Estrogen Plus Progestin and Colorectal Cancer: Long-Term Findings From the Women's Health Initiative Randomized Clinical Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We report long-term colorectal cancer findings from the Women's Health Initiative trial where 16,608 postmenopausal women with a uterus were randomly assigned to daily conjugated equine estrogen (CEE) 0.625 mg, plus medroxyprogesterone acetate (MPA) 2.5 mg, or placebo. When intervention ended after 5.6 years, although there were 44% fewer colorectal cancers in the intervention group (43 v 72, P = .003), the cancers were more commonly lymph node-positive (59.0% v 29.4%, P = .003). Now after cumulative 24-year follow-up, with 431 colorectal cancers, CEE plus MPA no longer influenced colorectal cancer incidence (215 [0.15, annualized rate %] v 216 [0.15], hazard ratio [HR], 0.95 [95% CI, 0.79 to 1.15]). Although not statistically significant, there were more colorectal cancer deaths with CEE plus MPA (87 [0.049] v 69 [0.041] deaths, HR, 1.20 [95% CI, 0.87 to 1.65], P = .26). Vaginal bleeding (54.1% v 5.2% at 6 months) and breast changes were more frequent in the intervention group. After adjusting for postrandomization vaginal bleeding and breast changes, bowel examinations were significantly delayed in intervention group participants (P = .005), potentially contributing to diagnostic delay. Taken together, the findings suggest no clinically meaningful benefit for about 5 years of CEE plus MPA use on colorectal cancer outcome.

Randomized trials of estrogen-alone and breast cancer incidence: a meta-analysis.

PURPOSE: In the Women's Health initiative (WHI) randomized clinical trial, conjugated equine estrogen (CEE)-alone significantly reduced breast cancer incidence (P = 0.005). As cohort studies had opposite findings, other randomized clinical trials were identified to conduct a meta-analysis of estrogen-alone influence on breast cancer incidence. METHODS: We conducted literature searches on randomized trials and: estrogen, hormone therapy, and breast cancer, and searches from a prior meta-analysis and reviews. In the meta-analysis, for trials with published relative risks (RR) and 95% confidence intervals (CI), each log-RR was multiplied by weight = 1/V, where V = variance of the log-RR, and V was derived from the corresponding 95% CI. For smaller trials with only breast cancer numbers, the corresponding log-RR = (O - E)/weight, where O is the observed case number in the oestrogen-alone group and E the corresponding expected case number, E = nP. RESULTS: Findings from 10 randomized trials included 14,282 participants and 591 incident breast cancers. In 9 smaller trials, with 1.2% (24 of 2029) vs 2.2% (33 of 1514) randomized to estrogen-alone vs placebo (open label, one trial) (RR 0.65 95% CI 0.38-1.11, P = 0.12). For 5 trials evaluating estradiol formulations, RR = 0.63 95% CI 0.34-1.16, P = 0.15. Combining the 10 trials, 3.6% (262 of 7339) vs 4.7% (329 of 6943) randomized to estrogen-alone vs placebo (overall RR 0.77 95% CI 0.65-0.91, P = 0.002). CONCLUSION: The totality of randomized clinical trial evidence supports a conclusion that estrogen-alone use significantly reduces breast cancer incidence.

Dietary Intervention Favorably Influences Physical Functioning: The Women's Health Initiative Randomized Dietary Modification Trial.

BACKGROUND: 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. OBJECTIVE: Therefore, the aim was to examine whether or not these lifestyle changes attenuated age-related physical functioning decline. DESIGN: 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. PARTICIPANTS AND SETTING: 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. MAIN OUTCOME MEASURES: 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. STATISTICAL ANALYSES PERFORMED: Semiparametric linear mixed effect models were used to contrast physical functioning trajectories by randomization groups. RESULTS: 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). CONCLUSIONS: 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.

Menopausal hormone therapy and change in physical activity in the Women's Health Initiative hormone therapy clinical trials.

OBJECTIVE: The menopausal transition results in a progressive decrease in circulating estrogen levels. Experimental evidence in rodents has indicated that estrogen depletion leads to a reduction of energy expenditure and physical activity. It is unclear whether treatment with estrogen therapy increases physical activity level in postmenopausal women. METHODS: A total of 27,327 postmenopausal women aged 50-79 years enrolled in the Women's Health Initiative randomized double-blind trials of menopausal hormone therapy. Self-reported leisure-time physical activity at baseline, and years 1, 3, and 6 was quantified as metabolic equivalents (MET)-h/wk. In each trial, comparison between intervention and placebo groups of changes in physical activity levels from baseline to follow-up assessment was examined using linear regression models. RESULTS: In the CEE-alone trial, the increase in MET-h/wk was greater in the placebo group compared with the intervention group at years 3 ( P = 0.002) and 6 ( P < 0.001). Similar results were observed when analyses were restricted to women who maintained an adherence rate ≥80% during the trial or who were physically active at baseline. In the CEE + MPA trial, the primary analyses did not show significant differences between groups, but the increase of MET-h/wk was greater in the placebo group compared with the intervention group at year 3 ( P = 0.004) among women with an adherence rate ≥80%. CONCLUSIONS: The results from this clinical trial do not support the hypothesis that estrogen treatment increases physical activity among postmenopausal women.

Healthy Lifestyle Index and Risk of Cardiovascular Disease Among Postmenopausal Women With Normal Body Mass Index.

Background A lifestyle comprising a healthy diet, light alcohol consumption, no smoking, and moderate or intense physical activity has been associated with reduced risk of cardiovascular disease (CVD). We examined the association of a healthy lifestyle index (HLI), derived from scores for each of these components plus waist circumference, with the risk of incident CVD and CVD subtypes in postmenopausal women with normal body mass index (18.5-<25.0 kg/m2). Methods and Results We studied 40 118 participants in the Women's Health Initiative, aged 50 to 79 years at enrollment, with a normal body mass index and no history of CVD. The HLI score was categorized into quintiles. We estimated multivariable adjusted hazard ratios (HR) and 95% CIs for the association of HLI with risk of CVD and CVD subtypes using Cox regression models. A total of 3821 cases of incident CVD were ascertained during a median follow-up of 20.1 years. Compared with the lowest quintile (unhealthiest lifestyle), higher HLI quintiles showed inverse associations with the risk of CVD (HRquintile-2=0.74 [95% CI, 0.67-0.81]; HRquintile-3=0.66 [95% CI, 0.60-0.72]; HRquintile-4=0.57 [95% CI, 0.51-0.63]; and HRquintile-5=0.48 [95% CI, 0.43-0.54], P-trend=<0.001). HLI was also inversely associated with risks of stroke, coronary heart disease, myocardial infarction, angina, and coronary revascularization. Subgroup analyses, stratified by age (≤63 years vs >63 years), body mass index (

The Efficacy of Individualized, Community-Based Physical Activity to Aid Smoking Cessation: A Randomized Controlled Trial.

Objective: The efficacy of individualized, community-based physical activity as an adjunctive smoking cessation treatment to enhance long-term smoking cessation rates was evaluated for the Lifestyle Enhancement Program (LEAP). Methods: The study was a two-arm, parallel-group, randomized controlled trial. All participants (n = 392) received cessation counseling and a nicotine patch and were randomized to physical activity (n = 199; YMCA membership and personalized exercise programming from a health coach) or an equal contact frequency wellness curriculum (n = 193). Physical activity treatment was individualized and flexible (with each participant selecting types of activities and intensity levels and being encouraged to exercise at the YMCA and at home, as well as to use "lifestyle" activity). The primary outcome (biochemically verified prolonged abstinence at 7-weeks (end of treatment) and 6- and 12-months postcessation) and secondary outcomes (7-day point prevalent tobacco abstinence (PPA), total minutes per week of leisure time physical activity and strength training) were assessed at baseline, 7 weeks, 6 months, and 12 months. Results: Prolonged abstinence in the physical activity and wellness groups was 19.6% and 25.4%, respectively, at 7-weeks, 15.1% and 16.6% at 6-months, and 14.1% and 17.1% at 12 months (all between-group P values >0.18). Similarly, PPA rates did not differ significantly between groups at any follow-up. Change from baseline leisure-time activity plus strength training increased significantly in the physical activity group at 7 weeks (P = 0.04). Across treatment groups, an increase in the number of minutes per week in strength training from baseline to 7 weeks predicted prolonged abstinence at 12 months (P ≤ 0.001). Further analyses revealed that social support, fewer years smoked, and less temptation to smoke were associated with prolonged abstinence over 12 months in both groups. Conclusions: Community-based physical activity programming, delivered as adjunctive treatment with behavioral/pharmacological cessation treatment, did not improve long-term quit rates compared to adjunctive wellness counseling plus behavioral/pharmacological cessation treatment. This trial is registered with https://beta.clinicaltrials.gov/study/NCT00403312, registration no. NCT00403312.

The Association of Total Knee Arthroplasty With Weight Loss in the Look AHEAD (Action for Health in Diabetes) Clinical Trial.

BACKGROUND: Patients who have obesity seldom lose weight after total knee arthroplasty (TKA). The Look AHEAD (Action for Health in Diabetes) trial randomized patients with type 2 diabetes who were overweight or had obesity to a 10-year intensive lifestyle intervention (ILI) or diabetes support and education (DSE). METHODS: Of the total 5,145 participants enrolled who had a median 14-year follow-up, a subset of 4,624 met inclusion criteria. The ILI aimed at achieving and maintaining a 7% weight loss and included weekly counseling the first 6 months, with decreasing frequency thereafter. This secondary analysis was undertaken to determine what effects a TKA had on patients participating in a known successful weight loss program and specifically if there was a negative impact on weight loss or their Physical Component Score. RESULTS: The analysis suggests that the ILI remained effective for maintaining or losing weight after TKA. Participants in ILI had significantly greater percent weight loss than those in DSE both before and after TKA (ILI-DSE before TKA: -3.6% (-5.0, -2.3); after TKA: -3.7% (-4.1, -3.3); both P < .0001). When comparing percent weight loss before to after TKA, there was no significant difference within either the DSE or ILI group (least square means ± standard error ILI: -0.36% ± 0.3, P = .21; DSE: -0.41% ± 0.29, P = .16). Physical Component Scores improved after TKA (P < .001), but no difference was found between TKA ILI and DSE groups before or after surgery. CONCLUSION: Participants who had a TKA did not have an altered ability to adhere to intervention goals to maintain weight loss or obtain further weight loss. The data suggest patients who have obesity can lose weight after TKA on a weight loss program.

Changes in Dietary Intake of Methionine, Folate/Folic Acid and Vitamin B12 and Survival in Postmenopausal Women with Breast Cancer: A Prospective Cohort Study.

BACKGROUND: Previous experimental studies showed that limiting methionine in the diet of animals or in cell culture media suppresses mammary cancer cell proliferation or metastasis. However, no previous study has investigated the associations of changes in methionine intake with survival among breast cancer survivors. We aimed to examine the association between changes in dietary intake of methionine, folate/folic acid, and vitamin B12 from before to after diagnosis of breast cancer, and mortality among breast cancer survivors. METHODS: We included 1553 postmenopausal women from the Women's Health Initiative who were diagnosed with invasive breast cancer and completed a food frequency questionnaire both before and after breast cancer diagnosis. Multivariable Cox proportional hazards regression models were used to estimate adjusted hazard ratios (HRs) and 95% confidence (CIs) of all-cause and breast cancer mortality associated with changes in methionine intake and changes in folate/folic acid and vitamin B12 intake. RESULTS: Relative to pre-diagnosis, 28% of women decreased methionine intake by ≥20%, 30% of women increased methionine intake by ≥20%, and 42% of women had a relatively stable methionine intake (±19.9%) following breast cancer diagnosis. During a mean 16.1 years of follow up, there were 772 deaths in total, including 195 deaths from breast cancer. Compared to women with relatively stable methionine intake, women with decreased methionine intake had lower risks of all-cause (HR 0.78, 95% CI 0.62-0.97) and breast cancer mortality (HR 0.58, 95% CI 0.37-0.91) in fully adjusted models. In contrast, increased methionine intake or changes in folate/folic acid or vitamin B12 intake were not associated with all-cause or breast cancer mortality. CONCLUSIONS: Among breast cancer survivors, decreased methionine intake after breast cancer diagnosis was associated with lower risk of all-cause and breast cancer mortality.

Association of cognition with leptin and vascular endothelial growth factor in individuals with type 2 diabetes mellitus.

OBJECTIVE: The 10-year intensive lifestyle intervention (ILI) of the Look AHEAD study left a legacy of relative deficits in cognitive function among participants who entered the clinical trial with obesity or a history of cardiovascular disease. We hypothesized that altered levels of two weight-sensitive proangiogenic cytokines, leptin and vascular endothelial growth factor (VEGF), accounted for this concerning finding. METHODS: Serum leptin and VEGF concentrations were determined in 1,279 Look AHEAD participants at baseline, proximal to cessation of the interventions (Epoch 1), and an average of 4 years later (Epoch 2). Up to four standardized assessments of attention, executive function, and memory were collected during follow-up. Mixed effects models were used to assess relative differences in leptin and VEGF concentrations between intervention groups and whether these accounted for changes in cognitive composite scores. RESULTS: ILI and diabetes support and education differences in VEGF, but not leptin, concentrations varied depending on baseline history of cardiovascular disease and obesity, but neither leptin nor VEGF concentrations accounted for the relative decrements in cognitive function in participants assigned to ILI. CONCLUSIONS: Alterations in two weight-sensitive proangiogenic cytokines did not account for the long-term adverse effects of ILI on cognitive function among adults with diabetes and either obesity or cardiovascular disease.

Associations between cognitive function and endogenous levels of estradiol and testosterone in adults with type 2 diabetes.

AIMS: To assess associations that endogenous estradiol and testosterone levels have with cognitive function in older adults with Type 2 diabetes mellitus (T2DM). METHODS: We use data from the Look AHEAD clinical trial of behavioral weight loss. Endogenous estradiol and total testosterone levels were determined using stored serum from 996 individuals, mean age 69 years, at two times (averaging 4 years apart) during years 8-18 of follow-up. One to four standardized assessments of attention, executive function, memory, and verbal fluency were collected during this follow-up. Mixed effects models and multiple imputation were used to assess associations that estradiol and total testosterone levels had with body mass index and cognitive function. RESULTS: Estradiol levels were not associated with cognitive function in either sex. Total testosterone levels were not associated with cognitive function in women, but greater total testosterone levels were associated with better verbal fluency in men (p < 0.001), most strongly among those carrying the APOE-e4 allele (interaction p = 0.02). The weight loss intervention left a legacy of relatively lower cognitive functioning among women, which was not mediated by current levels of sex hormones. CONCLUSIONS: Behavioral weight loss intervention does not affect cognitive functioning through mechanisms related to estradiol or testosterone. CLINICALTRIALS: gov Identifier: NCT00017953.

Association of Tea-drinking Habits with the Risk of Non-Hodgkin Lymphoma - A Prospective Cohort Study among Postmenopausal Women.

Although, biological evidence suggests that tea consumption may protect against non-Hodgkin lymphoma (NHL), epidemiologic evidence has been unclear. The aim of this study was to examine the association between tea-drinking habits and the risk of NHL in a large nationwide prospective cohort of postmenopausal US women. 68,854 women who were enrolled from 1993 through 1998 in the Women's Health Initiative Observational Study (WHI-OS) and responded to year 3 annual follow-up questionnaire comprised the analytic cohort. Newly diagnosed NHL cases after the year 3 visit were confirmed by medical and pathology reports. Multivariable-adjusted Cox proportional hazards models were performed to assess the associations of tea-drinking habits (specifically, the amounts of caffeinated/herbal/decaffeinated tea intake) with the overall risk of NHL and 3 major subtypes (Diffuse large B-cell lymphoma, DLBCL, (n=195, 0.3%), follicular lymphoma, FL, (n=128, 0.2%), and chronic lymphocytic leukemia/small lymphocytic lymphoma, CLL/SLL, (n=51, 0.1%)). Among 62,622 participants, a total of 663 (1.1%) women developed NHL during a median follow-up of 16.51(SD±6.20) years. Overall, different amounts of type-specific tea intake were not associated with the risk of NHL regardless of its histologic subtypes after adjustment for confounders. Our findings suggest that tea intake at the current consumption level does not influence the risk of NHL, regardless of its histologic types.

Biomarkers for Components of Dietary Protein and Carbohydrate with Application to Chronic Disease Risk in Postmenopausal Women.

BACKGROUND: We recently developed protein and carbohydrate intake biomarkers using metabolomics profiles in serum and urine, and used them to correct self-reported dietary data for measurement error. Biomarker-calibrated carbohydrate density was inversely associated with chronic disease risk, whereas protein density associations were mixed. OBJECTIVES: To elucidate and extend this earlier work through biomarker development for protein and carbohydrate components, including animal protein and fiber. METHODS: Prospective disease association analyses were undertaken in Women's Health Initiative (WHI) cohorts of postmenopausal US women, aged 50-79 y when enrolled at 40 US clinical centers. Biomarkers were developed using an embedded human feeding study (n = 153). Calibration equations for protein and carbohydrate components were developed using a WHI nutritional biomarker study (n = 436). Calibrated intakes were associated with chronic disease incidence in WHI cohorts (n = 81,954) over a 20-y (median) follow-up period, using HR regression methods. RESULTS: Previously reported elevations in cardiovascular disease (CVD) with higher-protein diets tended to be explained by animal protein density. For example, for coronary heart disease a 20% increment in animal protein density had an HR of 1.20 (95% CI: 1.02, 1.42) relative to the HR for total protein density. In comparison, cancer and diabetes risk showed little association with animal protein density beyond that attributable to total protein density. Inverse carbohydrate density associations with total CVD were mostly attributable to fiber density, with a 20% increment HR factor of 0.89 (95% CI: 0.83, 0.94). Cancer risk showed little association with fiber density, whereas diabetes risk had a 20% increment HR of 0.93 (95% CI: 0.88, 0.98) relative to the HRs for total carbohydrate density. CONCLUSIONS: In a population of postmenopausal US women, CVD risk was associated with high-animal-protein and low-fiber diets, cancer risk was associated with low-carbohydrate diets, and diabetes risk was associated with low-fiber/low-carbohydrate diets.

Four-Day Food Record Macronutrient Intake, With and Without Biomarker Calibration, and Chronic Disease Risk in Postmenopausal Women.

We recently evaluated associations of biomarker-calibrated protein intake, protein density, carbohydrate intake, and carbohydrate density with the incidence of cardiovascular disease, cancer, and diabetes among postmenopausal women in the Women's Health Initiative (1993-present, 40 US clinical centers). The biomarkers relied on serum and urine metabolomics profiles, and biomarker calibration used regression of biomarkers on food frequency questionnaires. Here we develop corresponding calibration equations using food records and dietary recalls. In addition, we use calibrated intakes based on food records in disease association estimation in a cohort subset (n = 29,294) having food records. In this analysis, more biomarker variation was explained by food records than by FFQs for absolute macronutrient intake, with 24-hour recalls being intermediate. However, the percentage of biomarker variation explained was similar for each assessment approach for macronutrient densities. Invasive breast cancer risk was related inversely to carbohydrate and protein densities using food records, in analyses that included (calibrated) total energy intake and body mass index. Corresponding analyses for absolute intakes did not differ from the null, nor did absolute or relative intakes associate significantly with colorectal cancer or coronary heart disease. These analyses do not suggest major advantages for food records or dietary recalls in comparison with less costly and logistically simpler food frequency questionnaires for these nutritional variables.

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

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

Estimating 24-Hour Urinary Excretion of Sodium and Potassium Is More Reliable from 24-Hour Urine Than Spot Urine Sample in a Feeding Study of US Older Postmenopausal Women.

BACKGROUND: Assessing estimated sodium (Na) and potassium (K) intakes derived from 24-h urinary excretions compared with a spot urine sample, if comparable, could reduce participant burden in epidemiologic and clinical studies. OBJECTIVES: In a 2-week controlled-feeding study, Na and K excretions from a 24-h urine collection were compared with a first-void spot urine sample, applying established algorithms and enhanced models to estimate 24-h excretion. Actual and estimated 24-h excretions were evaluated relative to mean daily Na and K intakes in the feeding study. METHODS: A total of 153 older postmenopausal women ages 75.4 ± 3.5 y participated in a 2-wk controlled-feeding study with a 4-d repeating menu cycle based on their usual intake (ClinicalTrials.gov Identifier: NCT00000611). Of the 150 participants who provided both a first-void spot urine sample and a 24-h urine collection on the penultimate study day, statistical methods included Pearson correlations for Na and K between intake, 24-h collections, and the 24-h estimated excretions using 4 established algorithms: enhanced biomarker models by regressing ln-transformed intakes on ln-transformed 24-h excretions or ln-transformed 24-h estimated excretions plus participant characteristics and sensitivity analyses for factors potentially influencing Na or K excretion (e.g., possible kidney disease estimated glomerular filtration rate <60 mL/min/1.73 m2 ). RESULTS: Pearson correlation coefficients between Na and K intakes and actual 24-h excretions were 0.57 and 0.38-0.44 for estimated 24-h excretions, depending on electrolyte and algorithm used. Enhanced biomarker model cross-validated R 2 (CVR2) for 24-h excretions were 38.5% (Na), 40.2% (K), and 42.0% (Na/K). After excluding participants with possible kidney disease, the CVR2 values were 43.2% (Na), 40.2% (K), and 38.1% (Na/K). CONCLUSIONS: Twenty-four-hour urine excretion measurement performs better than estimated 24-h excretion from a spot urine as a biomarker for Na and K intake among a sample of primarily White postmenopausal women.

Biomarker-Calibrated Macronutrient Intake and Chronic Disease Risk among Postmenopausal Women.

BACKGROUND: Knowledge about macronutrient intake and chronic disease risk has been limited by the absence of objective macronutrient measures. Recently, we proposed novel biomarkers for protein, protein density, carbohydrate, and carbohydrate density, using established biomarkers and serum and urine metabolomics profiles in a human feeding study. OBJECTIVES: We aimed to use these biomarkers to develop calibration equations for macronutrient variables using dietary self-reports and personal characteristics and to study the association between biomarker-calibrated intake estimates and cardiovascular disease, cancer, and diabetes risk in Women's Health Initiative (WHI) cohorts. METHODS: Prospective disease association analyses are based on WHI cohorts of postmenopausal US women aged 50-79 y when enrolled at 40 US clinical centers (n = 81,954). We used biomarker intake values in a WHI nutritional biomarker study (n = 436) to develop calibration equations for each macronutrient variable, leading to calibrated macronutrient intake estimates throughout WHI cohorts. We then examined the association of these intakes with chronic disease incidence over a 20-y (median) follow-up period using HR regression methods. RESULTS: In analyses that included doubly labeled water-calibrated total energy, HRs for cardiovascular diseases and cancers were mostly unrelated to calibrated protein density. However, many were inversely related to carbohydrate density, with HRs (95% CIs) for a 20% increment in carbohydrate density of 0.81 (0.69, 0.95) and 0.83 (0.74, 0.93), respectively, for primary outcomes of coronary heart disease and breast cancer, as well as 0.74 (0.60, 0.91) and 0.87 (0.81, 0.93) for secondary outcomes of heart failure and total invasive cancer. Corresponding HRs (95% CIs) for type 2 diabetes incidence in relation to protein density and carbohydrate density were 1.17 (1.09, 1.75) and 0.73 (0.66, 0.80), respectively. CONCLUSIONS: At specific energy intake, a diet high in carbohydrate density is associated with substantially reduced risk of major chronic diseases in a population of US postmenopausal women. This trial was registered at clinicaltrials.gov as NCT00000611.

Opioid Use Patterns After Primary Total Knee Replacement.

Orthopedic surgeries are associated with the prescription of more narcotics than any other surgical specialty, particularly for total knee replacement (TKR) surgery. The authors examined controlled substance prescriptions following TKR surgery in a sample of 560 TKR patients. Results indicated that of all the 5164 prescriptions documented on the controlled substance monitoring database, 64% were for opioid medications. More than half of the patients received controlled substances from both the surgery site provider and a nonsurgery site provider in the year following surgery. The authors recommend that providers consider the possibility of outside prescribing when prescribing opioid analgesic.

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.

Randomized Trial Evaluation of the Benefits and Risks of Menopausal Hormone Therapy Among Women 50-59 Years of Age.

The health benefits and risks of menopausal hormone therapy among women aged 50-59 years are examined in the Women's Health Initiative randomized, placebo-controlled trials using long-term follow-up data and a parsimonious statistical model that leverages data from older participants to increase precision. These trials enrolled 27,347 healthy postmenopausal women aged 50-79 years at 40 US clinical centers during 1993-1998, including 10,739 post-hysterectomy participants in a trial of conjugated equine estrogens and 16,608 participants with a uterus in the trial of these estrogens plus medroxyprogesterone acetate. Over a (median) 18-year follow-up period (1993-2016), risk for a global index (defined as the earliest of coronary heart disease, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and all-cause mortality) was reduced with conjugated equine estrogens with a hazard ratio of 0.82 (95% confidence interval: 0.71, 0.95), and with nominally significant reductions for coronary heart disease, breast cancer, hip fracture, and all-cause mortality. Corresponding global index hazard ratio estimates of 1.06 (95% confidence interval: 0.95, 1.19) were nonsignificant for combined estrogens plus progestin, but increased breast cancer risk and reduced endometrial cancer risk were observed. These results, among women 50-59 years of age, substantially agree with the worldwide observational literature, with the exception of breast cancer for estrogens alone.

Association of Sedentary Time and Incident Heart Failure Hospitalization in Postmenopausal Women.

BACKGROUND: The 2018 US Physical Activity Guidelines recommend reducing sedentary behavior (SB) for cardiovascular health. SB's role in heart failure (HF) is unclear. METHODS: We studied 80 982 women in the Women's Health Initiative Observational Study, aged 50 to 79 years, who were without known HF and reported ability to walk ≥1 block unassisted at baseline. Mean follow-up was 9 years for physician-adjudicated incident HF hospitalization (1402 cases). SB was assessed repeatedly by questionnaire. Time-varying total SB was categorized according to awake time spent sitting or lying down (≤6.5, 6.6-9.5, >9.5 h/d); sitting time (≤4.5, 4.6-8.5, >8.5 h/d) was also evaluated. Hazard ratios and 95% CI were estimated using Cox regression. RESULTS: Controlling for age, race/ethnicity, education, income, smoking, alcohol, menopausal hormone therapy, and hysterectomy status, higher HF risk was observed across incremental tertiles of time-varying total SB (hazard ratios [95% CI], 1.00 [referent], 1.15 [1.01-1.31], 1.42 [1.25-1.61], trend P<0.001) and sitting time (1.00 [referent], 1.14 [1.01-1.28], 1.54 [1.34-1.78], trend P<0.001). The inverse trends remained significant after further controlling for comorbidities including time-varying myocardial infarction and coronary revascularization (hazard ratios: SB, 1.00, 1.11, 1.27; sitting, 1.00, 1.09, 1.37, trend P<0.001 each) and for baseline physical activity (hazard ratios: SB 1.00, 1.10, 1.24; sitting 1.00, 1.08, 1.33, trend P<0.001 each). Associations with SB exposures were not different according to categories of baseline age, race/ethnicity, body mass index, physical activity, physical functioning, diabetes, hypertension, or coronary heart disease. CONCLUSIONS: SB was associated with increased risk of incident HF hospitalization in postmenopausal women. Targeted efforts to reduce SB could enhance HF prevention in later life.