Critical Challenges in Osteoporosis—Critical Challenges in Osteoporosis—From Patient Presentation ToFrom Patient Presentation ToTherapeutic Decision Points: Therapeutic Decision Points:

An Overview of Issues, Concepts,An Overview of Issues, Concepts,and Clinical Strategiesand Clinical Strategies

SCREEN AND INTERVENESCREEN AND INTERVENEEvidence-Basis for Patient ScreeningEvidence-Basis for Patient Screening

and Risk Stratification: Principles for Approaching aand Risk Stratification: Principles for Approaching aBroad Population of Patients at Risk for OsteoporosisBroad Population of Patients at Risk for Osteoporosis

► DefinitionsDefinitions

► EpidemiologyEpidemiology

► PathophysiologyPathophysiology

► Clinical FeaturesClinical Features

► DiagnosisDiagnosis

► TherapyTherapy

Program ContentsProgram Contents

1. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. JAMA. 2001;285:785-795.

DefinitionDefinition

Osteoporosis is defined as a skeletal Osteoporosis is defined as a skeletal disorder characterized by compromised disorder characterized by compromised bone strength predisposing a person to bone strength predisposing a person to increased risk of fractureincreased risk of fracture11

Key Features of OsteoporosisKey Features of Osteoporosis

► Bone involution in both sexes with Bone involution in both sexes with aging and a superimposed aging and a superimposed acceleration of bone loss in women acceleration of bone loss in women after the menopauseafter the menopause

► Low bone mass coupled with micro-Low bone mass coupled with micro-architectural deterioration leading to architectural deterioration leading to enhanced bone fragility and enhanced bone fragility and ultimately fractureultimately fracture

Risk Factors You Can’t ChangeRisk Factors You Can’t Change

ContentsContents

► EpidemiologyEpidemiology

PrevalencePrevalence

IncidenceIncidence

SitesSites

CostCost

Status of careStatus of care

► 44 million Americans have or are at risk of 44 million Americans have or are at risk of osteoporosisosteoporosis 55% of all people ages 55% of all people ages 50 years 50 years 10 million have osteoporosis10 million have osteoporosis 34 million more have low bone mass34 million more have low bone mass

► 50% of women aged 50% of women aged 50 years will 50 years will experience a fracture in their lifetimeexperience a fracture in their lifetime

► Prevalence is expected to increase with the Prevalence is expected to increase with the growth of the elderly populationgrowth of the elderly population

PrevalencePrevalence

Prevalence of Osteoporosis Will Increase Prevalence of Osteoporosis Will Increase With an Increasing Aging PopulationWith an Increasing Aging Population

Paiement GD, Perrier L. In: Comprehensive Management of Menopause. 1994:32-38. US Census Bureau. 2000.

0

5

10

15

20

%Projected Population

>65 Years

1900

1950

1985

2020

Osteoporotic Fracture Incidence Is HighOsteoporotic Fracture Incidence Is High

0

200,000

400,000

600,000

800,000

1,000,000

1,200,000

1,400,000

1,600,000

BreastCancer

HeartDisease

OsteoporoticFractures

Cas

es/Y

ear

Women’s Health Facts and Figures. Washington, DC: ACOG; 2000.

NIH/ORBD National Resource Center. October 2000.

Vertebral46%

(700,000)

Wrist16%

(250,000)

Hip19%

(300,000)

Other19%

(300,000)

Distribution of FracturesDistribution of Fractures

High Economic BurdenHigh Economic Burden

Estimated $13.8 billion/yearEstimated $13.8 billion/year

Outpatient Outpatient ($1.3)($1.3)

Hospitalization Hospitalization ($8.6)($8.6)

NursingNursingHomeHome($3.9)($3.9)

Ray NF et al. J Bone Miner Res. 1997;12:24-35.

► 3% to 5% of hip fracture patients are 3% to 5% of hip fracture patients are diagnosed for osteoporosis and diagnosed for osteoporosis and treated treated

► 3% of wrist fracture patients receive 3% of wrist fracture patients receive BMD testingBMD testing

► Only 12% of vertebral fractures are Only 12% of vertebral fractures are diagnosed and 2% are treateddiagnosed and 2% are treated

Current Status of CareCurrent Status of Care

Freedman KB et al. J Bone Joint Surg Am. 2000;82:1063-1070.Gehlbach SH et al. Osteoporosis Int. 2000;11:577-582.Wiktorowicz ME. J Bone Miner Res. 1997;12:S252.

► PathophysiologyPathophysiology

Bone RemodelingBone Remodeling

Types of Types of OsteoporosisOsteoporosis

ContentContent

OsteoclastOsteoclast

ResorptionResorption

OsteoblastOsteoblast

Osteoblast Osteoblast RecruitmentRecruitment

Osteoid Osteoid DepositionDeposition

MineralizationMineralization

Courtesy: Dr. Mone Zaidi

The Bone Remodeling CycleThe Bone Remodeling Cycle

► High Remodeling Hypogonadal (including post-menopausal)

Hyperparathyroidism

Hyperthyroidism

Others

► Low Remodeling Involutional (Aging)

Glucocorticoids (high dose)

HIV

Disordered Bone RemodelingDisordered Bone Remodelingas the Cause of Osteoporosisas the Cause of Osteoporosis

Pathogenesis of OsteoporosesPathogenesis of OsteoporosesResorption Must Exceed FormationResorption Must Exceed Formation

Normal RemodelingNormal Remodeling

OsteoOsteocclast Overactivitylast OveractivityHypogonadal StatesHypogonadal States

Parathyroid and ThyroidParathyroid and Thyroid

OsteoOsteobblast Dysfunctionlast DysfunctionInvolutional (Aging)Involutional (Aging)

GlucocorticoidsGlucocorticoidsHIVHIV

Courtesy: Mone Zaidi, MD Mount Sinai School of Medicine

► Clinical FeaturesClinical Features

Vertebral FracturesVertebral Fractures

Non-Vertebral Non-Vertebral FracturesFractures

Risk StratificationRisk Stratification

ContentContent

Vertebral FracturesVertebral Fractures

► Most common fractures (46%)Most common fractures (46%)

► InsidiousInsidious

► ProgressiveProgressive

► Often unrecognizedOften unrecognized

► Associated with Associated with

– Deformity, height loss, back pain Deformity, height loss, back pain

– Morbidity and mortalityMorbidity and mortality

► Predict future vertebral and non-vertebral Predict future vertebral and non-vertebral fracturesfractures

► Entire skeleton can be involvedEntire skeleton can be involved– WristWrist– AnkleAnkle– PelvisPelvis– HumerusHumerus– RibRib– OthersOthers

► Associated with significant disabilityAssociated with significant disability

NonVertebral FracturesNonVertebral Fractures

► Most serious clinical event Most serious clinical event ► Morbidity is highMorbidity is high

– 50% do not regain independence50% do not regain independence– 50% do not regain previous mobility50% do not regain previous mobility

► Mortality is highMortality is high– 1 in 5 patients die within 1 year1 in 5 patients die within 1 year

► Patients not treated for osteoporosisPatients not treated for osteoporosis

NIH Consensus Development Panel. JAMA. 2001;285:785-795.

Hip FractureHip Fracture

► Low BMDLow BMD► Fracture after 50 yearsFracture after 50 years► Age Age 65 years65 years► Maternal history of fracture after 50 yearsMaternal history of fracture after 50 years► Low body weight (Low body weight (125 lb)125 lb)► SmokingSmoking► Corticosteroid useCorticosteroid use► Other secondary causesOther secondary causes

Black DM et al. Osteoporosis Int. 2001;12:519-528.

All postmenopausal women with the following:

Risk of FractureRisk of Fracture

Klotzbuecher CM et al. J Bone Miner Res. 2000;15:721-739.

Future Fractures (Fold Increase)

Existing Fracture

Wrist

Vertebral

Hip

Hip

1.9

2.3

2.3

Vertebral

1.7

4.4

2.5

Wrist

3.3

1.4

-

A Fracture Begets a Future FractureA Fracture Begets a Future Fracture

Fracture Stratification Key Points Fracture Stratification Key Points

► Main risk factorsMain risk factors– Low BMD Low BMD – Presence of a fracture after 50 Presence of a fracture after 50

yearsyears

► Risk for fracture increases Risk for fracture increases

– With number of risk factorsWith number of risk factors

– With each subsequent fractureWith each subsequent fracture

► DiagnosisDiagnosis

Clinical AssessmentClinical Assessment

Diagnostic CriteriaDiagnostic Criteria

Bone DensitometryBone Densitometry

ContentContent

► HistoryHistory– Risk factor assessment Risk factor assessment – Medical historyMedical history– Family historyFamily history– Social history (smoking, alcohol)Social history (smoking, alcohol)– Evaluation of fall riskEvaluation of fall risk

► PhysicalPhysical– Height loss >1.5 inchesHeight loss >1.5 inches– KyphosisKyphosis

► TestsTests– BMDBMD– X-ray of thoracic/lumbar spineX-ray of thoracic/lumbar spine– Bone turnover markersBone turnover markers– Laboratory tests as necessaryLaboratory tests as necessary

AACE Guidelines. Endocr Pract. 2001;7:293-312.

Clinical EvaluationClinical Evaluation

The Kyphotic WomanThe Kyphotic Woman

► Likely has Likely has osteoporosis and osteoporosis and vertebral fracturesvertebral fractures

► Confirmatory spinal Confirmatory spinal x-ray for diagnosisx-ray for diagnosis

► Baseline BMDBaseline BMD

The Non-Kyphotic Woman► Spinal x-ray or DXA Spinal x-ray or DXA

if height loss >1.5 if height loss >1.5 inchesinches

► Atraumatic Atraumatic vertebral fractures = vertebral fractures = osteoporosis aosteoporosis a

Kyphotic vs. Non-KyphoticKyphotic vs. Non-Kyphotic

DiagnosisDiagnosis

BMD Criteria: Low T-Score BMD Criteria: Low T-Score

Non-BMD Criteria: Fragility FractureNon-BMD Criteria: Fragility Fracture

T-Score* T-Score* ClassificationClassification >> -1.0 -1.0 NormalNormal

-1.0 to -2.5-1.0 to -2.5 Osteopenia Osteopenia

<< -2.5 or lower -2.5 or lower OsteoporosisOsteoporosis

<< -2.5 + fracture -2.5 + fracture Severe osteoporosisSevere osteoporosis

WHO Diagnostic CriteriaWHO Diagnostic Criteria

The WHO Study Group. Geneva, 1994The WHO Study Group. Geneva, 1994

*T-score = number of standard deviations (SDs) below or above the peak bone massin young adults.

Risk Assessment/ Risk Assessment/ ResearchResearch►Peripheral DXA (pDXA)Peripheral DXA (pDXA)►UltrasoundUltrasound►Quantitative computed Quantitative computed

tomography (QCT)tomography (QCT)

DiagnosisDiagnosis

Central dual energy x-ray Central dual energy x-ray absorptiometry (DXA) absorptiometry (DXA) ► Gold standardGold standard► WHO criteria WHO criteria

appliedapplied

National Osteoporosis Foundation. Washington, DC; 1999.

TechniquesTechniques

Central DXACentral DXA► Establish or confirm Establish or confirm

diagnosis diagnosis ► Assess fracture riskAssess fracture risk► Follow upFollow up► Enhance patient complianceEnhance patient compliance

Peripheral DXA► Different from WHODifferent from WHO

T-score criteriaT-score criteria

► Fracture risk Fracture risk assessment in elderly assessment in elderly with low T-scoreswith low T-scores

Central vs Peripheral DXACentral vs Peripheral DXA

► Therapeutic ConsiderationsTherapeutic Considerations Mode of ActionMode of Action

Anti-resorptive AgentsAnti-resorptive Agents

Anabolic AgentsAnabolic Agents

Bisphosphonate FailureBisphosphonate Failure

Efficacy TestingEfficacy Testing

ContentContent

► Fracture preventionFracture prevention► Stabilize or increase bone massStabilize or increase bone mass► Provide tolerability and long-Provide tolerability and long-

term safetyterm safety► Ensure compliance and Ensure compliance and

adherenceadherence

Goals for TherapyGoals for Therapy

► Calcium intakeCalcium intake– Diet and/or supplementation: 1200 mg/dayDiet and/or supplementation: 1200 mg/day

► Vitamin D supplementationVitamin D supplementation– Diagnose and treat deficiency/insufficiencyDiagnose and treat deficiency/insufficiency

– Supplement: 400-800 IU/daySupplement: 400-800 IU/day

► Regular load-bearing and muscle-strengthening Regular load-bearing and muscle-strengthening exercise (no weight lifting if BMD in spine is low)exercise (no weight lifting if BMD in spine is low)

► Fall prevention adviceFall prevention advice

► Home safety evaluationHome safety evaluation

Nonpharmacologic ApproachesNonpharmacologic Approaches

YesYes **Parathyroid hormoneParathyroid hormone

(Forteo(Forteo®®))

YesYes YesYesRisedronate (ActonelRisedronate (Actonel®®))

YesYes YesYesAlendronate (FosamaxAlendronate (Fosamax®®))

YesYes YesYesRaloxifene (EvistaRaloxifene (Evista®®))

YesYes NoNoCalcitonin (MiacalcinCalcitonin (Miacalcin®®))

NoNo YesYesHormone replacementHormone replacement

TreatmentTreatmentPreventionPreventionFDA-ApprovedFDA-Approved

*Not considered.

YesYes YesYesIbandronate (BonivaIbandronate (Boniva®®))

YesYes YesYesIbandronate InjectionIbandronate Injection

(Boniva(Boniva®®))

MedicationsMedications

Osteoporosis TherapeuticsOsteoporosis Therapeutics

Decrease ResorptionDecrease Resorption Enhance Formation Enhance Formation ► Bisphosphonates Bisphosphonates

► Estrogen Estrogen

► RaloxifeneRaloxifene

► CalcitoninCalcitonin

► Parathyroid Parathyroid HormoneHormone

Anti-Resorptive Anti-Resorptive VersusVersus Anabolic Anabolic

High Turnover Bone LossHigh Turnover Bone Loss

Low Turnover Bone LossLow Turnover Bone Loss

Anti-ResorptiveAnti-Resorptive

PTH - AnabolicPTH - Anabolic

Courtesy: Mone Zaidi, MD Mount Sinai School of Medicine

Mode of Delivery = Bone ActivityMode of Delivery = Bone Activity

IntermittentIntermittent versus versus ContinuousContinuous==

OsteoblasticOsteoblastic versus versus OsteoclasticOsteoclastic==

FormationFormation versusversus Resorption Resorption==

Bone GainBone Gain versus versus Bone LossBone Loss

PTHPTH

Courtesy: Mone Zaidi, MD Mount Sinai School of Medicine

PTH – Anabolic ActionPTH – Anabolic Action

Receptor Binding and Signal Transduction

Enhanced Osteoblast Differentiation

Increased Osteoblast Survival

Net Increase in Number and Activity of Bone-Forming

Osteoblasts

Calcitonin

Courtesy: Mone Zaidi, MD Mount Sinai School of Medicine

PROOF: Three Year Analysis

Nasal Calcitonin: Efficacyat the Spine and Hip

Estrogen and RaloxifeneEstrogen and Raloxifene

► Reduce the birth (genesis) of new osteoclasts Reduce the birth (genesis) of new osteoclasts from bone marrowfrom bone marrow

► Does not inhibit the activity of mature resorbing Does not inhibit the activity of mature resorbing osteoclastsosteoclasts

► Osteoclast birth increases exponentially to a Osteoclast birth increases exponentially to a peak within the first few years of the peak within the first few years of the menopausal transitionmenopausal transition

► Maximum bio-efficacy in early menopause and Maximum bio-efficacy in early menopause and declines with age and disease severity/fracturesdeclines with age and disease severity/fractures

Zaidi, M., et. al. (2001) Journal of Bone and Mineral Research.

Structure of BisphosphonatesStructure of Bisphosphonates

OHOH OHOH

OHOHOHOH R1R1

R2R2

O = O = P – O – PP – O – P = O = O

OHOH OHOH

OHOHOHOH

BisphosphonateBisphosphonate PolyphosphatePolyphosphate

O = O = P – C – PP – C – P = O = O

Bisphosphonate Mechanism of ActionBisphosphonate Mechanism of Action

Courtesy: Mone Zaidi, MD Mount Sinai School of Medicine

Possible Causes of Poor Adherence?Possible Causes of Poor Adherence?

Disruption to daily routine?

(less frequent dosing)

Concern about side effects?

Osteoporosis eclipsed by

other chronic conditions?

Lack of positive reinforcement?

Complex dosing

guidelines?

Poor patient education?

POORADHERENCE

Adherence With Osteoporosis Adherence With Osteoporosis Medications Is PoorMedications Is Poor

Tosteson ANA, et al. Am J Med. 2003;115:209-216.

Pat

ien

ts A

ban

do

nin

gT

reat

men

t (%

)

30

25

20

15

10

5

0 Hormone Replacement Therapy(n=334)

Bisphosphonate(n=366)

Selective Estrogen Receptor Modulator

(n=256)

26%

19% 19%

Siris E, et al. Presented at: Sixth International Symposium on Osteoporosis. April 6-10, 2005; Washington, DC.

Long-term Compliance Reduces Long-term Compliance Reduces Fracture RiskFracture Risk

% P

atie

nts

Wit

h F

ract

ure

0

2

4

6

8

10

12

14

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

*

†

9.4%

12.6%

Ettinger M, et al. Arthritis Rheum. 2004;50(suppl):S513-S514. Abstract 1325. Data on file (Reference # 161-040), Hoffmann-La Roche Inc., Nutley, NJ 07110.

P<0.001 vs daily therapy

10

20

30

40

50

60

70

80

90

100

Oct2002

Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct2003

Pat

ien

ts o

n T

her

apy

(%)

Daily Bisphosphonates (n=33,767)

Weekly Bisphosphonates (n=177,552)

54.6%

36.9%

Daily vs. Weekly Bisphosphonates Has Led To Increased Compliance

Daily Weekly

BMD Changes: 30-Minute vs 60-Minute BMD Changes: 30-Minute vs 60-Minute Postdose Fast With Ibandronate-SodiumPostdose Fast With Ibandronate-SodiumBMD Changes: 30-Minute vs 60-Minute BMD Changes: 30-Minute vs 60-Minute

Postdose Fast With Ibandronate-SodiumPostdose Fast With Ibandronate-Sodium

Tankó LB, et al. Bone. 2003; 32:421-426.

30-minute postdose fast60-minute postdose fast

Although significant vs baseline, the BMD gains seen in the 30-minute postdose fast group were inferior to those seen in the 60-minute postdose group.

Spine (L1-L4) Trochanter Total Hip Femoral Neck

Mea

n %

Ch

an

ge

in B

MD

(95

% C

l)7

6

5

4

3

2

1

0

The FDA-mandated primary outcome measures The FDA-mandated primary outcome measures (end point) for all pivotal trials is the (end point) for all pivotal trials is the demonstration of efficacy in reducing vertebral demonstration of efficacy in reducing vertebral fracturefracture

Non-vertebral fractures, BMD and bone Non-vertebral fractures, BMD and bone remodeling markers are secondary end pointsremodeling markers are secondary end points

Secondary end points are never statistically Secondary end points are never statistically powered in terms of patient numbers to detect powered in terms of patient numbers to detect differences between placebo and drugdifferences between placebo and drug

Efficacy Testing OfEfficacy Testing OfAnti-osteoporosis DrugsAnti-osteoporosis Drugs

► Multiple non-vertebral sites, the definition of which varies across clinical trials

► Heterogenous group of bones, with different proportions of cortical and cancellous bone

► Differences in non-vertebral fracture incidence and disease severity in placebo groups

Non-Vertebral FracturesNon-Vertebral Fractures

ConclusionsConclusions

► Characterized by a loss of bone mass and architectureCharacterized by a loss of bone mass and architecture

► Inevitable consequence of aging in both sexesInevitable consequence of aging in both sexes

► Accelerated following menopause, disease and drugsAccelerated following menopause, disease and drugs

► Early detection and intervention is mandatoryEarly detection and intervention is mandatory

► Fracture stratification allows identification beyond Fracture stratification allows identification beyond

BMDBMD

► Bisphosphonates are the mainstay of therapy Bisphosphonates are the mainstay of therapy

► Ensuring compliance through less complex dosing Ensuring compliance through less complex dosing

should lead to greater therapeutic benefit should lead to greater therapeutic benefit

Fracture Risk ReportingFracture Risk Reporting

► Since the goal of osteoporosis therapy is Since the goal of osteoporosis therapy is fracture prevention, patient selection is fracture prevention, patient selection is best based on fracture riskbest based on fracture risk

► T-score alone does not provide a complete T-score alone does not provide a complete assessment of fracture riskassessment of fracture risk

► Combination of clinical risk factors with Combination of clinical risk factors with BMD may provide a better way of BMD may provide a better way of identifying patients for treatmentidentifying patients for treatment

Selection of Clinical Risk FactorsSelection of Clinical Risk Factors

► Independent of BMD (if BMD is known)Independent of BMD (if BMD is known)

► Validated in multiple populations Validated in multiple populations (sex, ethnicity, country) (sex, ethnicity, country)

► Easily obtainableEasily obtainable

► Amenable to intended treatmentAmenable to intended treatment

► IntuitiveIntuitive

Adapted from Kanis JA et al. Osteoporos Int. 2005;16:581-589.

Clinical Risk FactorsClinical Risk Factors

Femoral neck T-score +Femoral neck T-score +

► AgeAge

► Previous low trauma fracturePrevious low trauma fracture

► Current cigarette smokingCurrent cigarette smoking

► Rheumatoid arthritisRheumatoid arthritis

► High alcohol intake (> 2 units/day)High alcohol intake (> 2 units/day)

► Parental history of hip fractureParental history of hip fracture

► Prior or current glucocorticoid usePrior or current glucocorticoid use

Adapted from Kanis JA et al. Osteoporos Int. 2005;16:581-589.

Intervention ThresholdIntervention Threshold

► A fracture probability above which it A fracture probability above which it is is cost-effectivecost-effective to treat with to treat with pharmacological agentspharmacological agents

► Based on statistical modeling using Based on statistical modeling using many medical, social, and economic many medical, social, and economic assumptions assumptions