Among healthy postmenopausal women, calcium with vitamin D supplementation resulted in a small but significant improvement in hip bone density, did not significantly reduce hip fracture, and increased the risk of kidney stones. (ClinicalTrials.gov number, NCT00000611.).

The Women's Health Initiative Randomized Controlled Trial The Women's Health Initiative Steering Committee * E STROGEN THERAPY HAS BEEN available to postmenopausal women for more than 60 years. Proven benefits include relief of vasomotor symptoms and vaginal atrophy and prevention and treatment of osteoporosis. Observational studies primarily examining unopposed estrogen preparations have suggested a 30% to 50% reduction in coronary events, 1-3 and an 8% to 30% increase in breast cancer with extended use. 4-6 The Women's Health Initiative (WHI) clinical trials of hormone therapy were designed in 1991-1992 using the accumulated evidence available at the time. 7 Two parallel randomized, doubleblind, placebo-controlled clinical trials of hormone therapy were undertaken to determine whether conjugated equine estrogen (CEE) alone (for women with prior hysterectomy) or in combination with progestin (medroxyprogesterone acetate [MPA]) would reduce cardiovascular events in mostly healthy postmenopausal women. The WHI estrogen plus progestin trial was halted in July 2002 after a mean 5.2 years of follow-up because health risks exceeded benefits. 8 Coronary heart disease (CHD), stroke, and venous thromboembolic disease were all increased in women assigned to active treatment with estrogen plus progestin. Breast cancer was also increased while colorectal cancer, hip fracture, and other fractures were reduced. The lack of benefit for CHD was *Author/Steering Committee Information, Financial Disclosures, and WHI Investigators appear at the end of this article. Context Despite decades of use and considerable research, the role of estrogen alone in preventing chronic diseases in postmenopausal women remains uncertain. Objective To assess the effects on major disease incidence rates of the most commonly used postmenopausal hormone therapy in the United States. Design, Setting, and Participants A randomized, double-blind, placebocontrolled disease prevention trial (the estrogen-alone component of the Women's Health Initiative [WHI]) conducted in 40 US clinical centers beginning in 1993. Enrolled were 10739 postmenopausal women, aged 50-79 years, with prior hysterectomy, including 23% of minority race/ethnicity. Intervention Women were randomly assigned to receive either 0.625 mg/d of conjugated equine estrogen (CEE) or placebo. Main Outcome Measures The primary outcome was coronary heart disease (CHD) incidence (nonfatal myocardial infarction or CHD death). Invasive breast cancer incidence was the primary safety outcome. A global index of risks and benefits, including these primary outcomes plus stroke, pulmonary embolism (PE), colorectal cancer, hip fracture, and deaths from other causes, was used for summarizing overall effects. Results In February 2004, after reviewing data through November 30, 2003, the National Institutes of Health (NIH) decided to end the intervention phase of the trial early. Estimated hazard ratios (HRs) (95% confidence intervals [CIs]) for CEE vs placebo for the major clinical outcomes available through ...

BackgroundHigher intake of calcium and vitamin D has been associated with a reduced risk of colorectal cancer in epidemiologic studies and polyp recurrence in polyp-prevention trials. However, randomized-trial evidence that calcium with vitamin D supplementation is beneficial in the primary prevention of colorectal cancer is lacking. MethodsWe conducted a randomized, double-blind, placebo-controlled trial involving 36,282 postmenopausal women from 40 Women's Health Initiative centers: 18,176 women received 500 mg of elemental calcium as calcium carbonate with 200 IU of vitamin D 3 twice daily (1000 mg of elemental calcium and 400 IU of vitamin D 3 ) and 18,106 received a matching placebo for an average of 7.0 years. The incidence of pathologically confirmed colorectal cancer was the designated secondary outcome. Baseline levels of serum 25-hydroxyvitamin D were assessed in a nested case-control study. ResultsThe incidence of invasive colorectal cancer did not differ significantly between women assigned to calcium plus vitamin D supplementation and those assigned to placebo (168 and 154 cases; hazard ratio, 1.08; 95 percent confidence interval, 0.86 to 1.34; P = 0.51), and the tumor characteristics were similar in the two groups. The frequency of colorectal-cancer screening and abdominal symptoms was similar in the two groups. There were no significant treatment interactions with baseline characteristics. ConclusionsDaily supplementation of calcium with vitamin D for seven years had no effect on the incidence of colorectal cancer among postmenopausal women. The long latency associated with the development of colorectal cancer, along with the seven-year duration of the trial, may have contributed to this null finding. Ongoing follow-up will assess the longer-term effect of this intervention. (ClinicalTrials.gov number, NCT00000611.) Calcium plus Vitamin D and Colorectal-Cancer Risk n engl j med 354;7 www.nejm.org february 16, 2006 * Plus-minus values are means ±SD. SEER denotes Surveillance, Epidemiology, and End Results.† Hazard ratios, 95 percent confidence intervals (CIs), and P values were derived from Cox proportional-hazards analyses stratified according to age, randomized assignment in the Hormone Therapy and Dietary Modification trials, and presence or absence of corresponding prevalent condition. ‡ This category includes the cecum, the ascending colon, the hepatic flexure, and the transverse colon. § This category includes the splenic flexure, the descending colon, and the sigmoid colon. ¶ This category includes cancers of both the rectum and the rectosigmoid junction. ‖ Data were available only for centrally adjudicated cases. ** Information on intestinal polyps and kidney stones is from self-reported data and was not centrally confirmed.

GE-ASSOCIATED MEMORY impairment affects an estimated one fifth to one third of older individuals and has important individual, family, and societal costs. 1,2 In older postmenopausal women, the potential impact of declining levels of sex hormones on cognitive functioning has received particular attention because of estrogen's presumptive beneficial effects on neurotransmitters, 3 neuroconnectivity, 4,5 and neuroprotection. 6 Observational studies have suggested that long-term hormone therapy may attenuate cognitive aging in postmenopausal women, although ran-domized clinical trial results are inconsistent. 7-12 The Women's Health Initiative (WHI) includes 2 randomized trials of post-menopausal hormone therapy: the estrogen-alone trial of conjugated equine estrogen (CEE) therapy in women with a prior hysterectomy and the estrogen Author Affiliations and Financial Disclosures are listed at the end of this article.

These results support the robustness of the concept of frailty as a geriatric syndrome that predicts several poor outcomes in older women. Underweight, obesity, smoking, and depressive symptoms are strongly associated with the development of frailty and represent important targets for prevention.