Chunyuan Wu

Serum 25-Hydroxyvitamin D Concentrations and Risk for Hip Fractures

Context Vitamin D supplementation may help prevent fractures, but the relationship between blood vitamin D concentrations and fracture risk is unclear. Contribution These authors observed an increased risk for hip fracture among women with lower serum 25-hydroxyvitamin D [25(OH) vitamin D] concentrations that was independent of measures of frailty, body mass index, physical function, and falls. Caution The authors did not measure bone mineral density (BMD), so they could not determine whether 25(OH) vitamin D concentrations give different information about fracture risk than that offered by BMD. Implication Low serum 25(OH) vitamin D concentrations seem to be associated with a higher hip fracture risk. The Editors Vitamin D deficiency is common in older adults, especially during the winter (1) and in homebound populations (2), general medical inpatients (3), and community-dwelling women admitted to the hospital with acute hip fracture (4). A recently published evidence-based report on vitamin D and bone health (5) found the level of evidence for an association between serum 25-hydroxyvitamin D [25(OH) vitamin D] concentrations and fracture risk to be inconsistent (5). Since publication of that review, 1 prospective study (6) reported no relationship between serum 25(OH) vitamin D concentrations and fractures, whereas another (7) reported a significantly lower risk for hip fracture with 25(OH) vitamin D concentrations greater than 60 nmol/L. Vitamin D concentration could be associated with fractures in several ways. It could influence muscle strength and balance, both of which contribute to falls and disability (810). The association between 25(OH) vitamin D concentrations and fracture may also be influenced by renal function, because renal insufficiency has been linked to fracture (11) and to vitamin D deficiency (12). Several interactions between vitamin D and estrogen receptors have been described (13); hormone therapy has been shown to reverse abnormalities in vitamin D metabolism (14), and low vitamin D concentrations have also been linked to higher bone turnover (15, 16). Thus, sex-steroid hormones and bone turnover could contribute to the association between 25(OH) vitamin D concentration and fractures. We conducted a nested casecontrol study within the WHI-OS (Womens Health Initiative Observational Study) among 400 case-patients with adjudicated incident hip fracture and 400 control participants. We tested whether low serum 25(OH) vitamin D concentrations are associated with a higher risk for hip fractures in community-dwelling women and whether this relationship may be mediated by poor physical functioning, frailty, falls, sex-steroid hormones, renal function, or bone turnover. Methods Study Population Our study population came from the WHI-OS, a prospective cohort study that enrolled 93676 women between 1994 and 1998 at 40 U.S. clinical centers (age range, 50 to 79 years). Study methods are described in detail elsewhere (17). In brief, women were eligible if they were postmenopausal, were unlikely to move or die within 3 years, were not enrolled in the WHI clinical trials, and were not currently participating in any other clinical trial. The human subjects review committees from each participating institution approved the study. Follow-up and Outcome Ascertainment We sent women questionnaires annually to report any hospitalization and other outcomes, including fractures. As of August 2004, median follow-up duration was 7.1 years (range, 0.7 to 9.3 years). At that time, 3.7% of participants had withdrawn or were lost to follow-up and 5.3% had died. We reviewed medical records to verify cases of hip fracture, and blinded central adjudicators confirmed the cases (18). We excluded patients with pathologic hip fractures. Nested CaseControl Study Design The present study is a casecontrol study nested within the prospective design of WHI-OS. We excluded women who had a history of hip fracture; were receiving hormone therapy up to 1 year before enrollment; or were currently receiving androgens, selective estrogen receptor modulators, antiestrogens, or other osteoporosis treatments (bisphosphonates, calcitonin, or parathyroid hormone). We also excluded women with insufficient serum stored or of unknown ethnicity, leaving 39793 eligible participants. Of these, 404 women had a hip fracture. We randomly selected 400 of these women to form the incident hip fracture group. For each case-patient, we selected 1 control participant who was within 1 year of the case-patients age at screening, was of matching race or ethnicity, and had their blood drawn within 120 days of the case-patients blood draw date; 99% of case-patients and control participants were matched within 30 days. Baseline Clinical Variables We divided clinical centers into 3 geographic regions on the basis of latitude: northern (>40 N), middle (35 to 40 N), and southern (<35 N). We ascertained all covariates at baseline. Clinic interviewers recorded current use of prescription medications by direct inspection of medicine containers. We entered prescription names into the WHI database and assigned drug codes by using Medispan software (First DataBank, San Bruno, California). Average amounts of elemental calcium and vitamin D preparations were entered directly from supplement containers. Dietary intakes of calcium and vitamin D were assessed by using a semiquantitative food-frequency questionnaire (19). Total calcium and vitamin D intake was defined as the sum of diet and supplements. We used questionnaires to ascertain date of birth, race or ethnicity, age at menopause, history of any fracture after age 55 years, smoking, parental history of hip fracture, self-rated health status, and alcohol consumption. We classfied physical activity on the basis of frequency and duration of walking and mild, moderate, and strenuous activities in the previous week. We calculated kilocalories of energy expended in 1 week as the metabolic equivalent (kcal hours/week per kg) (20). We measured physical function by using the RAND Short Form-36 physical function scale, which comprises 10 items measuring whether health now limits physical function in moderate or vigorous activity (2 items); strength to lift, carry, stoop, bend, or stair climb (4 items); ability to walk various distances without difficulty (3 items); and self-care (1 item) (21). The scale is scored from 0 to 100, with higher scores indicating better physical function. We compared women with a score greater than 90 versus those with a score less than or equal to 90, a cutoff value corresponding to the median score. We computed a frailty score, which included self-reported muscle weakness and impaired walking speed (RAND Short Form-36 physical function scale score <75), exhaustion (RAND Short Form-36 vitality scale score <55), low physical activity (lowest quartile of physical activity), and unintended weight loss between baseline and 3 years of follow-up (22). A woman was considered frail if she reported 3 or more of these indicators. Weight was measured on a balance-beam scale with the participant dressed in indoor clothing without shoes. Height was measured by using a wall-mounted stadiometer. Body mass index was calculated as weight (in kg) divided by height (in m2). Laboratory Procedures Laboratory personnel blinded to casecontrol status obtained a 12-hour fasting blood sample at the baseline visit, which was processed and stored at 80C according to strict quality control procedures (23). Serum 25(OH) vitamin D concentrations and sex-steroid hormone levels were measured at the Reproductive Endocrine Research Laboratory at the University of Southern California. 25-Hydroxyvitamin vitamin D was measured by using a radioimmunoassay with DiaSorin reagents (DiaSorin, Stillwater, Minnesota). The sensitivity of the assay was 3.75 nmol/L. The interassay coefficients of variation were 11.7%, 10.5%, 8.6%, and 12.5% at 14.0, 56.8, 82.5, and 122.5 nmol/L, respectively. Estradiol and testosterone concentrations were quantified by using sensitive and specific radioimmunoassays after organic solvent extraction and celite column partition chromatography (2427). The intra- and interassay coefficients of variation were 7.9% and 8% to 12%, respectively, for estradiol and 6% and 10% to 12%, respectively, for testosterone. We calculated bioavailable hormone concentrations by using mass action equations (2830). We measured sex hormonebinding globulin by using a solid-phase, 2-site chemiluminescent immunoassay. The intra- and interassay coefficients of variation were 4.1% to 7.7% and 5.8% to 13%, respectively. Serum cystatin C, a marker of renal function that is independent of age and weight, was measured at Medical Research Laboratories International, Highland Heights, Kentucky, by using the Dade Behring BN-II nephelometer and Dade Behring reagents (Dade Behring, Ramsey, Minnesota) in a particle-enhanced immunonepholometric assay. Serum C-terminal telopeptide of type I collagen and aminoterminal procollagen extensions propeptide were measured by immunoassay (Synarc, Lyon, France). Statistical Analysis We used chi-square and t tests to compare baseline characteristics between case-patients with hip fracture and matched control participants. We assigned 25(OH) vitamin D concentrations to quartile categories defined on the basis of the distribution in the control participants. To further assess confounding, we compared baseline characteristics across quartiles of 25(OH) vitamin D concentrations in case-patients and control participants combined. We calculated the P values for trend by using logistic regression and coding the variable of interest as a continuous variable. We assessed the association between serum 25(OH) vitamin D concentrations and incident hip fracture in conditional logistic regression models that retained the matched casecontrol design. We first examined the unadjusted associations and then adjusted for age, b

Vasomotor symptoms and cardiovascular events in postmenopausal women

Objective:Emerging evidence suggests that women with menopausal vasomotor symptoms (VMS) have increased cardiovascular disease (CVD) risk as measured by surrogate markers. We investigated the relationships between VMS and clinical CVD events and all-cause mortality in the Womens Health Initiative Observational Study (WHI-OS). Methods:We compared the risk of incident CVD events and all-cause mortality between four groups of women (total N = 60,027): (1) no VMS at menopause onset and no VMS at WHI-OS enrollment (no VMS [referent group]), (2) VMS at menopause onset but not at WHI-OS enrollment (early VMS), (3) VMS at both menopause onset and WHI-OS enrollment (persistent VMS [early and late]), and (4) VMS at WHI-OS enrollment but not at menopause onset (late VMS). Results:For women with early VMS (n = 24,753), compared with no VMS (n = 18,799), hazard ratios (95% CIs) in fully adjusted models were as follows: major coronary heart disease (CHD), 0.94 (0.84-1.06); stroke, 0.83 (0.72-0.96); total CVD, 0.89 (0.81-0.97); and all-cause mortality, 0.92 (0.85-0.99). For women with persistent VMS (n = 15,084), there was no significant association with clinical events. For women with late VMS (n = 1,391), compared with no VMS, hazard ratios (95% CIs) were as follows: major CHD, 1.32 (1.01-1.71); stroke, 1.14 (0.82-1.59); total CVD, 1.23 (1.00-1.52); and all-cause mortality, 1.29 (1.08-1.54). Conclusions:Early VMS were not associated with increased CVD risk. Rather, early VMS were associated with decreased risk of stroke, total CVD events, and all-cause mortality. Late VMS were associated with increased CHD risk and all-cause mortality. The predictive value of VMS for clinical CVD events may vary with the onset of VMS at different stages of menopause. Further research examining the mechanisms underlying these associations is needed. Future studies will also be necessary to investigate whether VMS that develop for the first time in the later postmenopausal years represent a pathophysiologic process distinct from the classic perimenopausal VMS.

Mortality Risk Associated with Physical and Verbal Abuse in Women Aged 50 to 79

OBJECTIVES: To investigate whether midlife and older women who reported prior‐year physical abuse, verbal abuse, or both abuse types had higher mortality risk than peers who did not report prior‐year abuse.

Plasma Isoflavones and Fibrocystic Breast Conditions and Breast Cancer Among Women in Shanghai, China

Background: Proliferative benign breast conditions are associated with elevated risk of breast cancer, whereas nonproliferative conditions are not strongly associated with risk. Factors acting before onset of hyperplasia might be associated with both benign conditions and breast cancer, whereas those on the proliferative disease-to-cancer pathway would be associated only with cancer. Soy isoflavone exposure may influence breast cancer risk, but little is known of its association with benign conditions. Materials and Methods: We examined possible relationships between plasma genistein and daidzein concentrations and risk of breast disease in women, in a breast self-examination trial in Shanghai, China, diagnosed with breast cancer (n = 196) or a benign breast condition (n = 304), and 1,002 age-matched controls with no known breast disease. Benign conditions were classified as nonproliferative (n = 131) or proliferative with or without atypia (n = 173). Results: Isoflavone concentrations were inversely associated with risk of nonproliferative and proliferative benign fibrocystic conditions, as well as with breast cancer, both with and without concomitant proliferative changes in ipsilateral noncancerous mammary epithelium (Ptrend < 0.01 for all comparisons with controls). Women in the highest quartile of plasma genistein (>76.95 ng/mL) were less likely to have breast cancer (odds ratio, 0.26; 95% confidence interval, 0.13-0.50) or benign conditions (odds ratio, 0.40; 95% confidence interval, 0.23-0.70) compared with women in the lowest quartile (<9.42 ng/mL). Observed risks for breast cancer with and without surrounding proliferative changes were not different, respectively, from observed risks for benign proliferative and nonproliferative conditions alone. Conclusion: Isoflavone exposure was inversely associated with fibrocystic breast conditions and breast cancer, and the results suggest that effects on cancer risk occur early in carcinogenesis. (Cancer Epidemiol Biomarkers Prev 2007;16(12):2579–86)

Dietary Patterns and Fractures in Postmenopausal Women: Results From the Women's Health Initiative

IMPORTANCE Considerable efforts have been undertaken to relate single nutrients to bone health. To this point, results are inconsistent. Suboptimal single nutrient intake does not occur in isolation but rather reflects a poor diet quality. OBJECTIVE To assess the association between adherence to a diet quality index constructed on the basis of dietary recommendations or existing healthy dietary patterns and fractures in postmenopausal women. DESIGN, SETTING, AND PARTICIPANTS Post hoc analysis was conducted of longitudinal data from 40 clinical centers throughout the United States included in the Womens Health Initiative (WHI) observational study. Participants in the prospective cohort included 93 676 women who were eligible for the WHI if they were aged 50 to 79 years. Recruitment was conducted from October 1, 1993, to December 31, 1998, with the study ending August 29, 2014. The WHI food frequency questionnaire was used to derive nutrient and food intake at baseline. Diet quality and adherence were assessed by scores on the alternate Mediterranean Diet (aMED), a 9-category measure of adherence to a Mediterranean dietary pattern; the Healthy Eating Index 2010 (HEI-2010), a 100-point measure of 12 food components; the 11-item Alternate Healthy Eating Index 2010 (AHEI-2010); or the 8-component Dietary Approaches to Stop Hypertension (DASH) diet score. MAIN OUTCOMES AND MEASURES Outcome measures included incident total and hip fractures. Hazard ratios (HRs) by quintiles of dietary index scores were estimated using Cox proportional hazards regression analyses. RESULTS Of the 93 676 participants, 90 014 were included in the analysis (mean [SD] age, 63.6 [7.4]) years. During a median follow-up time of 15.9 years, there were 2121 cases of hip fractures and 28 718 cases of total fractures. Women scoring in the highest quintile (Q5) of the aMED index had a lower risk for hip fractures (HR, 0.80; 95% CI, 0.66-0.97), with an absolute risk reduction of 0.29% and a number needed to treat of 342 (95% CI, 249-502). No association between the aMED score and total fractures was observed (Q5 HR, 1.01; 95% CI, 0.95-1.07). Higher HEI-2010 or DASH scores tended to be inversely related to hip fracture risk, but the results were nonsignificant (Q5 HR, 0.87; 95% CI, 0.75-1.02; and Q5 HR, 0.89; 95% CI, 0.75-1.06, respectively). The AHEI-2010 score was associated with neither hip nor total fractures. CONCLUSIONS AND RELEVANCE Higher adherence to a Mediterranean diet is associated with a lower risk for hip fractures. These results support that a healthy dietary pattern may play a role in maintaining bone health in postmenopausal women.

Dietary and other risk factors in women having fibrocystic breast conditions with and without concurrent breast cancer: A nested case‐control study in Shanghai, China

Risk of breast cancer is increased in women with proliferative benign breast conditions. Most of these conditions, however, do not progress to breast cancer. The purpose of our study was to identify factors possibly associated with this progression. Women with proliferative fibrocystic breast conditions alone (214), and women with proliferative fibrocystic breast conditions and concurrent breast cancer (130), were compared to each other, and each of these groups of women were also compared to 1,070 controls; and 176 women with non‐proliferative benign breast conditions alone, and 155 also with breast cancer, were similarly compared. All study subjects were selected from a cohort of women enrolled in a trial of breast self‐examination in Shanghai. Women were interviewed to ascertain information on suspected risk factors for breast cancer and dietary habits. Conditional logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI). Increased risks of both proliferative fibrocystic breast conditions alone, and with breast cancer, were associated with low parity, a prior benign breast lump and breast cancer in a first‐degree relative. Decreasing trends in the risk of both conditions with increasing intake of fruits and vegetables were observed. No factors were significantly associated with risk of breast cancer relative to risk of proliferative changes. Similar, but in some instances weaker, associations were observed for non‐proliferative fibrocystic conditions with and without breast cancer. The possible risk or protective factors that were observed in our study most likely alter the risk of breast cancer at an early stage in the carcinogenic process, and probably do not alter risk of progression from proliferative fibrocystic breast conditions to breast cancer.

Prospective analysis of association between statin use and breast cancer risk in the women's health initiative.

Background: Statins are a class of cholesterol-lowering drugs that affect many intracellular pathways that may have implications for chemoprevention against cancer. Epidemiologic data on statins and breast cancer are conflicting. We analyzed updated data from the Womens Health Initiative (WHI) to assess the relationship between statins and breast cancer risk. Methods: The population included 154,587 postmenopausal women ages 50 to 79 years, with 7,430 pathologically confirmed cases of breast cancer identified over an average of 10.8 (SD, 3.3) years. Information on statins was collected at baseline and years one, three, six, and nine. Self- and interviewer-administered questionnaires were used to collect information on risk factors. Cox proportional hazards regression was used to calculate HRs with 95% confidence intervals (CI) to evaluate the relationship between statin use and cancer risk. Statistical tests were two-sided. Results: Statins were used by 11,584 (7.5%) women at baseline. The annualized rate of breast cancer was 0.42% among statin users and 0.42% among nonusers. The multivariable adjusted HR of breast cancer for users versus nonusers was 0.94 (95% CI, 0.83–1.06). In the multivariable-adjusted, time-dependent model, the HR for simvastatin was 0.87 (95% CI, 0.71–1.07). There was no significant trend by overall duration of use (P value for trend 0.68). There was no effect of tumor stage, grade, or hormone receptor status. Conclusion: Overall, statins were not associated with breast cancer risk. Impact: Our study is one of the largest prospective observational studies on this topic, and substantially adds to the literature suggesting no relationship between statins and breast cancer risk. Cancer Epidemiol Biomarkers Prev; 22(10); 1868–76. ©2013 AACR.

Shared Molecular Pathways and Gene Networks for Cardiovascular Disease and Type 2 Diabetes Mellitus in Women Across Diverse Ethnicities

Background—Although cardiovascular disease (CVD) and type 2 diabetes mellitus (T2D) share many common risk factors, potential molecular mechanisms that may also be shared for these 2 disorders remain unknown. Methods and Results—Using an integrative pathway and network analysis, we performed genome-wide association studies in 8155 blacks, 3494 Hispanic American, and 3697 Caucasian American women who participated in the national Women’s Health Initiative single-nucleotide polymorphism (SNP) Health Association Resource and the Genomics and Randomized Trials Network. Eight top pathways and gene networks related to cardiomyopathy, calcium signaling, axon guidance, cell adhesion, and extracellular matrix seemed to be commonly shared between CVD and T2D across all 3 ethnic groups. We also identified ethnicity-specific pathways, such as cell cycle (specific for Hispanic American and Caucasian American) and tight junction (CVD and combined CVD and T2D in Hispanic American). In network analysis of gene–gene or protein–protein interactions, we identified key drivers that included COL1A1, COL3A1, and ELN in the shared pathways for both CVD and T2D. These key driver genes were cross-validated in multiple mouse models of diabetes mellitus and atherosclerosis. Conclusions—Our integrative analysis of American women of 3 ethnicities identified multiple shared biological pathways and key regulatory genes for the development of CVD and T2D. These prospective findings also support the notion that ethnicity-specific susceptibility genes and process are involved in the pathogenesis of CVD and T2D.

Hypertension, Dietary Sodium, and Cognitive Decline: Results From the Women’s Health Initiative Memory Study

BACKGROUND To investigate the relationships of hypertension, antihypertensive treatment, and sodium intake on cognitive decline in older women. METHODS Prospective follow-up of 6,426 cognitively intact women aged 65-79 years enrolled in the Womens Health Initiative Memory Study (WHIMS) with a median follow-up of 9.1 years. Dietary sodium intake was determined by food frequency questionnaires. Hypertension was defined as self-report of current drug therapy for hypertension. Blood pressure (BP) control was assessed by treatment for hypertension and clinic measurement of systolic BP ≥ 140 mm Hg or diastolic BP ≥ 90 mm Hg at baseline. Cognitive functioning was assessed annually by global cognitive screening, neurocognitive, and neuropsychiatric evaluations. Cognitive decline was identified by the incidence of mild cognitive impairment (MCI) or probable dementia (PD). Cox proportional hazards analyses were used to calculate hazard ratios (HRs). RESULTS Hypertension was associated with an increased risk for cognitive decline (HR 1.20; 95% confidence interval (CI) 1.04, 1.39; P = 0.02). Among women with antihypertensive medication, those with BP ≥140/90 mm Hg (uncontrolled BP) were at highest risk for developing cognitive decline (HR 1.30; 95% CI 1.05, 1.60) compared to women without treatment and BP <140/90mm Hg (controlled BP). Sodium intake >1,500 mg/day did not alter the risk for cognitive decline in hypertensive women or women with antihypertensive treatment (P for interaction = 0.96 or 0.97). CONCLUSIONS Women with antihypertensive treatment and uncontrolled BP showed highest risk estimates for developing cognitive decline compared to non-hypertensive women. Sodium intake did not modify the risk for cognitive decline in women with hypertension or receiving antihypertensive medication. CLINICAL TRIAL REGISTRATION http://www.clinicaltrials.gov. Unique identifier: NCT00685009 and NCT00745056.

Fruit and Vegetable Intakes Are Associated with Lower Risk of Breast Fibroadenomas in Chinese Women

Fibroadenomas are common benign breast conditions among women and account for approximately 50% of breast biopsies performed. Dietary factors are known to influence benign breast conditions in the aggregate, but little is known of their association specifically with fibroadenoma. Our objective in this study was to evaluate the association between dietary and other factors and fibroadenoma risk. A case-control study, nested in a randomized trial of breast self-examination (BSE) in Chinese textile workers in Shanghai, China, was conducted between 1989 and 2000. The study sample included 327 affected women and 1070 controls. Women were administered a FFQ and a questionnaire that elicited reproductive and gynecological history and other information. Odds ratios, as estimates of relative risks, were calculated using multivariate conditional logistic regression. Significant decreasing trends in risk of fibroadenoma were observed with intake of fruits and vegetables and with number of live births, and a reduced risk was also associated with natural menopause, oral contraceptive use, and moderate exercise (walking and gardening). Increased risk of fibroadenoma was associated with heavy physical activity in ones 20s, breast cancer in a first-degree relative, and a history of prior benign breast lumps; and significant increasing trends in risk were observed with numbers of BSE per year and years of education. In conclusion, a diet rich in fruits and vegetables and the use of oral contraceptives may reduce risk of fibroadenoma.