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.

● 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

●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

● Intent to Treat

● Cox Proportional Hazard Models (95% CI)

● Hip Fractures: Adjusted CI–1 of 8 clinical outcomes monitored by DSMB

• All other Fractures: Nominal CI

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

* 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

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

Baseline Characteristics across Categories of Summary FRACTURE Risk Score

“Low” “Moderate” “High”

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

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

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

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

32%

58%

10%

53%

35%

12%

Normal

Low Bone Mass

Osteoporosis

P = 0.29

Estrogen Plus Progestin Placebo

0.0

0.5

1.0

1.5

2.0

2.5

3.0

E+P Placebo

0.0

0.5

1.0

1.5

2.0

2.5

3.0

E+P Placebo

Hip Fracture

0.11 0.16

35%

HR = 0.65

Total Fracture

24%

1.52

1.99nCI=0.47 tp 0.96aCI= 0.41 to 1.10

An

nu

aliz

ed I n

cid

ence

of

Fra

c tu

res

(%)

HR = 0.76nCI=0.69 to 0.83

24% Reduction35% Reduction

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

An

nu

aliz

ed I n

cid

ence

of

Fra

c tu

res

(%)

Effects of Estrogen plus Progestin on Hip and Total Fractures

52 hip fx

73 hip fx 733 fx

986 fx

Effects of Estrogen plus Progestin on Wrist and Vertebral Fractures

0.0

0.5

1.0

1.5

2.0

2.5

3.0

E+P Placebo0.0

0.5

1.0

1.5

2.0

2.5

3.0

E+P Placebo

Wrist/Lower Arm

0.430.59

28%

HR = 0.72

nC I= 0.60 to 0.87

n=nominal 95% CI

HR = 0.66

nCI = 0.44 to 0.98

Clinical Vertebral

31%

0.09 0.15

28% Reduction 31% Reduction

189 fx 245 fx 41 fx 60 fx

Age (y)

50-54

55-59

60-64

65-69

70-74

75-79

1.0 10.1

0.76*Favors E&PFavors E&P Favors PlaceboFavors Placebo

P(interaction) = 0.47* Overall HR Hazard Ratio (95% CI)

Effects of Estrogen Plus Progestin on Total Fractures by Age

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

All Interactions were Not Statistically Significant

Effects of Estrogen plus Progestin on Total Fractures by Summary FRACTURE

Risk Score

0.0

0.5

1.0

1.5

2.0

2.5

3.0

"Low" "Moderate" "High"

Fracture Summary Score

0.85 (0.70, 1.03)

0.68 (0.28, 0.81)

0.82 (0.66, 1.02)

p (interaction) = 0.54

1.101.33

1.41

1.99

2.33

2.74

PlaceboE+P

An

nu

aliz

ed I

nci

den

ce

of

Fra

ctu

re (

Per

cen

t

(341 fx) (434 fx) (672 fx)

Greenspan 1998

Komulainen 1997

Wilalawansa 1998

Hulley 1998

Hosking 1998

Alexandersen 1999

Pooled Estimate (HR=0.87)

Cauley (WHI) (HR=0.75)1 100.01 .1 10

Favors E&PFavors E&P Favors PlaceboFavors Placebo

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

Comparison of WHI E + P results on Non-Spine Fractures with ORAG* report

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

- 1

0

1

2

3

4

5

6

7

0 1 2 3

Follow-up, years

Ch

an

ge

in S

pin

e B

MD

fro

m B

ase

line

Va

lue

, %

E+PPlacebo

4.5% Difference

Effects of Estrogen plus Progestin on the Global Index by FRACTURE Risk Score

Tertiles

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

"Low" "Moderate" "High"Summary Score

p (interaction) = 0.54

PlaceboE+P

HR=1.20(0.93, 1.55)

0.960.81

1.55

1.89

HR=1.23(1.04, 1.46)

2.94 2.84

HR=1.03(0.86 – 1.24)

An

nu

aliz

ed (

%)

Inci

den

ce o

f G

lob

al

Ind

ex E

ven

t

Limitations

●One estrogen plus progestin regimen●Fracture risk score: ratio of highest to lowest

risk was modest 2.0No BMD measurementsNo prevalent Vertebral fractureMay have better benefit/risk profile in

women at higher risk. ●Clinical Vertebral Fractures●Global Index: Potentially life threatening illness

Vertebral fractures

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.

ConclusionGiven:

• 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.

Extra Slides

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

Vitamin D1 ? ?

Alendronate1 ? 24

Risedronate1 ? 43

Raloxifene1 ? ?

E+P(WHI) 106 ?

Low risk High Risk

WHI : women considered “low” risk 1. Cranney et al, 2002

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

Vitamin D1 2252 94

Alendronate1 1790 72

Risedronate1 2252 94

Raloxifene1 2381 99

E+P(WHI) 833 ---

Low risk High Risk

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

Lumbar spine

ORAGa 1 year

2 year

WHI 1 year

3 year

Femoral Neck

ORAG 1 year

2 year

WHI 1 year

3 year

0 10

Favors E & PFavors E & PFavors PlaceboFavors Placebo

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

Weighted Mean Difference (95% CI)5-5

Mean Difference in Percent Change in Bone Density after Treatment with E + P : ORAGa vs WHI

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

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