Context

The timing of initiation of hormone therapy may influence its effect on cardiovascular disease.

Objective

To explore whether the effects of hormone therapy on risk of cardiovascular disease vary by age or years since menopause began.

Design, setting, and participants

Secondary analysis of the Women's Health Initiative (WHI) randomized controlled trials of hormone therapy in which 10,739 postmenopausal women who had undergone a hysterectomy were randomized to conjugated equine estrogens (CEE) or placebo and 16,608 postmenopausal women who had not had a hysterectomy were randomized to CEE plus medroxyprogesterone acetate (CEE + MPA) or placebo. Women aged 50 to 79 years were recruited to the study from 40 US clinical centers between September 1993 and October 1998.

Main outcome measures

Statistical test for trend of the effect of hormone therapy on coronary heart disease (CHD) and stroke across categories of age and years since menopause in the combined trials.

Results

In the combined trials, there were 396 cases of CHD and 327 cases of stroke in the hormone therapy group vs 370 [corrected] cases of CHD and 239 cases of stroke in the placebo group. For women with less than 10 years since menopause began, the hazard ratio (HR) for CHD was 0.76 (95% confidence interval [CI], 0.50-1.16); 10 to 19 years, 1.10 (95% CI, 0.84-1.45); and 20 or more years, 1.28 (95% CI, 1.03-1.58) (P for trend = .02). The estimated absolute excess risk for CHD for women within 10 years of menopause was -6 per 10,000 person-years; for women 10 to 19 years since menopause began, 4 per 10,000 person-years; and for women 20 or more years from menopause onset, 17 per 10,000 person-years. For the age group of 50 to 59 years, the HR for CHD was 0.93 (95% CI, 0.65-1.33) and the absolute excess risk was -2 per 10,000 person-years; 60 to 69 years, 0.98 (95% CI, 0.79-1.21) and -1 per 10,000 person-years; and 70 to 79 years, 1.26 (95% CI, 1.00-1.59) and 19 per 10,000 person-years (P for trend = .16). Hormone therapy increased the risk of stroke (HR, 1.32; 95% CI, 1.12-1.56). Risk did not vary significantly by age or time since menopause. There was a nonsignificant tendency for the effects of hormone therapy on total mortality to be more favorable in younger than older women (HR of 0.70 for 50-59 years; 1.05 for 60-69 years, and 1.14 for 70-79 years; P for trend = .06).

Conclusions

Women who initiated hormone therapy closer to menopause tended to have reduced CHD risk compared with the increase in CHD risk among women more distant from menopause, but this trend test did not meet our criterion for statistical significance. A similar nonsignificant trend was observed for total mortality but the risk of stroke was elevated regardless of years since menopause. These data should be considered in regard to the short-term treatment of menopausal symptoms.

Trial registration

clinicaltrials.gov Identifier: NCT00000611.

Objectives

To examine the association between long-term bisphosphonate use and fracture in older women at high risk of fracture.

Design

Retrospective cohort.

Setting

Women's Health Initiative.

Participants

Older women who reported at least 2 years of bisphosphonate use in 2008-09 (N = 5,120).

Measurements

Exposure data were from a current medications inventory. Outcomes (hip, clinical vertebral, wrist or forearm, any clinical fracture) were ascertained annually. Using multivariate Cox proportional hazards models, the association between duration of bisphosphonate use (3-5, 6-9, 10-13 years) and fracture was estimated, using 2 years as the referent group.

Results

On average participants were 80 years old and were followed for 3.7 ± 1.2 years. There were 127 hip, 159 wrist or forearm, 235 clinical vertebral, and 1,313 clinical fractures. In multivariate-adjusted analysis, 10 to 13 years of bisphosphonate use was associated with higher risk of any clinical fracture than 2 years of use (hazard ratio (HR) = 1.29, 95% confidence interval (CI) = 1.07-1.57). This association persisted in analyses limited to women with a prior fracture (HR = 1.30, 95% CI = 1.01-1.67) and women with no history of cancer (HR = 1.36, 95% CI = 1.10-1.68). The association of 10 to 13 years of use, compared with 2 years of use, was not statistically significant for hip (HR = 1.66, 95% CI = 0.81-3.40), clinical vertebral (HR = 1.65, 95% CI = 0.99-2.76), or wrist fracture (HR = 1.16, 95% CI = 0.67-2.00).

Conclusion

In older women at high risk of fracture, 10 to 13 years of bisphosphonate use was associated with higher risk of any clinical fracture than 2 years of use. These results add to concerns about the benefit of very long-term bisphosphonate use.

Background

Calcium and vitamin D (CaD) supplementation trials including the Women's Health Initiative (WHI) trial of CaD have shown nonsignificant reductions in total mortality. This report examines intervention effects on total and cause-specific mortality by age and adherence.

Methods

The WHI CaD trial was a randomized, double-blind, placebo-controlled trial that enrolled 36,282 postmenopausal women aged 51-82 years from 40 U.S. clinical centers. Women were assigned to 1,000 mg of elemental calcium carbonate and 400 IU of vitamin D(3) daily or placebo with average follow-up of 7.0 years.

Results

The hazard ratio (HR) for total mortality was 0.91 (95% confidence interval [CI], 0.83-1.01) with 744 deaths in women randomized to CaD versus 807 deaths in the placebo group. HRs were in the direction of reduced risk but nonsignificant for stroke and cancer mortality, but near unity for coronary heart disease and other causes of death. HRs for total mortality were 0.89 in the 29,942 women younger than 70 years (95% CI, 0.79-1.01) and 0.95 in the 6,340 women aged 70 and older (95% CI, 0.80-1.12; p value for age interaction = .10). No statistically significant interactions were observed for any baseline characteristics. Treatment effects did not vary significantly by season.

Conclusions

In the WHI CaD trial, supplementation did not have a statistically significant effect on mortality rates but the findings support the possibility that these supplements may reduce mortality rates in postmenopausal women. These data can neither support nor refute recommendations for higher dose vitamin D supplementation to reduce cancer or total mortality.

Unlabelled

Further analyses from the Women's Health Initiative estrogen trial shows that CEE reduced fracture risk. The fracture reduction at the hip did not differ appreciably among risk strata. These data do not support overall benefit over risk, even in women at highest risk for fracture.

Introduction

The Women's Health Initiative provided evidence that conjugated equine estrogen (CEE) can significantly reduce fracture risk in postmenopausal women. Additional analysis of the effects of CEE on BMD and fracture are presented.

Materials and methods

Postmenopausal women 50-79 years of age with hysterectomy were randomized to CEE 0.625 mg daily (n = 5310) or placebo (n = 5429) and followed for an average 7.1 years. Fracture incidence was assessed by semiannual questionnaire and verified by adjudication of radiology reports. BMD was measured in a subset of women (N = 938) at baseline and years 1, 3, and 6. A global index was used to examine whether the balance of risks and benefits differed by baseline fracture risk.

Results

CEE reduced the risk of hip (hazard ratio [HR], 0.65; 95% CI, 0.45-0.94), clinical vertebral (HR, 0.64; 95% CI, 0.44-0.93), wrist/lower arm (HR, 0.58; 95% CI, 0.47-0.72), and total fracture (HR, 0.71; 95% CI, 0.64-0.80). This effect did not differ among strata according to age, oophorectomy status, past hormone use, race/ethnicity, fall frequency, physical activity, or fracture history. Total fracture reduction was less in women at the lowest predicted fracture risk in both absolute and relative terms (HR, 0.86; 95% CI, 0.68-1.08). CEE also provided modest but consistent positive effects on BMD. The HRs of the global index for CEE were relatively balanced across tertiles of summary fracture risk (lowest risk: HR, 0.81; 95% CI, 0.62-1.05; mid risk: HR, 1.09; 95% CI, 0.92-1.30; highest risk: HR, 1.04; 95% CI, 0.88-1.23; interaction, p = 0.42).

Conclusions

CEE reduces the risk of fracture and increases BMD in hysterectomized postmenopausal women. Even among the women with the highest risk for fractures, when considering the effects of estrogen on other important health outcomes, a summary of the burden of monitored effects does not indicate a significant net benefit.