A bone resorption marker as predictor of rate of change in femoral neck size and strength during the menopause transition.

We assessed whether a bone resorption marker, measured early in the menopause transition (MT), is associated with change in femoral neck size and strength during the MT. Higher levels of bone resorption were associated with slower increases in femoral neck size and faster decreases in femoral neck strength. PURPOSE: Composite indices of the femoral neck's ability to withstand compressive (compression strength index, CSI) and impact (impact strength index, ISI) forces integrate DXA-derived femoral neck width (FNW), bone mineral density (BMD), and body size. During the menopause transition (MT), FNW increases, and CSI and ISI decrease. This proof-of-concept study assessed whether a bone resorption marker, measured early in the MT, is associated with rates of change in FNW, CSI and ISI during the MT. METHODS: We used previously collected bone resorption marker (urine collagen type I N-telopeptide [U-NTX]) and femoral neck strength data from 696 participants from the Study of Women's Health Across the Nation (SWAN), a longitudinal study of the MT in a multi-ethnic cohort of community-dwelling women. RESULTS: Adjusted for MT stage (pre- vs. early perimenopause), age, body mass index (BMI), bone resorption marker collection time, and study site in multivariable linear regression, bone resorption in pre- and early perimenopause was not associated with transmenopausal decline rate in femoral neck BMD. However, each standard deviation (SD) increase in bone resorption level was associated with 0.2% per year slower increase in FNW (p = 0.03), and 0.3% per year faster declines in CSI (p = 0.02) and ISI (p = 0.01). When restricted to women in early perimenopause, the associations of bone resorption with change in FNW, CSI, and ISI were similar to those in the full sample. CONCLUSIONS: Measuring a bone resorption marker in pre- and early perimenopause may identify women who will experience the greatest loss in bone strength during the MT.

Predictors of Early and Late Mortality in Older Kidney Transplant Recipients.

BACKGROUND: Older kidney patients with chronic kidney disease benefit significantly from kidney transplantation. However, these older transplant recipients have greater mortality after transplantation than younger transplant recipients. Understanding the impact of comorbidities on post-transplant mortality can improve risk stratification and patient selection. METHODS: A single-center analysis of 3105 kidney transplant recipients was performed over a 12-year period. Comorbidities associated with death were evaluated in older and younger transplant recipients. RESULTS: The 2 most important factors associated with increased mortality in the first 100 days after transplant were recipient age ≥60 and receipt of deceased donor organs (adjusted odds ratios, 3.29 and 5.80, respectively), with no statistically significant impact of recipient comorbidities. In the later post-transplant period (after the first 100 days), recipient age ≥60 and receipt of deceased donor organs (adjusted hazard ratios [HR] of 2.14 and 2.29, respectively) remained predictors of mortality. We also found that donor age ≥60 and the recipient having cardiovascular disease and diabetes were independent predictors of increased mortality. There was a statistically significant interaction between diabetes and heart disease and recipient age ≥60, with a lesser impact on late mortality in older patients compared to younger patients. CONCLUSIONS: This analysis suggests that comorbidities have a larger impact later after transplantation, with less effect on older recipients. These observations suggest that certain comorbid conditions should be evaluated differently in older patients compared to younger ones.

Adult bone strength of children from single-parent families: the Midlife in the United States Study.

UNLABELLED: Bone health may be negatively impacted by childhood socio-environmental circumstances. We examined the independent associations of single-parent childhood and parental death or divorce in childhood with adult bone strength indices. Longer exposure to a single-parent household in childhood was associated with lower bone strength in adulthood. INTRODUCTION: Because peak bone mass is acquired during childhood, bone health may be negatively impacted by childhood socio-environmental disadvantage. The goal of this study was to determine whether being raised in a single-parent household is associated with lower bone strength in adulthood. METHODS: Using dual-energy X-ray absorptiometry data from 708 participants (mean age 57 years) in the Midlife in the United States Biomarker Project, we examined the independent associations of composite indices of femoral neck bone strength relative to load (in three failure modes: compression, bending, and impact) in adulthood with the experience of single-parent childhood and parental death or divorce in childhood. RESULTS: After adjustment for gender, race, menopause transition stage, age, and body mass index, each additional year of single-parent childhood was associated with 0.02 to 0.03 SD lower indices of adult femoral neck strength. In those with 9-16 years of single-parent childhood, the compression strength index was 0.41 SD lower, bending strength index was 0.31 SD lower, and impact strength index was 0.25 SD lower (all p values < 0.05). In contrast, parental death or divorce during childhood was not by itself independently associated with adult bone strength indices. The magnitudes of these associations were unaltered by additional adjustment for lifestyle factors and socioeconomic status in childhood and adulthood. CONCLUSIONS: Independent of parental death or divorce, growing up in a single-parent household is associated with lower femoral neck bone strength in adulthood, and this association is not entirely explained by childhood or adult socioeconomic conditions or lifestyle choices.

Socioeconomic status in relation to incident fracture risk in the Study of Women's Health Across the Nation.

UNLABELLED: We examined baseline and annual follow-up data (through annual follow-up visit 9) from a cohort of 2,234 women aged 42 to 52 years at baseline. Independent of financial status, higher educational level was associated with lower fracture incidence among non-Caucasian women but not among Caucasian women. INTRODUCTION: This study was conducted to determine the associations of education and income with fracture incidence among midlife women over 9 years of follow-up. METHODS: We examined baseline and annual follow-up data (through annual follow-up visit 9) from 2,234 participants of the Study of Women's Health Across the Nation, a cohort of women aged 42 to 52 years at baseline. We used Cox proportional hazards regression models to examine the associations of socioeconomic predictors (education, family-adjusted poverty-to-income ratio, and difficulty paying for basics) with time to first incident nontraumatic, nondigital, noncraniofacial fracture. RESULTS: Independent of family-adjusted poverty-to-income ratio, higher educational level was associated with decreased time to first incident fracture among non-Caucasian women but not among Caucasian women (p(interaction) 0.02). Compared with non-Caucasian women who completed no more than high school education, non-Caucasian women who attained at least some postgraduate education had 87% lower rates of incident nontraumatic fracture (adjusted hazard ratio 0.13, 95% confidence interval [CI] 0.03-0.60). Among non-Caucasian women, each additional year of education was associated with a 16% lower odds of nontraumatic fracture (adjusted odds ratio 0.84, 95% CI 0.73-0.97). Income, family-adjusted poverty-to-income ratio, and degree of difficulty paying for basic needs were not associated with time to first fracture in Caucasian or non-Caucasian women. CONCLUSIONS: Among non-Caucasian midlife women, higher education, but not higher income, was associated with lower fracture incidence. Elucidation of the mechanisms underlying the possible protective effects of higher educational level on nontraumatic fracture incidence may allow us to better target individuals at risk of future fracture.

Marital histories, marital support, and bone density: findings from the Midlife in the United States Study.

UNLABELLED: We examined the association between marital life history and bone mineral density (BMD) in a national sample from the US. In men, being stably married was independently associated with better lumbar spine BMD, and in women, more spousal support was associated with better lumbar spine BMD. INTRODUCTION: Adult bone mass may be influenced by stressors over the life course. We examined the association between marital life history and bone mineral density (BMD) net socioeconomic and behavioral factors known to influence bone mass. We sought evidence for a gender difference in the association between marital history and adult BMD. METHODS: We used data from 632 adult participants in the Midlife in the United States Study to examine associations between marital history and BMD, stratified by gender, and adjusted for age, weight, menopausal stage, medication use, childhood socioeconomic advantage, adult financial status, education, physical activity, smoking, and alcohol consumption. RESULTS: Compared to stably married men, men who were currently divorced, widowed, or separated, men who were currently married but previously divorced, widowed, or separated, and never married men had 0.33 (95% CI: 0.01, 0.65), 0.36 (95% CI: 0.10, 0.83), and 0.53 (95% CI: 0.23, 0.83) standard deviations lower lumbar spine BMD, respectively. Among men married at least once, every year decrement in age at first marriage (under age 25) was associated with 0.07 SD decrement in lumbar spine BMD (95% CI: 0.002, 0.13). In women, greater support from the spouse was associated with higher lumbar spine BMD. CONCLUSIONS: Our findings suggest that marriage before age 25 and marital disruptions are deleterious to bone health in men, and that marital quality is associated with better bone health in women.

Physical activity as determinant of femoral neck strength relative to load in adult women: findings from the hip strength across the menopause transition study.

UNLABELLED: Our objective was to examine associations of physical activity in different life domains with peak femoral neck strength relative to load in adult women. Greater physical activity in each of the domains of sport, active living, home, and work was associated with higher peak femoral neck strength relative to load. INTRODUCTION: Our objective was to examine the associations of physical activity in different life domains with peak femoral neck strength relative to load in adult women. Composite indices of femoral neck strength integrate body size with femoral neck size and bone mineral density to gauge bone strength relative to load during a fall, and are inversely associated with incident fracture risk. METHODS: Participants were 1,919 pre- and early perimenopausal women from the Study of Women's Health Across the Nation. Composite indices of femoral neck strength relative to load in three failure modes (compression, bending, and impact) were created from hip dual-energy X-ray absorption scans and body size. Usual physical activity within the past year was assessed with the Kaiser Physical Activity Survey in four domains: sport, home, active living, and work. We used multiple linear regression to examine the associations. RESULTS: Greater physical activity in each of the four domains was independently associated with higher composite indices, adjusted for age, menopausal transition stage, race/ethnicity, Study of Women's Health Across the Nation study site, smoking status, smoking pack-years, alcohol consumption level, current use of supplementary calcium, current use of supplementary vitamin D, current use of bone-adverse medications, prior use of any sex steroid hormone pills or patch, prior use of depo-provera injections, history of hyperthyroidism, history of previous adult fracture, and employment status: standardized effect sizes ranged from 0.04 (p < 0.05) to 0.20 (p < 0.0001). CONCLUSIONS: Physical activity in each domain examined was associated with higher peak femoral neck strength relative to load in pre- and early perimenopausal women.

Trajectories of femoral neck strength in relation to the final menstrual period in a multi-ethnic cohort.

UNLABELLED: The purpose of this study was to describe the evolution of femoral neck strength relative to load across the menopause transition. It declined significantly over the 10 years bracketing the final menstrual period, and the rate of decline was modified by body mass index, race/ethnicity, and smoking status. INTRODUCTION: Composite indices of femoral neck strength, which integrate dual energy X-ray absorptiometry (DXA)-derived bone mineral density and bone size with body size, are inversely associated with hip fracture risk. Our objective was to describe longitudinal trajectories of the strength indices across the menopausal transition. METHODS: Data came from the Study of Women's Health Across the Nation; participants were pre- or early peri-menopausal, ages 42-53 at baseline, and were followed up for 9.1 ± 1.8 years. Composite indices of femoral neck strength in different failure modes (compression, bending, and impact) were created in 921 women who had three or more hip DXA scans and had definable final menstrual period (FMP) dates. We used mixed effects models to fit piecewise linear growth curves to the baseline-normalized strength indices as a function of time to/after the FMP. RESULTS: Compression and impact strength indices did not decline until 1 year prior to the FMP, and declined rapidly thereafter, with some slowing of decline 1 year after the FMP. Bending strength index increased slightly until 2 years prior to the FMP, then plateaued, and began to decline at the FMP. Mean decline in strength indices over 10 years was 6.9 % (compression), 2.5 % (bending), and 6.8 % (impact). Women with higher body mass index had larger declines in two of the three indices. Other major modifiers of rates of decline were race/ethnicity and smoking status. CONCLUSIONS: Femoral neck strength relative to load declines significantly during the menopausal transition, with declines commencing 1 to 2 years prior to the FMP.

A comparison of DXA and CT based methods for estimating the strength of the femoral neck in post-menopausal women.

UNLABELLED: The study goal was to compare simple two-dimensional (2D) analyses of bone strength using dual energy x-ray absorptiometry (DXA) data to more sophisticated three-dimensional (3D) finite element analyses using quantitative computed tomography (QCT) data. DXA- and QCT-derived femoral neck geometry, simple strength indices, and strength estimates were well correlated. INTRODUCTION: Simple 2D analyses of bone strength can be done with DXA data and applied to large data sets. We compared 2D analyses to 3D finite element analyses (FEA) based on QCT data. METHODS: Two hundred thirteen women participating in the Study of Women's Health Across the Nation (SWAN) received hip DXA and QCT scans. DXA BMD and femoral neck diameter and axis length were used to estimate geometry for composite bending (BSI) and compressive strength (CSI) indices. These and comparable indices computed by Hip Structure Analysis (HSA) on the same DXA data were compared to indices using QCT geometry. Simple 2D engineering simulations of a fall impacting on the greater trochanter were generated using HSA and QCT femoral neck geometry; these estimates were benchmarked to a 3D FEA of fall impact. RESULTS: DXA-derived CSI and BSI computed from BMD and by HSA correlated well with each other (R=0.92 and 0.70) and with QCT-derived indices (R=0.83-0.85 and 0.65-0.72). The 2D strength estimate using HSA geometry correlated well with that from QCT (R=0.76) and with the 3D FEA estimate (R=0.56). CONCLUSIONS: Femoral neck geometry computed by HSA from DXA data corresponds well enough to that from QCT for an analysis of load stress in the larger SWAN data set. Geometry derived from BMD data performed nearly as well. Proximal femur breaking strength estimated from 2D DXA data is not as well correlated with that derived by a 3D FEA using QCT data.

Ethnic differences in composite indices of femoral neck strength.

UNLABELLED: Bone mineral density does not explain race/ethnicity differences in hip fracture risk. In this study, we demonstrated that race/ethnicity differences in composite hip strength indices were consistent with documented race/ethnicity differences in hip fracture risk, suggesting that unlike bone density, the composite indices may represent ethnicity-independent measures of bone strength. INTRODUCTION: African-American and Asian women have lower risks of hip fracture than Caucasian women, but such racial/ethnic variation in hip fracture risk cannot be explained by bone mineral density (BMD). The composite indices of femoral neck strength integrate femoral neck and body size with BMD and predict hip fracture risk in Caucasian women. We hypothesize that unlike race/ethnic differences in BMD, race/ethnic differences in the composite strength indices would be consistent with race/ethnic differences in hip fracture risk. METHODS: We studied a community-based sample of Caucasian (n = 968), African-American (n = 512), Chinese (n = 221), and Japanese (n = 239) women, premenopausal or in early perimenopause, from the Study of Women's Health Across the Nation. RESULTS: Unadjusted indices were similar in Caucasian and African-American women but higher in Asian women. After adjusting for age, body mass index, and menopause status, all three minority groups had higher composite strength indices than Caucasian women. Foreign-born Japanese women had higher unadjusted and adjusted composite strength indices than US-born Japanese women, but such differences by nativity were not observed in Chinese women. CONCLUSION: We concluded that composite strength indices have the potential to explain racial/ethnic differences in hip fracture risk, suggesting that composite strength indices may represent ethnicity-independent measures of bone strength. This contention needs to be verified by further research on the fracture predictive ability of composite strength indices in multi-ethnic longitudinal cohorts.

Socioeconomic status, race, and bone turnover in the Midlife in the US Study.

UNLABELLED: Among a group of 940 US adults, economic adversity and minority race status were associated with higher serum levels of markers of bone turnover. These results suggest that higher levels of social stress may increase bone turnover. INTRODUCTION: To determine socioeconomic status (SES) and race differences in levels of bone turnover. METHODS: Using data from the Biomarker Substudy of the Midlife in the US (MIDUS) study (491 men, 449 women), we examined cross-sectional associations of SES and race with serum levels of bone turnover markers (bone-specific alkaline phosphatase [BSAP], procollagen type I N-terminal propeptide [PINP], and N-telopeptide [Ntx]) separately in men and women. Linear multivariable regression was used to control for body weight, menopausal transition stage, and age. RESULTS: Among men, low family poverty-to-income ratio (FPIR) was associated with higher turnover, but neither education nor race was associated with turnover. Men with FPIR <3 had 1.808 nM BCE higher Ntx (P = 0.05), 3.366 U/L higher BSAP (P = 0.02), and 7.066 higher PINP (P = 0.02). Among women, neither education nor FPIR was associated with bone turnover, but Black women had 3.688 nM BCE higher Ntx (P = 0.001), 5.267 U/L higher BSAP (P = 0.005), and 11.906 µg/L higher PINP (P = 0.008) compared with non-Black women. CONCLUSIONS: Economic adversity was associated with higher bone turnover in men, and minority race status was associated with higher bone turnover in women, consistent with the hypothesis that higher levels of social stresses cause increased bone turnover. The magnitude of these associations was comparable to the effects of some osteoporosis medications on levels of turnover.

Do the effects of APOE-ε4 on cognitive function and decline depend upon vitamin status? MacArthur Studies of Successful Aging.

OBJECTIVES: To investigate whether gene nutrient interactions influence the risk of cognitive dysfunction among older persons. DESIGN: We performed a cross-sectional and longitudinal study of 499 adults aged 70-79 years from the Mac Arthur Study of Successful Aging to determine the effect of apolipoprotein E (APOE) in conjunction with plasma levels of homocysteine and of the related B vitamins on multiple domains of cognitive function and cognitive decline. RESULTS: The APOE-ε4 allele, high homocysteine, low folate, and low vitamin B6 levels were each associated with worse baseline cognitive function, and all but B6 and B12 were associated with seven year cognitive decline. There was no interaction between APOE-ε4, and homocysteine, folate, B6, or B12 in predicting baseline cognitive function (p-values: 0.12-0.94) or longitudinal decline (p-values: 0.52-0.91). Of five cognitive subtests, there was a significant interaction between the ε4 allele, low B6, and decline in correct naming response items (p=0.04). CONCLUSION: B vitamin status does not influence the risk of overall cognitive dysfunction in ε4 allele affected older adults.

The reliability and validity of three non-radiological measures of thoracic kyphosis and their relations to the standing radiological Cobb angle.

UNLABELLED: Hyperkyphosis is implicated in a mounting list of negative outcomes, including higher mortality. Hyperkyphosis research is hindered due to difficulties inherent in its measurement. By showing that three clinical measures of kyphosis are suitable for use in large scale, longitudinal, hyperkyphosis studies, we will facilitate much needed research in this field. INTRODUCTION: The objective of this study is to describe the reliability of three non-radiological kyphosis measures (Debrunner kyphosis angle, flexicurve kyphosis index, and flexicurve kyphosis angle) and their validity compared to the Cobb angle and to approximate a Cobb angle from non-radiological kyphosis measures. METHODS: We analyzed data from 113 participants aged ≥ 60 years with kyphosis angle ≥ 40°. Cobb angle was measured on a standing lateral thoracolumbar radiograph using bounds at T4 and T12. Non-radiological measures of kyphosis were made three times by a single rater and a 4th time by a blinded second rater. RESULTS: Intra- and inter-rater reliabilities for non-radiological assessments were high (intra-class correlations of 0.96 to 0.98) and did not differ from each other. Pearson correlations, estimating validity, ranged from 0.62 to 0.69 and did not differ. The Debrunner angle was close to the Cobb angle, with scaling factor of 1.067 and an offset of 5°. The Flexicurve kyphosis angle had to be scaled by 1.53 to obtain the equivalent Cobb angle. The scaling factor for the Flexicurve kyphosis index to Cobb angle was 315, with an offset of 5°. Compared to the measured Cobb angle, Cobb angles predicted using the non-radiological measures had similar magnitude errors (standard deviations of the differences ranging between 10.24 and 11.26). CONCLUSIONS: Each non-radiological measurement had similar reliability and validity. Low cost, ease of use, and robustness to variations in spine contour argue for the Flexicurve in longitudinal kyphosis assessments. The approximate conversion factors provided will permit translation of non-radiological measures to Cobb angles.

Effects of the menopause transition and hormone use on cognitive performance in midlife women.

BACKGROUND: There is almost no longitudinal information about measured cognitive performance during the menopause transition (MT). METHODS: We studied 2,362 participants from the Study of Women's Health Across the Nation for 4 years. Major exposures were time spent in MT stages, hormone use prior to the final menstrual period, and postmenopausal current hormone use. Outcomes were longitudinal performance in three domains: processing speed (Symbol Digit Modalities Test [SDMT]), verbal memory (East Boston Memory Test [EBMT]), and working memory (Digit Span Backward). RESULTS: Premenopausal, early perimenopausal, and postmenopausal women scored higher with repeated SDMT administration (p < or = 0.0008), but scores of late perimenopausal women did not improve over time (p = 0.2). EBMT delayed recall scores climbed during premenopause and postmenopause (p < or = 0.01), but did not increase during early or late perimenopause (p > or = 0.14). Initial SDMT, EBMT-immediate, and EBMT-delayed tests were 4%-6% higher among prior hormone users (p < or = 0.001). On the SDMT and EBMT, compared to the premenopausal referent, postmenopausal current hormone users demonstrated poorer cognitive performance (p < or = 0.05) but performance of postmenopausal nonhormone users was indistinguishable from that of premenopausal women. CONCLUSIONS: Consistent with transitioning women's perceived memory difficulties, perimenopause was associated with a decrement in cognitive performance, characterized by women not being able to learn as well as they had during premenopause. Improvement rebounded to premenopausal levels in postmenopause, suggesting that menopause transition-related cognitive difficulties may be time-limited. Hormone initiation prior to the final menstrual period had a beneficial effect whereas initiation after the final menstrual period had a detrimental effect on cognitive performance.

Hip axis length variation: its correlation with anthropometric measurements in women from three ethnic groups.

UNLABELLED: We compared hip axis length (HAL) in 157 non-Hispanic white women, 292 African-American women, and 210 Mexican-American women. After adjusting for maximal hip girth, there were no residual differences in HAL by ethnicity. Differences in hip fracture risk seen between these groups cannot be explained by ethnic differences in HAL. INTRODUCTION: Hip axis length (HAL) has been reported to be an independent predictor of hip fracture. Significant ethnic differences in HAL have been noted, but no direct comparison has been made between African-American, Mexican-American, and non-Hispanic white women using the same protocol. METHODS: We compared 157 non-Hispanic white women from the Rancho Bernardo Study, 292 women from the Health Assessment Study of African-American Women, and 210 women from the Skeletal Health of Mexican-American Women Project. A standardized questionnaire was used to obtain medical history; height, weight, waist girth, and hip girth were measured; and percentage body fat and HAL were obtained using dual energy X-ray absorptiometry. All HAL comparisons were adjusted for maximum hip girth to control for differences in size magnification by fan-beam absorptiometry. RESULTS: Though there were ethnic differences in the unadjusted HAL measurement, after adjusting for hip circumference, there were no residual differences in HAL with regard to ethnicity: 10.7 cm in Mexican-American women vs. 10.8 in non-Hispanic white women and African-American women (p = 0.61). CONCLUSIONS: There were no ethnic differences in HAL in women from the three ethnic groups. Differences in fracture risk among these groups cannot be explained by ethnic differences in HAL.

Kinetic evaluation of [11C]dihydrotetrabenazine by dynamic PET: measurement of vesicular monoamine transporter.

(+)-alpha-[11C]Dihydrotetrabenazine (DTBZ) binds to the vesicular monoamine transporter (VMAT2) located in presynaptic vesicles. The purpose of this work was to evaluate various model configurations for analysis of [11C]DTBZ with the aim of providing the optimal measure of monoamine vesicular transporter density obtainable from a single dynamic PET study. PET studies on seven young normal volunteer subjects, ages 20-35, were performed following i.v. injection of 666 +/- 37 MBq (18 +/- 1 mCi) of (+)-alpha-[11C]DTBZ. Dynamic acquisition consisted of a 15-frame sequence over 1 h. Analysis methods included both creation of pixel-by-pixel functional images of transport (K1) and binding (DVtot) and nonlinear least-squares analysis of volume-of-interest data. Pixel-by-pixel calculations were performed for both two-compartment weighted integral calculations and slope-intercept estimations from Logan plots. Nonlinear least-squares analysis was performed applying model configurations with both two-compartments, estimating K1 and DVtot and three compartments, estimating K1-k4. For the more complex configuration, we examined the stability of various binding-related parameters including k3 (konBmax'), k3/k4 (Bmax'/Kd), DVsp[(K1/k2)(k3/k4)], and DVtot [K1/k2(1 + k3/k4)]. The three-compartment model provided significantly improved goodness-of-fit compared to the two-compartment model, yet did not increase the uncertainty in the estimate of the DVtot. Without constraining parameters in the three-compartment model fits, DVtot was found to provide a more stable estimate of binding density than either k3, k3/k4, or DVsp. The two-compartment least-squares analysis yielded approximately 10% underestimations of the total distribution. However, this bias was found to be very consistent from region to region as well as across subjects as indicated by the correlation between two- and three-compartment DVtot estimates of 0.997. We conclude that (+)-alpha-[11C]DTBZ and PET can provide excellent measures of VMAT2 density in the human brain.