Jane A. Cauley , DrPH Andrea Z. LaCroix , PhD John A. Robbins, MD Joseph Larson, MS

1. Baseline Serum Estradiol and Fracture Reduction during Treatment with Hormone Therapy: The Women'sHealth Initiative Randomized Trial Jane A. Cauley , DrPH Andrea Z. LaCroix, PhD John A. Robbins, MD Joseph Larson, MS Robert Wallace, MD Jean Wactawski-Wende, PhD Zhao Chen, PhD Douglas C. Bauer, MD Steven R. Cummings, MD Rebecca Jackson, MD OsteoporosInt 2010 Jan;21(1):167-77.

2. 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.

3. 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 hxFx

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

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

6. OR (95% CI) of Fracture among Women Randomized to HT compared to PBO according to Levels of Bioavailable Estradiol (pg/mL) at Baseline

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

8. 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.

9. Odds Ratio (95% CI) of Fracture according to Levels of BIOE2 at Baseline: Hip FracturesMain Effects Cauley JA et al. OsteoporosInt 2010;21:167-177

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

11. 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 fxbut 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

12. 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

13. MV Adjusted Odds Ratio (95% CI) of Clinical Fractures Across Categories of 25(OH)D: WHI Adjusted for age, blood draw date, clinic, height , weight, physical activity, calcium intake, history of fractures Cauley JA, et al. J Bone Miner Res 2011

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

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

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

17. 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

18. 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?

19. Adjusted CHD Risk by Quartile of Bio-available E2 (pg/ml) for E+P Trial P for Trend = 0.007 Hazard Ratio 95% CI (10.3-27.3) (7.0-10.2) (1.4-5.2) (5.3-6.9) Q3 Q4 Q2 Q1 (ref)

20. Adjusted CHD Risk by Quartile of Bio-available E2 (pg/ml) for E-alone Trial P for Trend = 0.011 Hazard Ratio 95% CI (1.5-4.9) (10.2-26.6) (5.0-7.3) (7.4-10.3) Q1 (ref) Q 3 Q2 Q4

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

22. 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?

23. 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

24. 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