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BackgroundRecommended systolic blood pressure targets often do not consider the relationship of low diastolic blood pressure (DBP) levels with cardiovascular disease (CVD) and all-cause mortality risk, which is especially relevant for older people with concurrent comorbidities. We examined the relationship of DBP levels to CVD and all-cause mortality in older women in the Women's Health Initiative Long Life Study (WHI-LLS).MethodsThe study sample included 7,875 women (mean age: 79 years) who underwent a blood pressure measurement at an in-person home visit conducted in 2012-2013. CVD and all-cause mortality were centrally adjudicated. Hazard ratios (HRs) were obtained from adjusted Cox proportional hazards models.ResultsAfter 5 years follow-up, all-cause mortality occurred in 18.4% of women. Compared with a DBP of 80 mm Hg, the fully adjusted HR for mortality was 1.33 (95% confidence interval [CI]: 1.04-1.71) for a DBP of 50 mm Hg and 1.67 (95% CI: 1.29-2.16) for a DBP of 100 mm Hg. The HRs for CVD were 1.14 (95% CI: 0.78-1.67) for a DBP of 50 mm Hg and HR 1.50 (95% CI: 1.03-2.17) for a DBP of 100 mm Hg. The nadir DBP associated with lowest mortality risk was 72 mm Hg overall.ConclusionsIn older women, consideration should be given to the potential adverse effects of low and high DBP. Low DBP may serve as a risk marker. DBP target levels between 68 and 75 mm Hg may avoid higher mortality risk.

Background Prior studies suggested lower risk of heart failure (HF) in individuals taking H2 receptor antagonists (H2RA) compared with H2RA nonusers in relatively small studies. We evaluated the association of H2RA use and incident HF in postmenopausal women in the large-scale WHI (Women's Health Initiative) study. Methods and Results This study included postmenopausal women from the WHI without a history of HF at baseline. HF was defined as first incident hospitalization for HF and physician adjudicated. Multivariable Cox proportional hazards regression models evaluated the association of H2RA use as a time-varying exposure with HF risk, after adjustment for demographic, lifestyle, and medical history variables. Sensitivity analyses examined (1) risk of HF stratified by the ARIC (Atherosclerosis Risk in Communities) score, (2) propensity score matching on H2RA use, (3) use of proton pump inhibitors rather than H2RA nonuse as the referent, and (4) exclusion of those taking diuretics at baseline. The primary analysis included 158 854 women after exclusion criteria, of whom 9757 (6.1%) were H2RA users. During median 8.2 years of follow-up, 376 H2RA users (4.9 events/1000 person-years) and 3206 nonusers (2.7 events/1000 person-years) developed incident HF. After multivariable adjustment, there was no association between H2RA use and HF in the primary analysis (hazard ratio, 1.07; 95% CI, 0.94-1.22; P=0.31) or in any of the sensitivity analyses. Conclusions Clinical H2RA use was not associated with incident HF among postmenopausal women. Future studies are needed to evaluate potential effect modification by sex, HF severity, or patterns of use on H2RA exposure and HF risk. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT00000611.

ObjectiveWe studied associations between social support, social network size, social strain, or stressful life events and risk of coronary heart disease (CHD) in postmenopausal women with type 2 diabetes.Research design and methodsFrom the Women's Health Initiative, 5,262 postmenopausal women with type 2 diabetes at baseline were included. Cox proportional hazards regression models adjusted for demographics, depressive symptoms, anthropometric variables, and lifestyle factors were used to examine associations between social factors and CHD.ResultsA total of 672 case subjects with CHD were observed during an average 12.79 (SD 6.29) years of follow-up. There was a significant linear trend toward higher risk of CHD as the number of stressful life events increased (P for trend = 0.01; hazard ratio [HR] [95% CI] for the third and fourth quartiles compared with first quartile: 1.27 [1.03-1.56] and 1.30 [1.04-1.64]). Being married or in an intimate relationship was related to decreased risk of CHD (HR 0.82 [95% CI 0.69-0.97]).ConclusionsAmong postmenopausal women with type 2 diabetes, higher levels of stressful life events were associated with higher risk of CHD. Experience of stressful life events might be considered as a risk factor for CHD among women with type 2 diabetes.

The purpose of this study is to explore the impact of body weight change following intentional weight loss on incident fracture and bone mineral density (BMD) in overweight and obese adults with diabetes. A total of 1885 individuals with type 2 diabetes (baseline age: 58.5 ± 6.7 years, 58% women, body mass index: 35.7 ± 6.0 kg/m2) who participated in the Look AHEAD study and lost any weight 1 year after being randomized to an intensive lifestyle intervention were assessed. Body weight was measured annually and participants were categorized as weight regainers, weight cyclers, or continued losers/maintainers based on a ±3% annual change in weight from year 1 to year 4. Adjudicated overall fracture incidence was captured from years 4 through 13 (median follow-up duration 11.5 years). Hip and spine BMD was assessed in a subset of participants at baseline, year 4 (n = 468), and year 8 (n = 354), using dual-energy X-ray absorptiometry. Cox proportional hazards and linear regression models, adjusted for relevant covariates, were performed for fracture and BMD outcomes, respectively. Fifty-eight percent, 22%, and 20% of participants were classified as weight regainers, weight cyclers, and continued losers/maintainers, respectively; and 217 fractures (men n = 63; women n = 154) were recorded during the follow-up period. There were no statistically significant differences in total incident fracture rates for weight regainers (HR [95% CI]: 1.01 [95% CI, 0.71 to 1.44]) or weight cyclers (HR [95% CI]: 1.02 [95% CI, 0.68 to 1.53]) when compared to continued losers/maintainers (p = 0.99). Similarly, follow-up BMD estimates did not significantly vary by weight pattern group, although consistent trends for lowered BMD in the hip region were noted for continued losers/maintainers and weight cyclers compared with weight regainers. Patterns of weight change in the 3 years following 1 year of intentional weight loss were not associated with subsequent fracture or significantly reduced BMD in this cohort of overweight and obese adults with type 2 diabetes. © 2018 The Authors. JBMR Plus Published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

ObjectivesElevated 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.DesignPost hoc analysis of data from the Women's Health Initiative (WHI), USA.Setting40 clinical centres in the USA.ParticipantsThe 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.ExposuresPlasma Lp(a) levels were measured at baseline.Outcome measuresIncident 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 analysesCox 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.ResultsDuring 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.ConclusionsThese findings suggest that plasma Lp(a) levels are not related to hip BMD T-score or hip fracture events in postmenopausal women.Trial registration numberNCT00000611; Post-results.

Sleep disturbances are common and may influence falls and fracture directly by influencing bone turnover and muscle strength or indirectly through high comorbidity or poor physical function. To investigate the association between self-reported sleep and falls and fractures, we prospectively studied 157,306 women in the Women's Health Initiative (WHI) using information on sleep quality, sleep duration, and insomnia from questionnaires. Annual self-report of falling two or more times (ie, "recurrent falling") during each year of follow-up was modeled with repeated measures logistic regression models fit by generalized estimating equations. Cox proportional hazards models were used to investigate sleep disturbance and time to first fracture. We examined the risks of recurrent falls and fracture by sleep duration with 7 hours as referent. We examined the risks across categories of sleep disturbance, insomnia status, and sleep quality. The average follow-up time was 7.6 years for falls and 12.0 years for fractures. In multivariable adjusted models, including adjustment for comorbidity, medications, and physical function, women who were short (≤5 hours) and long (≥10 hours) sleepers had increased odds of recurrent falls (odds ratio [OR] 1.28; 95% confidence interval [CI], 1.23 to 1.34 and OR 1.25; 95% CI, 1.09 to 1.43, respectively). Poor sleep quality, insomnia, and more sleep disturbances were also associated with an increased odds of recurrent falls. Short sleep was associated with an increased risk of all fractures, and upper limb, lower limb, and central body fractures, but not hip fractures, with hazard ratios ranging from 1.10 to 1.13 (p

ObjectivesThis study prospectively examined physical activity levels and the incidence of heart failure (HF) in 137,303 women, ages 50 to 79 years, and examined a subset of 35,272 women who, it was determined, had HF with preserved ejection fraction (HFpEF) and HF with reduced EF (HFrEF).BackgroundThe role of physical activity in HF risk among older women is unclear, particularly for incidence of HFpEF or HFrEF.MethodsWomen were free of HF and reported ability to walk at least 1 block without assistance at baseline. Recreational physical activity was self-reported. The study documented 2,523 cases of total HF, and 451 and 734 cases of HFrEF and HFpEF, respectively, during a mean 14-year follow-up.ResultsAfter controlling for age, race, education, income, smoking, alcohol, hormone therapy, and hysterectomy status, compared with women who reported no physical activity (reference group), inverse associations were observed across incremental tertiles of total physical activity for overall HF (hazard ratio [HR]: Tertile 1 = 0.89, Tertile 2 = 0.74, Tertile 3 = 0.65; trend p < 0.001), HFpEF (HR: 0.93, 0.70, 0.68; p < 0.001), and HFrEF (HR: 0.81, 0.59, 0.68; p = 0.01). Additional controlling for potential mediating factors included attenuated time-varying coronary heart disease (CHD) (nonfatal myocardial infarction, coronary revascularization) diagnosis but did not eliminate the inverse associations. Walking, the most common form of physical activity in older women, was also inversely associated with HF risks (overall: 1.00, 0.98, 0.93, 0.72; p < 0.001; HFpEF: 1.00, 0.98, 0.87, 0.67; p < 0.001; HFrEF: 1.00, 0.75, 0.78, 0.67; p = 0.01). Associations between total physical activity and HF were consistent across subgroups, defined by age, body mass index, diabetes, hypertension, physical function, and CHD diagnosis. Analysis of physical activity as a time-varying exposure yielded findings comparable to those of baseline physical activity.ConclusionsHigher levels of recreational physical activity, including walking, are associated with significantly reduced HF risk in community-dwelling older women.

BackgroundThe higher risk of heart failure (HF) in African-American and Hispanic women compared with white women is related to the higher burden of risk factors (RFs) in minorities. However, it is unclear if there are differences in the association between the number of RFs for HF and the risk of development of HF and death within racial/ethnic groups.Methods and resultsIn the WHI (Women's Health Initiative; 1993-2010), African-American (n=11 996), white (n=18 479), and Hispanic (n=5096) women with 1, 2, or 3+ baseline RFs were compared with women with 0 RF within their respective racial/ethnic groups to assess risk of developing HF or all-cause mortality before and after HF, using survival analyses. After adjusting for age, socioeconomic status, and hormone therapy, the subdistribution hazard ratio (95% confidence interval) of developing HF increased as number of RFs increased (P

Physical activity has been associated with lower lung cancer incidence and mortality in several populations. We investigated these relationships in the Women's Health Initiative Observational Study (WHI-OS) and Clinical Trial (WHI-CT) prospective cohort of postmenopausal women. The WHI study enrolled 161,808 women aged 50-79 years between 1993 and 1998 at 40 U.S. clinical centers; 129,401 were eligible for these analyses. Cox proportional hazards models were used to assess the association of baseline physical activity levels [metabolic equivalent (MET)-min/week: none

BackgroundReproductive factors provide an early window into a woman's coronary heart disease (CHD) risk; however, their contribution to CHD risk stratification is uncertain.Methods and resultsIn the Women's Health Initiative Observational Study, we constructed Cox proportional hazards models for CHD including age, pregnancy status, number of live births, age at menarche, menstrual irregularity, age at first birth, stillbirths, miscarriages, infertility ≥1 year, infertility cause, and breastfeeding. We next added each candidate reproductive factor to an established CHD risk factor model. A final model was then constructed with significant reproductive factors added to established CHD risk factors. Improvement in C statistic, net reclassification index (or net reclassification index with risk categories of

BackgroundAs the proportion of the population aged 80 and over accelerates, so does the value of understanding the processes of aging well. The purposes of this article are to: (a) review contemporary theoretical and conceptual perspectives on aging well, (b) describe indicators of aging well that reflect key concepts and perspectives as assessed in the Women's Health Initiative (WHI) and (c) characterize the status of aging among women aged 80 and older using data obtained from WHI participants at the WHI Extension 2 follow-up.MethodsData from the Lifestyle Questionnaire, which was administered from 2011 to 2012 during the WHI Follow-up Study (Extension 2), were analyzed to provide a profile of the WHI cohort with respect to aging well.ResultsData revealed substantial diversity in the cohort with respect to the various measures of aging well. Although many reported physical functioning levels consistent with disability, most rated their health as good or better. Most reported moderately high levels of resilience, self-control, and self-mastery but lower levels of environmental mastery. Finally, the cohort reported high levels of optimal aging as reflected by their high levels of emotional well-being and moderately high levels of life satisfaction and social support, but more modest levels of personal growth and purpose in life.ConclusionsThe wide range of some dimensions of aging well suggest that further examination of predictors of positive coping and resilience in the face of aging-related disability could identify opportunities to support and facilitate aging well among U.S. women.

BackgroundCardiovascular disease (CVD) is highly prevalent at ages 80 and above. The association of physical functioning (PF), a key to an optimal aging trajectory, with CVD and specific CVD diagnosis in women who survive to age 80 and above has not been described previously and has important public health significance given our aging population.MethodsWomen's Health Initiative participants aged 80 years or older at the time of self-reporting PF (RAND SF-36) were studied in relationship to CVD diagnosis, whether present at study baseline (1993-1998) or diagnosed during follow-up through 2012. Cross-sectional analyses utilized demographic, medical, lifestyle, and psycho-social questionnaire data from baseline or updated at the time of self-reported PF.ResultsAmong 27,145 older Women's Health Initiative participants, 22.0% (N = 5,959) had been diagnosed with CVD, specifically: 11.3% (N = 3,071) with coronary heart disease; 4.7% (N = 1,279), stroke; 5.2% (N = 1,397), venous thromboembolism; 2.7% (N = 737), peripheral arterial disease; and 2.7% (N = 725), congestive heart failure. PF scores (mean ± SE) were significantly (p < .0001) higher without CVD (60.0 ± 26.9), compared with any CVD (47.9 ± 27.3), and for each specific CVD diagnosis: coronary heart disease (48.8 ± 27.1); stroke (44.8 ± 27.9); venous thromboembolism (48.9 ± 27.4); peripheral arterial disease (41.9 ± 2.2); and congestive heart failure (38.8 ± 26.1). Regardless of CVD diagnosis, higher PF was associated with: younger age at the time of PF assessment; lower body mass index; higher recreational physical activity; better self-reported general health; fewer hip fractures after age 55; no history of arthritis; and no recent use of non-steroidal anti-inflammatory drugs.ConclusionsOlder women with any CVD, and particularly women with congestive heart failure or peripheral arterial disease, reported significantly lower PF compared to women with no CVD. Regardless of CVD diagnosis, higher PF was strongly associated with a more active lifestyle and lower body mass index, suggesting potential intervention targets for more optimal aging.

ObjectivesTo determine whether statin treatment is associated with increased risk of haemorrhagic stroke (HS) in older women. A secondary objective was to evaluate HS risk in users of combined statin and antiplatelet treatment.DesignObservational study: secondary data analysis from the Women's Health Initiative (WHI) clinical trials.SettingWomen were recruited from 40 participating sites.ParticipantsCohort of 68,132 women followed through 2005 (parent study) and for an additional 5 years in the extension study.Main outcome measuresStatin use was assessed at baseline and at follow-up visits (1, 3, 6 and 9 years). Women brought medications in original containers for inventory. Strokes were ascertained semiannually and centrally adjudicated. Risk of HS by statin use (time-varying covariate, with the 'no use' category as the referent) was estimated from Cox proportional hazard regression models adjusted for age (model 1); risk factors for HS (model 2); and possible confounders by indication (model 3). Prespecified subgroup analyses were conducted by use of antiplatelet medications.ResultsFinal models included 67,882 women (mean age, 63±7 years). Over a mean follow-up of 12 years, incidence rates of HS were 6.4/10,000 person-years among statin users and 5.0/10,000 person-years among non-users (p=0.11). The unadjusted risk of HS in statin users was 1.21 (CI 0.96 to 1.53); after adjusting for age and HS risk factors the HR was 0.98 (CI 0.76 to 1.26). Risk of HS was higher among women on statins and antiplatelet agents versus women on antiplatelet medications alone (HR=1.59; CI 1.03 to 2.47); p for interaction=0.011.ConclusionsThis retrospective analysis did not show an association between statin use and HS risk among older women. HS risk was higher among women taking statins with antiplatelet agents. These findings warrant further investigation, given potential implications for clinical decision-making.

BackgroundThe purpose of this study was to describe the longitudinal trajectories and bidirectional relationships of the physical-social and emotional functioning (EF) dimensions of positive aging and to identify their baseline characteristics.MethodsWomen age 65 and older who enrolled in one or more Women's Health Initiative clinical trials (WHI CTs) and who had positive aging indicators measured at baseline and years 1, 3, 6, and 9 were included in these analyses (N = 2281). Analytic strategies included latent class growth modeling to identify longitudinal trajectories and multinomial logistic regression to examine the effects of baseline predictors on these trajectories.ResultsA five-trajectory model was chosen to best represent the data. For Physical-Social Functioning (PSF), trajectory groups included Low Maintainer (8.3%), Mid-Low Improver (10.4%), Medium Decliner (10.7%), Mid-High Maintainer (31.2%), and High Maintainer (39.4%); for EF, trajectories included Low Maintainer (3%), Mid-Low Improver (9%), Medium Decliner (7.7%), Mid-High Maintainer (22.8%), and High Maintainer (57.5%). Cross-classification of the groups of trajectories demonstrated that the impact of a high and stable EF on PSF might be greater than the reverse. Low depression symptoms, low pain, and high social support were the most consistent predictors of high EF trajectories.ConclusionAging women are heterogeneous in terms of positive aging indicators for up to 9 years of follow-up. Interventions aimed at promoting sustainable EF might have diffused effects on other domains of healthy aging.

BackgroundConclusive data about cardiovascular toxicity of nonsteroidal anti-inflammatory drugs (NSAIDs) are sparse. We hypothesized that regular NSAID use is associated with increased risk for cardiovascular events in postmenopausal women, and that this association is stronger with greater cyclooxygenase (cox)-2 when compared with cox-1 inhibition.Methods and resultsPostmenopausal women enrolled in the Women's Health Initiative were classified as regular users or nonusers of nonaspirin NSAIDs. Cox regression examined NSAID use as a time-varying covariate and its association with the primary outcome of total cardiovascular disease defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Secondary analyses considered the association of selective cox-2 inhibitors (eg, celecoxib), nonselective agents with cox-2>cox-1 inhibition (eg, naproxen), and nonselective agents with cox-1>cox-2 inhibition (eg, ibuprofen) with the primary outcome. Overall, 160 801 participants were available for analysis (mean follow-up, 11.2 years). Regular NSAID use at some point in time was reported by 53 142 participants. Regular NSAID use was associated with an increased hazard for cardiovascular events versus no NSAID use (hazard ratio [HR], 1.10; 95% confidence interval, 1.06-1.15; Pcox-1 inhibition (HR, 1.17; 1.10-1.24; Pcox-2 inhibition (HR, 1.01; 0.95-1.07; P=0.884 and ibuprofen only: HR, 1.00; 0.93-1.07; P=0.996).ConclusionsRegular use of selective cox-2 inhibitors and nonselective NSAIDs with cox-2>cox-1 inhibition showed a modestly increased hazard for cardiovascular events. Nonselective agents with cox-1>cox-2 inhibition were not associated with increased cardiovascular risk.Clinical trial registration urlwww.clinicaltrials.gov. Unique identifier: NCT00000611.

ObjectiveThis study aims to test the added value of calcium and vitamin D (CaD) in fracture prevention among women taking postmenopausal hormone therapy (HT).MethodsThis is a prospective, partial-factorial, randomized, controlled, double-blind trial among Women's Health Initiative postmenopausal participants aged 50 to 79 years at 40 centers in the United States with a mean follow-up of 7.2 years. A total of 27,347 women were randomized to HT (0.625 mg of conjugated estrogens alone, or 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate daily), and 36,282 women were randomized to 1,000 mg of elemental calcium (carbonate) plus 400 IU of vitamin D3 daily, each compared with placebo. A total of 16,089 women participated in both arms. The predefined outcomes were adjudicated hip fractures and measured bone mineral density.ResultsInteraction between HT and CaD on hip fracture (P interaction = 0.01) was shown. The effect of CaD was stronger among women assigned to HT (hazard ratio [HR], 0.59; 95% CI, 0.38-0.93) than among women assigned to placebo (HR, 1.20; 95% CI, 0.85-1.69). The effect of HT on hip fracture was stronger among women assigned to active CaD (HR, 0.43; 95% CI, 0.28-0.66) than among women assigned to placebo (HR, 0.87; 95% CI, 0.60-1.26). CaD supplementation enhanced the antifracture effect of HT at all levels of personal calcium intake. There was no interaction between HT and CaD on change in hip or spine bone mineral density.ConclusionsPostmenopausal women at normal risk for hip fracture who are on CaD supplementation experience significantly reduced incident hip fractures beyond HT alone at all levels of personal baseline total calcium intake.

BackgroundData collected as part of routine clinical practice could be used to detect cardiovascular outcomes in pragmatic clinical trials or clinical registry studies. The reliability of claims data for documenting outcomes is unknown.Methods and resultsWe linked records of Women's Health Initiative (WHI) participants aged ≥65 years to Medicare claims data and compared hospitalizations that had diagnosis codes for acute myocardial infarction or coronary revascularization with WHI outcomes adjudicated by study physicians. We then compared the hazard ratios for active versus placebo hormone therapy based solely on WHI-adjudicated events with corresponding hazard ratios based solely on claims data for the same hormone trial participants. Agreement between WHI-adjudicated outcomes and Medicare claims was good for the diagnosis of myocardial infarction (κ, 0.71-0.74) and excellent for coronary revascularization (κ, 0.88-0.91). The hormone:placebo hazard ratio for clinical myocardial infarction was 1.31 (95% confidence interval, 1.03-1.67) based on WHI outcomes and 1.29 (95% confidence interval, 1.00-1.68) based on Medicare data. The hazard ratio for coronary revascularization was 1.09 (95% confidence interval, 0.88-1.35) based on WHI outcomes and 1.10 (95% confidence interval, 0.89-1.35) based on Medicare data. The differences between hazard ratios derived from WHI and Medicare data were not significant in 1000 bootstrap replications.ConclusionsMedicare claims may provide useful data on coronary heart disease outcomes among patients aged ≥65 years in clinical research studies.Clinical trials registration informationURL: www.clinicaltrials.gov. Unique identifier: NCT00000611.

Using data from the Women's Health Initiative (1993-2009; n = 158,833 participants, of whom 84.1% were white, 9.2% were black, 4.1% were Hispanic, and 2.6% were Asian), we compared all-cause, cardiovascular, and cancer mortality rates in white, black, Hispanic, and Asian postmenopausal women with and without diabetes. Cox proportional hazard models were used for the comparison from which hazard ratios and 95% confidence intervals were computed. Within each racial/ethnic subgroup, women with diabetes had an approximately 2-3 times higher risk of all-cause, cardiovascular, and cancer mortality than did those without diabetes. However, the hazard ratios for mortality outcomes were not significantly different between racial/ethnic subgroups. Population attributable risk percentages (PARPs) take into account both the prevalence of diabetes and hazard ratios. For all-cause mortality, whites had the lowest PARP (11.1, 95% confidence interval (CI): 10.1, 12.1), followed by Asians (12.9, 95% CI: 4.7, 20.9), blacks (19.4, 95% CI: 15.0, 23.7), and Hispanics (23.2, 95% CI: 14.8, 31.2). To our knowledge, the present study is the first to show that hazard ratios for mortality outcomes were not significantly different between racial/ethnic subgroups when stratified by diabetes status. Because of the "amplifying" effect of diabetes prevalence, efforts to reduce racial/ethnic disparities in the rate of death from diabetes should focus on prevention of diabetes.

BackgroundClinical outcomes of the Women's Health Initiative (WHI) calcium plus vitamin D supplementation trial have been reported during 7.0 years of active intervention. We now report outcomes 4.9 years after the intervention stopped and cumulative findings.MethodsPostmenopausal women (N=36,282) were randomized; postintervention follow-up continued among 29,862 (86%) of surviving participants. Primary outcomes were hip fracture and colorectal cancer. Breast cancer, all cancers, cardiovascular disease (CVD), and total mortality were predetermined major study outcomes.ResultsHip fracture incidence was comparable in the supplement and the placebo groups, postintervention hazard ratio (HR)=0.95, 95% confidence interval (95% CI: 0.78, 1.15) and overall HR=0.91 (95% CI: 0.79, 1.05). Overall, colorectal cancer incidence did not differ between randomization groups, HR=0.95 (95% CI: 0.80, 1.13). Throughout, there also was no difference in invasive breast cancer, CVD, and all-cause mortality between groups. In subgroup analyses, the invasive breast cancer effect varied by baseline vitamin D intake (p=0.03 for interaction). Women with vitamin D intakes >600 IU/d, had an increased risk of invasive breast cancer, HR=1.28 (95% CI; 1.03, 1.60). Over the entire study period, in post hoc analyses, the incidence of vertebral fractures, HR=0.87 (95% CI: 0.76, 0.98) and in situ breast cancers, HR=0.82 (95% CI: 0.68, 0.99) were lower among women randomized to supplementation.ConclusionAfter an average of 11 years, calcium and vitamin D supplementation did not decrease hip fracture or colorectal cancer incidence. Exploratory analyses found lower vertebral fracture and in situ breast cancer incidence in the supplement users. There was no effect on CVD or all-cause mortality.

Using data from the Women's Health Initiative (1993-2009; n = 158,833 participants, of whom 84.1% were white, 9.2% were black, 4.1% were Hispanic, and 2.6% were Asian), we compared all-cause, cardiovascular, and cancer mortality rates in white, black, Hispanic, and Asian postmenopausal women with and without diabetes. Cox proportional hazard models were used for the comparison from which hazard ratios and 95% confidence intervals were computed. Within each racial/ethnic subgroup, women with diabetes had an approximately 2-3 times higher risk of all-cause, cardiovascular, and cancer mortality than did those without diabetes. However, the hazard ratios for mortality outcomes were not significantly different between racial/ethnic subgroups. Population attributable risk percentages (PARPs) take into account both the prevalence of diabetes and hazard ratios. For all-cause mortality, whites had the lowest PARP (11.1, 95% confidence interval (CI): 10.1, 12.1), followed by Asians (12.9, 95% CI: 4.7, 20.9), blacks (19.4, 95% CI: 15.0, 23.7), and Hispanics (23.2, 95% CI: 14.8, 31.2). To our knowledge, the present study is the first to show that hazard ratios for mortality outcomes were not significantly different between racial/ethnic subgroups when stratified by diabetes status. Because of the "amplifying" effect of diabetes prevalence, efforts to reduce racial/ethnic disparities in the rate of death from diabetes should focus on prevention of diabetes.

ImportanceMenopausal hormone therapy continues in clinical use but questions remain regarding its risks and benefits for chronic disease prevention.ObjectiveTo report a comprehensive, integrated overview of findings from the 2 Women's Health Initiative (WHI) hormone therapy trials with extended postintervention follow-up.Design, setting, and participantsA total of 27,347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers.InterventionsWomen with an intact uterus received conjugated equine estrogens (CEE; 0.625 mg/d) plus medroxyprogesterone acetate (MPA; 2.5 mg/d) (n = 8506) or placebo (n = 8102). Women with prior hysterectomy received CEE alone (0.625 mg/d) (n = 5310) or placebo (n = 5429). The intervention lasted a median of 5.6 years in CEE plus MPA trial and 7.2 years in CEE alone trial with 13 years of cumulative follow-up until September 30, 2010.Main outcomes and measuresPrimary efficacy and safety outcomes were coronary heart disease (CHD) and invasive breast cancer, respectively. A global index also included stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and death.ResultsDuring the CEE plus MPA intervention phase, the numbers of CHD cases were 196 for CEE plus MPA vs 159 for placebo (hazard ratio [HR], 1.18; 95% CI, 0.95-1.45) and 206 vs 155, respectively, for invasive breast cancer (HR, 1.24; 95% CI, 1.01-1.53). Other risks included increased stroke, pulmonary embolism, dementia (in women aged ≥65 years), gallbladder disease, and urinary incontinence; benefits included decreased hip fractures, diabetes, and vasomotor symptoms. Most risks and benefits dissipated postintervention, although some elevation in breast cancer risk persisted during cumulative follow-up (434 cases for CEE plus MPA vs 323 for placebo; HR, 1.28 [95% CI, 1.11-1.48]). The risks and benefits were more balanced during the CEE alone intervention with 204 CHD cases for CEE alone vs 222 cases for placebo (HR, 0.94; 95% CI, 0.78-1.14) and 104 vs 135, respectively, for invasive breast cancer (HR, 0.79; 95% CI, 0.61-1.02); cumulatively, there were 168 vs 216, respectively, cases of breast cancer diagnosed (HR, 0.79; 95% CI, 0.65-0.97). Results for other outcomes were similar to CEE plus MPA. Neither regimen affected all-cause mortality. For CEE alone, younger women (aged 50-59 years) had more favorable results for all-cause mortality, myocardial infarction, and the global index (nominal P

ContextThe Women's Health Initiative Estrogen-Alone Trial was stopped early after a mean of 7.1 years of follow-up because of an increased risk of stroke and little likelihood of altering the balance of risk to benefit by the planned trial termination date. Postintervention health outcomes have not been reported.ObjectiveTo examine health outcomes associated with randomization to treatment with conjugated equine estrogens (CEE) among women with prior hysterectomy after a mean of 10.7 years of follow-up through August 2009.Design, setting, and participantsThe intervention phase was a double-blind, placebo-controlled, randomized clinical trial of 0.625 mg/d of CEE compared with placebo in 10,739 US postmenopausal women aged 50 to 79 years with prior hysterectomy. Follow-up continued after the planned trial completion date among 7645 surviving participants (78%) who provided written consent.Main outcome measuresThe primary outcomes were coronary heart disease (CHD) and invasive breast cancer. A global index of risks and benefits included these primary outcomes plus stroke, pulmonary embolism, colorectal cancer, hip fracture, and death.ResultsThe postintervention risk (annualized rate) for CHD among women assigned to CEE was 0.64% compared with 0.67% in the placebo group (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.75-1.25), 0.26% vs 0.34%, respectively, for breast cancer (HR, 0.75; 95% CI, 0.51-1.09), and 1.47% vs 1.48%, respectively, for total mortality (HR, 1.00; 95% CI, 0.84-1.18). The risk of stroke was no longer elevated during the postintervention follow-up period and was 0.36% among women receiving CEE compared with 0.41% in the placebo group (HR, 0.89; 95% CI, 0.64-1.24), the risk of deep vein thrombosis was lower at 0.17% vs 0.27%, respectively (HR, 0.63; 95% CI, 0.41-0.98), and the risk of hip fracture did not differ significantly and was 0.36% vs 0.28%, respectively (HR, 1.27; 95% CI, 0.88-1.82). Over the entire follow-up, lower breast cancer incidence in the CEE group persisted and was 0.27% compared with 0.35% in the placebo group (HR, 0.77; 95% CI, 0.62-0.95). Health outcomes were more favorable for younger compared with older women for CHD (P = .05 for interaction), total myocardial infarction (P = .007 for interaction), colorectal cancer (P = .04 for interaction), total mortality (P = .04 for interaction), and global index of chronic diseases (P = .009 for interaction).ConclusionsAmong postmenopausal women with prior hysterectomy followed up for 10.7 years, CEE use for a median of 5.9 years was not associated with an increased or decreased risk of CHD, deep vein thrombosis, stroke, hip fracture, colorectal cancer, or total mortality. A decreased risk of breast cancer persisted.Trial registrationclinicaltrials.gov Identifier: NCT00000611.

BackgroundCalcium and vitamin D (CaD) supplementation trials including the Women's Health Initiative (WHI) trial of CaD have shown nonsignificant reductions in total mortality. This report examines intervention effects on total and cause-specific mortality by age and adherence.MethodsThe WHI CaD trial was a randomized, double-blind, placebo-controlled trial that enrolled 36,282 postmenopausal women aged 51-82 years from 40 U.S. clinical centers. Women were assigned to 1,000 mg of elemental calcium carbonate and 400 IU of vitamin D(3) daily or placebo with average follow-up of 7.0 years.ResultsThe hazard ratio (HR) for total mortality was 0.91 (95% confidence interval [CI], 0.83-1.01) with 744 deaths in women randomized to CaD versus 807 deaths in the placebo group. HRs were in the direction of reduced risk but nonsignificant for stroke and cancer mortality, but near unity for coronary heart disease and other causes of death. HRs for total mortality were 0.89 in the 29,942 women younger than 70 years (95% CI, 0.79-1.01) and 0.95 in the 6,340 women aged 70 and older (95% CI, 0.80-1.12; p value for age interaction = .10). No statistically significant interactions were observed for any baseline characteristics. Treatment effects did not vary significantly by season.ConclusionsIn the WHI CaD trial, supplementation did not have a statistically significant effect on mortality rates but the findings support the possibility that these supplements may reduce mortality rates in postmenopausal women. These data can neither support nor refute recommendations for higher dose vitamin D supplementation to reduce cancer or total mortality.

BackgroundThe relationship of loop diuretics to bone mineral density (BMD), falls, and fractures in postmenopausal women has not been established.MethodsWe examined whether loop diuretics are associated with changes in BMD, falls, and fractures in women enrolled in the Women's Health Initiative. We included the 133,855 women (3411 users and 130,444 nonusers of loop diuretics) who were enrolled in the WHI from October 29, 1993 to December 31, 1998 and determined incident falls and fractures for a mean of 7.7 years. Women who had BMD measurements at baseline and at year 3 (300 users and 9124 nonusers of loop diuretics) were also examined.ResultsAfter adjustment for covariates, no significant association was found between ever use of loop diuretics and total (hazard ratio [HR], 1.09; 95% confidence interval [CI], 1.00-1.19), hip (HR, 1.21; 95% CI, 0.91-1.60), and clinical vertebral fractures (HR, 1.17; 95% CI, 0.92-1.48) and falls (1.02; 0.96-1.08). An increased risk was found for other clinical fractures (1.16; 1.01-133) and total fractures (1.16; 1.03-1.31) with more than 3 years' use of loop diuretics. The BMD changes were not associated with loop diuretic use.ConclusionsAfter adjustment for confounding variables, no significant association was found between ever use of loop diuretics and changes in BMD, falls, and fractures. Loop diuretics were used by women in poor health who were already at risk for fractures. However, prolonged use of loop diuretics was associated with higher fracture risk in postmenopausal women.

This study was conducted to evaluate the extent to which disease‐modifying antirheumatic medications (DMARDs) used as part of a triple therapy for the treatment of rheumatoid arthritis (RA) including methotrexate, sulfasalazine, and hydroxychloroquine are associated with fractures in postmenopausal women with RA. Incident fractures following use of methotrexate, sulfasalazine, and/or hydroxychloroquine in postmenopausal women with RA in the Women's Health Initiative were estimated by Cox proportional hazards using hazard ratios (HRs) and 95% CIs after consideration of potential confounders. There were 1201 women with RA enrolled in the Women's Health Initiative included in these analyses, of which 74% were white, 17% were black, and 9% were of other or unknown race/ethnicity. Of the women with RA, 421 (35%) had not used methotrexate, sulfasalazine, or hydroxychloroquine, whereas 519 (43%) women had used methotrexate, 83 (7%) sulfasalazine, and 363 (30%) hydroxychloroquine alone or in combination at some time during study follow‐up. Over a median length of 6.46 years of follow‐up, in multivariable adjusted models, no statistically significant association was found between methotrexate (HR, 1.1; 95% CI, 0.8–1.6), sulfasalazine (HR, 0.6; 95% CI, 0.2–1.5), or hydroxychloroquine (HR, 1.0; 95% CI, 0.7–1.5) use and incident fractures or between combination therapy with methotrexate and sulfasalazine or methotrexate and hydroxychloroquine use (HR, 0.9; 95% CI, 0.5–1.6) and incident fractures. In conclusion, postmenopausal women with RA receiving any component of triple therapy should not be expected to have any substantial reduction in fracture risk from use of these DMARDs. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Background: The preferred macronutrient dietary composition, and the health consequences of dietary fat reduction specifically, have been debated for decades. Here we provide a comprehensive overview of long-term health outcomes in the Women's Health Initiative Dietary Modification (DM) trial.Objective: The DM trial aimed to examine whether a low-fat dietary pattern would reduce the risk of invasive breast cancer, colorectal cancer, and, secondarily, coronary heart disease (CHD), with various other health outcomes also considered.Methods: The DM trial is a randomized controlled trial conducted at 40 centers in the US, among 48,835 postmenopausal women aged 50-79 y with baseline intake of ≥32% energy from fat. Participants were randomly assigned to a low-fat dietary pattern intervention group or to a usual-diet comparison group, during 1993-1998. Intervention goals were to reduce fat intake from ∼35% to 20% of total energy, in conjunction with increasing vegetables and fruit to 5 servings/d and grains to 6 servings/d.Results: Over an 8.5-y (median) intervention period, intervention and comparison group differences included lower fat by 8-10%, and higher carbohydrate by 8-10%, of total energy, in conjunction with higher consumption of vegetables, fruit, and grains. Time-to-outcome analyses did not show significant differences between intervention and comparison groups for invasive breast cancer, colorectal cancer, or CHD, either over the intervention period or over longer-term cumulative follow-up. Additional analyses showed significant intervention group benefits related to breast cancer, CHD, and diabetes, without adverse effects. Over a 19.6-y (median) follow-up period, HRs (95% CIs) were 0.84 (0.74, 0.96) for breast cancer followed by death, and 0.87 (0.77, 0.98) for diabetes requiring insulin.Conclusions: Reduction in dietary fat with corresponding increase in vegetables, fruit, and grains led to benefits related to breast cancer, CHD, and diabetes, without adverse effects, among healthy postmenopausal US women.This trial was registered at clinicaltrials.gov as NCT00000611. [ABSTRACT FROM AUTHOR]

Background: Prior evidence of a possible link between vitamin D status and hematologic malignancy (HM) in humans comes from observational studies, leaving unresolved the question of whether a true causal relationship exists.Methods: The authors performed a secondary analysis of data from the Women's Health Initiative Calcium/Vitamin D (CaD) trial, a large randomized controlled trial of CaD supplementation compared with placebo in older women. Kaplan-Meier and Cox proportional hazards survival analysis methods were used to evaluate the relationship between treatment assignment and 1) incident HM and 2) HM-specific mortality over 10 years following randomization. HMs were classified by cell type (lymphoid, myeloid, or plasma cell) and analyzed as distinct endpoints in secondary analyses.Results: A total of 34,763 Women's Health Initiative CaD trial participants (median age, 63 years) had complete baseline covariate data and were eligible for analysis. Women assigned to CaD supplementation had a significantly lower risk of incident HM (hazard ratio [HR], 0.80; 95% confidence interval [95% CI], 0.65-0.99) but not HM-specific mortality (HR, 0.77 [95% CI, 0.53-1.11] for the entire cohort; and HR, 1.03 [95% CI, 0.70-1.51] among incident HM cases after diagnosis). In secondary analyses, protective associations were found to be most robust for lymphoid malignancies, with HRs of 0.77 (95% CI, 0.59-1.01) and 0.46 (95% CI, 0.24-0.89), respectively, for cancer incidence and mortality in those assigned to CaD supplementation.Conclusions: The current post hoc analysis of data from a large and well-executed randomized controlled trial demonstrates a protective association between modest CaD supplementation and HM risk in older women. Additional research concerning the relationship between vitamin D and HM is warranted. Cancer 2017;123:4168-4177. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: The effects of dietary protein on bone health are controversial. Objective: We examined the relation between protein intake with fracture and bone mineral density (BMD) within the Women's Health Initiative (WHI). Design: This prospective analysis included 144,580 women aged 50-79 y at baseline in the WHI clinical trials (CTs) and observational study (OS) that recruited participants in 1993-1998 with follow-up through 2011. Self-reported clinical fractures were collected semiannually through the original end of the trials (WHI CTs) and annually (WHI OS) by questionnaires. Hip fracture was adjudicated by a central review of radiology reports. BMDs for total body, hip, and spine were measured at baseline and 3 and 6 y in 9062 women at 3 WHI clinics by using dual-energy X-ray absorptiometry. Protein intake was assessed via food-frequency questionnaire and calibrated by using biomarkers of energy and protein intakes. Associations between protein intake and fracture were estimated by using Cox proportional hazards regression, and the relation between protein intake and BMD was estimated by using linear regression. Results: Median biomarker-calibrated protein intake was 15% of energy intake. Per 20% increase in calibrated protein intake (percentage of energy), there was no significant association with total fracture (HR: 0.99; 95% CI: 0.97, 1.02) or hip fracture (HR: 0.91; 95% CI: 0.84, 1.00), but there was an inverse association with forearm fracture (HR: 0.93; 95% CI: 0.88, 0.98). Each 20% increase in calibrated protein intake was associated with a significantly higher BMD for total body (mean 3-y change: 0.003 g/cm²; 95% CI: 0.001, 0.005 g/cm²) and hip (mean 3-y change: 0.002 g/cm²; 95% CI: 0.001, 0.004 g/cm²). Conclusions: Higher biomarker-calibrated protein intake within the range of usual intake was inversely associated with forearm fracture and was associated with better maintenance of total and hip BMDs. These data suggest higher protein intake is not detrimental to bone health in postmenopausal women. The WHI program was registered at clinicaltrials.gov as NCT00000611. [ABSTRACT FROM AUTHOR]

Background: Prospective epidemiologic data on the association between vitamin D and all-cause and cause-specific mortality are limited. Objective: This study aimed to determine whether 25-hydroxyvitamin D [25(OH)D] concentrations were prospectively and independently associated with cardiovascular disease (CVD), cancer, and all-cause mortality in postmenopausal women. Design: A substudy in 2429 postmenopausal women within the Women's Health Initiative (WHI) with measured baseline 25(OH)D concentrations were followed for 10 y for death from CVD, cancer, and all-cause mortality. Proportional hazards models were performed to evaluate quartiles of month-adjusted 25(OH)D concentrations, with adjustment for potential confounders. Sequential model building and analysis for multiplicative interaction were performed to evaluate the effects of central adiposity on the association of low 25(OH)D with all-cause mortality. Results: Of the 2429 women, 224 deaths occurred, with 79 deaths from CVD and 62 deaths from cancer. Multivariate-adjusted HRs that compared quartiles 1 (lowest) to 4 (highest) of 25(OH)D for all-cause mortality (HR: 1.25; 95% CI: 0.80, 1.95), CVD mortality (HR: 1.27; 95% CI: 0.81, 1.99), and cancer mortality (HR: 1.39; 95% CI: 0.88, 2.19) were not significant. There was a potential interaction (P = 0.08) between abdominal obesity and low 25(OH)D concentrations that showed an increased risk of the lowest quartile of 25(OH)D concentrations (HR: 1.85; 95% CI: 1.00, 3.44) with increased mortality in women with a normal waist circumference but no increased risk in women with abdominal obesity (HR: 0.96; 95% CI: 0.52, 1.76). Conclusion: Body fat distribution may play an important role in the modulation of the effect of low vitamin D concentrations on health. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Low 25-hydroxyvitamin D (25(OH) D) concentrations have been associated with radiologic worsening of osteoarthritis in some reports. However, the results are mixed and few studies have evaluated associations between 25(OH) D concentrations and both total vitamin D intake and clinical joint symptoms. Study design: Cross-sectional analyses of information from a subset of 1993 postmenopausal women obtained at baseline entry in the Women''s Health Initiative Calcium plus Vitamin D clinical trial. Main Outcome Measures: 25(OH) D concentration, total vitamin D intake (diet plus supplements), presence and severity of joint pain and joint swelling. Results: The 25(OH) D levels were commonly low with 53% having deficient (<50nmol/L) and only 17% having sufficient (>72nmol/L) levels. Joint pain (reported by 74%) and joint swelling (reported by 34%) were also commonly reported. 25(OH) D concentrations were modestly correlated with total vitamin D intake (R =0.29, p <0.0001); however, considerable variability in 25(OH) D concentrations for a given vitamin D intake was seen. In adjusted linear regression models, lower serum 25(OH) D concentrations were associated with higher average joint pain score (P =0.01 for trend) with differences most apparent in the lowest 25(OH) D levels sextile. Conclusions: Relatively low 25(OH) D levels and a high frequency of joint symptoms were common in this population of postmenopausal women. Total vitamin D intake was only modestly associated with 25(OH) D. Low serum 25(OH) D concentrations were associated with higher joint pain scores. These findings can inform the design of future intervention trials. [Copyright &y& Elsevier]

Background. Calcium and vitamin D (CaD) supplementation trials including the Women's Health Initiative (WHI) trial of CaD have shown nonsignificant reductions in total mortality. This report examines intervention effects on total and cause-specific mortality by age and adherence. Methods. The WHI CaD trial was a randomized, double-blind, placebo-controlled trial that enrolled 36,282 post- menopausal women aged 5 1-82 years from 40 U.S. clinical centers. Women were assigned to 1,000 mg of elemental calcium carbonate and 400 IU of vitamin D3 daily or placebo with average follow-up of 7.0 years. Results. The hazard ratio (HR) for total mortality was 0.91 (95% confidence interval[Cl], 0.83-1.01) with 744 deaths in women randomized to CaD versus 807 death~ in the placebo group. HRs were in the direction of reduced risk but nonsignificant for stroke and cancer mortality, but near unity for coronary heart disease and other causes of death. HRs for total mortality were 0.89 in the 29,942 women younger than 70 years (95% Cl, 0.79-1.01) and 0.95 in the 6,340 women aged 70 and older (95% CI, 0.80-1.12; p value for age interaction= .10). No statistically significant interactions were observed for any baseline characteristics. Treatment effects did not vary significantly by season. Conclusions. In the WHI CaD trial, supplementation did not have a statistically significant effect on mortality rates but the findings support the possibility that these supplements may reduce mortality rates in postmenopausal women. These data can neither support nor refute recommendations for higher dose vitamin D supplementation to reduce cancer or total mortality. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To examine the relationship between baseline hypertension, blood pressure, and the development of cognitive decline in participants in the Women's Health Initiative Memory Study (WHIMS). DESIGN: Prospective analyses. SETTING: Thirty-nine centers. PARTICIPANTS: Seven thousand one hundred forty-nine women aged 65 and older. MEASUREMENTS: The Modified Mini-Mental State Examination (3MS) was used to assess global cognitive functioning. Participants who scored below pre-established cutpoints were scheduled for more-extensive neurocognitive assessments. Results from these assessments were centrally adjudicated. RESULTS: The mean age of this group of 7,149 participants at baseline was 71.0 ± 3.8, and the mean 3MS score was 95.2 ± 4.3. During a mean follow-up period of 4.5 years, women without hypertension tended to have slightly higher 3MS scores than women with hypertension ( P=.001), but the difference was not seen after adjustment for covariates ( P=.17). Women with hypertension also appeared to be at greater risk for probable dementia or mild cognitive impairment (MCI) (hazard ratio=1.35, 95% confidence interval=1.07–1.70, P=.01), although when potential cofounders were accounted for, this association was no longer significant ( P=.06). CONCLUSION: Hypertension and high blood pressure at baseline were not independently associated with MCI or probable dementia over time in older, cognitively intact, postmenopausal women enrolled in WHIMS after other potential confounders were taken into account. These analyses should not be viewed as discouraging appropriate medical treatment for hypertension. [ABSTRACT FROM AUTHOR]

Background: Increased mammographic density reduces the sensitivity of screening mammography, is associated with increased breast cancer risk, and may be hormone related. We assessed the effect of estrogen-plus-progestin therapy on mammographic density. Methods: In a racially and ethnically diverse ancillary study of the Women's Health Initiative, we examined data from 413 postmenopausal women who had been randomly assigned to receive daily combined conjugated equine estrogens (0.625 mg) plus medroxyprogesterone acetate (i.e., progestin; 2.5 mg) (n = 202) or daily placebo (n = 211). We assessed the effect of estrogen plus progestin on measured mammographic percent density and abnormal findings over a 1-year and 2-year period. All tests of statistical significance were two-sided and were based on F tests or t tests from mixed-effects models. Results: Mean mammographic percent density increased by 6.0% at year 1, compared with baseline, in the estrogen-plus-progestin group but decreased by 0.9% in the placebo group (difference = 6.9%, 95% confidence interval [CI] = 5.3% to 8.5%; P<.001). The mean changes in mammographic density persisted but were attenuated slightly after 2 years, with an absolute increase of 4.9% in the estrogen-plus-progestin group and a decrease of 0.8% in the placebo group (difference = 5.7%, 95% CI = 4.3% to 7.3%; P«.001). These effects were consistent across racial/ethnic groups but were higher among women aged 70–79 years in the estrogen-plus-progestin group (mean increase at year 1 = 11.6%) than in the placebo group (mean decrease at year 1 = 0.1%) (difference of the means = 11.7%, 95% CI = 8.2% to 15.4%; P«.001, comparing across age groups). At year 1, women who were adherent to treatment in the estrogen-plus-progestin group had a mean increase in density of 7.7% (95% CI = 5.9% to 9.5%), and women in the placebo group had a mean decrease in density of 1.1% (95% CI = 0.3% to 1.9%). Use of estrogen plus progestin was associated with an increased risk of having an abnormal mammogram at year 1 (relative risk = 3.9, 95% CI = 1.5 to 10.2; P = .003), compared with placebo, that was not explained by an increase in density. Conclusions: Use of up 10 2 years of estrogen plus progestin was associated with increases in mammographic density. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Methods Results Conclusions Epidemiological studies have been inconsistent regarding an association between proton pump inhibitor (PPI) use and risk of primary cardiovascular disease (CVD) events.We studied 85,189 postmenopausal women (mean age 63 years at baseline) without known CVD at enrollment into the Women's Health Initiative Observational Study (1993–1998). PPI use was determined from medication inventories at baseline and Year‐3. CVD events were physician adjudicated and defined as a composite of coronary heart disease, stroke, and CVD mortality. Follow up was from baseline to September 2010. Multivariable Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for incident CVD according to baseline PPI use (no/yes), use duration (non‐user, < 1 year, 1–3 years, > 3 years), and time‐varying based on updated Year‐3 information. Propensity score adjustment was used to control for residual confounding.At baseline, 1747 (2.1%) women reported using PPIs. During a mean follow‐up of 11 years, 5778 (6.8%) cases of primary CVD were identified. PPI users had significantly higher risk of CVD compared with non‐users in the fully adjusted model (HR: 1.21, 95% CI: 1.02–1.43), and after propensity score adjustment (HR: 1.27, 95% CI: 1.21–1.32). Longer PPI use duration was associated with incrementally higher CVD risk (HRs: < 1 year: 1.11, 1–3 years: 1.27, > 3 years: 1.33; p for trend = 0.02).PPI use was associated with higher risk of incident primary CVD in older postmenopausal women. These findings underscore the importance of guideline‐directed PPI use to avoid unwanted adverse events. [ABSTRACT FROM AUTHOR]

In the Women's Health Initiative Dietary Modification randomized trial, the dietary intervention reduced breast cancer mortality by 21% (P =.02) and increased physical activity as well. Therefore, the aim was to examine whether or not these lifestyle changes attenuated age-related physical functioning decline. In a randomized trial, the influence of 8 years of a low-fat dietary pattern intervention was examined through 20 years of cumulative follow-up. From 1993 to 1998, 48,835 postmenopausal women, ages 50 to 79 years with no prior breast cancer and negative baseline mammogram were randomized at 40 US clinical centers to dietary intervention or usual diet comparison groups (40 out of 60). The intervention significantly reduced fat intake and increased vegetable, fruit, and grain intake. In post hoc analyses, physical functioning, assessed using the RAND 36-Item Short Form Health Survey, evaluated quality or limitations of 10 hierarchical physical activities. Longitudinal physical functioning, reported against a disability threshold (when assistance in daily activities is required) was the primary study outcome. Semiparametric linear mixed effect models were used to contrast physical functioning trajectories by randomization groups. Physical functioning score, assessed 495,317 times with 11.0 (median) assessments per participant, was significantly higher in the intervention vs comparison groups through 12 years of cumulative follow-up (P =.001), representing a reduction in age-related functional decline. The intervention effect subsequently attenuated and did not delay time to the disability threshold. Among women in the dietary intervention vs comparison groups, aged 50 to 59 years, who were physically inactive at entry, a persistent, statistically significant, favorable influence on physical functioning with associated delay in crossing the disability threshold by approximately a year was seen (P value for interaction =.007). In the Women's Health Initiative Dietary Modification randomized trial, a dietary intervention that significantly reduced breast cancer mortality also significantly reduced age-related functional decline through 12 years, which was attenuated with longer follow-up. [ABSTRACT FROM AUTHOR]

The authors further analyzed results from the Womens Health Initiative randomized trials (1993–2004) of conjugated equine estrogens, with or without medroxyprogesterone acetate, focusing on health benefits versus risks among women who initiated hormone therapy soon after menopause. Data from the Womens Health Initiative observational study (1993–2004) were included in some analyses for additional precision. Results are presented here for incident coronary heart disease, stroke, venous thromboembolism, breast cancer, colorectal cancer, endometrial cancer, or hip fracture; death from other causes; a summary global index; total cancer; and total mortality. Hazard ratios for breast cancer and total cancer were comparatively higher (P < 0.05) among women who initiated hormone therapy soon after menopause, for both regimens. Among these women, use of conjugated equine estrogens appeared to produce elevations in venous thromboembolism and stroke and a reduction in hip fracture. Estrogen plus progestin results among women who initiated use soon after menopause were similar for venous thromboembolism, stroke, and hip fracture but also included evidence of longer-term elevations in breast cancer, total cancer, and the global index. These analyses provide little support for the hypothesis of favorable effects among women who initiate postmenopausal estrogen use soon after menopause, either for coronary heart disease or for health benefits versus risk indices considered. [ABSTRACT FROM AUTHOR]

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. To examine the relationship between coffee intake and NHL incidence in a large prospective study of postmenopausal US women. 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. 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). 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. 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. 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. [ABSTRACT FROM AUTHOR]

Abstract: Background: Low vitamin D intake and levels have been associated with increased joint symptoms in some observational studies but the findings are mixed and evidence from randomized trials sparse. Objective: To evaluate the influence of supplemental calcium and vitamin D on joint symptoms in the Women’s Health Initiative randomized, placebo-controlled, clinical trial. Design: In post hoc analyses, the results of the Women’s Health Initiative randomized clinical trial in which 36,282 postmenopausal women were randomized to receive calcium carbonate (1,000 mg as elemental calcium) with vitamin D-3 (400 IU) daily or placebo were examined in the 6% subgroup of 1,911 participants, oversampled for minorities, who had serial joint symptom assessment. Qualitative information on joint pain and joint swelling was collected by questionnaire before entry and 2 years after randomization. Logistic regression models were used to compare the occurrence and severity of joint symptoms across randomization groups. Results: At baseline, total calcium and vitamin D intakes from diet and supplements were similar in the two randomization groups. In addition, both joint pain (reported by 73%) and joint swelling (reported by 34%) were commonly reported and comparable in the supplement and placebo groups. Two years after randomization, no statistically significant differences between supplement and placebo groups were seen for joint pain frequency (74.6% compared with 75.1% [P=0.79] for supplement and placebo groups, respectively) or joint swelling frequency (34.6% compared with 32.4% [P=0.29], respectively) or in severity scores for either outcome. Subgroup analyses suggested study participants also using nonprotocol calcium supplements at study entry may have less joint pain with supplement group randomization (interaction P=0.02). Conclusions: Joint symptoms are relatively common in postmenopausal women. However, daily supplementation with 1,000 mg calcium carbonate and 400 IU vitamin D-3 in a randomized, placebo-controlled clinical trial setting did not reduce the self-reported frequency or severity of joint symptoms. [Copyright &y& Elsevier]

Background: There is a high prevalence of women in South Africa with overweight and obesity which is associated with an increased risk of cardiometabolic disorders. Perceived barriers such as lack of time and motivation reduce engagement in beneficial activity behaviours for health. High-intensity interval training (HIIT) is a time-efficient and effective way to improve cardiometabolic risk profile regardless of a loss in body mass or change in body composition. This randomized controlled trial aims to determine the effects on cardiorespiratory fitness, body composition and cardiometabolic health and feasibility of a home-based 14-week HIIT program in women with overweight/obesity or normal body mass. Methods: One hundred and twenty women (18–40 years old) with a body mass index between 20 and 35 kg/m2, will be stratified according to their BMI (normal, BMI 20–24.9 kg/m2; or high BMI ≥25 kg/m2) and randomized into a HIIT exercising group (HIIT) or a non-exercising control group (CON). HIIT participants will perform exercises for 11 min/session six times per week for a period of 14 weeks. The 2 × 4 HIIT protocol will require a work phase of own-body weight exercise lasting 2 minutes (85% VO2peak), repeated four times and separated by a one-minute active rest phase (65% VO2peak). CON participants will be asked to maintain their normal habitual lifestyle. Outcomes of cardiorespiratory fitness, body composition, echocardiography, central blood pressure, arterial stiffness and biomarkers of cardiometabolic health will be measured before and after the 14-week intervention. Every 4 weeks during the intervention, an objective estimation of compliance to the study protocol will be assessed by measuring participant physical activity over 7 days using an Actigraph GT3X accelerometer. Discussion: Supervised laboratory-based HIIT interventions are effective in improving cardiometabolic health. More pragmatic exercise protocols may however show to be successful for mitigating barriers to the engagement in physical activity and exercise resulting in positive benefits to health. Investigation into home-based HIIT regimens are important in women, where globally the rising trend of overweight and obesity overshadows that of men. The results from this study may therefore inform future research on effective exercise prescription for women's health. Trial registration: Pan African Clinical Trial Registry (www.pactr.org - id no: PACTR201806003434299), 6th June 2018. [ABSTRACT FROM AUTHOR]

Summary: Methodological limitations preclude determination of the association between sleep duration and bone mineral density (BMD) from existing literature. This was the first study to use objective sleep duration to determine its association with BMD. Nocturnal sleep duration, assessed objectively (actigraphy) or subjectively (questionnaire), was not independently associated with BMD in postmenopausal women. Introduction: Both long and short self-reported sleep durations are associated with low bone mineral density (BMD) in men and women. The association between sleep duration measured by actigraphy and BMD in postmenopausal women is unknown. Methods: The Study of Osteoporotic Fractures (SOF) ancillary sleep study was used to determine the association between sleep duration and BMD at the total hip and femoral neck in postmenopausal women ≥ 75 years old. Sleep duration was assessed by wrist actigraphy (average 4 nights) and questionnaire. BMD was compared between postmenopausal women with short (< 6 h/night) vs. NIH-recommended (7–8 h/night) sleep durations. Data were analyzed using a 2-sample t test (unadjusted) and multivariate regression model (adjusted). Simple linear regression was used to estimate the difference in BMD per additional hour of sleep when sleep duration was considered as a continuous, rather than dichotomized, variable. Results: Total hip BMD was higher in women with actigraphically assessed shorter sleep duration in unadjusted models only. No clinically or statistically significant differences in total hip or femoral neck BMD were observed according to nocturnal sleep duration after adjusting for body mass index (BMI) in dichotomized (N = 874) or continuous (N = 1624) sleep duration models or when subjective sleep duration was used. When sleep duration included daytime naps, longer sleep duration was associated with lower total hip BMD (β = − 0.005, p = 0.04). Conclusions: Nocturnal sleep duration, whether assessed objectively (actigraphy) or subjectively (questionnaire), was not independently associated with BMD in older postmenopausal women. [ABSTRACT FROM AUTHOR]

Background/objective: Many studies have shown a U-shaped association of sleep duration with mortality; however, this association is difficult to interpret owing to possible reverse causation, residual confounding, and measurement issues. We used data from the Women's Health Initiative to examine the associations of sleep duration, insomnia, and use of sleep aids with death from cardiovascular disease (CVD), cancer, "other" causes, and all causes combined.Methods: Cox proportional hazards models were used in the analysis of baseline data and in time-dependent analyses of repeated measures to estimate associations of sleep-related factors with mortality. Among 158,203 women with information regarding sleep, 30,400 total deaths, 8857 CVD deaths, 9284 cancer deaths, and 11,928 other deaths were ascertained over a median of 17.8 years.Results: In both baseline and time-dependent analyses, both short (≤5 h) and long sleep (≥9 h) durations were associated with increased risk of total, CVD, and "other" deaths, but not with cancer deaths. Insomnia showed no association with mortality, whereas use of sleep medications was associated with an increased mortality risk.Conclusions: While our findings showed a small but robust association of sleep duration with mortality in postmenopausal women, studies including objective measurements of sleep quality and efficiency are needed to clarify these associations. [ABSTRACT FROM AUTHOR]

Background: Osteoporotic fractures are associated with high morbidity, mortality, and cost.Methods: We performed a post hoc analysis of the Women's Health Initiative (WHI) clinical trials data to assess osteoporosis treatment and identify participant characteristics associated with utilization of osteoporosis medication(s) after new diagnoses of osteoporosis or fracture. Information from visits prior to and immediately subsequent to the first fracture event or osteoporosis diagnosis were evaluated for medication use. A full logistic regression model was used to identify factors predictive of osteoporosis medication use after a fracture or a diagnosis of osteoporosis.Results: The median length of follow-up from enrollment to the last WHI clinic visit for the study cohort was 13.9 years. Among the 13,990 women who reported new diagnoses of osteoporosis or fracture between enrollment and their final WHI visit, and also had medication data available, 21.6% reported taking an osteoporosis medication other than estrogen. Higher daily calcium intake, diagnosis of osteoporosis alone or both osteoporosis and fracture (compared with diagnosis of fracture alone), Asian or Pacific Islander race/ethnicity (compared with White/Caucasian), higher income, and hormone therapy use (past or present) were associated with significantly higher likelihood of osteoporosis pharmacotherapy. Women with Black/African American race/ethnicity (compared with White/Caucasian), body mass index ≥30 (compared with body mass index of 18.5-24.9), current tobacco use (compared with past use or lifetime nonusers), and history of arthritis were less likely to use osteoporosis treatment.Conclusion: Despite well-established treatment guidelines in postmenopausal women with osteoporosis or history of fractures, pharmacotherapy use was suboptimal in this study. Initiation of osteoporosis treatment after fragility fracture may represent an opportunity to improve later outcomes in these high-risk women. Specific attention needs to be paid to increasing treatment among women with fragility fractures, obesity, current tobacco use, history of arthritis, or of Black race/ethnicity. [ABSTRACT FROM AUTHOR]

Objective: To analyze the treatment effect of calcium+vitamin D supplementation, hormone therapy, both, and neither on cardiovascular disease risk factors.Methods: We conducted a prospective, randomized, double-blind, placebo-controlled trial among Women's Health Initiative (WHI) participants. The predefined primary outcome was low-density lipoprotein cholesterol (LDL-C).Results: Between September 1993 and October 1998, a total of 68,132 women aged 50-79 years were recruited and randomized to the WHI-Dietary Modification (n=48,835) and WHI-Hormone Therapy trials (n=27,347). Subsequently, 36,282 women from WHI-Hormone Therapy (16,089) and WHI-Dietary Modification (n=25,210) trials were randomized in the WHI-Calcium+Vitamin D trial to 1,000 mg elemental calcium carbonate plus 400 international units vitamin D3 daily or placebo. Our study group included 1,521 women who participated in both the hormone therapy and calcium+vitamin D trials and were in the 6% subsample of trial participants with blood sample collections at baseline and years 1, 3, and 6. The average treatment effect with 95% confidence interval, for LDL-C, compared with placebo, was -1.6, (95% confidence interval [CI] -5.5 to 2.2) mg/dL for calcium+vitamin D alone, -9.0 (95% CI -13.0 to -5.1) mg/dL for hormone therapy alone, and -13.8 (95% CI -17.8 to -9.8) mg/dL for the combination. There was no evidence of a synergistic effect of calcium+vitamin D+hormone therapy on LDL-C (P value for interaction=.26) except in those with low total intakes of vitamin D, for whom there was a significant synergistic effect on LDL (P value for interaction=.03).Conclusion: Reductions in LDL-C were greater among women randomized to both calcium+vitamin D and hormone therapy than for those randomized to either intervention alone or to placebo. The treatment effect observed in the calcium+vitamin D+hormone therapy combination group may be additive rather than synergistic. For clinicians and patients deciding to begin calcium+vitamin D supplementation, current use of hormone therapy should not influence that decision.Clinical Trial Registration: ClinicalTrials.gov, https://clinicaltrials.gov, NCT00000611. [ABSTRACT FROM AUTHOR]

Background It is unknown whether supplementation with calcium and vitamin D has an impact on menopause-related symptoms. Methods As part of the Women's Health Initiative Calcium/Vitamin D Supplementation Trial (CaD), women were randomized at 40 clinical sites to elemental calcium carbonate 1000 mg with vitamin D 400 IU daily or placebo. At the CaD baseline visit (year 1 or year 2) and during a mean follow-up of 5.7 years, participants provided data on menopause-related symptoms via questionnaires. Generalized linear mixed effects techniques were used to address research questions. Results After excluding participants with missing data ( N = 2125), we compared menopause-related symptoms at follow-up visits of 17,101 women randomized to CaD with those of 17,056 women given the placebo. Women in the CaD arm did not have a different number of symptoms at follow-up compared to women taking the placebo ( p = 0.702). Similarly, there was no difference between sleep disturbance, emotional well-being, or energy/fatigue at follow-up in those who were randomized to CaD supplementation compared to those taking the placebo. Conclusions Our data suggest that supplementation with 1000 mg of calcium plus 400 IU of vitamin D does not influence menopause-related symptoms over an average of 5.7 years of follow-up among postmenopausal women with an average age of 64 at the WHI baseline visit. [ABSTRACT FROM AUTHOR]