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.

Cocoa Extract Supplementation and Risk of Type 2 Diabetes: The Cocoa Supplement and Multivitamin Outcomes Study (COSMOS) Randomized Clinical Trial.

OBJECTIVE: Observational studies have indicated that cocoa flavanol supplementation may be a promising strategy for type 2 diabetes (T2D) prevention. We aimed to directly evaluate its clinical efficacy in a large randomized clinical trial (RCT). RESEARCH DESIGN AND METHOD: The Cocoa Supplement and Multivitamin Outcomes Study (COMSOS) was a 2 × 2 factorial RCT performed from June 2015 to December 2020 that tested cocoa extract and a multivitamin for the prevention of cardiovascular disease (CVD) and cancer. A total of 21,442 U.S. adults free of CVD and recent cancer, including 12,666 women aged ≥65 years and 8,776 men aged ≥60 years, were randomly assigned to receive cocoa extract [500 mg/day cocoa flavanols, including 80 mg (-)-epicatechin] or placebo. In this study, we included 18,381 participants without diabetes at enrollment and examined the effect of cocoa extract supplementation on incident self-reported T2D in intention-to-treat analyses. RESULTS: During a median follow-up of 3.5 years, 801 incident T2D cases were reported. Compared with placebo, taking a cocoa extract supplement did not reduce T2D (adjusted hazard ratio 1.04, 95% CI 0.91-1.20, P = 0.58). Stratification analyses showed that the effect of cocoa extract supplementation was not significantly modified by sex, race, BMI, smoking, physical activity, dietary quality, flavanol status at baseline, or randomized multivitamin assignment. CONCLUSIONS: Middle-aged and older adults taking a cocoa extract supplement for a median of 3.5 years did not reduce their risk of incident T2D. Further studies of cocoa extract supplementation beginning earlier in adulthood and in populations with different background diets are warranted.

Efficacy of vitamin D3 supplementation on cancer mortality: Systematic review and individual patient data meta-analysis of randomised controlled trials.

To evaluate the effect of vitamin D3 supplementation on cancer mortality in the general population and on prognosis in cancer patients, a systematic review and meta-analysis of randomised, placebo-controlled trials (RCTs) and individual patient data (IPD) was conducted. Overall, 14 RCTs with a total of 104,727 participants (2015 cancer deaths) were identified and 7 RCTs, including 90 % of all study participants (n = 94,068), could be included in the IPD meta-analyses. The main meta-analysis of the 14 RCTs yielded a statistically non-significant reduction in cancer mortality by 6 % (risk ratio (RR) [95%-confidence interval (95%CI)]: 0.94 [0.86-1.02]). Subgroup analyses revealed a 12 % lower cancer mortality in the vitamin D3 group compared with the placebo group in 10 trials with a daily dosing regimen (RR [95%CI]: 0.88 [0.78-0.98]), whereas no mortality reduction was seen in 4 trials using a bolus regimen (RR [95%CI]: 1.07 [0.91-1.24]; p-value for interaction: 0.042). The IPD meta-analysis (RR [95%CI]: 0.93 [0.84; 1.02]) confirmed the finding of all trials. The IPD were used to test effect modification by age, sex, body mass index, ethnicity, baseline serum 25-hydroxyvitamin D concentration, adherence and cancer-related factors but no statistically significant findings were obtained in meta-analyses of all trials. When restricted to trials with daily dosing in a post-hoc analysis, adults aged ≥ 70 years (RR [95%CI]: 0.83 [0.77; 0.98]) and subjects with vitamin D3 therapy initiation before cancer diagnosis (RR [95%CI]: 0.87 [0.69; 0.99]) appeared to benefit most from daily vitamin D3 supplementation. Measurements of baseline 25-hydroxyvitamin D levels and inclusion of other than non-Hispanic White adults were too sparse in the trials to draw conclusions. Results for all-cause and cancer-specific survival of participants with cancer were comparable to those obtained in the general population for cancer mortality. In conclusion, vitamin D3 did not reduce cancer mortality in the main meta-analysis of all RCTs because the observed risk reduction by 6 % was not statistically significant. However, a subgroup analysis revealed that vitamin D3 administered daily, in contrast to bolus supplementation, reduced cancer mortality by 12 %.

Association of calcium and vitamin D supplementation with cancer incidence and cause-specific mortality in Black women: Extended follow-up of the Women's Health Initiative calcium-vitamin D trial.

Low circulating vitamin D levels are more prevalent in Black than White individuals. We analyzed the Women's Health Initiative (WHI) calcium plus vitamin D (CaD) randomized clinical trial extended follow-up data to evaluate associations between calcium plus vitamin D supplementation and incident cancer, cardiovascular disease (CVD), and cause-specific mortality endpoints among Black women. Intent-to-treat analysis was performed. Among 3325 Black women in the CaD trial who were randomized into either daily calcium (1000 mg of calcium carbonate) plus vitamin D (400 IU D3) or placebos for an average of 7 years, there were 813 deaths, 588 incident cancers, and 837 CVD events during an average of 15.7 years of follow up (52 230 total person-years). Using Cox's proportional hazards models, we calculated hazard ratios and their confidence intervals for outcomes ascertained during the trial period, posttrial follow-up period and overall periods combined. We found that total mortality, cause-specific mortality, and total cancer incidence were almost identical between CaD and placebo groups. These results suggest that calcium plus vitamin D supplementation does not reduce risks of cancer, CVD, or other major causes of death in Black women overall and, thus, other medical, behavioral or social interventions should be considered to narrow health disparities related to these outcomes. However, other finer endpoints, such as colorectal cancer, warrants further investigation.

No Association Observed between Coffee Intake and Risk of Non-Hodgkin Lymphoma among Postmenopausal Women.

BACKGROUND: Some preliminary studies indicate that components in coffee may have anticarcinogenic effects. However, the association between coffee-drinking habits and the risk of non-Hodgkin lymphoma (NHL) remain controversial. OBJECTIVE: To examine the relationship between coffee intake and NHL incidence in a large prospective study of postmenopausal US women. DESIGN AND PARTICIPANTS/SETTING: The participants included 74,935 women from the Women's Health Initiative Observational Study who were recruited from 1993 through 1998. Information about coffee-drinking habits was collected at baseline via self-administered questionnaires. MAIN OUTCOME MEASURES: Newly diagnosed NHL was validated by medical records and pathology records. Separate analyses were performed for the following three subtypes of NHL: diffuse large B-cell lymphoma (n = 244), follicular lymphoma (n = 166), and chronic lymphocytic leukemia/small lymphocytic lymphoma (n = 64). STATISTICAL ANALYSES PERFORMED: Age-adjusted and multivariable-adjusted Cox proportional hazards models were used to determine associations of coffee intake (specifically, the total amount of coffee consumed daily, coffee types, and coffee preparation methods) with risk of NHL. RESULTS: A total of 851 women developed NHL during a median 18.34 years of follow-up (range = 0.01 to 24.30 years; ± 6.63 years). Overall, no associations were observed between coffee intake and risk of NHL regardless of the total amount of daily coffee intake (P value for trend = 0.90), caffeinated (P = 0.55) or decaffeinated coffee intake (P = 0.78), and filtered or unfiltered coffee intake (P = 0.91) after controlling for sociodemographic factors, lifestyle risk factors, and clinical risk factors/current medical conditions. No significant associations were observed between coffee intake with specific subtypes of NHL. A statistically significant interaction was found between alcohol intake, coffee intake, and incident NHL (P value for interaction = 0.02) based on the adjusted analysis. Specifically, among women who frequently consumed alcohol (> 7 drinks/week), those who had moderate coffee intake (2 to 3 c coffee/day) had a significantly reduced risk of developing NHL (hazard ratio 0.61, 95% CI 0.36 to 0.98), compared with those who did not drink coffee. CONCLUSIONS: The findings from this study do not support an association between coffee consumption and NHL risk, irrespective of the total amount of daily coffee intake, coffee types, or coffee preparation methods.

A Randomized Trial of Calcium Plus Vitamin D Supplementation and Risk of Ductal Carcinoma In Situ of the Breast.

Background: The effect of calcium plus vitamin D (CaD) supplementation on risk of ductal carcinoma in situ (DCIS) of the breast, a nonobligate precursor of invasive ductal carcinoma, is not well understood. In this secondary analysis, we examined this association in the Women's Health Initiative CaD trial over approximately 20 years of follow-up. Methods: A total of 36 282 cancer-free postmenopausal women (50-79 years) were randomly assigned to daily (d) calcium (1000 mg) plus vitamin D (400 IU) supplementation or to a placebo. Personal supplementation with vitamin D (≤600 IU/d, subsequently raised to 1000 IU/d) and calcium (≤1000 mg/d) was allowed. The intervention phase (median = 7.1 years), was followed by a postintervention phase (additional 13.8 years), which included 86.0% of the surviving women. A total of 595 incident DCIS cases were ascertained. Hazard ratios (HRs) plus 95% confidence intervals (CIs) were calculated. Results: The intervention group had a lower risk of DCIS throughout follow-up (HR = 0.82, 95% CI = 0.70 to 0.96) and during the postintervention phase (HR = 0.76, 95% CI = 0.61 to 0.94). The group that used CaD personal supplements in combination with the trial intervention had a lower risk of DCIS compared with the trial placebo group that did not use personal supplementation (HR = 0.72, 95% CI = 0.56 to 0.91). Conclusions: CaD supplementation in postmenopausal women was associated with reduced risk of DCIS, raising the possibility that consistent use of these supplements might provide long-term benefits for the prevention of DCIS.

n-3 Fatty Acid Biomarkers and Incident Type 2 Diabetes: An Individual Participant-Level Pooling Project of 20 Prospective Cohort Studies.

OBJECTIVE: Prospective associations between n-3 fatty acid biomarkers and type 2 diabetes (T2D) risk are not consistent in individual studies. We aimed to summarize the prospective associations of biomarkers of α-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) with T2D risk through an individual participant-level pooled analysis. RESEARCH DESIGN AND METHODS: For our analysis we incorporated data from a global consortium of 20 prospective studies from 14 countries. We included 65,147 participants who had blood measurements of ALA, EPA, DPA, or DHA and were free of diabetes at baseline. De novo harmonized analyses were performed in each cohort following a prespecified protocol, and cohort-specific associations were pooled using inverse variance-weighted meta-analysis. RESULTS: A total of 16,693 incident T2D cases were identified during follow-up (median follow-up ranging from 2.5 to 21.2 years). In pooled multivariable analysis, per interquintile range (difference between the 90th and 10th percentiles for each fatty acid), EPA, DPA, DHA, and their sum were associated with lower T2D incidence, with hazard ratios (HRs) and 95% CIs of 0.92 (0.87, 0.96), 0.79 (0.73, 0.85), 0.82 (0.76, 0.89), and 0.81 (0.75, 0.88), respectively (all P < 0.001). ALA was not associated with T2D (HR 0.97 [95% CI 0.92, 1.02]) per interquintile range. Associations were robust across prespecified subgroups as well as in sensitivity analyses. CONCLUSIONS: Higher circulating biomarkers of seafood-derived n-3 fatty acids, including EPA, DPA, DHA, and their sum, were associated with lower risk of T2D in a global consortium of prospective studies. The biomarker of plant-derived ALA was not significantly associated with T2D risk.

Associations of Coffee and Tea Consumption With Survival to Age 90 Years Among Older Women.

BACKGROUND: Coffee and tea are two of the most widely consumed beverages worldwide and have been associated with reduced risk of mortality in some studies. However, it is unknown whether consumption of these beverages is associated with survival to an advanced age. OBJECTIVE: To examine associations of coffee and tea consumption with survival to age 90 years. DESIGN: Prospective cohort study among participants from the Women's Health Initiative, recruited during 1993 to 1998 and followed up until March 31, 2018. SETTING: The setting included 40 US clinical centers. PARTICIPANTS: A racially and ethnically diverse cohort of 27,480 older women, aged 65 to 81 years at baseline. MEASUREMENTS: Women were classified as having either survived to age 90 years or died before this age. Consumption of caffeinated and decaffeinated coffee and caffeinated tea was assessed at baseline and categorized as 0, 1, 2 to 3, or 4 or more cups/day. Associations of coffee and tea consumption with survival to age 90 years were examined using logistic regression models adjusted for sociodemographic characteristics, lifestyle behaviors, dietary quality, and chronic disease history. RESULTS: A total of 14,659 (53.3%) women survived to age 90 years during follow-up. Caffeinated coffee, decaffeinated coffee, or caffeinated tea consumption was not significantly associated with survival to age 90 years after adjusting for confounders. Findings did not significantly vary by smoking, body mass index, or race/ethnicity. CONCLUSION: No amount of coffee or tea consumption was associated with late-age survival among older women. These findings may be reassuring to older women who consume coffee and tea as part of their daily diets but do not support drinking these beverages to achieve longevity.

Associations of social, physical, and financial factors with diet quality among older, community-dwelling women.

OBJECTIVE: This analysis examined whether specific social, physical, and financial factors were associated with diet quality among older, community-dwelling women. METHODS: This cross-sectional analysis was conducted in a subset of 6,094 community-dwelling Women's Health Initiative participants who completed a food frequency questionnaire, administered from 2012 to 2013, and a self-administered supplemental questionnaire, administered approximately 1 year later. The supplemental questionnaire included five questions assessing social, physical, and financial factors related to eating. Diet quality was assessed with the Healthy Eating Index-2010 (HEI-2010; range of 0-100; higher score indicates a higher quality diet). The total HEI-2010 score was calculated by summing individual scores representing the intake of nine adequacy components (beneficial food groups) and three moderation components (food groups to limit). Associations of responses to the five questions on the supplemental questionnaire with HEI-2010 scores were examined with multiple linear regression, adjusting for relevant covariates. RESULTS: Mean ±â€Šstandard deviation age of participants was 78.8 ±â€Š6.7 years. Reporting eating fewer than two meals per day, having dental or other mouth problems causing problems with eating, and not always being able to shop, cook, or feed oneself were associated with statistically significantly lower HEI-2010 scores, compared with those not reporting these issues, after multivariable adjustment: 5.37, 2.98, and 2.39 lower scores, respectively (all P values <0.0001). Reporting eating alone most of the time and not always having enough money to buy food were not associated with HEI-2010 scores. CONCLUSIONS: Among older, community-dwelling women, eating fewer than two meals per day, dental and other mouth problems, and diminished ability to shop for food, prepare meals, and feed oneself were associated with lower diet quality. These are potential targets for interventions to improve diet quality in older women. : Video Summary:http://links.lww.com/MENO/A561.

Video Summary:http://links.lww.com/MENO/A561.

The Association between Prebiotic Fiber Supplement Use and Colorectal Cancer Risk and Mortality in the Women's Health Initiative.

BACKGROUND: Fiber-based prebiotic supplements are marketed for maintaining bowel health and promoting beneficial gut bacteria. However, the association between prebiotic supplement use and colorectal cancer risk and mortality is unknown. METHODS: The association between prebiotic use and colorectal cancer risk and mortality was evaluated in postmenopausal women in the Women's Health Initiative study. Self-reported prebiotic use was documented at study enrollment. Adjudicated colorectal cancer cases and mortality were captured using medical and death records. Cox proportional hazards models were used to estimate the HR related to prebiotic use and colorectal cancer risk and mortality. RESULTS: In total, 3,032 colorectal cancer cases were diagnosed during an average 15.4 years of follow-up. Overall, 3.7% of women used a prebiotic with psyllium, the major fiber type. Use of any prebiotic supplement was not associated with colorectal cancer risk or mortality. The type of prebiotic supplement (none vs. insoluble or soluble) was not associated with colorectal cancer risk; however, use of insoluble fiber prebiotics compared with none was associated with higher colorectal cancer mortality [HR, 2.79; 95% confidence interval (CI), 1.32-5.90; P = 0.007]. Likelihood ratio tests indicated no significant interactions between prebiotic use and other colorectal cancer risk factors, including metabolic syndrome. CONCLUSIONS: Prebiotic fiber supplement use was not associated with colorectal cancer risk. Insoluble, but not soluble, prebiotic fiber use was associated with higher colorectal cancer mortality. These findings do not support the promotion of prebiotic fiber supplements to reduce colorectal cancer risk or colorectal cancer mortality. IMPACT: Further investigation is warranted for findings regarding insoluble prebiotic fiber and higher colorectal cancer mortality in postmenopausal women.

Lipoprotein(a) plasma levels, bone mineral density and risk of hip fracture: a post hoc analysis of the Women's Health Initiative, USA.

OBJECTIVES: Elevated Lipoprotein(a) (Lp[a]) is a well-known risk factor for cardiovascular disease. However, its roles in bone metabolism and fracture risk are unclear. We therefore investigated whether plasma Lp(a) levels were associated with bone mineral density (BMD) and incident hip fractures in a large cohort of postmenopausal women. DESIGN: Post hoc analysis of data from the Women's Health Initiative (WHI), USA. SETTING: 40 clinical centres in the USA. PARTICIPANTS: The current analytical cohort consisted of 9698 white, postmenopausal women enrolled in the WHI, a national prospective study investigating determinants of chronic diseases including heart disease, breast and colorectal cancers and osteoporotic fractures among postmenopausal women. Recruitment for WHI took place from 1 October 1993 to 31 December 1998. EXPOSURES: Plasma Lp(a) levels were measured at baseline. OUTCOME MEASURES: Incident hip fractures were ascertained annually and confirmed by medical records with follow-up through 29 August 2014. BMD at the femoral neck was measured by dual X-ray absorptiometry in a subset of participants at baseline. STATISTICAL ANALYSES: Cox proportional hazards and logistic regression models were used to evaluate associations of quartiles of plasma Lp(a) levels with hip fracture events and hip BMD T-score, respectively. RESULTS: During a mean follow-up of 13.8 years, 454 incident cases of hip fracture were observed. In analyses adjusting for confounding variables including age, body mass index, history of hysterectomy, smoking, physical activity, diabetes mellitus, general health status, cardiovascular disease, use of menopausal hormone therapy, use of bisphosphonates, calcitonin or selective-oestrogen receptor modulators, baseline dietary and supplemental calcium and vitamin D intake and history of fracture, no significant association of plasma Lp(a) levels with low hip BMD T-score or hip fracture risk was detected. CONCLUSIONS: These findings suggest that plasma Lp(a) levels are not related to hip BMD T-score or hip fracture events in postmenopausal women. TRIAL REGISTRATION NUMBER: NCT00000611; Post-results.