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Estrogen plus Progestin, BMD and Fractures: Women’s Health Initiative . Jane A. Cauley University of Pittsburgh. JAMA 2003; 290 (13) :1729-1738. Objectives. To present final analysis of fracture endpoints, thru July 7, 2002.

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estrogen plus progestin bmd and fractures women s health initiative

Estrogen plus Progestin, BMD and Fractures: Women’s Health Initiative

Jane A. Cauley

University of Pittsburgh

JAMA 2003; 290 (13) :1729-1738

objectives
Objectives
  • To present final analysis of fracture endpoints, thru July 7, 2002.
  • To test the hypothesis that the effect of E+P on fracture differed by risk factors for fracture.
  • To report BMD results.
  • To test whether the risk-benefit profile of E+P differs in women at higher vs. lower risk of hip fracture.
outcomes
Outcomes
  • All Fractures except ribs, chest/sternum, skull/face, fingers, toes and cervical vertebrae;
    • Radiographically confirmed;
    • Hip Fractures centrally adjudicated
  • BMD : baseline, years 1 and 3
  • Global Index
statistical analyses
Statistical Analyses
  • Intent to Treat
  • Cox Proportional Hazard Models (95% CI)
  • Hip Fractures: Adjusted CI
      • 1 of 8 clinical outcomes monitored by DSMB
  • All otherFractures: Nominal CI
summary fracture risk score
Summary FRACTURE Risk Score

Age 1.14 0-7*

Prior Fracture > age 55 2.22 2

Current Smoker 2.31 2

Low BMI 1.91 1

Risk Factor OR Points

ROC Curve AUC = 0.79 (95% CI 0.73-0.84)

*Age 50-53 = 0; age 54-57 = 1; age 58-61=2; age 62-64=3; age 65-68=4; age 69-72=5; age 73-75=6; age 76-79=7

Black D et al, Osteoporosis Int 2001;12:519-529

baseline characteristics across categories of summary fracture risk score
Baseline Characteristics across Categories of Summary FRACTURE Risk Score

“Low” “Moderate” “High”

(n) (4743) (5871) (3146)

  • Age (y) 56 65 72
  • BMI (kg/m2) 30 29 27
  • Caucasian (%) 77 85 90
  • Past HT (%) 19 19 22
  • Current HT (%) 10 5 3
  • Current Smoke (%) 3 13 16
  • Fracture History (%) 24 28 59
  • Osteoporotic (%) a 12 23 41

a = T-score <-2.5, n=1024

prevalence of osteoporosis by dxa femoral neck t scores who n 1024

Normal

Low Bone Mass

Osteoporosis

Prevalence of Osteoporosis by DXA:Femoral Neck T-scores (WHO) (n=1024)

Estrogen Plus Progestin

Placebo

P = 0.29

slide8

Effects of Estrogen plus Progestin on

Hip and Total Fractures

Hip Fracture

Total Fracture

24% Reduction

35% Reduction

HR = 0.76

nCI=0.69 to 0.83

24%

HR = 0.65

nCI=0.47 tp 0.96

Annualized Incidence

of Fractures (%)

Annualized Incidence

of Fractures (%)

1.99

aCI= 0.41 to 1.10

1.52

35%

0.11

0.16

73 hip fx

733 fx

986 fx

52 hip fx

n= nominal 95% CI a= adjusted 95% CI

effects of estrogen plus progestin on wrist and vertebral fractures
Effects of Estrogen plus Progestin on Wrist and Vertebral Fractures

Wrist/Lower Arm

Clinical Vertebral

28% Reduction

31% Reduction

HR = 0.72

nC I= 0.60 to 0.87

HR = 0.66

nCI = 0.44 to 0.98

28%

0.59

31%

0.43

0.15

0.09

245 fx

189 fx

41 fx

60 fx

n=nominal 95% CI

effects of estrogen plus progestin on total fractures by age
Effects of Estrogen Plus Progestin on Total Fractures by Age

Favors E&P

Favors Placebo

0.76*

Age (y)

50-54

55-59

60-64

65-69

70-74

75-79

10

.1

1.0

P(interaction) = 0.47

* Overall HR

Hazard Ratio (95% CI)

the effect of estrogen progestin on fractures was similar in different subgroups
Years Since menopause

Race/ethnicity

BMI

Smoking

Falls

Calcium Intake

Parental History of Fracture

Personal History Of Fracture

Past use of HT

BMD

Summary Fracture risk score

The Effect of Estrogen + Progestin on Fractures was similar in different subgroups

All Interactions were Not Statistically Significant

effects of estrogen plus progestin on total fractures by summary fracture risk score
Effects of Estrogen plus Progestin on Total Fractures by Summary FRACTURE Risk Score

0.85 (0.70, 1.03)

2.74

0.68 (0.28, 0.81)

2.33

Annualized Incidenceof Fracture (Percent

1.99

E+P

0.82 (0.66, 1.02)

Placebo

1.41

1.33

1.10

(341 fx)

(434 fx)

(672 fx)

p (interaction) = 0.54

Fracture Summary Score

comparison of whi e p results on non spine fractures with orag report
Comparison of WHI E + P results on Non-Spine Fractures with ORAG* report

Favors Placebo

Favors E&P

Greenspan 1998

Komulainen 1997

Wilalawansa 1998

Hulley 1998

Hosking 1998

Alexandersen 1999

Pooled Estimate (HR=0.87)

Cauley (WHI) (HR=0.75)

100

.1

.01

10

1

*Wells G et al Endocrine Reviews 2002;23:529-539

slide14
Mean change from baseline in bone mineral density (BMD) at the Lumbar Spine during 3 years of follow-up

7

6

4.5% Difference

5

Change in Spine BMD

from Baseline Value, %

4

E+P

3

Placebo

2

1

0

-

1

0

1

2

3

Follow-up, years

effects of estrogen plus progestin on the global index by fracture risk score tertiles
Effects of Estrogen plus Progestin on the Global Index by FRACTURE Risk Score Tertiles

HR=1.03

(0.86 – 1.24)

2.94

HR=1.23

2.84

(1.04, 1.46)

E+P

Annualized (%)Incidence of Global Index Event

Placebo

HR=1.20

1.89

(0.93, 1.55)

1.55

0.96

0.81

Summary Score

p (interaction) = 0.54

limitations
Limitations
  • One estrogen plus progestin regimen
  • Fracture risk score: ratio of highest to lowest risk was modest 2.0
      • No BMD measurements
      • No prevalent Vertebral fracture
      • May have better benefit/risk profile in women at higher risk.
  • Clinical Vertebral Fractures
  • Global Index: Potentially life threatening illness
      • Vertebral fractures
summary
Summary
  • Estrogen plus Progestin increases BMD and reduces the risk of fracture in healthy pre-dominantly non-osteoporotic women.
  • Decreased risk of fracture was present in all subgroups of women examined
  • The Effect of E+P on fracture is consistent with recent Meta-analyses.
  • The effect of E+P on the Global Index did not differ across tertiles of fracture risk. There was no evidence of a net benefit in women at high risk of fracture.
conclusion
Conclusion
  • Given:
    • Overall unfavorable risk- benefit ratio
    • Availability of other agents for the prevention and treatment of osteoporosis
  • Estrogen plus progestin cannot be recommended for the prevention or the treatment of osteoporosis in asymptomatic women.
  • Before the combination of estrogen and progestin is considered for the purpose of fracture prevention, women should be fully informed about the potential adverse effects.
comparison of osteoporosis therapies orag
Comparison of Osteoporosis Therapies: ORAG

Intervention No. of trials/patients RR(95% CI) p

Calcium 2(222) 0.86 (0.43,1.72) 0.54

Vit D 6(6187) 0.77 (0.57,1.04) 0.09

Alen.(5mg) 8(8603) 0.87 (0.73,1.02) 0.09

Alen. (10-40) 6(3723) 0.51 (0.38,0.69) <0.01

Raloxifene 7(6961) 0.91 (0.79,1.06) 0.24

Calcitonin 1(1245) 0.80 (0.59,1.09) 0.16

Risedr. 7(12958) 0.73 (0.61,0.87) <0.01

HT-pre WHI 6(3986) 0.87 (0.71,1.08) 0.10

HT WHI 1(16608) 0.75 (0.68,0.83) <0.05

Cranney A et al Endocrine Reviews 2002; 23(4): 570

nnt for 2 years to prevent a non vertebral fracture low and high risk group
NNT for 2 years to prevent a non-vertebral fracture: Low and High risk group

Low risk High Risk

Vitamin D1 ? ?

Alendronate1 ? 24

Risedronate1 ? 43

Raloxifene 1 ? ?

E+P(WHI) 106 ?

WHI : women considered “low”risk

1. Cranney et al, 2002

WHI: women considered “low” risk

nnt for 2 years to prevent a vertebral fracture low and high risk group
NNT for 2 years to prevent a vertebral fracture: Low and High risk group

Low risk High Risk

Vitamin D1 2252 94

Alendronate1 1790 72

Risedronate1 2252 94

Raloxifene1 2381 99

E+P(WHI) 833 ---

WHI: Clinical Vertebral Fractures ; women considered “low”risk. 1. Cranney et al, 2002

mean difference in percent change in bone density after treatment with e p orag a vs whi
Mean Difference in Percent Change in Bone Density after Treatment with E + P : ORAGa vs WHI

Favors Placebo

Favors E & P

Lumbar spine

ORAGa1 year

2 year

WHI 1 year

3 year

Femoral Neck

ORAG 1 year

2 year

WHI 1 year

3 year

10

0

-5

5

Weighted Mean Difference (95% CI)

aWells G et al Endocrine Reviews 2002;23(4):529-539

bone mineral density by randomized group
Bone Mineral Density by Randomized Group

Total Hip 546 0.83 478 0.84 0.77

Lumbar Spine 528 0.94 461 0.95 0.87

T-score

Total Hip 546 -0.94 478 -0.91 0.79

Lumbar Spine 528 -1.30 461 -1.26 0.87

BMD (g/cm2) (n) E+P (n) Placebo p

distribution of summary fracture risk score by randomized group
Distribution of Summary Fracture Risk Score By Randomized Group

Summary Risk Score E&P Placebo

(points) n (%) n(%)

Low (0-2) 2393 (34.5) 2350 (34.4)

Moderate (3-5) 2691 (42.7) 2910 (42.6)

High (>5) 1575 (22.7) 1571 (23.0)

P=0.93