Baseline Serum Estradiol and Fracture Reduction during Treatment with Hormone Therapy: The

Women'sHealth Initiative Randomized Trial

Jane A. Cauley , DrPHAndrea Z. LaCroix, PhDJohn A. Robbins, MD

Joseph Larson, MSRobert Wallace, MD

Jean Wactawski-Wende, PhDZhao Chen, PhD

Douglas C. Bauer, MDSteven R. Cummings, MD

Rebecca Jackson, MD

Osteoporos Int 2010 Jan;21(1):167-77.

Hypotheses

Primary

• Hormone therapy decreases risk of fracture to a greater degree among women with the lowest circulating estrogen levels.

Secondary

• Women with lowest baseline estradiol will have a higher risk of fracture.

Design• WHI E+P and E-alone trials.

• Nested case-control study.

• All confirmed cases of hip fracture (n=248) & random sample of other fx until 750 pairs.

• Controls matched on age, ethnicity, HT trial RV date, hysterectomy status and past hx Fx

Baseline Biomarkers by Case-control Status & by Randomized Group: All Fracture

Cases Controls

E+P , E (n=304)

PBO (n=446) P

Value*

E+P , E (n=304)

PBO(n=333) P

Value*P

Value**Mean MeanTotal Estradiol(pg/mL)

12.62 12.31 0.79 13.94 12.64 0.44 0.35

Free Estradiol (pg/mL)

0.32 0.31 0.65 0.35 0.32 0.45 0.32

Bio E2(pg/mL)

8.26 7.93 0.66 9.08 8.35 0.45 0.25

SHBG (μg/dL) 1.40 1.48 0.18 1.36 1.34 0.79 0.01

*P value from a linear model modeling the biomarker of interest as a function of HT status. ** P value from a linear model modeling the biomarker of interest as a function of cases-control status.

Baseline Biomarkers by Case-Control Status & by Randomized Group: Hip Fracture

Cases Controls

E+P, E (n=95)

PBO (n=136) P

Value*

E+P, E (n=134)

PBO(n=97) P

Value*P

Value**Mean MeanTotal Estradiol(pg/mL)

11.69 10.19 0.19 12.32 13.24 0.70 0.15

Free Estradiol (pg/mL)

0.29 0.25 0.17 0.32 0.32 0.94 0.05

Bio E2(pg/mL)

7.23 6.25 0.20 8.23 8.41 0.90 0.03

SHBG (μg/dL) 1.56 1.73 0.09 1.37 1.36 0.84 <0.0001

*P value from a linear model modeling the biomarker of interest as a function of HT status. ** P value from a linear model modeling the biomarker of interest as a function of cases-control status.

All fractures Hip fractures

E+P , E PBO OR95% CI

for fracture

Inter-action

P-Value

E+P , E

PBO OR95% CI

for fracture

Inter-action

P-Value

0.937 0.854

<4 84 146 0.50(0.34, 0.74)

26 56 0.41(0.20, 0.83)

>4-6.1 51 80 0.46(0.28, 0.74)

19 26 0.47(0.20, 1.06)

>6.1-9.9 73 107 0.55(0.36, 0.84)

24 33 0.74(0.34, 1.57)

>9.9 72 90 0.55(0.35, 0.85)

18 16 0.50(0.20, 1.28)

Adjusted for age, ethnicity, randomization date, fracture history and hysterectomy status.

OR (95% CI) of Fracture among Women Randomized to HT compared to PBO according to Levels of

Bioavailable Estradiol (pg/mL) at Baseline

All fractures Hip fracturesE+P , E PBO OR

95% CI for

fracture

Inter-action

P-Value

E+P , E PBO OR95% CI

for fracture

Inter-action

P-Value

SHBG (μg/dL) 0.139 0.157

<0.87 62 93 0.54(0.35, 0.84)

8 14 0.35(0.12, 1.03)

>0.87-1.21 94 101 0.78(0.52, 1.17)

28 24 0.98(0.45, 2.15)

>1.21-1.67 70 97 0.47(0.31, 0.72)

30 36 0.60(0.29, 1.23)

>1.67 76 150 0.41(0.27, 0.61)

28 62 0.31(0.15, 0.64)

Adjusted for age, ethnicity, randomization date, fracture history and hysterectomy status.

OR (95% CI) of Fracture among Women Randomized to HT compared to PBO according to Levels of SHBG (μg/dL) at

Baseline

Hypotheses

Primary

• Hormone therapy decreases risk of fracture to a greater degree among women with the lowest circulating estrogen levels.

Secondary

• Women with lowest baseline estradiol will have a higher risk of fracture.

Odds Ratio (95% CI) of Fracture according to Levels of BIOE2 at Baseline: Hip Fractures Main Effects

Model 1 Base Model*

OR 95% CI for fracture

P trend

Bio E2 (pg/mL) 0.056

<4 1.00

>4-6.1 0.56(0.33, 0.94)

6.1-9.9 0.66(0.40, 1.08)

>9.9 0.50(0.28, 0.89)

* Base model adjusted for age, ethnicity, randomization date, fracture history and hysterectomy status. Additional adjustment for BMI, treated diabetes and self-reported health.

Model 2 Adjusted for Base Model**

OR 95% CI for fracture

P trend

0.404

1.00

0.63(0.37, 1.08)

0.80(0.47, 1.35)

0.75(0.40, 1.39)

Cauley JA et al. Osteoporos Int 2010;21:167-177

Odds Ratio (95% CI) of Fracture according to Levels of SHBG at Baseline : ALL Fractures and Hip Fractures

ALL Fractures

OR 95% CI for fracture

P trend

SHBG (μg/dL) 0.048

<0.87 1.00

>0.87-1.21 1.29(0.95,1.74)

>1.21-1.67 1.12(0.82, 1.58)

>1.67 1.53(1.11, 2.12)

* Base model adjusted for age, ethnicity, randomization date, fracture history and hysterectomy status. Additional adjustment for BMI, treated diabetes and self-reported health.

Hip Fx

OR 95% CI for fracture

P trend

0.002

1.00

2.11(1.08, 4.14)

2.69(1.37, 5.39)

4.01(1.98, 8.15)

Summary– The effect of HT on fracture reduction is

independent of Baseline E2 and SHBG.

• Similar results for E&P and E alone

– There was no association between E2 and all fx.

• Women with higher E2 at baseline had a lower risk of Hip fx but this was attenuated in models with BMI.

– Women with higher levels of SHBG have a higher risk of All Fx and specifically hip fractures.

• Independent of BMI and other confounding variables and Bio E2

Sex Steroid Hormones and Fracture in Multi-Ethnic Women

– Nested case Control design: WHI OS

–All fractures in Blacks, Hispanics, Asians and Native Americans; Random sample of 400 White women with FX

–Cases and Controls matched on age, race/ethnicity and date of randomization

–USC Endocrine lab

–Poster this evening

MV Adjusted Odds Ratio (95% CI) of Clinical Fractures Across Categories of 25(OH)D: WHI

<20 20-<30 >300.00

0.50

1.00

1.50

2.00

2.50

(Ref)1.00 0.82

0.56

WhitesP trend=0.02

25(OH)D levels

Odd

s Ra

tio

Cauley JA, et al. J Bone Miner Res 2011

<20 20 - <30 >300.00

0.50

1.00

1.50

2.00

2.50

(Ref)1.00

1.48 1.33

BlacksP trend=0.04

25(OH)D levels

Odd

s Ra

tio

Adjusted for age, blood draw date, clinic, height , weight, physical activity, calcium intake, history of fractures

N cases 150 156 84 241 108 30

N controls 120 165 105 267 85 27

Tertiles P trend1 2 3

Whites 1,2,3 Ref 0.71 (0.48, 1.05) 0.52 (0.33, 0.80) 0.003

Blacks 1,2,3 Ref 0.65 (0.40, 1.04) 0.52 (0.32, 0.86) 0.012

Hispanics 1,2,3 Ref 1.33 (0.68, 2.61) 1.08 (0.52, 2.23) 0.86

Asians 1,2,3 Ref 0.74 (0.38, 1.47) 1.01 (0.44, 2.30) 0.88

Native Americans 1,2,3 Ref 0.36 (0.05, 2.87) 0.22 (0.03, 1.54) 0.13

1 Matched on age, race, date of blood draw. 2 MV model: adjusted for weight, height, physical activity, calcium intake, history of fracture. 3 Tertile cutoffs = <4.83, >4.83-8.21, >8.21.

Odds Ratio (95% CI) of Fracture across Tertiles of Bioavailable Estradiol (pg/ml)

Tertiles P trend1 2 3

Whites 1,2,3 Ref 1.02(0.76, 1.46)

0.79(0.54, 1.16) 0.25

Blacks 1,2,3 Ref 0.90(0.57, 1.40)

0.54(0.34, 0.85) 0.004

Hispanics 1,2,3 Ref 1.04(0.58, 1.87)

1.02(0.54, 1.91) 0.95

Asians 1,2,3 Ref 0.89(0.47, 1.67)

0.64(0.28, 1.49) 0.32

Native Americans1,2,3 Ref 0.34 (0.06, 1.90)

0.10(0.01, 0.81) 0.03

1 Matched on age, race, date of blood draw. 2 MV model: adjusted for weight, height, physical activity, calcium intake, history of fracture. 3

Tertile cutoffs = <8.46, >8.46-13.4, >13.4

Odds Ratio (95% CI) of Fracture across Tertiles of Bioavailable Testosterone (pg/ml)

Tertiles P trend1 2 3

Whites 1,2,3 Ref 0.81(0.56, 1.16)

0.65(0.44, 0.96) 0.032

Blacks 1,2,3 Ref 1.60(1.08, 2.37)

1.51(0.98, 2.32) 0.039

Hispanics 1,2,3 Ref 1.04(0.57, 1.90)

0.90(0.46, 1.76) 0.81

Asians 1,2,3 Ref 2.14(0.90, 5.08)

0.84(0.37, 1.95) 0.74

Native Americans1,2,3 Ref 1.36(0.38, 4.81)

0.56(0.12, 2.48) 0.38

1 Matched on age, race, date of blood draw. 2 MV model: adjusted for weight, height, physical activity, calcium intake, history of fracture. 3 Tertile cutoffs = <38, >38-58.2, >58.2.

Odds Ratio (95% CI) of Fracture across Tertiles of Sex Hormone Binding Globulin (nmol/L)

Endogenous Estrogen Levels and CHD Outcomes in the WHI Trials

DC Bauer, G Farhat, JA Cauley, A Huang, A LaCroix, J Lee, D Grady, K Yaffe, J Manson, N Parimi, E Vittinghof and

SR Cummings for the Women’s Health Initiative (WHI) Research Group

Coordinating Center

Research Questions

Among women randomized to E-alone or E+P in the WHI:

• Are pre-randomization estradiol levels associated with CHD risk?

• Do pre-randomization estradiol levels modify the effects of either E-alone or E+P on CHD risk?

Adjusted CHD Risk by Quartile of Bio-available E2 (pg/ml) for E+P Trial

Q1 (ref) Q2 Q3 Q4

Haz

ard

Ratio

95%

CI

(5.3-6.9) (7.0-10.2) (10.3-27.3)(1.4-5.2)

P for Trend = 0.007

0

0.2

0.4

0.6

0.8

1

1.2

1.4

Adjusted CHD Risk by Quartile of Bio-available E2 (pg/ml) for E-alone Trial

Q1 (ref) Q2 Q 3 Q4

Haz

ard

Ratio

95%

CI

(1.5-4.9) (5.0-7.3) (7.4-10.3) (10.2-26.6)

P for Trend = 0.011

0

0.2

0.4

0.6

0.8

1

1.2

1.4

Adjusted* CHD Risk in Lowest Quartile Vs. Other Three Quartiles

RH (95% CI)

E-alone E+ P

Total E2 1.6 ( 0.9-

2.7)

2.8 ( 1.7-

4.7)Bio-available E2

2.1 ( 1.2 –

3.8)

1.8 ( 1.1 -

3.2)SHBG 0.8

( 0.5- 1.4)

1.4

( 0.8 -2.5)*Adjusted for treatment, age, education, time since menopause, current smoking, alcohol, waist circumference, prior HT use, prior oral contraceptive use, high blood pressure, diabetes, high cholesterol, history of heart disease, aspirin use, and statin use

Research Questions

Among women randomized to E alone or E + P in the WHI:

• Are pre-randomization estradiol levels associated with CHD risk?

• Do pre-randomization estradiol levels modify the effects of either E-alone or E+P on CHD risk?

Pre-randomization E2 and Effect of Treatment on CHD Risk

• E-alone vs. placebo– Risk of CHD independent of E2 levels– Interaction p-value=0.18

• E+P vs. placebo– Risk of CHD independent of E2 levels– Interaction p-value=0.73

Summary

• Among postmenopausal women enrolled in the WHI trials– Higher endogenous E2 associated with

reduced risk of CHD– Independent of many known CV risk factors– SHBG not associated with CHD risk

• No evidence that the effects of E-alone or E+P on CHD risk differ by pre-randomization estradiol levels