Long-Term Effect of Randomization to Calcium and Vitamin D Supplementation on Health in Older Women : Postintervention Follow-up of a Randomized Clinical Trial.

BACKGROUND: Although calcium and vitamin D (CaD) supplementation may affect chronic disease in older women, evidence of long-term effects on health outcomes is limited. OBJECTIVE: To evaluate long-term health outcomes among postmenopausal women in the Women's Health Initiative CaD trial. DESIGN: Post hoc analysis of long-term postintervention follow-up of the 7-year randomized intervention trial of CaD. (ClinicalTrials.gov: NCT00000611). SETTING: A multicenter (n = 40) trial across the United States. PARTICIPANTS: 36 282 postmenopausal women with no history of breast or colorectal cancer. INTERVENTION: Random 1:1 assignment to 1000 mg of calcium carbonate (400 mg of elemental calcium) with 400 IU of vitamin D3 daily or placebo. MEASUREMENTS: Incidence of colorectal, invasive breast, and total cancer; disease-specific and all-cause mortality; total cardiovascular disease (CVD); and hip fracture by randomization assignment (through December 2020). Analyses were stratified on personal supplement use. RESULTS: For women randomly assigned to CaD versus placebo, a 7% reduction in cancer mortality was observed after a median cumulative follow-up of 22.3 years (1817 vs. 1943 deaths; hazard ratio [HR], 0.93 [95% CI, 0.87 to 0.99]), along with a 6% increase in CVD mortality (2621 vs. 2420 deaths; HR, 1.06 [CI, 1.01 to 1.12]). There was no overall effect on other measures, including all-cause mortality (7834 vs. 7748 deaths; HR, 1.00 [CI, 0.97 to 1.03]). Estimates for cancer incidence varied widely when stratified by whether participants reported supplement use before randomization, whereas estimates on mortality did not vary, except for CVD mortality. LIMITATION: Hip fracture and CVD outcomes were available on only a subset of participants, and effects of calcium versus vitamin D versus joint supplementation could not be disentangled. CONCLUSION: Calcium and vitamin D supplements seemed to reduce cancer mortality and increase CVD mortality after more than 20 years of follow-up among postmenopausal women, with no effect on all-cause mortality. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute of the National Institutes of Health.

Breast cancer incidence and mortality by metabolic syndrome and obesity: The Women's Health Initiative.

BACKGROUND: In the Women's Health Initiative (WHI) randomized trial, dietary intervention significantly reduced breast cancer mortality, especially in women with more metabolic syndrome (MetS) components. Therefore, this study investigated the associations of MetS and obesity with postmenopausal breast cancer after long-term follow-up in the WHI clinical trials. METHODS: A total of 68,132 postmenopausal women, without prior breast cancer and with normal mammogram, were entered into WHI randomized clinical trials; 63,330 women with an entry MetS score comprised the study population. At entry, body mass index (BMI) was determined; MetS score (0, 1-2, and 3-4) included the following: (1) high waist circumference (≥88 cm), (2) high blood pressure (systolic ≥130 mm Hg and/or diastolic ≥85 mm Hg, or hypertension history), (3) high-cholesterol history, and (4) diabetes history. Study outcomes included breast cancer incidence, breast cancer mortality, deaths after breast cancer, and results by hormone receptor status. RESULTS: After a >20-year mortality follow-up, a higher MetS score (3-4), adjusted for BMI, was significantly associated with more poor prognosis, estrogen receptor (ER)-positive, progesterone receptor (PR)-negative cancers (p = .03), 53% more deaths after breast cancer (p < .001), and 44% higher breast cancer mortality (p = .03). Obesity status, adjusted for MetS score, was significantly associated with more good prognosis, ER-positive, PR-positive cancers (p < .001), more total breast cancers (p < .001), and more deaths after breast cancer (p < .001), with higher breast cancer mortality only in women with severe obesity (BMI, ≥35 kg/m2; p < .001). CONCLUSIONS: MetS and obesity status have independent, but differential, adverse associations with breast cancer receptor subtypes and breast cancer mortality risk. Both represent separate targets for breast cancer prediction and prevention strategies.

The association between reproductive history and abdominal adipose tissue among postmenopausal women: results from the Women's Health Initiative.

STUDY QUESTION: What is the association between reproductive health history (e.g. age at menarche, menopause, reproductive lifespan) with abdominal adiposity in postmenopausal women? SUMMARY ANSWER: Higher visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) tissue levels were observed among women with earlier menarche, earlier menopause, and greater parity. WHAT IS KNOWN ALREADY: Postmenopausal women are predisposed to accumulation of VAT and SAT. Reproductive health variables are known predictors of overall obesity status in women, defined by BMI. STUDY DESIGN, SIZE, DURATION: This study is a secondary analysis of data collected from the baseline visit of the Women's Health Initiative (WHI). The WHI is a large prospective study of postmenopausal women, including both a randomized trial and observational study. There were 10 184 women included in this analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data were collected from a reproductive health history questionnaire, dual-energy x-ray absorptiometry scans, and anthropometric measures at WHI baseline. Reproductive history was measured via self-report, and included age at menarche, variables related to pregnancy, and age at menopause. Reproductive lifespan was calculated as age at menopause minus age at menarche. Statistical analyses included descriptive analyses and multivariable linear regression models to examine the association between reproductive history with VAT, SAT, total body fat, and BMI. MAIN RESULTS AND THE ROLE OF CHANCE: Women who reported early menarche (<10 years) or early menopause (<40 years) had the highest levels of VAT. Adjusted multivariable linear regression results demonstrate women who experienced menarche >15 years had 23 cm2 less VAT (95% CI: -31.4, -14.4) and 47 cm2 less SAT (95% CI: -61.8, -33.4) than women who experienced menarche at age 10 years or earlier. A similar pattern was observed for age at menopause: compared to women who experienced menopause <40 years, menopause at 50-55 years was associated with 19.3 cm2 (95% CI: -25.4, -13.3) less VAT and 27.4 cm2 (-29.6, 10.3) less SAT. High parity (>3 pregnancies) was also associated with VAT and SAT. For example, adjusted beta coefficients for VAT were 8.36 (4.33, 12.4) and 17.9 (12.6, 23.2) comparing three to four pregnancies with the referent, one to two pregnancies. LIMITATIONS, REASONS FOR CAUTION: The WHI reproductive health history questionnaire may be subject to poor recall owing to a long look-back window. Residual confounding may be present given lack of data on early life characteristics, such as maternal and pre-menarche characteristics. WIDER IMPLICATIONS OF THE FINDINGS: This study contributes to our understanding of reproductive lifespan, including menarche and menopause, as an important predictor of late-life adiposity in women. Reproductive health has also been recognized as a sentinel marker for chronic disease in late life. Given established links between adiposity and cardiometabolic outcomes, this research has implications for future research, clinical practice, and public health policy that makes use of reproductive health history as an opportunity for chronic disease prevention. STUDY FUNDING/COMPETING INTEREST(S): HRB and AOO are supported by the National Institute of Health National Institute of Aging (R01AG055018-04). JWB reports royalties from 'ACSM'S Body Composition Assessment Book' and consulting fees from the WHI. The remaining authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.