MaryFran Sowers

The Obese Without Cardiometabolic Risk Factor Clustering and the Normal Weight With Cardiometabolic Risk Factor Clustering Prevalence and Correlates of 2 Phenotypes Among the US Population (NHANES 1999-2004)

BACKGROUND The prevalence and correlates of obese individuals who are resistant to the development of the adiposity-associated cardiometabolic abnormalities and normal-weight individuals who display cardiometabolic risk factor clustering are not well known. METHODS The prevalence and correlates of combined body mass index (normal weight, < 25.0; overweight, 25.0-29.9; and obese, > or = 30.0 [calculated as weight in kilograms divided by height in meters squared]) and cardiometabolic groups (metabolically healthy, 0 or 1 cardiometabolic abnormalities; and metabolically abnormal, > or = 2 cardiometabolic abnormalities) were assessed in a cross-sectional sample of 5440 participants of the National Health and Nutrition Examination Surveys 1999-2004. Cardiometabolic abnormalities included elevated blood pressure; elevated levels of triglycerides, fasting plasma glucose, and C-reactive protein; elevated homeostasis model assessment of insulin resistance value; and low high-density lipoprotein cholesterol level. RESULTS Among US adults 20 years and older, 23.5% (approximately 16.3 million adults) of normal-weight adults were metabolically abnormal, whereas 51.3% (approximately 35.9 million adults) of overweight adults and 31.7% (approximately 19.5 million adults) of obese adults were metabolically healthy. The independent correlates of clustering of cardiometabolic abnormalities among normal-weight individuals were older age, lower physical activity levels, and larger waist circumference. The independent correlates of 0 or 1 cardiometabolic abnormalities among overweight and obese individuals were younger age, non-Hispanic black race/ethnicity, higher physical activity levels, and smaller waist circumference. CONCLUSIONS Among US adults, there is a high prevalence of clustering of cardiometabolic abnormalities among normal-weight individuals and a high prevalence of overweight and obese individuals who are metabolically healthy. Further study into the physiologic mechanisms underlying these different phenotypes and their impact on health is needed.

Semiparametric Stochastic Mixed Models for Longitudinal Data

Abstract We consider inference for a semiparametric stochastic mixed model for longitudinal data. This model uses parametric fixed effects to represent the covariate effects and an arbitrary smooth function to model the time effect and accounts for the within-subject correlation using random effects and a stationary or nonstationary stochastic process. We derive maximum penalized likelihood estimators of the regression coefficients and the nonparametric function. The resulting estimator of the nonparametric function is a smoothing spline. We propose and compare frequentist inference and Bayesian inference on these model components. We use restricted maximum likelihood to estimate the smoothing parameter and the variance components simultaneously. We show that estimation of all model components of interest can proceed by fitting a modified linear mixed model. We illustrate the proposed method by analyzing a hormone dataset and evaluate its performance through simulations.

Bone Mineral Density and Its Change in White Women: Estrogen and Vitamin D Receptor Genotypes and Their Interaction

Low bone mineral density (BMD) is a major risk factor for development of osteoporosis; increasing evidence suggests that attainment and maintenance of peak bone mass as well as bone turnover and bone loss have strong genetic determinants. We examined the association of BMD levels and their change over a 3‐year period, and polymorphisms of the estrogen receptor (ER), vitamin D receptor (VDR), type I collagen, osteonectin, osteopontin, and osteocalcin genes in pre‐ and perimenopausal women who were part of the Michigan Bone Health Study, a population‐based longitudinal study of BMD. Body composition measurements, reproductive hormone profiles, bone‐related serum protein measurements, and life‐style characteristics were also available on each woman. Based on evaluation of women, ER genotypes (identified by PvuII [n = 253] and XbaI [n = 248]) were significantly predictive of both lumbar spine (p < 0.05) and total body BMD level, but not their change over the 3‐year period examined. The VDR BsmI restriction fragment length polymorphism was not associated with baseline BMD, change in BMD over time, or any of the bone‐related serum and body composition measurements in the 372 women in whom it was evaluated. Likewise, none of the other polymorphic markers was associated with BMD measurements. However, we identified a significant gene × gene interaction effect (p < 0.05) for the VDR locus and PvuII (p < 0.005) and XbaI (p < 0.05) polymorphisms, which impacted BMD levels. Women who had the (−/−) PvuII ER and bb VDR genotype combination had a very high average BMD, while individuals with the (−/−) PvuII ER and BB VDR genotype had significantly lower BMD levels. This contrast was not explained by differences in serum levels of osteocalcin, parathyroid hormone, 1,25‐dihydroxyvitamin D, or 25‐dihydroxyvitamin D. These data suggest that genetic variation at the ER locus, singly and in relation to the vitamin D receptor gene, influences attainment and maintenance of peak bone mass in younger women, which in turn may render some individuals more susceptible to osteoporosis than others.

The evolving role of obesity in knee osteoarthritis

Purpose of reviewThe frequency of knee osteoarthritis continues to accelerate, likely because of the increasing proliferation of obesity, particularly in men and women 40–60 years of age at the leading edge of the ‘baby boom’ demographic expansion. The increasing pervasiveness of obesity and the growing appreciation of obesitys accompanying metabolic/inflammatory activities suggest rethinking the knee osteoarthritis paradigm. Recent findingsWhereas once knee osteoarthritis was considered a ‘wear-and-tear’ condition, it is now recognized that knee osteoarthritis exists in the highly metabolic and inflammatory environments of adiposity. Cytokines associated with adipose tissue, including leptin, adiponectin, and resistin, may influence osteoarthritis though direct joint degradation or control of local inflammatory processes. Further, pound-for-pound, not all obesity is equivalent for the development of knee osteoarthritis; development appears to be strongly related to the co-existence of disordered glucose and lipid metabolism. Additionally, obesity loads may be detected by mechanoreceptors on chondrocyte surfaces triggering intracellular signaling cascades of cytokines, growth factors, and metalloproteinases. SummaryThis review summarizes recent literature about obesity, knee osteoarthritis and joint pain. Consideration of adipocytokines, metabolic factors, and mechanical loading-metabolic factor interactions will help to broaden the thinking about targets for both prevention and intervention for knee osteoarthritis.

Longitudinal Change in Reproductive Hormones and Depressive Symptoms Across the Menopausal Transition: Results From the Study of Women’s Health Across the Nation (SWAN)

CONTEXT The contribution of reproductive hormones to mood has been the focus of considerable research. Results from clinical and epidemiological studies have been inconsistent. It remains unclear whether alterations in serum hormone levels across the menopausal transition are linked to depressive symptoms. OBJECTIVES To evaluate the relationship between serum hormone levels and high depressive symptoms and whether hormone levels or their change might explain the association of menopausal status with depressive symptoms previously reported in a national sample of midlife women. DESIGN A longitudinal, community-based, multisite study of menopause. Data were collected at baseline and annually from December 1995 to January 2008 on a range of factors. Early follicular phase serum samples were assayed for levels of estradiol, follicle-stimulating hormone, testosterone, and dehydroepiandrosterone sulfate. SETTING Seven communities nationwide. PARTICIPANTS A community-based sample of 3302 multiethnic women, aged 42 to 52 years, still menstruating and not using exogenous reproductive hormones. Main Outcome Measure Depressive symptoms assessed with the Center for Epidemiological Studies Depression Scale (CES-D). The primary outcome was a CES-D score of 16 or higher. RESULTS In multivariable random-effects logistic regression models, log-transformed testosterone level was significantly positively associated with higher odds of a CES-D score of 16 or higher (odds ratio = 1.15; 95% confidence interval, 1.01-1.31) across 8 years, and a larger increase in log-transformed testosterone from baseline to each annual visit was significantly associated with increased odds of a CES-D score of 16 or higher (odds ratio = 1.23; 95% confidence interval, 1.04-1.45). Less education, being Hispanic, and vasomotor symptoms, stressful life events, and low social support at each visit were each independently associated with a CES-D score of 16 or higher. No other hormones were associated with a CES-D score of 16 or higher. Being perimenopausal or postmenopausal compared with being premenopausal remained significantly associated with a CES-D score of 16 or higher in all analyses. CONCLUSIONS Higher testosterone levels may contribute to higher depressive symptoms during the menopausal transition. This association is independent of menopausal status, which remains an independent predictor of higher depressive symptoms.

Epidemiology of risk factors for osteoarthritis: systemic factors.

Osteoarthritis (OA) appears to be a mechanically driven but chemically mediated disease process in which there is attempted (or aberrant) repair. Well established risk factors for OA include aging, obesity, gender, and, in selected subgroups, congenital anomalies. This review addresses less well established risk factors for OA that can impact joints through their effect on systemic metabolism rather than their contribution to local joint geometry and structure. These systemic risk factors include obesity; bone and bone density; nutrients, particularly those that function as antioxidants; and genetic factors. There is great opportunity for new prevention and intervention strategies as we expand our understanding of the role of these systemic risk factors.

The associations of bone mineral density and bone turnover markers with osteoarthritis of the hand and knee in pre- and perimenopausal women

OBJECTIVE To determine whether Caucasian women ages 28-48 years with newly defined osteoarthritis (OA) would have greater bone mineral density (BMD) and less bone turnover over time than would women without OA. METHODS Data were derived from the longitudinal Michigan Bone Health Study. Period prevalence and 3-year incidence of OA were based on radiographs of the dominant hand and both knees, scored with the Kellgren/Lawrence (K/L) scale. OA scores were related to BMD, which was measured by dual-energy x-ray absorptiometry, and to serum osteocalcin levels, which were measured by radioimmunoassay. RESULTS The period prevalence of OA (K/L grade > or =2 in the knees or the dominant hand) was 15.3% (92 of 601), with 8.7% for the knees and 6.7% for the hand. The 3-year incidence of knee OA was 1.9% (9 of 482) and of hand OA was 3.3% (16 of 482). Women with incident knee OA had greater average BMD (z-scores 0.3-0.8 higher for the 3 BMD sites) than women without knee OA (P < 0.04 at the femoral neck). Women with incident knee OA had less change in their average BMD z-scores over the 3-year study period. Average BMD z-scores for women with prevalent knee OA were greater (0.4-0.7 higher) than for women without knee OA (P < 0.002 at all sites). There was no difference in average BMD z-scores or their change in women with and without hand OA. Average serum osteocalcin levels were lower in incident cases of hand OA (>60%; P = 0.02) or knee OA (20%; P not significant). The average change in absolute serum osteocalcin levels was not as great in women with incident hand OA or knee OA as in women without OA (P < 0.02 and P < 0.05, respectively). CONCLUSION Women with radiographically defined knee OA have greater BMD than do women without knee OA and are less likely to lose that higher level of BMD. There was less bone turnover among women with hand OA and/or knee OA. These findings suggest that bone-forming cells might show a differential response in OA of the hand and knee, and may suggest a different pathogenesis of hand OA and knee OA.

Ethnic Differences in C-Reactive Protein Concentrations

BACKGROUND Limited data exist regarding the ethnic differences in C-reactive protein (CRP) concentrations, an inflammatory marker associated with risk of cardiovascular disease (CVD). We hypothesized that known CVD risk factors, including anthropometric characteristics, would explain much of the observed ethnic variation in CRP. METHODS We performed a cross-sectional analysis of 3154 women, without known CVD and not receiving hormone therapy, enrolled in the Study of Womens Health Across the Nation (SWAN), a multiethnic prospective study of pre- and perimenopausal women. RESULTS The study population was 47.4% white, 27.7% African-American, 8.5% Hispanic, 7.7% Chinese, and 8.6% Japanese; mean age was 46.2 years. African-American women had the highest median CRP concentrations (3.2 mg/L), followed by Hispanic (2.3 mg/L), white (1.5 mg/L), Chinese (0.7 mg/L), and Japanese (0.5 mg/L) women (all pairwise P < 0.001 compared with white women). Body mass index (BMI) markedly attenuated the association between ethnicity and CRP. After adjusting for age, socioeconomic status, BMI, and other risk factors, African-American ethnicity was associated with CRP concentrations >3 mg/L (odds ratio 1.37, 95% CI 1.07-1.75), whereas Chinese and Japanese ethnicities were inversely related (0.58, 0.35-0.95, and 0.43, 0.26-0.72, respectively). CONCLUSIONS Modifiable risk factors, particularly BMI, account for much but not all of the ethnic differences in CRP concentrations. Further study is needed of these ethnic differences and their implications for the use of CRP in CVD risk prediction.

The association of endogenous hormone concentrations and bone mineral density measures in pre- and perimenopausal women of four ethnic groups: SWAN

Abstract We evaluated bone mineral density (BMD), hormone concentrations and menstrual cycle status to test the hypothesis that greater variations in reproductive hormones and menstrual bleeding patterns in mid-aged women might engender an environment permissive for less bone. We studied 2336 women, aged 42–52 years, from the Study of Womens Health Across the Nation (SWAN) who self-identified as African-American (28.2%), Caucasian (49.9%), Japanese (10.5%) or Chinese (11.4%). Outcome measures were lumbar spine, femoral neck and total hip BMD by dual-energy X-ray densitometry (DXA). Explanatory variables were estradiol, testosterone, sex hormone binding globulin (SHBG) and follicle stimulating hormone (FSH) from serum collected in the early follicular phase of the menstrual cycle or menstrual status [premenopausal (menses in the 3 months prior to study entry without change in regularity) or early perimenopause (menstrual bleeding in the 3 months prior to study entry but some change in the regularity of cycles)]. Total testosterone and estradiol concentrations were indexed to SHBG for the Free Androgen Index (FAI) and the Free Estradiol Index (FEI). Serum logFSH concentrations were inversely correlated with BMD (r = −10 for lumbar spine [95% confidence interval (CI): −0.13, −0.06] and r = −0.08 for femoral neck (95% CI: −0.11, −0.05). Lumbar spine BMD values were approximately 0.5% lower for each successive FSH quartile. There were no significant associations of BMD with serum estradiol, total testosterone, FEI or FAI, respectively, after adjusting for covariates. BMD tended to be lower (p values = 0.009 to 0.06, depending upon the skeletal site) in women classified as perimenopausal versus premenopausal, after adjusting for covariates. Serum FSH but not serum estradiol, testosterone or SHBG were significantly associated with BMD in a multiethnic population of women classified as pre- versus perimenopausal, supporting the hypothesis that alterations in hormone environment are associated with BMD differences prior to the final menstrual period.

Knee osteoarthritis in obese women with cardiometabolic clustering

OBJECTIVE To assess the role of obesity and metabolic dysfunctionality with knee osteoarthritis (OA), knee joint pain, and physical functioning performance, adjusted for joint space width (JSW) asymmetry. METHODS Knee OA was defined as a Kellgren/Lawrence score > or =2 on weight-bearing radiographs. Obesity was defined as a body mass index > or =30 kg/m2. Cardiometabolic clustering classification was based on having > or =2 of the following factors: low levels of high-density lipoprotein cholesterol; elevated levels of low-density lipoprotein cholesterol, triglycerides, blood pressure, C-reactive protein, waist:hip ratio, or glucose; or diabetes mellitus. The difference between lateral and medial knee JSW was used to determine joint space asymmetry. RESULTS In a sample of women (n = 482, mean age 47 years), prevalences of knee OA and persistent knee pain were 11% and 30%, respectively. The knee OA prevalence in nonobese women without cardiometabolic clustering was 4.7%, compared with 12.8% in obese women without cardiometabolic clustering and 23.2% in obese women with cardiometabolic clustering. Nonobese women without cardiometabolic clustering were less likely to perceive themselves as limited compared with women in all other obesity/cardiometabolic groups (P < 0.05). Similar associations were seen with knee pain and physical functioning measures. The inclusion of a joint space asymmetry measure was associated with knee OA but not with knee pain or physical functioning. CONCLUSION Knee OA was twice as frequent in obese women with cardiometabolic clustering compared with those without, even when considering age and joint asymmetry. Obesity/cardiometabolic clustering was also associated with persistent knee pain and impaired physical functioning.