Postmenopausal Postmenopausal Osteoporosis OverviewOsteoporosis Overview

Bruce Ettinger, MD Bruce Ettinger, MD Senior InvestigatorSenior Investigator

Division of ResearchDivision of Research

Kaiser Permanente Medical Care ProgramKaiser Permanente Medical Care Program

Oakland, CaliforniaOakland, California

Summary of Summary of PresentationPresentation

Importance of Osteoporotic FractureImportance of Osteoporotic Fracture Making the diagnosisMaking the diagnosis Drug TreatmentsDrug Treatments

what workswhat works who should be treatedwho should be treated changing treatmentschanging treatments

* * Morphometric 3SD deformities Morphometric 3SD deformities Wasnich RD: Primer Metabolic Bone Diseases and Disorders of Mineral Wasnich RD: Primer Metabolic Bone Diseases and Disorders of Mineral Metabolism. 1999 Metabolism. 1999

Incidence Rates for Vertebral, Wrist and Hip Fractures in Women

After Age 50

4.04.0

3.03.0

2.02.0

1.01.0

Vertebrae*Vertebrae*

HipHip

WristWrist

Annual Annual incidence/100incidence/100

50 60 50 60 Age (yrs) 70 80Age (yrs) 70 80

Effect of Preexisting Vertebral Effect of Preexisting Vertebral Fracture on Risk of Subsequent Fracture on Risk of Subsequent

Vertebral FractureVertebral Fracture

R Lindsay, et al. R Lindsay, et al. JAMAJAMA 2001;285:320-23 2001;285:320-23

2725 2725 postmenopausal women randomized to placebo.postmenopausal women randomized to placebo.

00

55

1010

1515% % new new

vertebralvertebralfracturefracture

Number baseline vertebral fracturesNumber baseline vertebral fractures

RR = 7.3RR = 7.3

RR = 2.6RR = 2.6

00 11 22

Cumulative Hip Fracture Cumulative Hip Fracture ProbabilityProbability

20.720.7 21.421.4

10.610.610.310.3

00

55

1010

1515

2020

2525

HawaiiHawaii MinnesotaMinnesota HawaiiHawaii All JapanAll Japan

CaucasianCaucasian JapaneseJapanese

Relative Risk of Death Following Relative Risk of Death Following FracturesFractures

Fracture Intervention Trial (FIT)* Fracture Intervention Trial (FIT)*

JA Cauley, et al. JA Cauley, et al.

Osteoporos IntOsteoporos Int. 2000;11:556-61.. 2000;11:556-61.*6459 *6459 postmenopausal women, 55-81 yr, postmenopausal women, 55-81 yr, followed for an average of 3.8 years.followed for an average of 3.8 years.

Any ClinicalAny Clinical

Age-Adjusted Relative Risk (95% CI)Age-Adjusted Relative Risk (95% CI)00 1.01.0 2.02.0 5.05.0

Non-spineNon-spine

OtherOther

ForearmForearm

SpineSpine

HipHip

10.010.0

6.76.7

8.68.6

Mortality Rates by Number Mortality Rates by Number of of

Prevalent Vertebral Prevalent Vertebral FracturesFractures

Age-adjustedAge-adjustedmortalitymortality (per 1000 (per 1000

person-years)person-years)

DM Kado, et al. DM Kado, et al. Arch Intern MedArch Intern Med 1999;159:1215-20 1999;159:1215-20

Number baseline vertebral fracturesNumber baseline vertebral fracturesp for trend <.001

00

55

1010

1515

2020

2525

3030

3535

4040

00 11 22 33 44 5+5+

45

KyphosisKyphosis

Height loss Height loss

Ribs compress Ribs compress abdomen abdomen

Acute and chronic pain Acute and chronic pain

Limited activityLimited activity

Breathing difficultiesBreathing difficulties

Indigestion Indigestion Gastric refluxGastric reflux

Depression Depression

Impaired quality of lifeImpaired quality of life

Consequences of Vertebral Fractures

Vertebral Fractures Are Vertebral Fractures Are OverlookedOverlooked

Radiologist fail to diagnose vertebral Radiologist fail to diagnose vertebral deformities in routine x-raysdeformities in routine x-rays

Physicians fail to diagnose vertebral Physicians fail to diagnose vertebral fractures clinicallyfractures clinically Back pain is commonBack pain is common Painful vertebral fractures are Painful vertebral fractures are

not common not common Height and stature are not assessedHeight and stature are not assessed

Symptoms:Symptoms:• Acute and severeAcute and severe• Mid-back Mid-back • Localized Localized • May radiate anteriorlyMay radiate anteriorly

Signs:Signs:• Point tenderness over specific vertebraPoint tenderness over specific vertebra• Tender paravertebral muscles Tender paravertebral muscles • Pain increases with motionPain increases with motion

Distinguishing Vertebral Distinguishing Vertebral Fracture Fracture

From Other Back ProblemsFrom Other Back Problems

Prevalence and Site of Prevalence and Site of Vertebral FractureVertebral Fracture

0

10

20

30

40

T4 T5 T6 T7 T8 T9 T10 T11 T12 L1 L2 L3 L4 L5

0

10

20

30

40

T4 T5 T6 T7 T8 T9 T10 T11 T12 L1 L2 L3 L4 L5

0

10

20

30

40

T4 T5 T6 T7 T8 T9 T10 T11 T12 L1 L2 L3 L4 L5

Japanese in HawaiiJapanese in Hawaii

Japanese in HiroshimaJapanese in Hiroshima

Caucasian in MinnesotaCaucasian in Minnesota

WEDGE

ENDPLATE

CRUSH

Case FindingCase Findingfor Primary Care for Primary Care

PhysiciansPhysicians

ThinnessThinness SmokingSmoking Family historyFamily history History of fracturesHistory of fractures

HistoryHistory Height lossHeight loss KyphosisKyphosis Lateral spine filmLateral spine film Bone densityBone density

ExaminationExamination

Review of Clinical Trials of Review of Clinical Trials of Drugs for Treatment of Drugs for Treatment of

OsteoporosisOsteoporosis Double-blind, placebo-controlledDouble-blind, placebo-controlled Adequate power to detect effectAdequate power to detect effect Fracture endpointFracture endpoint

spine fracturesspine fractures non-spine fracturesnon-spine fractures

Osteoporosis DrugsOsteoporosis Drugs

Calcium with Vitamin DCalcium with Vitamin D Hormone TherapyHormone Therapy RaloxifeneRaloxifene BisphosphonatesBisphosphonates

alendronatealendronate risedronaterisedronate

Parathyroid hormone-teriparatideParathyroid hormone-teriparatide

Effects of Calcium (500mg) Effects of Calcium (500mg) Plus Vitamin D (700 IU) on Plus Vitamin D (700 IU) on Fractures in Elderly* Men Fractures in Elderly* Men

and Womenand Women

00 66 1212 1818 2424MonthsMonths

3030 3636

1515

1010

55

00

Calcium +Calcium +vitamin Dvitamin D

PlaceboPlacebo

Cu

mu

lati

veC

um

ula

tive

frac

ture

frac

ture

inci

den

ce (

%)

inci

den

ce (

%)

B Dawson Hughes, et al. NEJM 1997; 337:670B Dawson Hughes, et al. NEJM 1997; 337:670

* * All >65 yrsAll >65 yrs

mean 71 yrsmean 71 yrs

Effects of Vitamin D (800 IU) and Effects of Vitamin D (800 IU) and Calcium (1200 mg) in Elderly* Calcium (1200 mg) in Elderly*

WomenWomen

TreatmentTreatment PlaceboPlacebo % Reduction% Reduction

FracturesFractures n=872n=872 n=893n=893 in riskin risk

HipHip 109109 155155 2929

Non-vertebralNon-vertebral 218218 284284 2424

36 36 Months Follow-upMonths Follow-up

MC Chapuy, et al. NEJM 1992;327:1637MC Chapuy, et al. NEJM 1992;327:1637MC Chapuy, et al. BMJ 1994;308:1081MC Chapuy, et al. BMJ 1994;308:1081

**All in care centersAll in care centers

Mean age 84 yrsMean age 84 yrs

Use Combination of Calcium Use Combination of Calcium and Vitamin D in the Elderlyand Vitamin D in the Elderly

After age 65, calcium intake is low After age 65, calcium intake is low and absorption is inefficient. and absorption is inefficient.

Vitamin D alone does not reduce Vitamin D alone does not reduce fracture risk. * fracture risk. *

Calcium with Vitamin D form the Calcium with Vitamin D form the cornerstone of treatment but may cornerstone of treatment but may not be enough. not be enough.

* * HE Meyer, et al. JBMR 2002;17:709HE Meyer, et al. JBMR 2002;17:709* P Lips, et al. Ann Intern Med 1996;124:400* P Lips, et al. Ann Intern Med 1996;124:400

MORE StudyMORE StudyMMultiple ultiple OOutcomes of utcomes of RRaloxifene aloxifene

EEvaluationvaluation Multicenter, double-blind, placebo-controlled- 4 year studyMulticenter, double-blind, placebo-controlled- 4 year study Raloxifene 60 mg, 120 mg, or placebo (with calcium and Raloxifene 60 mg, 120 mg, or placebo (with calcium and

vitamin D)vitamin D) 7705 women, mean age 67-68 years7705 women, mean age 67-68 years

EndpointsEndpoints Primary: Primary: vertebral fracturevertebral fracture BMD BMD Secondary: Secondary: non-vertebral fracturenon-vertebral fracture, , CVD, breast cancer, uterine safety, CVD, breast cancer, uterine safety, cognitive function cognitive function

Effect of Raloxifene in WomenEffect of Raloxifene in WomenWith or Without Prevalent FracturesWith or Without Prevalent Fractures

Four YearsFour Years

No Prevalent FracturesNo Prevalent Fractures Prevalent FracturesPrevalent Fractures

%

% In

cid

ent

Fra

ctu

reIn

cid

ent

Fra

ctu

re

RR 0.51RR 0.51

RR 0.66RR 0.66

RR 0.62RR 0.62

RR 0.54RR 0.54

00

55

1010

1515

2020

2525

PlaceboPlaceboRLX 60RLX 60RLX120RLX120

K Harper, K Harper, ASBMR,ASBMR, 2000 2000

Efficacy of Raloxifene Through 4 Years

PD Delmas, et al. JCEM 87: 3609-17, 2002PD Delmas, et al. JCEM 87: 3609-17, 2002

Months of ExposureMonths of Exposure00 2424 3636 4848

00

55

1010

1515

Incidence of New Incidence of New Vertebral Fractures Vertebral Fractures

(%)(%) PlaceboPlaceboRLX 60 mg/dRLX 60 mg/d

1212

First Scheduled First Scheduled RadiographRadiograph

P<0.001P<0.001

Design of the Design of the Fracture Fracture

Intervention TrialIntervention Trial

FIT-1FIT-1 FIT-2FIT-2

Follow-up: 4.25 yearsFollow-up: 4.25 yearsFollow-up: 3 yearsFollow-up: 3 years

Vertebral fracture armVertebral fracture arm

n=2027n=2027

Baseline visitsBaseline visits BMDBMD EligibilityEligibility Spinal radiographSpinal radiograph

Clinical Fracture armClinical Fracture arm

n=4432n=4432

DM Black, et al. DM Black, et al. Lancet Lancet 348:1535, 1996348:1535, 1996

Effect of Alendronate* on RiskEffect of Alendronate* on Riskof Vertebral Fracturesof Vertebral Fractures

FIT-1 & FIT-2FIT-1 & FIT-2

DM Black,et al. DM Black,et al. Lancet Lancet 348:1535, 1996348:1535, 1996SR Cummings, et al. SR Cummings, et al. JAMA JAMA 280:2077, 1998280:2077, 1998

No Prevalent FracturesNo Prevalent Fractures Prevalent FracturesPrevalent Fractures

%

% In

cid

ent

Fra

ctu

reIn

cid

ent

Fra

ctu

re

RR 0.56RR 0.56

RR 0.54RR 0.54

00

55

1010

1515

2020

PlaceboPlaceboAlendronateAlendronate

* 5* 5mg/day for 2 yr, mg/day for 2 yr, then 10mg/daythen 10mg/day

VERT StudyVERT Study

5 5 years post-menopausalyears post-menopausal 85 years of age85 years of age Multi-National (n = 1226)Multi-National (n = 1226)**

2 vertebral fractures (T4-L4)2 vertebral fractures (T4-L4) North American (n = 2458)North American (n = 2458)****

2 vertebral fractures (T4-L4), or2 vertebral fractures (T4-L4), or 1 vertebral fracture and lumbar 1 vertebral fracture and lumbar

spine T-score spine T-score -2 -2

Inclusion CriteriaInclusion Criteria

* * J-Y Reginster, et al. J-Y Reginster, et al. Osteopor Int Osteopor Int 11:83, 200011:83, 2000** ** ST Harris, et al. ST Harris, et al. JAMA JAMA 282:1344, 1999282:1344, 1999

Effect of Risedronate on Effect of Risedronate on Incident Vertebral FracturesIncident Vertebral Fractures

VERT - North American VERT - North American VERT - Multi-National VERT - Multi-National

%

% w

tih

fra

ctu

rew

tih

fra

ctu

re

MonthsMonths MonthsMonths

J-Y Reginster et al, Osteopor Int 11:83, 2000J-Y Reginster et al, Osteopor Int 11:83, 2000ST Harris et al, ST Harris et al, JAMAJAMA 282: 1344, 1999 282: 1344, 1999

** 5.0 5.0 mg vs. mg vs. placeboplacebo p < 0.01 p < 0.01

00

55

1010

1515

2020

2525

3030

00 1212 2424 3636

**

**

**

00

55

1010

1515

2020

2525

3030

00 1212 2424 3636

**

**

**

PlaceboPlacebo Risedronate 5 mgRisedronate 5 mg

65% 65%

41% 41% 61% 61%

49% 49%

Secondary Endpoint: Secondary Endpoint: Incident Non-Vertebral Incident Non-Vertebral

FractureFracture

Ascertained by direct questioning Ascertained by direct questioning at each clinic visit at each clinic visit

ExcludedExcluded fractures due to severe traumafractures due to severe trauma finger, toe, face, and skull finger, toe, face, and skull

fracturesfractures pathologic fracturespathologic fractures

Effect of Raloxifene on Effect of Raloxifene on Risk of Risk of

Non-Vertebral FracturesNon-Vertebral FracturesFour YearsFour Years

RR=0.99RR=0.99

RR=0.87RR=0.87

00

22

44

66

88

1010

1212

1414

PlaceboPlacebo RaloxifeneRaloxifene60 mg60 mg

RaloxifeneRaloxifene120 mg120 mg

%

% In

cid

ent

Fra

ctu

reIn

cid

ent

Fra

ctu

re

PD Delmas, et al. JCEM 87: 3609-17, 2002PD Delmas, et al. JCEM 87: 3609-17, 2002

Risk of Nonvertebral* Fracture Risk of Nonvertebral* Fracture in Women With Baseline SQ in Women With Baseline SQ

Grade 3Grade 3MORE Trial - 3 YearsMORE Trial - 3 Years

00

55

1010

1515

2020

% % with with 1 1 non-vertebral fracturenon-vertebral fracture

RH = 0.53RH = 0.53 ( 0.29-0.99)( 0.29-0.99)

PlaceboPlacebo Raloxifene 60 mg/dRaloxifene 60 mg/d

* * Clavicle, humerus, wrist, pelvis, hip, legClavicle, humerus, wrist, pelvis, hip, leg

P Delmas, et al. Osteoporosis Int, 2002, Suppl.1 (presented at IOF)P Delmas, et al. Osteoporosis Int, 2002, Suppl.1 (presented at IOF)

Effect of Alendronate on Effect of Alendronate on RiskRisk of Non-vertebral Fracturesof Non-vertebral Fractures

FIT-1 plus selected FIT-2FIT-1 plus selected FIT-2

00 66 1212 1818 2424 3030 3636

1616

1010

66

00

MonthsMonths

AlendronateAlendronate

%

% In

cid

ent

Fra

ctu

reIn

cid

ent

Fra

ctu

re PlaceboPlacebo

D Black, et al. D Black, et al. JCEMJCEM 85:4118, 2000 85:4118, 2000

44

88

1212

1414

22

27%27%

Alendronate Fracture Risk Alendronate Fracture Risk ReductionReduction

Depends on Degree of Depends on Degree of OsteoporosisOsteoporosis

Relative risk vs. placeboRelative risk vs. placebo

Femoral Neck t-score Vert. Fx Clinical FxFemoral Neck t-score Vert. Fx Clinical Fx -1.6 to - 2.0 -1.6 to - 2.0 0.80.8 1.11.1 -2.5 to - 2.0-2.5 to - 2.0 0.50.5 1.01.0 below - 2.5below - 2.5 0.50.5 0.60.6

FIT-2FIT-2

SR Cummings, et al. SR Cummings, et al. JAMA JAMA 280:2077, 1998 280:2077, 1998

Effect of Risedronate on Risk Effect of Risedronate on Risk of of

Non-Vertebral Fractures Non-Vertebral Fractures

MonthsMonths MonthsMonths

00

55

1010

1515

2020

00 1212 2424 363600

55

1010

1515

2020

00 1212 2424 3636

North American North American Multi-National Multi-National

%

% w

ith

Fra

ctu

rew

ith

Fra

ctu

re

Harris et. al. Harris et. al. JAMA.JAMA. 1999;282(14):1344-52. 1999;282(14):1344-52. Reginster et al. Reginster et al. Osteoporos IntOsteoporos Int. 2000;11:83-91.. 2000;11:83-91.

PlaceboPlacebo Risedronate 5 mgRisedronate 5 mg

Effect of Risedronate Effect of Risedronate on Incidence of Hip Fractureon Incidence of Hip Fracture

39%39%

%

% w

ith

fra

ctu

rew

ith

fra

ctu

re

PlaceboPlacebo

RisedronateRisedronate

00

11

22

33

44

55

66

00 66 1212 1818 2424 3030 3636

MonthsMonths

Low Bone Density Group (Group 1)Low Bone Density Group (Group 1)

MR McClung, et al. MR McClung, et al. NEJMNEJM 344:333, 2001 344:333, 2001

Risedronate May Not Reduce Hip Fracture Risedronate May Not Reduce Hip Fracture

Risk in Non-Osteoporotic WomenRisk in Non-Osteoporotic Women

Risk Reduction Risk Reduction Cohort Cohort Hip Fracture Hip Fracture 70-79 years with70-79 years with t-score <3.0 t-score <3.0 39% 39% 80+ years80+ years

allall 18% 18% t-score <2.5t-score <2.5 26% 26%

M McClung, et al. NEJM 344:333, 2001M McClung, et al. NEJM 344:333, 2001

Fracture Risk Reductions Fracture Risk Reductions Observed Observed

in Trials of Anti-resorptive in Trials of Anti-resorptive TherapiesTherapies

SpineSpine

3 yr 1 yr3 yr 1 yr

45% 60%45% 60%

43% 68%*43% 68%*

45% 63%45% 63%

AlendronateAlendronate

RaloxifeneRaloxifene

RisedronateRisedronate

Non-SpineNon-Spine

3 yr 3 yr

12, 22, 27%12, 22, 27%

12, 48%12, 48%

12, 33, 18, 39%12, 33, 18, 39%

* * M Maricic, et al. Arch Intern Med 162:1140-1143, 2002M Maricic, et al. Arch Intern Med 162:1140-1143, 2002

EEvista vista VVersus ersus AAlendronatelendronate

EVAEVA Outcome- any osteoporotic Outcome- any osteoporotic

fracturefracture 3000 osteoporotic women3000 osteoporotic women

(hip t-score -2.5 to - 4.0) (hip t-score -2.5 to - 4.0) Start 2002, Finish 2007Start 2002, Finish 2007

CASE 1CASE 1

50 50 year-old womanyear-old woman Natural menopause 2 years agoNatural menopause 2 years ago Vasomotor symptomsVasomotor symptoms Bone density: t-score -1.6Bone density: t-score -1.6 Tried HRT but stopped due to Tried HRT but stopped due to

breast tenderness and bloatingbreast tenderness and bloating

Not a candidate for raloxifene or alendronateNot a candidate for raloxifene or alendronate

CASE 2CASE 2

65 65 year-old womenyear-old women Concerned about memoryConcerned about memory No menopausal symptomsNo menopausal symptoms Wrist fracture 3 years agoWrist fracture 3 years ago Bone density: t-score -3.0Bone density: t-score -3.0

High risk of fracture- requires treatmentHigh risk of fracture- requires treatment

Rationale for Raloxifene Use for Rationale for Raloxifene Use for Postmenopausal Women with Postmenopausal Women with

OsteoporosisOsteoporosis

To reduce risk of osteoporotic fractureTo reduce risk of osteoporotic fracture To reduce the risk of breast cancerTo reduce the risk of breast cancer To reduce risk of CHDTo reduce risk of CHD To prevent cognitive declineTo prevent cognitive decline Long-term safety and acceptanceLong-term safety and acceptance

CASE 3CASE 3

75 75 year-old womanyear-old woman prior wrist fractureprior wrist fracture presents with a painful L-1 crush presents with a painful L-1 crush

fracturefracture X-ray shows wedging T-7 and T-8X-ray shows wedging T-7 and T-8 Bone density t-score -3.5Bone density t-score -3.5

Needs strong, rapidly acting osteoporosis drugNeeds strong, rapidly acting osteoporosis drug

Antiresorptive Drugs Increase Antiresorptive Drugs Increase BMD but Not Bone VolumeBMD but Not Bone Volume

• Early BMD increase is due to filling in of remodelling Early BMD increase is due to filling in of remodelling (resorption) space(resorption) space

• Later BMD increase is due to increased mineralization Later BMD increase is due to increased mineralization of BMUof BMU

• Most of BMD effect can be explained by mineralizationMost of BMD effect can be explained by mineralization

GY Boivin, et al. Bone 27:687-694, 2000GY Boivin, et al. Bone 27:687-694, 2000CJ Hernandez, et al. Bone 29:511-516, 2001CJ Hernandez, et al. Bone 29:511-516, 2001

Excessive Suppression of Bone TurnoverExcessive Suppression of Bone Turnover

ProlongedProlongedMineralizationMineralization

Insufficient RepairInsufficient Repairof Microdamageof Microdamage

Damage AccumulationDamage Accumulation

Decrease in Bone ToughnessDecrease in Bone Toughness

Long-term Safety?Long-term Safety?

Relationship Between Excessive Suppression Of Bone Turnover and Damage Accumulation

Hypothetical Effects of Hypothetical Effects of Increasing Bone Mineralization Increasing Bone Mineralization

DisplacementDisplacementCH Turner Osteoporos Int 13:97-104, 2002CH Turner Osteoporos Int 13:97-104, 2002

ForceForce

OptimumOptimum

Hypo-mineralizedHypo-mineralized

Hyper-mineralizedHyper-mineralizedxx

xx

xx

Hypothetical Effects of Hypothetical Effects of Increasing Bone Mineralization Increasing Bone Mineralization

Percentage MineralizationPercentage Mineralization

ResistanceResistance to fracture to fracture forcesforces

Improved resistance to Improved resistance to bending = stiffnessbending = stiffness

Increasing brittlenessIncreasing brittleness

Safety Concerns Safety Concerns RegardingRegarding

Long-term AlendronateLong-term Alendronate Rate of clinical spine fractures during Rate of clinical spine fractures during

years 5-7 was 3 times higher years 5-7 was 3 times higher than during years 1-3than during years 1-3

Height loss (1.2mm/yr) during Height loss (1.2mm/yr) during years 5-7 tended to be higheryears 5-7 tended to be higherthan during years 1-3 (1.0mm/yr)than during years 1-3 (1.0mm/yr)

RP Tonino, et al. JCEM 85:3109, 2000RP Tonino, et al. JCEM 85:3109, 2000

Eff

icac

yE

ffic

acy

TimeTime00

Drug ADrug A

Drug BDrug B

Concept of Sustained vs. Concept of Sustained vs. Unsustained EfficacyUnsustained Efficacy

For Severe Osteoporosis:For Severe Osteoporosis:Prescribe SequentiallyPrescribe Sequentially

Short-termShort-term “quick-fix” with a strong “quick-fix” with a strong bone-specific agentbone-specific agent

Long-termLong-term bone maintenance with bone maintenance with a milder (and safer) effect:a milder (and safer) effect: multipurpose drug - raloxifenemultipurpose drug - raloxifene

Key Messages for Key Messages for Primary Care PhysiciansPrimary Care Physicians

Osteoporosis is frequently overlookedOsteoporosis is frequently overlooked Osteoporosis is treatableOsteoporosis is treatable Drug treatment should be encouraged Drug treatment should be encouraged

for those at highest risk for those at highest risk