results) Overall Monthly vs Weekly Persistence and Overall Monthly vs Weekly Persistence and Compliance at 1 Year (Unadjusted Results) Compliance at 1 Year (Unadjusted Results)

Healthcore Managed Care Database, Poster 173, ISCD, March 14, 2007

Healthcore

Cox Proportional Hazard Regression Results Cox Proportional Hazard Regression Results for Persistence for Persistence —— HealthCoreHealthCore

<<.0001.00011.021.02––1.031.031.021.02Number of Rx classesNumber of Rx classes<<.0001.00010.670.67––0.730.730.700.70Prior DXA scanPrior DXA scan.0603.06030.820.82––1.001.000.910.91Prior fracturePrior fracture.1034.10341.001.00––1.001.001.001.00DeyoDeyo--CCICCI<<.0001.00011.051.05––1.101.101.071.07Mean ageMean age

<<.0001.00010.730.73––0.760.760.740.74>>3030--day supplyday supply

<<.0001.00011.151.15––1.251.251.201.20Patient paid per day Patient paid per day (high vs low)(high vs low)

<<.0001.00010.580.58––0.680.680.620.62Cohort: monthly vs Cohort: monthly vs weeklyweekly

PP--ValueValue95% CI95% CIHazard Hazard Ratio Ratio

EstimateEstimate

38% Less likely todiscontinue

Healthcore Managed Care Database, Poster 173, ISCD, March 14, 2007

84

OnceOnce--Monthly Monthly IbandronateIbandronate Patients Are Patients Are More Likely to Stay on Therapy More Likely to Stay on Therapy

• Patients taking monthly ibandronate were ~31% less likely to discontinue therapy than patients on weekly bisphosphonate therapy at 1 year

• Cox proportional hazard models were used to control for age, copay, comorbidities, prior fracture and DXA scan, and prescription supply

Monthly Ibandronate

WeeklyTherapy

*P<.0001

Rel

ativ

e Pe

rsis

tenc

e

0.9

0.6

0.8

1.0

0.7

0.5

HealthCore study

1.3

1.2

1.1

(n=1,006)(n=10,658)

i3 Innovus study(n=13,967) (n=3,512)

0.9

0.6

0.8

1.0

0.7

0.5

1.3

1.2

1.1

38% Less likely to discontinue*

25% Less likely to discontinue*

Rel

ativ

e Pe

rsis

tenc

e

Silverman SL, et al. Silverman SL, et al. Am Am CollColl Rheum. Rheum. 2006; Abstract 14252006; Abstract 1425

SummarySummary

►► Monthly Monthly ibandronateibandronate patients were more patients were more persistent and compliant at 1 year compared persistent and compliant at 1 year compared with patients on weekly bisphosphonate with patients on weekly bisphosphonate treatmentstreatments

Patients taking monthly Patients taking monthly ibandronateibandronate were ~31% were ~31% less likely to discontinue therapyless likely to discontinue therapy

►► Results were consistent between both databasesResults were consistent between both databases

85

Prescription Record DatabasesPrescription Record Databases

Retail Pharmacy Retail Pharmacy DatabasesDatabases

Types of DatabasesTypes of Databases

Managed Care Claims Databases

Managed Care Claims DatabasesManaged Care Claims Databases

►► StrengthsStrengths

Both pharmacy Both pharmacy and medical dataand medical dataCan be adjusted Can be adjusted for confounding for confounding medical data medical data variablesvariables

►► LimitationsLimitations

Time lag to Time lag to capture datacapture dataDonDon’’t capture t capture samples or samples or vouchersvouchers

86

Prescription Record DatabasesPrescription Record Databases

Types of DatabasesTypes of Databases

Retail Pharmacy Databases

Managed Care Claims Databases

Retail Pharmacy DatabasesRetail Pharmacy Databases

►► StrengthsStrengthsFaster data Faster data capturecaptureLarger numbersLarger numbers

►► LimitationsLimitationsMay not have May not have access to health access to health claims dataclaims dataHarder to adjust Harder to adjust for confounding for confounding medical datamedical dataDonDon’’t capture t capture samplessamples

87

Patient Persistence Rates with Weekly Patient Persistence Rates with Weekly Risedronate Risedronate vsvs Monthly IbandronateMonthly Ibandronate

D. T. Gold1, W. Safi*2, H. Trinh*2. 1Psychiatry and Behavioral SciencesDuke University Medical Center, Durham, NC, USA, 2Procter and Gamble, Mason, OH, USA

Mean Patient Persistence Rate Monthly vs Weekly Dosing

020406080

100120140160180

Once-Monthly Ibandronate(n=3,309)

Weekly Risedronate (n=22,718)

6 Months

Mea

n Pe

rsis

tenc

e(d

ays) 92.08 days

103.52 daysP<.0001

IMS longitudinal prescription database

Persistence Rates Across WeeklyPersistence Rates Across Weeklyand Monthly Bisphosphonatesand Monthly Bisphosphonates

Mean Patient Persistence Rate Monthly vs Weekly Dosing

0

10

20

30

40

Weekly Alendronate(n=141,847)

Weekly Risedronate(n=89,119)

Monthly Ibandronate (n=41,547)

6 Months

Mea

n Pe

rsis

tenc

e(1

80 d

ays)

T. W. Weiss1, H. von Allmen*2, S. C. Henderson*2, S. S. Sajjan*1, C. A. McHorney*1, L. E. Markson*1

Outcomes Research, Merck & Co., Inc., West Point, PA, USA, 2IMS Health, Plymouth Meeting, PA, USA

IMS longitudinal prescription database P<.000132.0% 29.7%

25.2%

88

Conclusions From DatabasesConclusions From Databases

►► Persistence results for weekly Persistence results for weekly vsvs monthly monthly therapy are conflicting between managed care therapy are conflicting between managed care claims and prescription records databasesclaims and prescription records databases

►► Evidence shows differences between patients Evidence shows differences between patients taking monthly and weekly therapiestaking monthly and weekly therapies

►► When persistence results are adjusted for When persistence results are adjusted for differences between patients prescribed differences between patients prescribed monthly monthly vsvs weekly bisphosphonate therapy, weekly bisphosphonate therapy, the data show an increased likelihood that the data show an increased likelihood that patients will stay on monthly therapypatients will stay on monthly therapy

►► Although compliance may be improved with Although compliance may be improved with monthly therapy, it remains suboptimalmonthly therapy, it remains suboptimal

SummarySummary

►► Persistence is not as good as you think it isPersistence is not as good as you think it isPatients who take their medications as prescribed have better Patients who take their medications as prescribed have better outcomes and lower fracture riskoutcomes and lower fracture risk

►► Data have shown that adherence is better with weekly Data have shown that adherence is better with weekly dosing than with daily dosingdosing than with daily dosing

►► Data have also shown that adherence with monthly Data have also shown that adherence with monthly dosing is better than with weekly dosingdosing is better than with weekly dosing

““If you match patients comparably, it gets betterIf you match patients comparably, it gets better””Adjust for differences, there does appear to be improved Adjust for differences, there does appear to be improved persistencepersistence

►► Patients starting weekly Patients starting weekly vsvs monthly bisphosphonate monthly bisphosphonate therapy were differenttherapy were different

►► All studies have shown that continued reinforcement All studies have shown that continued reinforcement by the physician is the simplest and most effective by the physician is the simplest and most effective interventionintervention