The efficacy of calcium with vitamin D supplementation for preventing hip and other fractures in healthy postmenopausal women remains equivocal. We recruited 36,282 postmenopausal women, 50 to 79 years of age, who were already enrolled in a Women's Health Initiative (WHI) clinical trial. We randomly assigned participants to receive 1000 mg of elemental calcium as calcium carbonate with 400 IU of vitamin D₃ daily or placebo. Fractures were ascertained for an average follow-up period of 7.0 years. Bone density was measured at three WHI centers. Hip bone density was 1.06 percent higher in the calcium plus vitamin D group than in the placebo group (P<0.01). Intention-to-treat analysis indicated that participants receiving calcium plus vitamin D supplementation had a hazard ratio of 0.88 for hip fracture (95 percent confidence interval, 0.72 to 1.08), 0.90 for clinical spine fracture (0.74 to 1.10), and 0.96 for total fractures (0.91 to 1.02). The risk of renal calculi increased with calcium plus vitamin D (hazard ratio, 1.17; 95 percent confidence interval, 1.02 to 1.34). Censoring data from women when they ceased to adhere to the study medication reduced the hazard ratio for hip fracture to 0.71 (95 percent confidence interval, 0.52 to 0.97). Effects did not vary significantly according to prerandomization serum vitamin D levels. 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.)

Clinical trials and observational studies have identified strong associations between low-density lipoprotein cholesterol (LDL-C) level and other cardiovascular disease (CVD) risk factors and dietary intake of fats, particularly saturated and trans fats, cholesterol, plant products, and grains or fiber. Epidemiologic studies have demonstrated that diets low in saturated fat and cholesterol are associated with lower rates of CVD and have implicated several nutrients as determinants of CVD risk.^1-6 Replacing saturated fat with polyunsaturated fat reduced cardiovascular events in some early trials.^7-9 In more recent secondary prevention trials, a Mediterranean-type dietary pattern^10,11 or a very low-fat eating pattern¹² prevented recurrent events, and meta-analyses^13,14 of recent trials of lipid-lowering drugs have documented a strong relationship between changes in LDL-C level and decreased incidence of coronary heart disease (CHD).

Higher 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. We 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 D₃ twice daily (1000 mg of elemental calcium and 400 IU of vitamin D₃) 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. The 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. Daily 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.)

Declining cognitive function is a growing public health concern for older adults, given the well-documented pattern of age-associated decrements in many areas of cognitive performance¹ and the increasing proportion of elderly individuals in the US population. The prevalence of age-associated memory impairment in the general older population is estimated to be between 17% and 34%.^2-4 In postmenopausal women, the effect of reduced sex hormones, especially estrogen and progesterone, on cognitive decline is of particular interest because of their modulating effects on neurotransmitters,⁵ neuroconnectivity,^6,7 and neuroprotection.⁸ Estrogen receptors are widely distributed throughout the brain, but particularly in the hippocampus,⁹ which has suggested a role of estrogen in episodic memory function.¹⁰ Less is known about the effects of progesterone on the brain^11,12 although progesterone could theoretically amplify, modulate, or antagonize the effect of estrogen.^13,14

Age-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 randomized clinical trial results are inconsistent.^7-12