Associations of empirically derived dietary patterns and cognitive performance in older men: Results of the Osteoporotic Fractures in Men (MrOS) study.

OBJECTIVE: The aim of this study was to examine associations between empirically derived dietary pattern scores and cognition, as well as risk of cognitive decline, over an average of 4.6 (± 0.3) years in older men. MATERIALS AND METHODS: This analysis was conducted as part of the Osteoporotic Fractures in Men (MrOS) prospective cohort study. Diet was assessed at Visit 1 (3/2000-4/2002) by food frequency questionnaire, and dietary patterns (Western and Prudent) were derived by factor analysis. The analytic cohort comprised 4231 community-dwelling American men who were aged 65 years or more. Cognitive function was assessed with the Modified Mini-Mental State exam (3MS) and the Trails B test at Visit 1 and at Visit 2 (3/2005-5/2006). Associations between dietary pattern score and cognition and risk of cognitive decline were estimated using mixed effects regression models. Model 1 was adjusted for age, clinic site and total energy intake (TEI). Model 2 was further adjusted for calcium and vitamin D supplement use, body mass index (BMI), physical activity, smoking, diabetes and hypertension (Western diet group) and education, calcium and vitamin D supplement use, depression, BMI, physical activity, smoking and stroke (Prudent diet group). RESULTS: Adherence to the Western dietary pattern was associated with higher 3MS scores and shorter Trails B test time at Visit 1 in Model 2. Adherence to the Prudent dietary pattern was associated with higher 3MS scores in Model 1 but not Model 2. There were no independent associations between dietary pattern scores and risk of cognitive decline 4.6 (± 0.3) years later at Visit 2. CONCLUSION: The results do not support a robust protective effect of the Prudent dietary pattern on cognition in the MrOS cohort. Associations between the Western dietary pattern and better cognitive scores should be interpreted with caution. Further research is needed to understand the complex interactions between dietary patterns and cognition in older men.

Untargeted serum metabolomic profiles and breast density in young women.

PURPOSE OF THE STUDY: Breast density is an established risk factor for breast cancer. However, little is known about metabolic influences on breast density phenotypes. We conducted untargeted serum metabolomics analyses to identify metabolic signatures associated with breast density phenotypes among young women. METHODS: In a cross-sectional study of 173 young women aged 25-29 who participated in the Dietary Intervention Study in Children 2006 Follow-up Study, 449 metabolites were measured in fasting serum samples using ultra-high-performance liquid chromatography-tandem mass spectrometry. Multivariable-adjusted mixed-effects linear regression identified metabolites associated with magnetic resonance imaging measured breast density phenotypes: percent dense breast volume (%DBV), absolute dense breast volume (ADBV), and absolute non-dense breast volume (ANDBV). Metabolite results were corrected for multiple comparisons using a false discovery rate adjusted p-value (q). RESULTS: The amino acids valine and leucine were significantly inversely associated with %DBV. For each 1 SD increase in valine and leucine, %DBV decreased by 20.9% (q = 0.02) and 18.4% (q = 0.04), respectively. ANDBV was significantly positively associated with 16 lipid and one amino acid metabolites, whereas no metabolites were associated with ADBV. Metabolite set enrichment analysis also revealed associations of distinct metabolic signatures with %DBV, ADBV, and ANDBV; branched chain amino acids had the strongest inverse association with %DBV (p = 0.002); whereas, diacylglycerols and phospholipids were positively associated with ANDBV (p ≤ 0.002), no significant associations were observed for ADBV. CONCLUSION: Our results suggest an inverse association of branched chain amino acids with %DBV. Larger studies in diverse populations are needed.

Childhood adiposity, serum metabolites and breast density in young women.

BACKGROUND: Childhood adiposity is inversely associated with young adult percent dense breast volume (%DBV) and absolute dense breast volume (ADBV), which could contribute to its protective effect for breast cancer later in life. The objective of this study was to identify metabolites in childhood serum that may mediate the inverse association between childhood adiposity and young adult breast density. METHODS: Longitudinal data from 182 female participants in the Dietary Intervention Study in Children (DISC) and the DISC 2006 (DISC06) Follow-Up Study were analyzed. Childhood adiposity was assessed by anthropometry at the DISC visit with serum available that occurred closest to menarche and expressed as a body mass index (BMI) z-score. Serum metabolites were measured by untargeted metabolomics using ultra-high-performance liquid chromatography-tandem mass spectrometry. %DBV and ADBV were measured by magnetic resonance imaging at the DISC06 visit when participants were 25-29 years old. Robust mixed effects linear regression was used to identify serum metabolites associated with childhood BMI z-scores and breast density, and the R package mediation was used to quantify mediation. RESULTS: Of the 115 metabolites associated with BMI z-scores (FDR < 0.20), 4 were significantly associated with %DBV and 6 with ADBV before, though not after, adjustment for multiple comparisons. Mediation analysis identified 2 unnamed metabolites, X-16576 and X-24588, as potential mediators of the inverse association between childhood adiposity and dense breast volume. X-16576 mediated 14% (95% confidence interval (CI) = 0.002, 0.46; P = 0.04) of the association of childhood adiposity with %DBV and 11% (95% CI = 0.01, 0.26; P = 0.02) of its association with ADBV. X-24588 also mediated 7% (95% CI = 0.001, 0.18; P = 0.05) of the association of childhood adiposity with ADBV. None of the other metabolites examined contributed to mediation of the childhood adiposity-%DBV association, though there was some support for contributions of lysine, valine and 7-methylguanine to mediation of the inverse association of childhood adiposity with ADBV. CONCLUSIONS: Additional large longitudinal studies are needed to identify metabolites and other biomarkers that mediate the inverse association of childhood adiposity with breast density and possibly breast cancer risk.

Screening for Prediabetes and Type 2 Diabetes in Children and Adolescents: Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Of youths diagnosed with type 2 diabetes, many develop microvascular complications by young adulthood. Objective: To review the evidence on benefits and harms of screening children and adolescents for prediabetes and type 2 diabetes to inform the US Preventive Services Task Force (USPSTF). Data Sources: PubMed/MEDLINE, Cochrane Library, and trial registries through May 3, 2021; references; experts; literature surveillance through July 22, 2022. Study Selection: English-language controlled studies evaluating screening or interventions for prediabetes or type 2 diabetes that was screen detected or recently diagnosed. Data Extraction and Synthesis: Dual review of abstracts, full-text articles, and study quality; qualitative synthesis of findings. Main Outcomes and Measures: Mortality, cardiovascular morbidity, diabetes-related morbidity, development of diabetes, quality of life, and harms. Results: This review included 8 publications (856 participants; mean age, 14 years [range, 10-17 years]). Of those, 6 were from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. No eligible studies directly evaluated the benefits or harms of screening. One randomized clinical trial (RCT) (TODAY; n = 699 adolescents with obesity; mean age, 14 years) comparing metformin, metformin plus rosiglitazone, and metformin plus lifestyle intervention reported that 2 youths with recently diagnosed diabetes developed kidney impairment (0 vs 1 vs 1, respectively; P > .99) and 11 developed diabetic ketoacidosis (5 vs 3 vs 3, respectively; P = .70). One RCT of 75 adolescents (mean age, 13 years) with obesity with prediabetes compared an intensive lifestyle intervention with standard care and reported that no participants in either group developed diabetes, although follow-up was only 6 months. Regarding harms of interventions, 2 RCTs assessing different comparisons enrolled youths with recently diagnosed diabetes. Major hypoglycemic events were reported by less than 1% of participants. Minor hypoglycemic events were more common among youths treated with metformin plus rosiglitazone than among those treated with metformin or metformin plus lifestyle intervention in TODAY (8.2% vs 4.3% vs 3.4%, P = .05). In 1 study, gastrointestinal adverse events were more commonly reported by those taking metformin than by those taking placebo (abdominal pain: 25% vs 12%; nausea/vomiting: 17% vs 10%; P not reported). Conclusions and Relevance: No eligible studies directly evaluated the benefits or harms of screening for prediabetes and type 2 diabetes in children and adolescents. For youths with prediabetes or recently diagnosed (not screen-detected) diabetes, the only eligible trials reported few health outcomes and found no difference between groups, although evidence was limited by substantial imprecision and a duration of follow-up likely insufficient to assess health outcomes.

Cumulative Endogenous Estrogen Exposure Is Associated With Postmenopausal Fracture Risk: The Women's Health Initiative Study.

We aimed to evaluate the relationship between cumulative endogenous estrogen exposure and fracture risk in 150,682 postmenopausal women (aged 50 to 79 years at baseline) who participated in the Women's Health Initiative. We hypothesized that characteristics indicating lower cumulative endogenous estrogen exposure would be associated with increased fracture risk. We determined ages at menarche and menopause as well as history of irregular menses from baseline questionnaires and calculated years of endogenous estrogen exposure from ages at menarche and menopause. Incident clinical fractures were self-reported over an average 16.7 years of follow-up. We used multivariable proportional hazards models to assess the associations between the estrogen-related variables and incidence of any clinical fracture. In fully adjusted models, those with the fewest years of endogenous estrogen exposure (<30) had an 11% higher risk of developing central body fractures and a 9% higher risk of lower extremity fractures than women with 36 to 40 years of endogenous estrogen exposure (the reference category). In contrast, women with the most years of endogenous estrogen exposure (more than 45 years) had a 9% lower risk of lower extremity fractures than the reference category. Women with irregular (not monthly) menstrual cycles were 7% to 8% more likely to experience lower extremity fractures than women with regular monthly cycles. Our findings support the hypothesis that characteristics signifying lower cumulative endogenous estrogen exposure are associated with higher fracture risk. © 2022 American Society for Bone and Mineral Research (ASBMR).

The relationship between sleep and weight change among women diagnosed with breast cancer participating in the Women's Health Initiative.

PURPOSE: Short and long sleep duration and poor sleep quality are risk factors for weight gain and cancer mortality. The purpose of this study is to investigate the relationship between sleep and weight change among postmenopausal breast cancer survivors. METHODS: Women participating in the Women's Health Initiative who were diagnosed with incident breast cancer between year one and year three were included. Self-reported sleep duration was categorized as ≤ 5 h (short), 6 h, 7-8 h (optimal), and ≥ 9 h (long). Self-reported sleep quality was categorized as poor, average, and above average. Post-diagnosis weight change was the difference of weight closest to, but preceding diagnosis, and year 3 weight. We used linear regression to evaluate sleep duration and sleep quality associations with post-diagnosis weight change adjusted for potential confounders. RESULTS: Among 1156 participants, 63% were weight stable after diagnosis; average weight gain post cancer diagnosis was 3.2 kg. Six percent of women reported sleeping ≤ 5 h, 26% reported 6 h, 64% reported 7-8 h, and 4% reported ≥ 9 h. There were no differences in adjusted estimates of weight change among participants with short duration (0.37 kg; 95% CI - 0.88, 1.63), or long duration (- 0.56 kg; 95% CI - 2.03, 0.90) compared to optimal duration, nor was there a difference among poor quality (- 0.51 kg; 95% CI - 1.42, 0.41) compared to above average quality. CONCLUSION: Among postmenopausal breast cancer survivors, sleep duration and quality were not associated with weight change after breast cancer diagnosis. Future studies should consider capturing change in adiposity and to expand beyond self-reported sleep.

Proinflammatory and Hyperinsulinemic Dietary Patterns Are Associated With Specific Profiles of Biomarkers Predictive of Chronic Inflammation, Glucose-Insulin Dysregulation, and Dyslipidemia in Postmenopausal Women.

Background: Dietary patterns promoting hyperinsulinemia and chronic inflammation, including the empirical dietary index for hyperinsulinemia (EDIH) and empirical dietary inflammatory pattern (EDIP), have been shown to strongly influence risk of weight gain, type 2 diabetes, cardiovascular disease, and cancer. EDIH was developed using plasma C-peptide, whereas EDIP was based on plasma C-reactive protein (CRP), interleukin-6, and tumor necrosis factor alpha receptor 2 (TNF-αR2). We investigated whether these dietary patterns were associated with a broader range of relevant biomarkers not previously tested. Methods: In this cross-sectional study, we included 35,360 women aged 50-79 years from the Women's Health Initiative with baseline (1993-1998) fasting blood samples. We calculated EDIH and EDIP scores from baseline food frequency questionnaire data and tested their associations with 40 circulating biomarkers of insulin response/insulin-like growth factor (IGF) system, chronic systemic inflammation, endothelial dysfunction, lipids, and lipid particle size. Multivariable-adjusted linear regression was used to estimate the percent difference in biomarker concentrations per 1 standard deviation increment in dietary index. FDR-adjusted p < 0.05 was considered statistically significant. Results: Empirical dietary index for hyperinsulinemia (EDIH) and empirical dietary inflammatory pattern (EDIP) were significantly associated with altered concentrations of 25 of the 40 biomarkers examined. For EDIH, the percent change in biomarker concentration in the insulin-related biomarkers ranged from +1.3% (glucose) to +8% (homeostatic model assessment for insulin resistance) and -9.7% for IGF-binding protein-1. EDIH impacted inflammation and endothelial dysfunction biomarkers from +1.1% (TNF-αR2) to +7.8% (CRP) and reduced adiponectin by 2.4%; and for lipid biomarkers: +0.3% (total cholesterol) to +3% (triglycerides/total cholesterol ratio) while reducing high-density lipoprotein cholesterol by 2.4%. EDIP showed a similar trend of associations with most biomarkers, although the magnitude of association was slightly weaker for the insulin-related biomarkers and stronger for lipids and lipid particle size. Conclusions: Dietary patterns with high potential to contribute to insulin hypersecretion and to chronic systemic inflammation, based on higher EDIH and EDIP scores, were associated with an unfavorable profile of circulating biomarkers of glucose-insulin dysregulation, chronic systemic inflammation, endothelial dysfunction and dyslipidemia. The broad range of biomarkers further validates EDIH and EDIP as mechanisms-based dietary patterns for use in clinical and population-based studies of metabolic and inflammatory diseases.

Screening for Vitamin D Deficiency in Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Low serum vitamin D levels have been associated with adverse clinical outcomes; identifying and treating deficiency may improve outcomes. Objective: To review the evidence about screening for vitamin D deficiency in adults. Data Sources: PubMed, EMBASE, the Cochrane Library, and trial registries through March 12, 2020; bibliographies from retrieved articles, outside experts, and surveillance of the literature through November 30, 2020. Study Selection: Fair- or good-quality, English-language randomized clinical trials (RCTs) of screening with serum 25-hydroxyvitamin D (25[OH]D) compared with no screening, or treatment with vitamin D (with or without calcium) compared with placebo or no treatment conducted in nonpregnant adults; nonrandomized controlled intervention studies for harms only. Treatment was limited to studies enrolling or analyzing participants with low serum vitamin D levels. Data Extraction and Synthesis: Two reviewers assessed titles/abstracts and full-text articles, extracted data, and assessed study quality; when at least 3 similar studies were available, meta-analyses were conducted. Main Outcomes and Measures: Mortality, incident fractures, falls, diabetes, cardiovascular events, cancer, depression, physical functioning, and infection. Results: Forty-six studies (N = 16 205) (77 publications) were included. No studies directly evaluated the health benefits or harms of screening. Among community-dwelling populations, treatment was not significantly associated with mortality (pooled absolute risk difference [ARD], 0.3% [95% CI, -0.6% to 1.1%]; 8 RCTs, n = 2006), any fractures (pooled ARD, -0.3% [95% CI, -2.1% to 1.6%]; 6 RCTs, n = 2186), incidence of diabetes (pooled ARD, 0.1% [95% CI, -1.3% to 1.6%]; 5 RCTs, n = 3356), incidence of cardiovascular disease (2 RCTs; hazard ratio, 1.00 [95% CI, 0.74 to 1.35] and 1.09 [95% CI, 0.68 to 1.76]), incidence of cancer (2 RCTs; hazard ratio, 0.97 [95% CI, 0.68 to 1.39] and 1.01 [95% CI, 0.65 to 1.58], or depression (3 RCTs, various measures reported). The pooled ARD for incidence of participants with 1 or more falls was -4.3% (95% CI, -11.6% to 2.9%; 6 RCTs). The evidence was mixed for the effect of treatment on physical functioning (2 RCTs) and limited for the effect on infection (1 RCT). The incidence of adverse events and kidney stones was similar between treatment and control groups. Conclusions and Relevance: No studies evaluated the direct benefits or harms of screening for vitamin D deficiency. Among asymptomatic, community-dwelling populations with low vitamin D levels, the evidence suggests that treatment with vitamin D has no effect on mortality or the incidence of fractures, falls, depression, diabetes, cardiovascular disease, cancer, or adverse events. The evidence is inconclusive about the effect of treatment on physical functioning and infection.

Vitamin D Supplementation for Prevention of Cancer: The D2d Cancer Outcomes (D2dCA) Ancillary Study.

CONTEXT: Observational studies suggest that low vitamin D status may be a risk factor for cancer. OBJECTIVE: In a population with prediabetes and overweight/obesity that is at higher risk of cancer than the general population, we sought to determine if vitamin D supplementation lowers the risk of cancer and precancers. METHODS: The Vitamin D and type 2 diabetes (D2d) cancer outcomes study (D2dCA) is an ancillary study to the D2d study, which was conducted at 22 academic medical centers in the United States. Participants had prediabetes and overweight/obesity and were free of cancer for the previous 5 years. Participants were randomized to receive vitamin D3 4000 IU daily or placebo. At scheduled study visits (4 times/year), cancer and precancer events were identified by questionnaires. Clinical data were collected and adjudicated for all reported events. Cox proportional hazard models compared the hazard ratio (HR) of incident cancers and precancers between groups. RESULTS: Over a median follow-up period of 2.9 years, among 2385 participants (mean age 60 years and 25-hydroxyvitamin D 28 ng/mL), there were 89 cases of cancer. The HR of incident cancer for vitamin D vs placebo was 1.07 (95% CI 0.70, 1.62). Of 241 participants with incident precancers, 239 had colorectal adenomatous polyps. The HR for colorectal polyps for vitamin D vs placebo was 0.83 (95% CI 0.64, 1.07). CONCLUSION: In the D2d population of participants with prediabetes and overweight/obesity, not selected for vitamin D insufficiency, vitamin D supplementation did not have a significant effect on risk of incident cancer or colorectal polyps.

The severity of vasomotor symptoms and number of menopausal symptoms in postmenopausal women and select clinical health outcomes in the Women's Health Initiative Calcium and Vitamin D randomized clinical trial.

OBJECTIVE: This study evaluated whether vasomotor symptom (VMS) severity and number of moderate/severe menopausal symptoms (nMS) were associated with health outcomes, and whether calcium and vitamin D (CaD) modified the risks. METHODS: The Women's Health Initiative CaD study was a double blind, randomized, placebo-controlled trial, which tested 400 IU of 25-hydroxyvitamin-D and 1,000 mg of calcium per day in women aged 50 to 79 years. This study included 20,050 women (median follow-up of 7 y). The outcomes included hip fracture, colorectal cancer, invasive breast cancer, all-cause mortality, coronary heart disease, stroke, cardiovascular death, and total cardiovascular disease (CVD). MS included: hot flashes, night sweats, dizziness, heart racing, tremors, feeling restless, feeling tired, difficulty concentrating, forgetfulness, mood swings, vaginal dryness, breast tenderness, migraine, and waking up several times at night. Associations between VMS severity and nMS with outcomes were tested. RESULTS: No association between VMS severity and any outcome were found. In contrast, nMS was associated with higher stroke (hazard ratio [HR] 1.40 95% confidence interval [CI] 1.04-1.89 for ≥ 2 MS vs none; HR 1.20 95% CI 0.89-1.63 for 1 MS vs none, P trend = 0.03) and total CVD (HR 1.35, 95% CI, 1.18-1.54 for ≥ 2 MS vs none; HR 0.99, 95% CI, 0.87-1.14 for 1 MS vs none P trend < 0.001). CaD did not modify any association. CONCLUSION: Severity of VMS was not associated with any outcome. Having ≥2 moderate or severe MS was associated with an increased risk for CVD. The number of moderate/severe MS may be a marker for higher CVD risk. : Video Summary:http://links.lww.com/MENO/A669.

Video Summary:http://links.lww.com/MENO/A669.

Pubertal timing and breast density in young women: a prospective cohort study.

BACKGROUND: Earlier age at onset of pubertal events and longer intervals between them (tempo) have been associated with increased breast cancer risk. It is unknown whether the timing and tempo of puberty are associated with adult breast density, which could mediate the increased risk. METHODS: From 1988 to 1997, girls participating in the Dietary Intervention Study in Children (DISC) were clinically assessed annually between ages 8 and 17 years for Tanner stages of breast development (thelarche) and pubic hair (pubarche), and onset of menses (menarche) was self-reported. In 2006-2008, 182 participants then aged 25-29 years had their percent dense breast volume (%DBV) measured by magnetic resonance imaging. Multivariable, linear mixed-effects regression models adjusted for reproductive factors, demographics, and body size were used to evaluate associations of age and tempo of puberty events with %DBV. RESULTS: The mean (standard deviation) and range of %DBV were 27.6 (20.5) and 0.2-86.1. Age at thelarche was negatively associated with %DBV (p trend = 0.04), while pubertal tempo between thelarche and menarche was positively associated with %DBV (p trend = 0.007). %DBV was 40% higher in women whose thelarche-to-menarche tempo was 2.9 years or longer (geometric mean (95%CI) = 21.8% (18.2-26.2%)) compared to women whose thelarche-to-menarche tempo was less than 1.6 years (geometric mean (95%CI) = 15.6% (13.9-17.5%)). CONCLUSIONS: Our results suggest that a slower pubertal tempo, i.e., greater number of months between thelarche and menarche, is associated with higher percent breast density in young women. Future research should examine whether breast density mediates the association between slower tempo and increased breast cancer risk.

Intentional Weight Loss and Obesity-Related Cancer Risk.

BACKGROUND: Epidemiologic studies regarding weight loss and subsequent cancer risk are sparse. The study aim was to evaluate the association between weight change by intentionality and obesity-related cancer incidence in the Women's Health Initiative Observational Study. Eleven cancers were considered obesity related: breast, ovary, endometrium, colon and rectum, esophagus, kidney, liver, multiple myeloma, pancreas, stomach, and thyroid. METHODS: Postmenopausal women (n = 58 667) aged 50-79 years had body weight and waist circumference (WC) measured at baseline and year 3. Weight or WC change was categorized as stable (change < ±5%), loss (≥5%), and gain (≥5%). Self-report at year 3 characterized weight loss as intentional or unintentional. During the subsequent 12 years (mean) of follow-up, 6033 incident obesity-related cancers were identified. Relationships were evaluated using multivariable Cox proportional hazards regression models. RESULTS: Compared to women with stable weight, women with intentional weight loss had lower obesity-related cancer risk (hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.80 to 0.98). A similar result was observed for intentional WC reduction (HR = 0.88, 95% CI = 0.80 to 0.96). Among all cancers, intentional weight loss was most strongly associated with endometrial cancer (HR = 0.61, 95% CI = 0.42 to 0.88). Intentional WC loss was also associated with lower colorectal cancer risk (HR = 0.79, 95% CI = 0.63 to 0.99). Unintentional weight loss or weight gain was not associated with overall obesity-related cancer risk. CONCLUSION: Intentional weight or WC loss in postmenopausal women was associated with lower risk of obesity-related cancer. These findings suggest that postmenopausal women who intentionally lose weight can reduce their obesity-related cancer risk.

Associations Between Parity, Breastfeeding, and Risk of Maternal Type 2 Diabetes Among Postmenopausal Women.

OBJECTIVE: To examine associations among parity, breastfeeding history, and risk of developing type 2 diabetes among postmenopausal women. METHODS: A prospective cohort study was conducted. One hundred thirty-six thousand six hundred fifty-two postmenopausal women aged 50-79 years participating in the Women's Health Initiative recruited from 40 clinical centers throughout the United States between 1993 and 1998, without baseline cancer or diabetes were followed for 14.2 years. Parity and breastfeeding data were collected by questionnaires administrated to all participants at baseline. Incident diabetes was assessed via validated self-report of physician-diagnosed diabetes treated with insulin or other hypoglycemic medications. Multivariable Cox proportional hazards regression models were used to assess associations between parity, breastfeeding and diabetes incidence, and racial-ethnic differences in the associations. RESULTS: During follow-up, 18,812 cases of incident diabetes were identified. Overall, a greater number of term pregnancies was associated with increased risk of diabetes (P for trend=.002), and longer duration of breastfeeding was associated with lower risk of diabetes (P for trend <.01). After further adjusting for adult weight gain among a subset of the cohort (n=75,558) with 9,110 cases, the association between parity and risk of diabetes were attenuated and became nonsignificant. Also, parous women with fewer than five term pregnancies did not have increased diabetes risk when breastfeeding for 3 months or more per child, which was associated with less weight gain. CONCLUSION: The results of this large, prospective study showed that the association between parity and risk of type 2 diabetes was most likely confounded by adult weight gain among postmenopausal women.

Vitamin D supplementation for prevention of cancer: The D2d cancer outcomes (D2dCA) study.

Evidence on biological plausibility from mechanistic studies and data from observational studies suggest that vitamin D may be linked to risk of several types of cancer. However, evidence from clinical trials evaluating the effect of vitamin D supplementation on cancer risk is limited. The Vitamin D and Type 2 Diabetes (D2d) study is a multi-center, randomized, placebo-controlled clinical trial conducted to examine the causal relationship between oral vitamin D supplementation and development of diabetes among overweight adults with prediabetes. The D2d study provides a unique opportunity to assess the effect of vitamin D supplementation at a higher dose (4000 IU/day) than has been used in other clinical trials with cancer outcomes, in a population at higher than average risk for cancer. This paper provides: Krishnan and Feldman (2011) a) baseline characteristics of the D2d population included in the D2d cancer outcomes secondary study (D2dCA) and comparison to other large trials of vitamin D supplementation and cancer risk; Leyssens et al. (2013) b) description of data that are being collected during the trial and the planned statistical analyses to test whether vitamin D supplementation at a dose of 4000 IU/day has an effect on incident cancer overall, on incidence of certain types of cancer, and on incidence of precancerous lesions. Results of D2dCA will help guide future research and clinical recommendations related to vitamin D and cancer risk.

Women's Health Initiative clinical trials: potential interactive effect of calcium and vitamin D supplementation with hormonal therapy on cardiovascular disease.

OBJECTIVE: Data in humans and nonhuman primates have suggested a possible synergistic effect of vitamin D and calcium (CaD) and estrogen on the cardiovascular disease (CVD) risk factors. Using randomized trial data we explored whether the effect of menopausal hormone therapy (HT) on CVD events is modified by CaD supplementation. METHODS: A prospective, randomized, double-blind, placebo-controlled trial was implemented among postmenopausal women in the Women's Health Initiative. A total of 27,347 women were randomized to the HT trials (0.625 mg/d of conjugated equine estrogens [CEE] alone for women without a uterus vs placebo; or 0.625 mg of CEE in addition to 2.5 mg of medroxyprogesterone acetate daily [CEE + MPA] for women with a uterus vs placebo). After 1 year, 16,089 women in the HT trial were randomized to the CaD trial and received either 1,000 mg of elemental calcium carbonate and 400 IU of vitamin D3 daily or placebo. The mean (SD) duration of follow-up after CaD randomization was 6.2 (1.3) years for the CEE trial and 4.6 (1.1) years for the CEE + MPA trial. CVD and venous thromboembolism events evaluated in this subgroup analysis included coronary heart disease, stroke, pulmonary embolism, all-cause mortality, plus select secondary endpoints (total myocardial infarction, coronary revascularization, deep venous thrombosis, cardiovascular death, and all CVD events). Time-to-event methods were used and models were fit with a Cox proportional hazards regression model. RESULTS: In the CEE trial, CaD significantly modified the effect of CEE on stroke (P interaction = 0.04). In the CaD-placebo group, CEE's effect on stroke was harmful (hazard ratio [95% confidence interval] = 2.19[1.34-3.58]); however, it was neutral in the CaD-supplement group (hazard ratio [95% confidence interval] = 1.07[0.66-1.73]). We did not observe significant CEE-CaD interactions for coronary heart disease, total CVD events, or any of the remaining endpoints. In the CEE + MPA trial, there was no evidence that the effect of CEE + MPA on any of CVD endpoints was modified by CaD supplementation. CONCLUSIONS: CaD did not consistently modify the effect of CEE therapy or CEE + MPA therapy on CVD events. However, the increased risk of stroke due to CEE therapy appears to be mitigated by CaD supplementation. In contrast, CaD supplementation did not influence the risk of stroke due to CEE + MPA.

Racial and Ethnic Differences in Anthropometric Measures as Risk Factors for Diabetes.

OBJECTIVE: The study objective was to examine the impact of race/ethnicity on associations between anthropometric measures and diabetes risk. RESEARCH DESIGN AND METHODS: A total of 136,112 postmenopausal women aged 50-79 years participating in the Women's Health Initiative without baseline cancer or diabetes were followed for 14.6 years. BMI, waist circumference (WC), and waist-to-hip ratio (WHR) were measured in all participants, and a subset of 9,695 had assessment of whole-body fat mass, whole-body percent fat, trunk fat mass, and leg fat mass by DXA. Incident diabetes was assessed via self-report. Multivariate Cox proportional hazards regression models were used to assess associations between anthropometrics and diabetes incidence. RESULTS: During follow-up, 18,706 cases of incident diabetes were identified. BMI, WC, and WHR were all positively associated with diabetes risk in each racial and ethnic group. WC had the strongest association with risk of diabetes across all racial and ethnic groups. Compared with non-Hispanic whites, associations with WC were weaker in black women (P < 0.0001) and stronger in Asian women (P < 0.0001). Among women with DXA determinations, black women had a weaker association with whole-body fat (P = 0.02) but a stronger association with trunk-to-leg fat ratio (P = 0.03) compared with white women. CONCLUSIONS: In postmenopausal women across all racial/ethnic groups, WC was a better predictor of diabetes risk, especially for Asian women. Better anthropometric measures that reflect trunk-to-leg fat ratio may improve diabetes risk assessment for black women.

Behavioral and Pharmacotherapy Weight Loss Interventions to Prevent Obesity-Related Morbidity and Mortality in Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Overweight and obesity have been associated with adverse health effects. Objective: To systematically review evidence on benefits and harms of behavioral and pharmacotherapy weight loss and weight loss maintenance interventions in adults to inform the US Preventive Services Task Force. Data Sources: MEDLINE, PubMed Publisher-Supplied Records, PsycINFO, and the Cochrane Central Register of Controlled Trials for studies published through June 6, 2017; ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform for ongoing trials through August 2017; and ongoing surveillance in targeted publications through March 23, 2018. Studies from previous reviews were reevaluated for inclusion. Study Selection: Randomized clinical trials (RCTs) focusing on weight loss or weight loss maintenance in adults. Data Extraction and Synthesis: Data were abstracted by one reviewer and confirmed by another. Random-effects meta-analyses were conducted for weight loss outcomes in behavior-based interventions. Main Outcomes and Measures: Health outcomes, weight loss or weight loss maintenance, reduction in obesity-related conditions, and adverse events. Results: A total of 122 RCTs (N = 62 533) and 2 observational studies (N = 209 993) were identified. Compared with controls, participants in behavior-based interventions had greater mean weight loss at 12 to 18 months (-2.39 kg [95% CI, -2.86 to -1.93]; 67 studies [n = 22065]) and less weight regain (-1.59 kg [95% CI, -2.38 to -0.79]; 8 studies [n = 1408]). Studies of medication-based weight loss and maintenance interventions also reported greater weight loss or less weight regain in intervention compared with placebo groups at 12 to 18 months (range, -0.6 to -5.8 kg; no meta-analysis). Participants with prediabetes in weight loss interventions had a lower risk of developing diabetes compared with controls (relative risk, 0.67 [95% CI, 0.51 to 0.89]). There was no evidence of other benefits, but most health outcomes such as mortality, cardiovascular disease, and cancer were infrequently reported. Small improvements in quality of life in some medication trials were noted but were of unclear clinical significance. There was no evidence of harm such as cardiovascular disease from behavior-based interventions; higher rates of adverse events were associated with higher dropout rates in medication groups than in placebo groups. Conclusions and Relevance: Behavior-based weight loss interventions with or without weight loss medications were associated with more weight loss and a lower risk of developing diabetes than control conditions. Weight loss medications, but not behavior-based interventions, were associated with higher rates of harms. Long-term weight and health outcomes data, as well as data on important subgroups, were limited.

Long-Term Weight Trajectory and Risk of Hip Fracture, Falls, Impaired Physical Function, and Death.

OBJECTIVES: To determine the association between weight trajectory, health status, and mortality in older women. DESIGN: Cohort study. SETTING: Study of Osteoporotic Fractures. PARTICIPANTS: Older community-dwelling women (age: baseline (1986-88), mean 68, range 65-81; Year 20 (2006-08), mean 88, range 83-102 (N = 1,323)). MEASUREMENTS: Body weight measured repeatedly over 20 years (mean 8 times). Logistic and Cox proportional hazard models were used to evaluate whether 20-year weight trajectory measures were associated with hip fracture, falls, physical performance, and mortality. RESULTS: In models adjusted for age, clinic, calcium use, Year 20 weight, walking speed, comorbidity score, smoking, self-reported health, and walking for exercise, women with moderate weight loss (>9.0 kg) over 20 years had a 74% greater risk of death (hazard ratio (HR) = 1.74, 95% confidence interval (CI) = 1.37-2.20) in the 5 years after the Year 20 visit than those with no weight loss and more than twice the risk of hip fracture (HR = 2.56, 95% CI = 1.39-4.70). They were 3.6 times (odds ratio (OR) = 3.60, 95% CI = 1.86-6.95) as likely to have poor physical function at the Year 20 visit as women with no weight loss but no greater risk of 2 or more falls in the 1.5 years after the Year 20 visit. Weight variability and abrupt weight decline were not associated with adverse health oucomes (falls, fractures, mortality), but those in the highest quartile of variability were 2.3 times (OR = 2.26, 95% CI = 1.34-3.80) as likely to have poor physical function scores. CONCLUSION: In women surviving past 80 years of age, moderate weight loss over 20 years was associated with greater risk of hip fracture, poor physical function, and mortality but not of falls. Future work should separate voluntary from involuntary weight loss.

Intake of dietary carbohydrates in early adulthood and adolescence and breast density among young women.

PURPOSE: Carbohydrate intake increases postprandial insulin secretion and may affect breast density, a strong risk factor for breast cancer, early in life. We examined associations of adolescent and early adulthood intakes of total carbohydrates, glycemic index/load, fiber, and simple sugars with breast density among 182 young women. METHODS: Diet was assessed using three 24-h recalls at each of five Dietary Intervention Study in Children (DISC) clinic visits when participants were age 10-19 years and at the DISC06 Follow-Up Study clinic visit when participants were age 25-29 years. Associations between energy-adjusted carbohydrates and MRI-measured percent dense breast volume (%DBV) and absolute dense breast volume (ADBV) at 25-29 years were quantified using multivariable-adjusted mixed-effects linear models. RESULTS: Adolescent sucrose intakes and premenarcheal total carbohydrates intakes were modestly associated with higher %DBV (mean %DBVQ1 vs Q4, 16.6 vs 23.5% for sucrose; and 17.2 vs 22.3% for premenarcheal total carbohydrates, all Ptrend ≤ 0.02), but not with ADBV. However, adolescent intakes of fiber and fructose were not associated with %DBV and ADBV. Early adulthood intakes of total carbohydrates, glycemic index/load, fiber, and simple sugars were not associated with %DBV and ADBV. CONCLUSIONS: Insulinemic carbohydrate diet during puberty may be associated with adulthood breast density, but our findings need replication in larger studies. Clinical Trials Registration ClinicalTrials.gov Identifier, NCT00458588 April 9, 2007; NCT00000459 October 27, 1999.

Vitamin D, Calcium, or Combined Supplementation for the Primary Prevention of Fractures in Community-Dwelling Adults: Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Osteoporotic fractures result in significant morbidity and mortality. Objective: To update the evidence for benefits and harms of vitamin D, calcium, or combined supplementation for the primary prevention of fractures in community-dwelling adults to inform the US Preventive Services Task Force. Data Sources: PubMed, EMBASE, Cochrane Library, and trial registries through March 21, 2017; references; and experts. Surveillance continued through February 28, 2018. Study Selection: English-language randomized clinical trials (RCTs) or observational studies of supplementation with vitamin D, calcium, or both among adult populations; studies of populations that were institutionalized or had known vitamin D deficiency, osteoporosis, or prior fracture were excluded. Data Extraction and Synthesis: Dual, independent review of titles/abstracts and full-text articles and study quality rating using predefined criteria. Random-effects meta-analysis used when at least 3 similar studies were available. Main Outcomes and Measures: Incident fracture, mortality, kidney stones, cardiovascular events, and cancer. Results: Eleven RCTs (N = 51 419) in adults 50 years and older conducted over 2 to 7 years were included. Compared with placebo, supplementation with vitamin D decreased total fracture incidence (1 RCT [n = 2686]; absolute risk difference [ARD], -2.26% [95% CI, -4.53% to 0.00%]) but had no significant association with hip fracture (3 RCTs [n = 5496]; pooled ARD, -0.01% [95% CI, -0.80% to 0.78%]). Supplementation using vitamin D with calcium had no effect on total fracture incidence (1 RCT [n = 36 282]; ARD, -0.35% [95% CI, -1.02% to 0.31%]) or hip fracture incidence (2 RCTs [n = 36 727]; ARD from the larger trial, -0.14% [95% CI, -0.34% to 0.07%]). The evidence for calcium alone was limited, with only 2 studies (n = 339 total) and very imprecise results. Supplementation with vitamin D alone or with calcium had no significant effect on all-cause mortality or incident cardiovascular disease; ARDs ranged from -1.93% to 1.79%, with CIs consistent with no significant differences. Supplementation using vitamin D with calcium was associated with an increased incidence of kidney stones (3 RCTs [n = 39 213]; pooled ARD, 0.33% [95% CI, 0.06% to 0.60%]), but supplementation with calcium alone was not associated with an increased risk (3 RCTs [n = 1259]; pooled ARD, 0.00% [95% CI, -0.87% to 0.87%]). Supplementation with vitamin D and calcium was not associated with an increase in cancer incidence (3 RCTs [n = 39 213]; pooled ARD, -1.48% [95% CI, -3.32% to 0.35%]). Conclusions and Relevance: Vitamin D supplementation alone or with calcium was not associated with reduced fracture incidence among community-dwelling adults without known vitamin D deficiency, osteoporosis, or prior fracture. Vitamin D with calcium was associated with an increase in the incidence of kidney stones.