Osteoporosis Management: What Does the Data Support? Osteoporosis Definition 2001: Compromised bone strength predisposing to increased risk of fragility

Osteoporosis Management:What Does the Data Support?

Osteoporosis Definition 2001Osteoporosis Definition 2001: :

Compromised bone strength Compromised bone strength

predisposing to increased risk predisposing to increased risk

of fragility fracturesof fragility fractures

Osteoporosis - DiagnosisFragility Fractures

Spine ~ 700,000/year in USSpine ~ 700,000/year in US

Hip ~ 300,000/year in USHip ~ 300,000/year in US

Wrist ~ 250,000/year in USWrist ~ 250,000/year in US

Normal Normal T-score > -1.0T-score > -1.0

Osteopenia Osteopenia T-score = -1.0 to -2.5T-score = -1.0 to -2.5

Osteoporosis Osteoporosis T-score < -2.5T-score < -2.5

Established in Postmenopausal Women

Osteoporosis - DiagnosisBone Densitometry Criteria

Bone Densitometry Report

-4.5-4

-3.5-3

-2.5-2

-1.5-1

-0.50

20 30 40 50 60 70 80 90 100Age (years)

SD

(T

-sco

re)

x

T-score

T-score = -3.0

T-score predicts fracture risk

Who to Treat?

All Patients With Existing Osteoporotic Fractures (Hip, Spine, Wrist) or . . .

National Osteoporosis Foundation. Washington, DC. 1998.

Who to Treat?

Therapy Decision

High Risk

Treat

Moderate Risk

Treat if other risk factors

Low Risk

Check again in 1-2 years

T-Score*

Below -2.0

-1.5 to -2.0

Above -1.5


* Based on measurements from central DXA.

Case Presentation

A 56 year old woman inquires about her A 56 year old woman inquires about her osteoporosis risk. No prior fractures.osteoporosis risk. No prior fractures.PMH: negative PMH: negative Family Hx: mother - osteoporosisFamily Hx: mother - osteoporosisDietary calcium: 600 mg/dayDietary calcium: 600 mg/dayMeds: calcium 600 mg/day, vitaminsMeds: calcium 600 mg/day, vitaminsPE: Ht 5’7’’ 128 lb. no kyphosisPE: Ht 5’7’’ 128 lb. no kyphosis

BMD:BMD: T-scoreT-score Z-scoreZ-scoreSpine (L2-L4) -1.91Spine (L2-L4) -1.91 -1.31 -1.31Femoral NeckFemoral Neck -1.68 -1.68 -1.08 -1.08

What does the data support?

Therapy Decision

High Risk

Treat

Moderate RiskTreat if other risk factors

Low Risk


T-Score*

Below -2.0

-1.5 to -2.0

Above -1.5



0

0.5

1

T-Score <= -2.5 T-Score > -2.5

Ev

en

ts p

er

10

0 P

YR Placebo

Alendronate

Black et al, ASBMR M352 2002

37% Reduction

P=0.044

60% Reduction

P=0.005

Treatment of Patients with OsteopeniaClinical Fracture Prevention - Alendronate

Osteoporosis Osteopenia

Case Presentation

A 75 year old woman with 2 past vertebral A 75 year old woman with 2 past vertebral fractures. No back pain at present.fractures. No back pain at present.PMH: HTN, DJDPMH: HTN, DJD Fam Hx: no osteoporosisFam Hx: no osteoporosisDietary calcium: 300 mg/day Dietary calcium: 300 mg/day Meds: lisinopril, calcium 500 mg/day, Meds: lisinopril, calcium 500 mg/day, vitamins vitamins PE: Ht 5’4’’ 116 lb. dorsal kyphosisPE: Ht 5’4’’ 116 lb. dorsal kyphosis

BMD:BMD: T-scoreT-score Z-scoreZ-scoreSpine (L2-L4) -3.69Spine (L2-L4) -3.69 -1.42 -1.42Femoral NeckFemoral Neck -2.98 -2.98 -1.01 -1.01

Therapy Decision

High RiskTreat

Moderate Risk

Treat if other risk factors

Low Risk


T-Score*

Below -2.0

-1.5 to -2.0

Above -1.5



What does the data support?

OsteoporosisNon-Pharmacological Measures

Calcium: 1500 mg/dayCalcium: 1500 mg/day Vitamin D: 400-800 units/dayVitamin D: 400-800 units/day ExerciseExercise

AerobicAerobic ResistanceResistance

Hip ProtectorsHip Protectors Fall Prevention Fall Prevention Habit Alteration (cigarettes, alcohol)Habit Alteration (cigarettes, alcohol)





Dietary Calcium Intake Estimate

300 mg calcium in general diet300 mg calcium in general diet 300 mg calcium in every dairy serving300 mg calcium in every dairy serving

1 cup of milk1 cup of milk1 oz. of cheese1 oz. of cheese1 cup of yogurt1 cup of yogurt1 cup of calcium fortified citrus drink1 cup of calcium fortified citrus drink

Calcium SupplementsSolubility and Absorption

Heaney R, Calc Tissue Int 1990; 46:300-304

Fractional Fractional Solubility Absorption Absorption

Preparation (mM/liter) w Meal w/o Meal

Calcium carbonate 0.14 30% 24%

Tricalcium phosphate 0.97 25%

Calcium citrate 7.3 24%

Calcium citrate malate 80 36%

352 calcium absorption studies in normal subjectsDouble isotope (45Ca, 47Ca) or single isotope (45Ca)

0

10

20

30

40

50

60

Previous Fracture No Previous Fracture

PlaceboCalcium

Osteoporosis TreatmentCalcium Supplementation

RCT: 197 healthy women (mean age: 73.5 yr.)(< 1 gm Ca/day) Previous fracture (n=94); No previous fracture (n=103) Calcium carbonate (1,200 mg/d) vs. Placebo x 4 years

Recker R, J Bone Min Res 1996; 11:1961-6

% WhoFractured

P=.023

P=.435

42% reduction

No reduction





0

2

4

6

8

10

12

14

Nonvertebral Fracture

PlaceboCalcium + Vitamin D

Osteoporosis TreatmentVitamin D Supplementation

RCT: 389 ambulatory subjects (mean age: 71 yr; 213 F, 176 M) Vitamin D (700 U/d) + Calcium (500 mg/d) vs. Placebo

Dawson-Hughes, NEJM 1997; 337:670-6

% WhoFractured

P=.02

55% reduction

0

20

40

60

80

100

120

Hip Fracture NonvertebralFracture

ControlCalcium + Vitamin D

Osteoporosis TreatmentCalcium and Vitamin D

RCT: 3270 healthy elderly women (mean age: 84 yr.) Calcium (1,200 mg/d) + Vitamin D (800 U/d) vs. Control

Chapuy M, NEJM 1992; 327:1637-42

Numberof

Fractures

P=.043

P=.015

43% reduction

32% reduction





Osteoporosis TreatmentExercise

-0.6

-0.4

-0.2

0

0.2

0.4

0.6

0.8

1

1.2

1.4

Nelson M, JAMA 1994; 272:1909-14

Control Exercise

P=.03

RCT: 39 women, sedentary, no estrogen (Age: 50-70 yr.) Strength training (n=20) vs. Controls (n=19) for 1 year

-3

-2.5

-2

-1.5

-1

-0.5

0

0.5

1

1.5

FemoralNeckLumbarSpine

Mu

scle

Mas

s C

han

ge (

Kg)

BM

D C

han

ge (

%)

Control Exercise

P=.02P=.04





Osteoporosis TreatmentHip Protectors

05

10152025

3035404550

Control Hip Protector

Hip Fracturesper 1000patient years

Kannus P, NEJM 2000; 343:1506-13

P = .008

60% reduction

RCT: 1801 elderly adults (mean age: 82 yr.) (1409 F, 392 M) Hip protector group (n=653) vs. Control group (n=1148)




Hip ProtectorsHip Protectors Fall PreventionFall Prevention Habit Alteration (cigarettes, alcohol)Habit Alteration (cigarettes, alcohol)

Osteoporosis TreatmentFall Prevention

0

10

20

30

40

50

60

Control Intervention

Jensen J, Ann Intern Med 2002; 136:733-41

0

1

2

3

4

5

6

7

Control Intervention

% Who Fell % Who Fractured Hip

22% reduction 77% reduction

RCT: 402 Nursing home residents (age > 65 yr.; median 83 yr.)Multiple Risk Factor Intervention (n=194) vs. Control (n=208)

OCOB

OB

OBOldBone

NewBone

Ca P04

Bone Remodeling

OCOB

OB

OBOldBone

NewBone

Ca P04

Osteoporosis TreatmentAnti-Resorptive AgentsBisphosphonatesRaloxifeneCalcitoninEstrogens

Anabolic AgentsParathyroid hormoneGrowth hormoneTestosteroneFluoride

OCOB

OB

OBOldBone

NewBone

Ca P04



Women’s Health Initiative - HRTVertebral Fracture Prevention

RCT: 16,608 postmenopausal women treated with Premarin + Provera for 5.2 years – RCT: 16,608 postmenopausal women treated with Premarin + Provera for 5.2 years – baseline bone status unknownbaseline bone status unknown

0

0.25

0.50

0.75

PlaceboHRT

N=60 N=41

% Women

With New Vertebral Fracture

1.0

34%*

Nominal 95% CI:0.44-0.98

Adjusted 95% CI:0.32-1.34

Writing Group. JAMA. 2002;288(3):321–333.

Women’s Health Initiative - HRTHip Fracture Prevention

RCT: 16,608 postmenopausal women treated with Premarin + Provera for 5.2 years – RCT: 16,608 postmenopausal women treated with Premarin + Provera for 5.2 years – baseline bone status unknownbaseline bone status unknown

Nominal 95% CI:0.45-0.98

Adjusted 95% CI:0.33-1.33


0

0.25

0.50

0.75

PlaceboHRT

N=62 N=44

1.0

34%*%

Women With New

HipFracture

OCOB

OB

OBOldBone

NewBone

Ca P04



0

10

20

30

40 Placebo

100 IU/day

200 IU/day

400 IU/day

RCT: 1255 women with PMO and vertebral fracture treated for 5 yearsRCT: 1255 women with PMO and vertebral fracture treated for 5 years

Calcitonin: PROOF Study Vertebral Fracture Prevention

* Relative risk reduction, P=0.03 vs placebo. N = number of women with new fracture.

Chesnut CH, Am J Med. 2000;109:267-276

33%*%

Women With 1 New VertebralFracture

N=70 N=51N=59 N=61

OCOB

OB

OBOldBone

NewBone

Ca P04



0

5

10

15

20

25Placebo

Raloxifene (60 mg/day)

Raloxifene: MORE Study Vertebral Fracture PreventionRCT: 7705 women with PMO, with and without vertebral RCT: 7705 women with PMO, with and without vertebral fracture, treated for 3 yearsfracture, treated for 3 years

30%*% Women

With New VertebralFracture

Preexisting Fractures*P<0.05. N = number of women with new fracture.

Ettinger B, JAMA. 1999;282:637-645

N=163

50%*N=113 N=68 N=35

No Preexisting Fractures

OCOB

OB

OBOldBone

NewBone

Ca P04



0

10

20Placebo Risedronate (5 mg/day)



Harris ST, JAMA. 1999;282:1344-1352

Risedronate: VERT NA Trial Vertebral Fracture Reduction

% Women


41%*

N=93 N=61

Vertebral Fx

0.69

Non-Vertebral Fx

Harris0.64

Pooled Estimate0.64 (0.54 - 0.77) (n=2604)

0.60

0.70

0.64 Harris

Clemensen

Fogelman

Reginster

0.73 (0.61 - 0.87) (n=12958)

1.52

0.76 0.620.710.71

ClemensenMcClungFogelmanReginsterMcClung

Risedronate Treatment Meta-analysisRisedronate Treatment Meta-analysis Fracture PreventionFracture Prevention

Cranney A, Endocrine Reviews 2002; 23:495-578

36% 27%

Low BMD Group

70-79 years oldOsteoporosis

Femoral Neck T-Score < -4or

Femoral Neck T-Score < -3plus 1 Risk Factor

Clinical Risk Factor(s) Group

80 years oldNo BMD Requirement

1 Risk Factor or

Femoral Neck T-Score < -4Femoral Neck T-Score < -3

and Hip Axis 11.1 cm

RCT: 9331 women with PMO and/or non-skeletal risk factors treated for 3 years

McClung MR, N Engl J Med. 2001;344:333-340.

Risedronate: Hip Study Hip Fracture Reduction

0

2

4

6Placebo

Risedronate (2.5 and 5 mg/day)

Relative risk reduction: * P=0.02 vs placebo; ** P=0.009 vs placebo.N = number of women with new fracture.

McClung MR, N Engl J Med. 2001;344:333-340.

Overall Low BMD Clinical Risk Factor(s)

30%*40%**

% Women

With Hip Fracture

N=95 N=137 N=46 N=55 N=49 N=82

RCT: 9331 women with PMO and/or non-skeletal risk factors treated for 3 years

Risedronate: Hip Study Hip Fracture Reduction

0

10

20Placebo

Alendronate (5 mg/day [2 years] + 10 mg/day [1 year])

Alendronate: FIT Trial Vertebral Fracture Prevention

% Women


* Relative risk reduction, P<0.001.N = number of women with new fracture.

Black DM, Lancet. 1996;348:1535-1541


47%*

N=145 N=78

Alendronate Treatment Meta-analysisAlendronate Treatment Meta-analysis Fracture PreventionFracture Prevention

0.36

Vertebral Fx Non-Vertebral Fx

Cranney A, Endocrine Reviews 2002; 23:495-578

0.51

0.510.530.520.520.250.68

0.53 (0.43 - 0.65) (n=8005)

Pooled Estimate

ChesnutBone

Liberman (USA)Liberman (INT)

Adami

Black

0.55

0.49 (0.36-0.67) (n=3456)

0.43

0.650.470.35 Rosen

AdamiChesnut

Liberman (USA)

Liberman (INT)

PolsCummings

(25.47)

47% 51%

0

1

2

3Placebo

Alendronate (5 mg/day [2 years] +10 mg/day [1 year])

51%*

% Women

With HipFracture


Black DM, Lancet. 1996;348:1535-1541

N=22 N=11

Alendronate: FIT Trial Hip Fracture Prevention


0

1

2

3

4

5

Lumbar Spine Femoral Neck (Hip)

Risedronate (5 mg/day)

Risedronate (35 mg/week)

Risedronate: Weekly vs DailySpine and Hip BMD No Fracture Data

% Increasein BMD

Lindsay R, November 2001. Abstract.

1456 women with PMO and an existing vertebral fracture treated for 1 year

N = number of women with BMD measurement.

N=480 N=485 N=485N=480

0

1

2

3

4

5

6

Spine Femoral Neck (Hip)

Alendronate (10 mg/day)

Alendronate (70 mg/week)

Alendronate: Weekly vs Daily Spine and Hip BMD No Fracture Data

% Change

From Baselinein BMD

N = number of women with

BMD measurement. Schnitzer T, Aging Clin Exp Res. 2000;12:1-12

1258 women with PMO and vertebral fracture treated for 1 year1258 women with PMO and vertebral fracture treated for 1 year

N=370 N=519 N=519N=370

Intravenous BisphosphonatesVertebral BMD Change

8%

6%

4%

2%

0%PamidronateNa Fluoride

Pamidronate 30 mg (250-500 cc NS) IV over 2 hours every 3 months

Thiebaud D, Osteoporosis Int 4:76-83, 1994

8%

6%

4%

2%

0%Placebo

Zoledronate Intravenously

Reid IR, NEJM 346:653-61, 2002

1 mg q 3mos

2 mg q 6mos

4 mg q year

Spine

Hip

Intravenous BisphosphonatesBMD Change

Osteoporosis TreatmentAlendronate added to ongoing HRT

4%

2%

0%

BMD Change

Lindsay R, JCEM 84:3076-81, 1999

HRT +Placebo

HRT +Alend

Spine Hip

OCOB

OB

OBOldBone

NewBone

Ca P04



PTH: Mode of Delivery Determines Bone Activity

Continuous exposure results in increased osteoclastic bone resorption

Intermittent exposure results in increased osteoblast number and bone formation.

Dobnig & Turner. Endocrinology 1997;138:4607-4612

RCT: 1637 postmenopausal women with previous vertebral fracturesPTH (n=1093) vs placebo (n=544)

BMDChange

PTH 1-34 Therapy 18 Month BMD Data

Neer R, NEJM 344:1434, 2001

15%

0%

+14%

HipSpine

+10%

+5%+3%

HipSpine

PTH 20 ug/d PTH 40 ug/d

RCT: 1637 postmenopausal women with previous vertebral fracturesPTH (n=1093) vs placebo (n=544)

FractureReduction

PTH 1-34 Therapy 18 Month Fracture Data

Neer R, NEJM 344:1434, 2001

0%

-75% -69%

Non-spineSpine

-65%-40%-35%

PTH 20 ug/d PTH 40 ug/d

Non-spineSpine

BMD Monitoring on Treatment

Response Patterns

Anti-resorptive Agent Anabolic Agent

Least Significant Change*

2.7% in Spine5.7% in Hip *must be established

for each instrument

Risk BenefitStroke

Coronary Artery DiseaseBreast Cancer

Plan to Study Until 2005

Additional Benefits:• Osteoporosis• Colon Cancer• Overall Mortality

Additional Risks:• VTE

Writing Group. JAMA. 2002;288:321-333.

Women’s Health InitiativeHormone Replacement Hypotheses

Women’s Health InitiativeHormone Replacement Design

Hysterectomy

Premarin0.625 mg/d

Placebo Premarin/Provera0.625/2.5 mg/d

YESN=10,739

NON=16,608

Placebo

(Age: 50-79; mean 63 yr.)

Study Duration8.5 years with interim analysis at 5.2 years

Writing Group, JAMA 2002; 288:321-333

26% Increase Breast Cancer

WHI HRT Study5.2 Year Findings in Premarin/Provera Group

211% increase VTE

37% Colon Cancer reduction 34% Fracture reduction

Early STOP=Clear Harm

29% Increase Coronary Artery

Disease41% Increase Stroke

Risk Benefit

Writing Group. JAMA. 2002;288:321-333.

Women’s Health InitiativeInterim Analysis at 5.2 Years

Hysterectomy

Premarin0.625 mg/d

Placebo Premarin/Provera0.625/2.5 mg/d

YESN=10,739

NON=16,608

Placebo

ERT ArmContinued

Writing Group, JAMA 2002; 288:321-333

HRT ArmStopped

Coronary Heart DiseaseCoronary Heart Disease 7 more cases 7 more cases Breast CancerBreast Cancer 8 more cases8 more cases VTEVTE 8 more cases8 more cases StrokeStroke 8 more cases8 more cases Colon CancerColon Cancer 6 fewer cases6 fewer cases Hip FractureHip Fracture 5 fewer cases5 fewer cases

Women’s Health InitiativeAttributable Risk of HRT – 5.2 Year Analysis

10,000 patient years (2000 patients treated for 5 years)


These results do not address:These results do not address:

Premarin alone (data analysis in 2005)Premarin alone (data analysis in 2005)

Oral estradiol +/- progesterone/norethindroneOral estradiol +/- progesterone/norethindrone

Patch estradiol +/- progesterone/norethindronePatch estradiol +/- progesterone/norethindrone

Women under age 50Women under age 50

Quality of LifeQuality of Life

Women’s Health InitiativeCaveats – 5.2 Year Analysis

Vertebral Fracture Reduction RCTs in Women with PMO and Vertebral Fractures

0%-10%-20%-30%-40%-50%

Calcitonin Raloxifene Estrogen Risedronate Alendronate

PROOF MORE WHI VERT-NA FIT

Chesnut C, AM J Med 2000, 109:267 Harris S, JAMA 1999, 282:1344Ettinger B, JAMA 1999, 282:637 Black D, Lancet 1996, 348:1535Writing Group, JAMA 2002, 288:321

33% 30%34%

41%47%

Hip Fracture Reduction RCTs in Women with PMO

0%-10%-20%-30%-40%-50%

Calcitonin Raloxifene Estrogen Risedronate Alendronate

WHI HIP FIT

Writing Group, JAMA 2002, 288:321 McClung M, NEJM 2001, 344:333 Black D, Lancet 1996, 348:1535

34%40%

51%

Documents

Osteoporosis Management: What Does the Data Support? Osteoporosis Definition 2001: Compromised bone strength predisposing to increased risk of fragility