Search

UNLABELLED: Hip fracture risk assessment is an important but challenging task. Quantitative CT-based patient-specific finite element (FE) analysis (FEA) incorporates bone geometry and bone density in the proximal femur. We developed a global FEA-computed fracture risk index to increase the prediction accuracy of hip fracture incidence. PURPOSE: Quantitative CT-based patient-specific finite element (FE) analysis (FEA) incorporates bone geometry and bone density in the proximal femur to compute the force (fracture load) and energy necessary to break the proximal femur in a particular loading condition. The fracture loads and energies-to-failure are individually associated with incident hip fracture, and provide different structural information about the proximal femur. METHODS: We used principal component analysis (PCA) to develop a global FEA-computed fracture risk index that incorporates the FEA-computed yield and ultimate failure loads and energies-to-failure in four loading conditions of 110 hip fracture subjects and 235 age- and sex-matched control subjects from the AGES-Reykjavik study. Using a logistic regression model, we compared the prediction performance for hip fracture based on the stratified resampling. RESULTS: We referred the first principal component (PC1) of the FE parameters as the global FEA-computed fracture risk index, which was the significant predictor of hip fracture (p-value

PurposePatients with non-Hodgkin lymphoma (NHL) have a median age of 67, with 70% surviving over 5 years. Chemotherapy for aggressive NHL includes cyclophosphamide, anthracycline, and high doses of corticosteroids, which can impair bone health. By reviewing clinical characteristics and standard-of-care CT scans, we evaluate the prevalence and incidence of fractures and the clinical correlates of fractures in patients treated for aggressive B-cell NHL.MethodsWe retrospectively reviewed patients seen at the University of California San Francisco lymphoma clinic from January 1, 2016, to March 31, 2017 who had (1) aggressive B-cell NHL, (2) received first-line therapy with R-CHOP-like regimens, and had (3) CT scans pre- and post-treatment available for review. Associations between clinical variables and vertebral, rib, and pelvic fracture outcomes were assessed, and multivariate logistic regression models were used to identify predictors of prevalent and incident fractures.ResultsWe identified 162 patients who met the inclusion criteria. Median age at diagnosis was 60 years. Of the 162 patients, 38 patients (28%) had prevalent fractures prior to receiving chemotherapy. Within 1 year after treatment, 16 patients (10%) developed new fractures. Having a prevalent fracture strongly predicted developing a new fracture after treatment, with incident fractures occurring in 12 of 38 patients with prevalent fractures versus 4 of 124 without prevalent fractures (odds ratio 10.45, p

ObjectiveThis study aimed to investigate how skeletal muscle attenuation and adipose tissue (AT) attenuation of the quadriceps, hamstrings, paraspinal muscle groups and the psoas muscle vary according to the targeted muscles, sex, and age.DesignPopulation-based cross-sectional study.SettingCommunity-dwelling old population in Reykjavik, Iceland.SubjectsA total of 5331 older adults (42.8% women), aged 66-96 years from the Age, Gene/Environment Susceptibility (AGES)- Reykjavik Study, who participated in the baseline visit (between 2002 and 2006) and had valid thigh and abdominal computed tomography (CT) scans were studied.MethodsMuscle attenuation and AT attenuation of the quadriceps, hamstrings, paraspinal muscle groups and the psoas muscle were determined using CT. Linear mixed model analysis of variance was performed for each sex, with skeletal muscle or AT attenuation as the dependent variable.ResultsMuscle attenuation decreased, and AT attenuation increased with age in both sexes, and these differences were specific for each muscle, although not in all age groups. Age-related differences in muscle and AT attenuation varied with specific muscle. In general, for both sexes, skeletal muscle attenuation of the hamstrings declined more than average with age. Men and women displayed a different pattern in the age differences in AT attenuation for each muscle.ConclusionsOur data support the hypotheses that skeletal muscle attenuation decreases, and AT attenuation increases with aging. In addition, our data add new evidence, supporting that age-related differences in skeletal muscle and AT attenuation vary between muscles.

Theoretically, panic disorder and agoraphobia pathology can be conceptualized as a cascade of dynamically changing defensive responses to threat cues from inside the body. Guided by this trans-diagnostic model we tested the interaction between defensive activation and vagal control as a marker of prefrontal inhibition of subcortical defensive activation. We investigated ultra-short-term changes of vagally controlled high frequency heart rate variability (HRV) during a standardized threat challenge (entrapment) in n = 232 patients with panic disorder and agoraphobia, and its interaction with various indices of defensive activation. We found a strong inverse relationship between HRV and heart rate during threat, which was stronger at the beginning of exposure. Patients with a strong increase in heart rate showed a deactivation of prefrontal vagal control while patients showing less heart rate acceleration showed an increase in vagal control. Moreover, vagal control collapsed in case of imminent threat, i.e., when body symptoms increase and seem to get out of control. In these cases of defensive action patients either fled from the situation or experienced a panic attack. Active avoidance, panic attacks, and increased sympathetic arousal are associated with an inability to maintain vagal control over the heart suggesting that teaching such regulation strategies during exposure treatment might be helpful to keep prefrontal control, particularly during the transition zone from post-encounter to circa strike defense.Trial Registration Number: ISRCTN80046034.

INTRODUCTION: In addition to well-established links with cardiovascular and respiratory diseases, cigarette smoking may affect skeletal muscle; however, associations with quadriceps atrophy, density, and function are unknown. This study explored the associations of current and former smoking with quadriceps muscle area and attenuation as well as muscle force (assessed as knee extension peak torque) and rate of torque development-a measure of muscle power in older adults. METHODS: Data from 4469 older adults, aged 66-95 years at baseline in the Age, Gene/Environment Susceptibility-Reykjavik Study with measurements of thigh computed tomography, isometric knee extension testing, self-reported smoking history, and potential covariates were analyzed. RESULTS: Sex differences were observed in these data; therefore, our final analyses are stratified by sex. In men, both former smokers and current smokers had lower muscle area (with β= -0.10, 95% confidence interval [CI] = -0.17 to -0.03 and β = -0.19, 95% CI = -0.33 to -0.05, respectively) and lower muscle attenuation (ie, higher fat infiltration, β = -0.08, 95% CI = -0.16 to -0.01 and β = -0.17, 95% CI = -0.34 to -0.01, respectively) when compared with never smokers. Smoking status was not associated with male peak torque or rate of torque development. In women, current smoking was associated with lower muscle attenuation (β = -0.24, 95% CI = -0.34 to -0.13) compared to never smoking. Among female smokers (current and former), muscle attenuation and peak torque were lower with increasing pack-years. CONCLUSIONS: Results suggest that cigarette smoking is related to multiple muscle properties at older age and that these relationships may be different among men and women. IMPLICATIONS: This article presents novel data, as it examined for the first time the relationship between smoking and computed tomography-derived quadriceps muscle size (cross-sectional area) and attenuation. This study suggests that current cigarette smoking is related to higher muscle fat infiltration, which may have significant health implications for the older population, because of its known association with poor physical function, falls, and hip fractures.

IntroductionIn addition to well-established links with cardiovascular and respiratory diseases, cigarette smoking may affect skeletal muscle; however, associations with quadriceps atrophy, density, and function are unknown. This study explored the associations of current and former smoking with quadriceps muscle area and attenuation as well as muscle force (assessed as knee extension peak torque) and rate of torque development-a measure of muscle power in older adults.MethodsData from 4469 older adults, aged 66-95 years at baseline in the Age, Gene/Environment Susceptibility-Reykjavik Study with measurements of thigh computed tomography, isometric knee extension testing, self-reported smoking history, and potential covariates were analyzed.ResultsSex differences were observed in these data; therefore, our final analyses are stratified by sex. In men, both former smokers and current smokers had lower muscle area (with β= -0.10, 95% confidence interval [CI] = -0.17 to -0.03 and β = -0.19, 95% CI = -0.33 to -0.05, respectively) and lower muscle attenuation (ie, higher fat infiltration, β = -0.08, 95% CI = -0.16 to -0.01 and β = -0.17, 95% CI = -0.34 to -0.01, respectively) when compared with never smokers. Smoking status was not associated with male peak torque or rate of torque development. In women, current smoking was associated with lower muscle attenuation (β = -0.24, 95% CI = -0.34 to -0.13) compared to never smoking. Among female smokers (current and former), muscle attenuation and peak torque were lower with increasing pack-years.ConclusionsResults suggest that cigarette smoking is related to multiple muscle properties at older age and that these relationships may be different among men and women.ImplicationsThis article presents novel data, as it examined for the first time the relationship between smoking and computed tomography-derived quadriceps muscle size (cross-sectional area) and attenuation. This study suggests that current cigarette smoking is related to higher muscle fat infiltration, which may have significant health implications for the older population, because of its known association with poor physical function, falls, and hip fractures.

Physical activity (PA) enhances proximal femur bone mass, as assessed using projectional imaging techniques. However, these techniques average data over large volumes, obscuring spatially heterogeneous adaptations. The current study used quantitative computed tomography, statistical parameter mapping, and subject-specific finite element (FE) modeling to explore spatial adaptation of the proximal femur to PA. In particular, we were interested in adaptation occurring at the superior femoral neck and improving strength under loading from a fall onto the greater trochanter. High/long jump athletes (n = 16) and baseball pitchers (n = 16) were utilized as within-subject controlled models as they preferentially load their take-off leg and leg contralateral to their throwing arm, respectively. Controls (n = 15) were included but did not show any dominant-to-nondominant (D-to-ND) leg differences. Jumping athletes showed some D-to-ND leg differences but less than pitchers. Pitchers had 5.8% (95% confidence interval [CI] 3.9%-7.6%) D-to-ND leg differences in total hip volumetric bone mineral density (vBMD), with increased vBMD in the cortical compartment of the femoral neck and trochanteric cortical and trabecular compartments. Voxel-based morphometry analyses and cortical bone mapping showed pitchers had D-to-ND leg differences within the regions of the primary compressive trabeculae, inferior femoral neck, and greater trochanter but not the superior femoral neck. FE modeling revealed pitchers had 4.1% (95% CI 1.4%-6.7%) D-to-ND leg differences in ultimate strength under single-leg stance loading but no differences in ultimate strength to a fall onto the greater trochanter. These data indicate the asymmetrical loading associated with baseball pitching induces proximal femur adaptation in regions associated with weight bearing and muscle contractile forces and increases strength under single-leg stance loading. However, there were no benefits evident at the superior femoral neck and no measurable improvement in ultimate strength to common injurious loading during aging (ie, fall onto the greater trochanter), raising questions as to how to better target these variables with PA. © 2019 American Society for Bone and Mineral Research.

Bone marrow adiposity (BMA) is associated with aging and osteoporosis, but whether BMA can predict bone loss and fractures remains unknown. Using data from the Age Gene/Environment Susceptibility (AGES)-Reykjavik study, we investigated the associations between 1 H-MRS-based measures of vertebral bone marrow adipose tissue (BMAT), annualized change in bone density/strength by quantitative computed tomography (QCT) and DXA, and secondarily, with incident clinical fractures and radiographic vertebral fractures among older adults. The associations between BMAT and annualized change in bone density/strength were evaluated using linear regression models, adjusted for age, body mass index (BMI), diabetes, estradiol, and testosterone. Cox proportional hazards models were used to evaluate the associations between baseline BMAT and incident clinical fractures, and logistic regression models for incident vertebral fractures. At baseline, mean ± SD age was 80.9 ± 4.2 and 82.6 ± 4.2 years in women (n = 148) and men (n = 150), respectively. Mean baseline BMAT was 55.4% ± 8.1% in women and 54.1% ± 8.2% in men. Incident clinical fractures occurred in 7.4% of women over 2.8 years and in 6.0% of men over 2.2 years. Incident vertebral fractures occurred in 12% of women over 3.3 years and in 17% of men over 2.7 years. Each 1 SD increase in baseline BMAT was associated with a 3.9 mg2 /cm4 /year greater loss of spine compressive strength index (p value = .003), a 0.9 mg/cm3 /year greater loss of spine trabecular BMD (p value = .02), and a 1.2 mg/cm3 /year greater loss of femoral neck trabecular BMD (p value = .02) in women. Among men, there were no associations between BMAT and changes in bone density/strength. There were no associations between BMAT and incident fractures in women or men. In conclusion, we found greater BMAT is associated with greater loss of trabecular bone at the spine and femoral neck, and greater loss of spine compressive strength, in older women. © 2019 American Society for Bone and Mineral Research.

Studies using quantitative computed tomography (QCT) and data-driven image analysis techniques have shown that trabecular and cortical volumetric bone mineral density (vBMD) can improve the hip fracture prediction of dual-energy X-ray absorptiometry areal BMD (aBMD). Here, we hypothesize that (1) QCT imaging features of shape, density and structure derived from data-driven image analysis techniques can improve the hip fracture discrimination of classification models based on mean femoral neck aBMD (Neck.aBMD), and (2) that data-driven cortical bone thickness (Ct.Th) features can improve the hip fracture discrimination of vBMD models. We tested our hypotheses using statistical multi-parametric modeling (SMPM) in a QCT study of acute hip fracture of 50 controls and 93 fragility fracture cases. SMPM was used to extract features of shape, vBMD, Ct.Th, cortical vBMD, and vBMD in a layer adjacent to the endosteal surface to develop hip fracture classification models with machine learning logistic LASSO. The performance of these classification models was evaluated in two aspects: (1) their hip fracture classification capability without Neck.aBMD, and (2) their capability to improve the hip fracture classification of the Neck.aBMD model. Assessments were done with 10-fold cross-validation, areas under the receiver operating characteristic curve (AUCs), differences of AUCs, and the integrated discrimination improvement (IDI) index. All LASSO models including SMPM-vBMD features, and the majority of models including SMPM-Ct.Th features performed significantly better than the Neck.aBMD model; and all SMPM features significantly improved the hip fracture discrimination of the Neck.aBMD model (Hypothesis 1). An interesting finding was that SMPM-features of vBMD also captured Ct.Th patterns, potentially explaining the superior classification performance of models based on SMPM-vBMD features (Hypothesis 2). Age, height and weight had a small impact on model performances, and the model of shape, vBMD and Ct.Th consistently yielded better performances than the Neck.aBMD models. Results of this study clearly support the relevance of bone density and quality on the assessment of hip fracture, and demonstrate their potential on patient and healthcare cost benefits.

ContextBariatric surgery results in reduced muscle mass as weight is lost, but postoperative changes in muscle strength and performance are incompletely understood.ObjectiveTo examine changes in body composition, strength, physical activity, and physical performance following Roux-en-Y gastric bypass (RYGB).Design, participants, outcomesIn a prospective cohort of 47 adults (37 women, 10 men) aged 45 ± 12 years (mean ± SD) with body mass index (BMI) 44 ± 8 kg/m2, we measured body composition by dual-energy X-ray absorptiometry, handgrip strength, physical activity, and physical performance (chair stand time, gait speed, 400-m walk time) before and 6 and 12 months after RYGB. Relative strength was calculated as absolute handgrip strength/BMI and as absolute strength/appendicular lean mass (ALM).ResultsParticipants experienced substantial 12-month decreases in weight (-37 ± 10 kg or 30% ± 7%), fat mass (-48% ± 12%), and total lean mass (-13% ± 6%). Mean absolute strength declined by 9% ± 17% (P < 0.01). In contrast, relative strength increased by 32% ± 25% (strength/BMI) and 9% ± 20% (strength/ALM) (P < 0.01 for both). There were clinically significant postoperative improvements in all physical performance measures, including mean improvement in gait speed of >0.1 m/s (P < 0.01) and decrease in 400-m walk time of nearly a full minute.ConclusionsIn the setting of dramatic weight loss, lean mass and absolute grip strength declined after RYGB. However, relative muscle strength and physical function improved meaningfully and are thus noteworthy positive outcomes of gastric bypass.

BackgroundLean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass.ObjectivesTo determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci.MethodsWe performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms).ResultsSeven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection.ConclusionsIn conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.

Bone marrow adiposity is associated with aging, osteoporosis, and reduced hematopoiesis, as well as anorexia nervosa, but little is known about the underlying mechanisms that affect marrow adiposity. Chronic kidney disease (CKD) may influence bone marrow adipose tissue (BMAT), possibly through loss of lean mass or higher circulating levels of sclerostin. To test these hypotheses, we investigated the cross-sectional association between estimated glomerular filtration rate (eGFR) as a measure of kidney function and 1 H-MRS-based measurement of vertebral BMAT (L1 to L4) in 475 older adults from the Age Gene/Environment Susceptibility (AGES)-Reykjavik study. Mean BMAT was compared in those with eGFR >60 (n = 297) versus those with eGFR 45 to 60 (n = 120) or eGFR 60 (adjusted mean 53.8%; 95% CI, 52.8 to 54.8) (p = 0.0002). BMAT did not differ in those with eGFR 45 to 60 (adjusted mean 54.3%; 95% CI, 52.8 to 55.9) compared with those with eGFR >60 (p = 0.58). In a subgroup of participants with serum sclerostin available (n = 253), additional adjustment for sclerostin attenuated the difference in adjusted mean vertebral BMAT between those with eGFR 60 from 3.7% (p = 0.04) to 2.4% (p = 0.20). CKD stage 3b or worse was associated with greater bone marrow adiposity; this association may be partially mediated by sclerostin. © 2018 American Society for Bone and Mineral Research.

In this case-cohort study, we used data-driven computational anatomy approaches to assess within and between sex spatial differences in proximal femoral bone characteristics in relation to incident hip fracture. One hundred male and 234 female incident hip fracture cases, and 1047 randomly selected noncase subcohort participants (562 female) were chosen from the population-based AGES-Reykjavik study (mean age of 77 years). The baseline -i.e. before hip fracture- hip quantitative computed tomography scans of these subjects were analyzed using voxel-based morphometry, tensor-based morphometry, and surface-based statistical parametric mapping to assess the spatial distribution of volumetric bone mineral density (vBMD), internal structure, and cortical bone properties (thickness, vBMD and trabecular vBMD adjacent to the endosteal surface) of the proximal femur, respectively, in relation to incident hip fracture. Results showed that in both men and women: 1) the superior aspect of the femoral neck and the trochanteric region (except for cortical bone thickness) were consistently identified as being associated with incident hip fracture, and 2) differences in bone properties between noncases and incident hip fracture cases followed similar trends, were located at compatible regions, and manifested heterogeneity in the spatial distribution of their magnitude with focal regions showing larger differences. With respect to sex differences, most of the regions with a significant interaction between fracture group and sex showed: 1) differences of greater magnitude in men between noncases and incident hip fracture cases with different spatial distributions for all bone properties with the exception of cortical bone thickness, and 2) that while most of these regions showed better bone quality in male cases than in female cases, female cases showed higher vBMD in the principal compressive group and higher endotrabecular vBMD at several regions including the anterior, posterior, and lateral aspects of the proximal femur. These findings indicate the value of these image analysis techniques by providing unique information about the specific patterns of bone deterioration associated with incident hip fracture and their sex differences, highlighting the importance of looking to men and women separately in the assessment of hip fracture risk.

This study aimed to explore the relationships of several indicators of cigarette smoking habits (smoking status, pack-years, age at smoking initiation and smoking cessation) with quantitative computed tomographic (QCT)-derived proximal femur bone measures (trabecular vBMD, integral vBMD and the ratio of cortical to total tissue volume (cvol/ivol)) and with subsequent change in these measures over the next five years. A total of 2673 older adults (55.9% women), aged 66-92 years at baseline from the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study, who had two QCT scans of the hip were studied. In multivariable linear regression models, compared to never-smokers, current smokers had lower cvol/ivol at baseline and former-smokers had poorer measures on all outcomes (lower trabecular vBMD, integral vBMD and cvol/ivol), even when adjusted for several potential confounders. Further, among former smokers, those with higher pack-years had worse bone outcomes and those with longer duration since smoking cessation had better bone health at baseline. Analyses of change in bone measures revealed that compared to never-smokers, current smokers had significantly greater loss of trabecular vBMD, integral vBMD, and cvol/ivol. The regression models included adjustment for sex, age, education, and baseline body mass index, creatinine, % weight change from age 50, 25OHD, physical activity level, high-sensitive C-Reactive protein levels, alcohol and coffee consumption, history of diabetes mellitus, arthritis, and respiratory diseases. In conclusion, both current and former smoking showed adverse associations with bone health assessed with QCT. Results suggest that current smoking in particular may aggravate the rate of bone loss at older age and highlight implications for targeting this risk factor in populations that present higher smoking prevalence and vulnerability to bone fragility.

ContextHigher bone marrow fat (BMF)1 is associated with osteoporosis and reduced hematopoiesis. Exogenous estradiol reduces BMF in older women, but effects of endogenous sex hormones are unknown.ObjectiveTo determine if endogenous sex hormones are associated with BMF in older men and women.Design, setting and participantsCross-sectional study in the Age Gene/Environment Susceptibility (AGES) Reykjavik cohort. Participants using medications that may affect BMF were excluded.Main outcome measuresVertebral BMF was measured with magnetic resonance spectroscopy. Estradiol, testosterone and sex hormone binding globulin were measured on archived serum. Linear regression models were adjusted for age, total percent body fat and visit window.ResultsAnalyses included 244 men and 226 women, mean age 81.5 (SD 4.1) years. Mean BMF was 54.1% (SD 8.6) (men) and 54.7% (SD 8.1) (women). In adjusted models, per 1pg/ml increase in total estradiol, there was a statistically significant 0.26% decrease in BMF in men (95% CI: -0.41, -0.11) and a non-significant 0.20% decrease in women (95% CI: -0.55, 0.15), with no evidence of interaction by gender (p=0.88). Per 10ng/dl increase in total testosterone, there was a significant 0.10% decrease in BMF in men (95% CI: -0.17, -0.03) and a non-significant 0.13% (95% CI: -0.79, 0.53) decrease in women, with no evidence of interaction by gender (p=0.97).ConclusionHigher bone marrow fat is associated with lower total estradiol and testosterone levels in older men, with a similar but statistically non-significant association in older women. Sex hormone levels appear to play a role in the regulation of bone marrow fat in older adults.

There is little knowledge about the spatial distribution differences in volumetric bone mineral density and cortical bone structure at the proximal femur between femoral neck fractures and trochanteric fractures. In this case-control study, a total of 93 women with fragility hip fractures, 72 with femoral neck fractures (mean ± SD age: 70.6 ± 12.7 years) and 21 with trochanteric fractures (75.6 ± 9.3 years), and 50 control subjects (63.7 ± 7.0 years) were included for the comparisons. Differences in the spatial distributions of volumetric bone mineral density, cortical bone thickness, cortical volumetric bone mineral density, and volumetric bone mineral density in a layer adjacent to the endosteal surface were investigated using voxel-based morphometry (VBM) and surface-based statistical parametric mapping (SPM). We compared these spatial distributions between controls and both types of fracture, and between the two types of fracture. Using VBM, we found spatially heterogeneous volumetric bone mineral density differences between control subjects and subjects with hip fracture that varied by fracture type. Interestingly, femoral neck fracture subjects, but not subjects with trochanteric fracture, showed significantly lower volumetric bone mineral density in the superior aspect of the femoral neck compared with controls. Using surface-based SPM, we found that compared with controls, both fracture types showed thinner cortices in regions in agreement with the type of fracture. Most outcomes of cortical and endocortical volumetric bone mineral density comparisons were consistent with VBM results. Our results suggest: 1) that the spatial distribution of trabecular volumetric bone mineral density might play a significant role in hip fracture; 2) that focal cortical bone thinning might be more relevant in femoral neck fractures; and 3) that areas of reduced cortical and endocortical volumetric bone mineral density might be more relevant for trochanteric fractures in Chinese women. © 2017 American Society for Bone and Mineral Research.

Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p

BackgroundAlthough the importance of sleep on preservation of several physiological functions is well known, the relationship with the two interconnected tissues - muscle and bone is less understood.ObjectivesThis study aimed to examine the association of 24-hour sleep duration with mid-thigh muscle composition and proximal femur volumetric bone mineral density (vBMD).Methods2438 men and 3326 women aged 66 to 96years, residents in the Reykjavik area, were included in this cross-sectional study. Proximal femur integral vBMD, mid-thigh muscle area and muscle attenuation were assessed with computed tomography. Sleep and nap habits were assessed using a questionnaire.ResultsWe found that after adjustment for age and BMI long sleep duration (>8h/d) was negatively associated with thigh lean area in both men (B=-2.21, 95% confidence interval (CI): -4.01, -0.40) and women (B=-2.39, 95% CI: -3.75, -1.03) and with muscle attenuation (B=-0.95, 95% CI: -1.47, -0.43) only in women. After adjustments for age, health and lifestyle factors the association between long sleep duration and muscle lean area was attenuated and became nonsignificant while associations with muscle attenuation remained marginally significant (B=-0.51, 95% CI: -1.03, -0.002). Sleep duration was not associated with proximal femur integral vBMD in the multivariate models.ConclusionLong sleep duration, particularly in old women, can affect thigh muscle attenuation (increase in intramuscular fat). Whether optimization of sleep can ameliorate age-associated intramuscular or intermuscular adipose tissue warrants further studies.

Bone mineral density (BMD) has been linked to mortality, but little is known about the independent contribution of each endosteal bone compartment and also the rate of bone loss to risk of mortality. We examined the relationships between (1) baseline trabecular and cortical volumetric BMD (vBMD) at the proximal femur, and (2) the rate of trabecular and cortical bone loss and all-cause mortality in older adults from the AGES-Reykjavik study. The analysis of trabecular and cortical vBMD and mortality was based on the baseline cohort of 4654 participants (aged ≥66 years) with a median follow-up of 9.4 years; the association between rate of bone loss and mortality was based on 2653 participants with bone loss data (median follow-up of 5.6 years). Analyses employed multivariable Cox-proportional models to estimate hazard ratios (HRs) with time-varying fracture status; trabecular and cortical variables were included together in all models. Adjusted for important confounders, Cox models showed that participants in the lowest quartile of trabecular vBMD had an increased risk of mortality compared to participants in other quartiles (HR = 1.12; 95% confidence interval (CI), 1.01 to 1.25); baseline cortical vBMD was not related to mortality (HR = 1.08; 95% CI, 0.97 to 1.20). After adjustment for time-dependent fracture status, results were attenuated and not statistically significant. A faster loss (quartile 1 versus quartiles 2-4) in both trabecular and cortical bone was associated with higher mortality risk (HR = 1.37 and 1.33, respectively); these associations were independent of major potential confounders including time-dependent incident fractures (HR = 1.32 and 1.34, respectively). Overall, data suggest that faster bone losses over time in both the trabecular and cortical bone compartments are associated with mortality risk and that measurements of change in bone health may be more informative than single-point measurements in explaining mortality differences in older adults. © 2017 American Society for Bone and Mineral Research.

ObjectiveThe objective of this study was to determine if clinical dynamic PET/CT imaging with 11C-L-methyl-methionine (11C-MET) in healthy older women can provide an estimate of tissue-level post-absorptive and post-prandial skeletal muscle protein synthesis that is consistent with the more traditional method of calculating fractional synthesis rate (FSR) of muscle protein synthesis from skeletal muscle biopsies obtained during an infusion of L-[ring 13C6] phenylalanine (13C6-Phe).MethodsHealthy older women (73 ± 5 years) completed both dynamic PET/CT imaging with 11C-MET and a stable isotope infusion of 13C6-Phe with biopsies to measure the skeletal muscle protein synthetic response to 25 g of a whey protein supplement. Graphical estimation of the Patlak coefficient Ki from analysis of the dynamic PET/CT images was employed as a measure of incorporation of 11 C-MET in the mid-thigh muscle bundle.ResultsPost-prandial values [mean ± standard error of the mean (SEM)] were higher than post-absorptive values for both Ki (0.0095 ± 0.001 vs. 0.00785 ± 0.001 min-1, p

HR-pQCT enables in vivo multi-parametric assessments of bone microstructure in the distal radius and distal tibia. Conventional HR-pQCT image analysis approaches summarize bone parameters into global scalars, discarding relevant spatial information. In this work, we demonstrate the feasibility and reliability of statistical parametric mapping (SPM) techniques for HR-pQCT studies, which enable population-based local comparisons of bone properties. We present voxel-based morphometry (VBM) to assess trabecular and cortical bone voxel-based features, and a surface-based framework to assess cortical bone features both in cross-sectional and longitudinal studies. In addition, we present tensor-based morphometry (TBM) to assess trabecular and cortical bone structural changes. The SPM techniques were evaluated based on scan-rescan HR-pQCT acquisitions with repositioning of the distal radius and distal tibia of 30 subjects. For VBM and surface-based SPM purposes, all scans were spatially normalized to common radial and tibial templates, while for TBM purposes, rescans (follow-up) were spatially normalized to their corresponding scans (baseline). VBM was evaluated based on maps of local bone volume fraction (BV/TV), homogenized volumetric bone mineral density (vBMD), and homogenized strain energy density (SED) derived from micro-finite element analysis; while the cortical bone framework was evaluated based on surface maps of cortical bone thickness, vBMD, and SED. Voxel-wise and vertex-wise comparisons of bone features were done between the groups of baseline and follow-up scans. TBM was evaluated based on mean square errors of determinants of Jacobians at baseline bone voxels. In both anatomical sites, voxel- and vertex-wise uni- and multi-parametric comparisons yielded non-significant differences, and TBM showed no artefactual bone loss or apposition. The presented SPM techniques demonstrated robust specificity thus warranting their application in future clinical HR-pQCT studies.

UNLABELLED: In this study, we determined that operator positioning precision contributes significant measurement error in high-resolution peripheral quantitative computed tomography (HR-pQCT). Moreover, we developed software to quantify intra- and inter-operator variability and demonstrated that standard positioning training (now available as a web-based application) can significantly reduce inter-operator variability. INTRODUCTION: HR-pQCT is increasingly used to assess bone quality, fracture risk, and anti-fracture interventions. The contribution of the operator has not been adequately accounted in measurement precision. Operators acquire a 2D projection (scout view image) and define the region to be scanned by positioning a reference line on a standard anatomical landmark. In this study, we (i) evaluated the contribution of positioning variability to in vivo measurement precision, (ii) measured intra- and inter-operator positioning variability, and (iii) tested if custom training software led to superior reproducibility in new operators compared to experienced operators. METHODS: To evaluate the operator in vivo measurement precision, we compared precision errors calculated in 64 co-registered and non-co-registered scan-rescan images. To quantify operator variability, we developed software that simulates the positioning process of the scanners software. Eight experienced operators positioned reference lines on scout view images designed to test intra- and inter-operator reproducibility. Finally, we developed modules for training and evaluation of reference line positioning. We enrolled six new operators to participate in a common training, followed by the same reproducibility experiments performed by the experienced group. RESULTS: In vivo precision errors were up to threefold greater (Tt.BMD and Ct.Th) when variability in scan positioning was included. The inter-operator precision errors were significantly greater than the short-term intra-operator precision (p

UNLABELLED: Association between serum bone formation and resorption markers and cortical and trabecular bone loss and the concurrent periosteal apposition in a population-based cohort of 1069 older adults was assessed. BTM levels moderately reflect the cellular events at the endosteal and periosteal surfaces but are not associated with fracture risk. INTRODUCTION: We assessed whether circulating bone formation and resorption markers (BTM) were individual predictors for trabecular and cortical bone loss, periosteal expansion, and fracture risk in older adults aged 66 to 93 years from the AGES-Reykjavik study. METHODS: The sample for the quantitative computed tomography (QCT)-derived cortical and trabecular BMD and periosteal expansion analysis consisted of 1069 participants (474 men and 595 women) who had complete baseline (2002 to 2006) and follow-up (2007 to 2011) hip QCT scans and serum baseline BTM. During the median follow-up of 11.7 years (range 5.4-12.5), 54 (11.4 %) men and 182 (30.6 %) women sustained at least one fracture of any type. RESULTS: Increase in BTM levels was associated with faster cortical and trabecular bone loss at the femoral neck and proximal femur in men and women. Higher BTM levels were positively related with periosteal expansion rate at the femoral neck in men. Markers were not associated with fracture risk. CONCLUSION: This data corroborates the notion from few previous studies that both envelopes are metabolically active and that BTM levels may moderately reflect the cellular events at the endosteal and periosteal surfaces. However, our results do not support the routine use of BTM to assess fracture risk in older men and women. In light of these findings, further studies are justified to examine whether systemic markers of bone turnover might prove useful in monitoring skeletal remodeling events and the effects of current osteoporosis drugs at the periosteum.

Genome-wide association studies (GWASs) have revealed numerous loci for areal bone mineral density (aBMD). We completed the first GWAS meta-analysis (n = 15,275) of lumbar spine volumetric BMD (vBMD) measured by quantitative computed tomography (QCT), allowing for examination of the trabecular bone compartment. SNPs that were significantly associated with vBMD were also examined in two GWAS meta-analyses to determine associations with morphometric vertebral fracture (n = 21,701) and clinical vertebral fracture (n = 5893). Expression quantitative trait locus (eQTL) analyses of iliac crest biopsies were performed in 84 postmenopausal women, and murine osteoblast expression of genes implicated by eQTL or by proximity to vBMD-associated SNPs was examined. We identified significant vBMD associations with five loci, including: 1p36.12, containing WNT4 and ZBTB40; 8q24, containing TNFRSF11B; and 13q14, containing AKAP11 and TNFSF11. Two loci (5p13 and 1p36.12) also contained associations with radiographic and clinical vertebral fracture, respectively. In 5p13, rs2468531 (minor allele frequency [MAF] = 3%) was associated with higher vBMD (β = 0.22, p = 1.9 × 10-8 ) and decreased risk of radiographic vertebral fracture (odds ratio [OR] = 0.75; false discovery rate [FDR] p = 0.01). In 1p36.12, rs12742784 (MAF = 21%) was associated with higher vBMD (β = 0.09, p = 1.2 × 10-10 ) and decreased risk of clinical vertebral fracture (OR = 0.82; FDR p = 7.4 × 10-4 ). Both SNPs are noncoding and were associated with increased mRNA expression levels in human bone biopsies: rs2468531 with SLC1A3 (β = 0.28, FDR p = 0.01, involved in glutamate signaling and osteogenic response to mechanical loading) and rs12742784 with EPHB2 (β = 0.12, FDR p = 1.7 × 10-3 , functions in bone-related ephrin signaling). Both genes are expressed in murine osteoblasts. This is the first study to link SLC1A3 and EPHB2 to clinically relevant vertebral osteoporosis phenotypes. These results may help elucidate vertebral bone biology and novel approaches to reducing vertebral fracture incidence. © 2016 American Society for Bone and Mineral Research.

UNLABELLED: Association between serum bone formation and resorption markers and bone mineral, structural, and strength variables derived from quantitative computed tomography (QCT) in a population-based cohort of 1745 older adults was assessed. The association was weak for lumbar spine and femoral neck areal and volumetric bone mineral density. INTRODUCTION: The aim of this study was to examine the relationship between levels of bone turnover markers (BTMs; osteocalcin (OC), C-terminal cross-linking telopeptide of type I collagen (CTX), and procollagen type 1N propeptide (P1NP)) and quantitative computed tomography (QCT)-derived bone density, geometry, and strength indices in the lumbar spine and femoral neck (FN). METHODS: A total of 1745 older individuals (773 men and 972 women, aged 66-92 years) from the Age, Gene/Environment Susceptibility (AGES)-Reykjavik cohort were studied. QCT was performed in the lumbar spine and hip to estimate volumetric trabecular, cortical, and integral bone mineral density (BMD), areal BMD, bone geometry, and bone strength indices. Association between BTMs and QCT variables were explored using multivariable linear regression. RESULTS: Major findings showed that all BMD measures, FN cortical index, and compressive strength had a low negative correlation with the BTM levels in both men and women. Correlations between BTMs and bone size parameters were minimal or not significant. No associations were found between BTMs and vertebral cross-sectional area in women. BTMs alone accounted for only a relatively small percentage of the bone parameter variance (1-10 %). CONCLUSION: Serum CTX, OC, and P1NP were weakly correlated with lumbar spine and FN areal and volumetric BMD and strength measures. Most of the bone size indices were not associated with BTMs; thus, the selected bone remodeling markers do not reflect periosteal bone formation. These results confirmed the limited ability of the most sensitive established BTMs to predict bone structural integrity in older adults.

Muscle composition may affect mortality risk, but prior studies have been limited to specific samples or less precise determination of muscle composition. We evaluated associations of thigh muscle composition, determined using computed tomography imaging, and knee extension strength with mortality risk among 4,824 participants aged 76.4 (standard deviation (SD), 5.5) years from the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study (2002-2006). Cox proportional hazards models were used to estimate hazard ratios. After 8.8 years of follow-up, there were 1,942 deaths. For men, each SD-increment increase in muscle lean area, muscle quality, and strength was associated with lower mortality risk, with decreases ranging between 11% and 22%. Each SD-increment increase in intermuscular adipose tissue and intramuscular adipose tissue was associated with higher mortality risk (hazard ratio (HR) = 1.13 (95% confidence interval (CI): 1.06, 1.22) and HR = 1.23 (95% CI: 1.15, 1.30), respectively). For women, each SD-increment increase in muscle lean area, muscle quality, and strength was associated with lower mortality risk, with decreases ranging between 12% and 19%. Greater intramuscular adipose tissue was associated with an 8% higher mortality risk (HR = 1.08, 95% CI: 1.01, 1.16). This study shows that muscle composition is associated with mortality risk. These results also show the importance of improving muscle strength and area and lowering muscle adipose tissue infiltration.

Muscle composition may affect mortality risk, but prior studies have been limited to specific samples or less precise determination of muscle composition. We evaluated associations of thigh muscle composition, determined using computed tomography imaging, and knee extension strength with mortality risk among 4,824 participants aged 76.4 (standard deviation (SD), 5.5) years from the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study (2002-2006). Cox proportional hazards models were used to estimate hazard ratios. After 8.8 years of follow-up, there were 1,942 deaths. For men, each SD-increment increase in muscle lean area, muscle quality, and strength was associated with lower mortality risk, with decreases ranging between 11% and 22%. Each SD-increment increase in intermuscular adipose tissue and intramuscular adipose tissue was associated with higher mortality risk (hazard ratio (HR) = 1.13 (95% confidence interval (CI): 1.06, 1.22) and HR = 1.23 (95% CI: 1.15, 1.30), respectively). For women, each SD-increment increase in muscle lean area, muscle quality, and strength was associated with lower mortality risk, with decreases ranging between 12% and 19%. Greater intramuscular adipose tissue was associated with an 8% higher mortality risk (HR = 1.08, 95% CI: 1.01, 1.16). This study shows that muscle composition is associated with mortality risk. These results also show the importance of improving muscle strength and area and lowering muscle adipose tissue infiltration.

Nonpharmacologic approaches to preserve or increase bone mineral density (BMD) include whole-body vibration (WBV), but its efficacy in elderly persons is not clear. Therefore, we conducted the Vibration to Improve Bone in Elderly Subjects (VIBES) trial, a randomized, placebo-controlled trial of 10 minutes of daily WBV (0.3g at 37 Hz) in seniors recruited from 16 independent living communities. The primary outcomes were volumetric BMD of the hip and spine measured by quantitative computed tomography (QCT) and biochemical markers of bone turnover. We randomized 174 men and women (89 active, 85 placebo) with T-scores -1 to -2.5 who were not taking bone active drugs and had no diseases affecting the skeleton (mean age 82 ± 7 years, range 65 to 102). Participants received daily calcium (1000 mg) and vitamin D (800 IU). Study platforms were activated using radio frequency ID cards providing electronic adherence monitoring; placebo platforms resembled the active platforms. In total, 61% of participants in the active arm and 73% in the placebo arm completed 24 months. The primary outcomes, median percent changes (interquartile range [IQR]) in total volumetric femoral trabecular BMD (active group (2.2% [-0.8%, 5.2%]) versus placebo 0.4% [-4.8%, 5.0%]) and in mid-vertebral trabecular BMD of L1 and L2 (active group (5.3% [-6.9%, 13.3%]) versus placebo (2.4% [-4.4%, 11.1%]), did not differ between groups (all p values > 0.1). Changes in biochemical markers of bone turnover (P1NP and sCTX) also were not different between groups (p = 0.19 and p = 0.97, respectively). In conclusion, this placebo-controlled randomized trial of daily WBV in older adults did not demonstrate evidence of significant beneficial effects on volumetric BMD or bone biomarkers; however, the high variability in vBMD changes limited our power to detect small treatment effects. The beneficial effects of WBV observed in previous studies of younger women may not occur to the same extent in elderly individuals.

BackgroundPolyunsaturated fatty acids (PUFAs) may play a role in fracture, but studies have been largely confined to estimates of dietary intake.ObjectiveWe aimed to examine associations between fatty acids measured in late life and fish-oil consumption in early life, midlife, and late life with osteoporotic fracture risk.DesignOsteoporotic fractures were determined from medical records over 5-9 y of follow-up in men and women aged 66-96 y. Data were analyzed from 1438 participants including 898 participants who were randomly selected from the Age, Gene/Environment Susceptibility Study, which is an observational study, and 540 participants with incident fracture. Plasma phospholipid fatty acids were assessed by using gas chromatography. Fish-oil consumption was assessed by using validated questionnaires as never (referent), less than daily, or daily. HRs and 95% CIs adjusted for age, education, height, weight, diabetes, physical activity, and medications were estimated by using Cox regression.ResultsIn men, the highest tertile of PUFAs, n-3 (ω-3), and eicosapentaenoic acid were associated with decreased fracture risk [HRs (95% CIs): 0.60 (95% CI: 0.41, 0.89), 0.66 (0.45, 0.95), and 0.59 (0.41, 0.86), respectively]. In women, PUFAs tended to be inversely associated with fracture risk (P-trend = 0.06), but tertiles 2 and 3 were not independently associated with risk. Tertile 2 of n-6 and arachidonic acid was associated with fracture risk in women [HRs (95% CIs): 1.43 (1.10, 1.85) and 1.42 (1.09, 1.85), respectively]. Daily fish-oil consumption in late life was associated with lower fracture risk in men (HR: 0.64; 95% CI: 0.45, 0.91). Daily fish-oil consumption in midlife was associated with lower fracture risk in women (HR: 0.75; 95% CI: 0.58, 0.98).ConclusionsGreater PUFA concentrations may be associated with lower osteoporotic fracture risk in older adults, particularly in men. Critical time periods for n-3 fatty acid consumption may differ by sex.

Quantitative computed tomography (QCT) is increasingly used in osteoporosis studies to assess volumetric bone mineral density (vBMD), bone quality and strength. However, QCT is confronted by technical issues in the clinical research setting, such as potentially confounding effects of body size on vBMD measurements and lack of standard approaches to scanner cross-calibration, which affects measurements of vBMD in multicenter settings. In this study, we addressed systematic inter-scanner differences and subject-dependent body size errors using a novel anthropomorphic hip phantom, containing a calibration hip to estimate correction equations, and a contralateral test hip to assess the quality of the correction. We scanned this phantom on four different scanners and we applied phantom-derived corrections to in vivo images of 16 postmenopausal women scanned on two scanners. From the phantom study, we found that vBMD decreased with increasing phantom size in three of four scanners and that inter-scanner variations increased with increasing phantom size. In the in vivo study, we observed that inter-scanner corrections reduced systematic inter-scanner mean vBMD differences but that the inter-scanner precision error was still larger than expected from known intra-scanner precision measurements. In conclusion, inter-scanner corrections and body size influence should be considered when measuring vBMD from QCT images.

ContextOsteocyte activity is crucial to the maintenance of bone quality. Sclerostin, an osteocyte product, inhibits bone formation, yet higher circulating sclerostin is associated with higher bone density. Bone marrow fat (MF) is associated with osteoporosis, but little is known about the relationship between osteocyte activity and MF.ObjectiveOur objective was to assess the relationships between circulating sclerostin, vertebral MF, volumetric bone mineral density (vBMD), and other fat depots in older adults.Design, setting, and participantsWe conducted a cross-sectional study in the Age Gene/Environment Susceptibility-Reykjavik cohort.Main outcome measuresOutcome measures included vertebral MF (L1-L4) measured with magnetic resonance spectroscopy and vBMD (spine and hip) and abdominal fat measured with quantitative computed tomography.ResultsAfter excluding subjects with bone-active medication use (n = 50), inadequate serum (n = 2), or inadequate magnetic resonance spectroscopy (n = 1), analyses included 115 men and 134 women (mean age 79 y, mean body mass index 27.7 kg/m(2)). In men, but not women, vertebral MF was greater in those with higher serum sclerostin levels. MF was 52.2 % in the lowest tertile of serum sclerostin and 56.3% in the highest tertile in men (P for trend

ContextOsteocyte activity is crucial to the maintenance of bone quality. Sclerostin, an osteocyte product, inhibits bone formation, yet higher circulating sclerostin is associated with higher bone density. Bone marrow fat (MF) is associated with osteoporosis, but little is known about the relationship between osteocyte activity and MF.ObjectiveOur objective was to assess the relationships between circulating sclerostin, vertebral MF, volumetric bone mineral density (vBMD), and other fat depots in older adults.Design, setting, and participantsWe conducted a cross-sectional study in the Age Gene/Environment Susceptibility-Reykjavik cohort.Main outcome measuresOutcome measures included vertebral MF (L1-L4) measured with magnetic resonance spectroscopy and vBMD (spine and hip) and abdominal fat measured with quantitative computed tomography.ResultsAfter excluding subjects with bone-active medication use (n = 50), inadequate serum (n = 2), or inadequate magnetic resonance spectroscopy (n = 1), analyses included 115 men and 134 women (mean age 79 y, mean body mass index 27.7 kg/m(2)). In men, but not women, vertebral MF was greater in those with higher serum sclerostin levels. MF was 52.2 % in the lowest tertile of serum sclerostin and 56.3% in the highest tertile in men (P for trend

In multicenter studies and longitudinal studies that use two or more different quantitative computed tomography (QCT) imaging systems, anthropomorphic standardization phantoms (ASPs) are used to correct inter-scanner differences and allow pooling of data. In this study, in vivo imaging of 20 women on two imaging systems was used to evaluate inter-scanner differences in hip integral BMD (iBMD), trabecular BMD (tBMD), cortical BMD (cBMD), femoral neck yield moment (My) and yield force (Fy), and finite-element derived strength of the femur under stance (FEstance) and fall (FEfall) loading. Six different ASPs were used to derive inter-scanner correction equations. Significant (p

Understanding the skeletal effects of resistance exercise involves delineating the spatially heterogeneous response of bone to load distributions from different muscle contractions. Bone mineral density (BMD) analyses may obscure these patterns by averaging data from tissues with variable mechanoresponse. To assess the proximal femoral response to resistance exercise, we acquired pretraining and posttraining quantitative computed tomography (QCT) images in 22 subjects (25-55 years, 9 males, 13 females) performing two resistance exercises for 16 weeks. One group (SQDL, n = 7) performed 4 sets each of squats and deadlifts, a second group (ABADD, n = 8) performed 4 sets each of standing hip abductions and adductions, and a third group (COMBO, n = 7) performed two sets each of squat/deadlift and abduction/adduction exercise. Subjects exercised three times weekly, and the load was adjusted each session to maximum effort. We used voxel-based morphometry (VBM) to visualize BMD distributions. Hip strength computations used finite element modeling (FEM) with stance and fall loading conditions. We used QCT analysis for cortical and trabecular BMD, and cortical tissue volume. For muscle size and density, we analyzed the cross-sectional area (CSA) and mean Hounsfield unit (HU) in the hip extensor, flexor, abductor, and adductor muscle groups. Whereas SQDL increased vertebral BMD, femoral neck cortical BMD and volume, and stance hip strength, ABADD increased trochanteric cortical volume. The COMBO group showed no changes in any parameter. VBM showed different effects of ABADD and SQDL exercise, with the former causing focal changes of trochanteric cortical bone, and the latter showing diffuse changes in the femoral neck and head. ABADD exercise increased adductor CSA and HU, whereas SQDL exercise increased the hip extensor CSA and HU. In conclusion, we observed different proximal femoral bone and muscle tissue responses to SQDL and ABADD exercise. This study supports VBM and volumetric QCT (vQCT) to quantify the spatially heterogeneous effects of types of muscle contractions on bone.

BackgroundKnowledge of adipose composition in relation to mortality may help delineate inconsistent relationships between obesity and mortality in old age. We evaluated relationships between abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) density, mortality, biomarkers, and characteristics.MethodsVAT and SAT density were determined from computed tomography scans in persons aged 65 and older, Health ABC (n = 2,735) and AGES-Reykjavik (n = 5,131), and 24 nonhuman primates (NHPs). Associations between adipose density and mortality (4-13 years follow-up) were assessed with Cox proportional hazards models. In NHPs, adipose density was related to serum markers and tissue characteristics.ResultsHigher density adipose tissue was associated with mortality in both studies with adjustment for risk factors including adipose area, total fat, and body mass index. In women, hazard ratio and 95% CI for the densest quintile (Q5) versus least dense (Q1) for VAT density were 1.95 (1.36-2.80; Health ABC) and 1.88 (1.31-2.69; AGES-Reykjavik) and for SAT density, 1.76 (1.35-2.28; Health ABC) and 1.56 (1.15-2.11; AGES-Reykjavik). In men, VAT density was associated with mortality in Health ABC, 1.52 (1.12-2.08), whereas SAT density was associated with mortality in both Health ABC, 1.58 (1.21-2.07), and AGES-Reykjavik, 1.43 (1.07-1.91). Higher density adipose tissue was associated with smaller adipocytes in NHPs. There were no consistent associations with inflammation in any group. Higher density adipose tissue was associated with lower serum leptin in Health ABC and NHPs, lower leptin mRNA expression in NHPs, and higher serum adiponectin in Health ABC and NHPs.ConclusionVAT and SAT density provide a unique marker of mortality risk that does not appear to be inflammation related.

Bone mineral density (BMD) and geometric bone measures are individually associated with prevalent osteoporotic fractures. Whether an aggregate of these measures would better associate with fractures has not been examined. We examined relationships between self-reported fractures and selected bone measures acquired by quantitative computerized tomography (QCT), a composite bone score, and QCT-acquired dual-energy X-ray absorptiometry-like total femur BMD in 2110 men and 2682 women in the Age, Gene/Environment Susceptibility-Reykjavik Study. The combined bone score was generated by summing gender-specific Z-scores for 4 QCT measures: vertebral trabecular BMD, femur neck cortical thickness, femur neck trabecular BMD, and femur neck minimal cross-sectional area. Except for the latter measure, lower scores for QCT measures, singly and combined, showed positive (p

Fractures of the proximal femur are the most devastating outcome of osteoporosis. It is generally understood that age-related changes in hip structure confer increased risk, but there have been few explicit comparisons of such changes in healthy subjects to those with hip fracture. In this study, we used quantitative computed tomography and tensor-based morphometry (TBM) to identify three-dimensional internal structural patterns of the proximal femur associated with age and with incident hip fracture. A population-based cohort of 349 women representing a broad age range (21-97years) was included in this study, along with a cohort of 222 older women (mean age 79±7years) with (n=74) and without (n=148) incident hip fracture. Images were spatially normalized to a standardized space, and age- and fracture-specific morphometric features were identified based on statistical maps of shape features described as local changes of bone volume. Morphometric features were visualized as maps of local contractions and expansions, and significance was displayed as Student's t-test statistical maps. Significant age-related changes included local expansions of regions low in volumetric bone mineral density (vBMD) and local contractions of regions high in vBMD. Some significant fracture-related features resembled an accentuated aging process, including local expansion of the superior aspect of the trabecular bone compartment in the femoral neck, with contraction of the adjoining cortical bone. However, other features were observed only in the comparison of hip fracture subjects with age-matched controls including focal contractions of the cortical bone at the superior aspect of the femoral neck, the lateral cortical bone just inferior to the greater trochanter, and the anterior intertrochanteric region. Results of this study support the idea that the spatial distribution of morphometric features is relevant to age-related changes in bone and independent to fracture risk. In women, the identification by TBM of fracture-specific morphometric alterations of the proximal femur, in conjunction with vBMD and clinical risk factors, may improve hip fracture prediction.

ContextThe conventional view that obesity is beneficial for bone strength has recently been challenged by studies that link obesity, particularly visceral obesity, to low bone mass and fractures. It is controversial whether effects of obesity on bone are mediated by increased bone resorption or decreased bone formation.ObjectiveThe objective of the study was to evaluate bone microarchitecture and remodeling in healthy premenopausal women of varying weights.DesignWe measured bone density and trunk fat by dual-energy x-ray absorptiometry in 40 women and by computed tomography in a subset. Bone microarchitecture, stiffness, remodeling, and marrow fat were assessed in labeled transiliac bone biopsies.ResultsBody mass index (BMI) ranged from 20.1 to 39.2 kg/m(2). Dual-energy x-ray absorptiometry-trunk fat was directly associated with BMI (r = 0.78, P < .001) and visceral fat by computed tomography (r = 0.79, P < .001). Compared with women in the lowest tertile of trunk fat, those in the highest tertile had inferior bone quality: lower trabecular bone volume (20.4 ± 5.8 vs 29.1 ± 6.1%; P = .001) and stiffness (433 ± 264 vs 782 ± 349 MPa; P = .01) and higher cortical porosity (8.8 ± 3.5 vs 6.3 ± 2.4%; P = .049). Bone formation rate (0.004 ± 0.002 vs 0.011 ± 0.008 mm(2)/mm · year; P = .006) was 64% lower in the highest tertile. Trunk fat was inversely associated with trabecular bone volume (r = -0.50; P < .01) and bone formation rate (r = -0.50; P < .001). The relationship between trunk fat and bone volume remained significant after controlling for age and BMI.ConclusionsAt the tissue level, premenopausal women with more central adiposity had inferior bone quality and stiffness and markedly lower bone formation. Given the rising levels of obesity, these observations require further investigation.

ContextBone marrow fat (BMF) and bone mineral density (BMD) by dual x-ray energy absorptiometry (DXA) are negatively correlated. However, little is known about the association of BMF with fracture or with separate trabecular and cortical bone compartments.ObjectiveOur objective was to assess the relationships between vertebral BMF, BMD by quantitative computed tomography, and fracture in older adults.Design, setting, and participantsWe conducted a cross-sectional study in the Age Gene/Environment Susceptibility-Reykjavik cohort.Main outcome measuresOutcomes measures included vertebral BMF (L1-L4) measured with magnetic resonance spectroscopy, quantitative computed tomography and DXA scans of the hip and spine, and DXA vertebral fracture assessments. Previous clinical fracture was determined from medical records.ResultsIn 257 participants without recent bone-active medication use, mean age was 79 (SD 3.1) years. Mean BMF was 53.5% ± 8.1% in men and 55.0% ± 8.4% in women. Those with prevalent vertebral fracture (21 men, 32 women) had higher mean BMF in models adjusted for BMD. In separate models by sex, the difference was statistically significant only in men (57.3% vs 52.8%, P = 0.02). BMF was associated with lower trabecular volumetric BMD (vBMD) at the spine (-10.5% difference for each 1 SD increase in BMF, P < 0.01), total hip, and femoral neck, but not with cortical vBMD, in women. In men, BMF was marginally associated with trabecular spine vBMD (-6.1%, P = 0.05). Total hip and spine areal BMD (aBMD) were negatively correlated with BMF in women only.ConclusionHigher marrow fat correlated with lower trabecular, but not cortical, BMD in older women but not men. Higher marrow fat was associated with prevalent vertebral fracture in men, even after adjustment for BMD.

Hip fracture risk rises exponentially with age, but there is little knowledge about how fracture-related alterations in hip structure differ from those of aging. We employed computed tomography (CT) imaging to visualize the three-dimensional (3D) spatial distribution of bone mineral density (BMD) in the hip in relation to age and incident hip fracture. We used intersubject image registration to integrate 3D hip CT images into a statistical atlas comprising women aged 21 to 97 years (n = 349) and a group of women with (n = 74) and without (n = 148) incident hip fracture 4 to 7 years after their imaging session. Voxel-based morphometry was used to generate Student's t test statistical maps from the atlas, which indicated regions that were significantly associated with age or with incident hip fracture. Scaling factors derived from intersubject image registration were employed as measures of bone size. BMD comparisons of young, middle-aged, and older American women showed preservation of load-bearing cortical and trabecular structures with aging, whereas extensive bone loss was observed in other trabecular and cortical regions. In contrast, comparisons of older Icelandic fracture women with age-matched controls showed that hip fracture was associated with a global cortical bone deficit, including both the superior cortical margin and the load-bearing inferior cortex. Bone size comparisons showed larger dimensions in older compared to younger American women and in older Icelandic fracture women compared to controls. The results indicate that older Icelandic women who sustain incident hip fracture have a structural phenotype that cannot be described as an accelerated pattern of normal age-related loss. The fracture-related cortical deficit noted in this study may provide a biomarker of increased hip fracture risk that may be translatable to dual-energy X-ray absorptiometry (DXA) and other clinical images.

ContextIdiopathic osteoporosis (IOP) affects otherwise healthy young individuals with intact gonadal function and no secondary cause of bone fragility. In premenopausal women with IOP, a low trauma fracture is evidence of impaired bone quality and strength. The extent to which low bone mineral density (BMD) by dual-energy x-ray absorptiometry (DXA) reflects low volumetric BMD, bone microstructure, and strength is uncertain in the absence of low trauma fracture.ObjectiveThe objective of the study was to compare three-dimensional volumetric BMD and bone stiffness in premenopausal women with IOP based on fracture history, those with idiopathic low BMD (Z score ≤ -2.0) and no low trauma fracture, and normal age-matched controls.DesignWe measured volumetric BMD and bone geometry by central quantitative computed tomography (cQCT) scans of the spine and hip and estimated bone stiffness by finite element analysis of cQCT data sets in 32 premenopausal women with IOP, 12 with idiopathic low BMD, and 34 controls.ResultsSubjects had comparable decreases in total and trabecular volumetric BMD, cortical thickness, and whole-bone stiffness compared with controls, regardless of fracture history. These differences remained significant after controlling for age, body mass index, and bone size. The positive predictive values of a DXA Z score of -2.0 or less for a cQCT volumetric BMD Z score of -2.0 or less were 95% at the lumbar spine, 90% at the total hip, and 86% at the femoral neck.ConclusionWomen with idiopathic low BMD alone and those with low trauma fractures had comparable deficits in bone mass, structure, and stiffness. Low areal BMD by DXA is fairly accurate for predicting low volumetric BMD by cQCT. These results are consistent with three-dimensional bone imaging at the iliac crest, radius, and tibia in premenopausal IOP and suggest that the term osteoporosis may be appropriate in women with Z scores below -2.0, whether or not there is a history of fracture.

Astronauts experience bone loss after the long spaceflight missions. Identifying specific regions that undergo the greatest losses (e.g. the proximal femur) could reveal information about the processes of bone loss in disuse and disease. Methods for detecting such regions, however, remains an open problem. This paper focuses on statistical methods to detect such regions. We perform statistical parametric mapping to get t-maps of changes in images, and propose a new cross-validation method to select an optimum suprathreshold for forming clusters of pixels. Once these candidate clusters are formed, we use permutation testing of longitudinal labels to derive significant changes.

Fatty infiltration of muscle, myosteatosis, increases with age and results in reduced muscle strength and function and increased fall risk. However, it is unknown if increased fatty infiltration of muscle predisposes to hip fracture. We measured the mean Hounsfield unit (HU) of the lean tissue within the midthigh muscle bundle (thigh muscle HU, an indicator of intramuscular fat), its cross-sectional area (CSA, a measure of muscle mass) by computed tomography (CT), bone mineral density (BMD) of the hip and total-body percent fat by dual X-ray absorptiometry (DXA), isokinetic leg extensor strength, and the Short Physical Performance Battery (SPPB) in 2941 white and black women and men aged 70 to 79 years. Sixty-three hip fractures were validated during 6.6 years of follow-up. Proportional hazards regression analysis was used to assess the relative risk (RR) of hip fracture across variations in thigh muscle attenuation, CSA, muscle strength, and physical function for hip fracture. In models adjusted by age, race, gender, body mass index, and percentage fat, decreased thigh muscle HU resulted in increased risk of hip fracture [RR/SD = 1.58; 95% confidence interval (CI) 1.10-1.99], an association that continued to be significant after further adjustment for BMD. In models additionally adjusted by CSA, muscle strength, and SPPB score, decreased thigh muscle HU but none of the other muscle parameters continued to be associated with an increased risk of hip fracture (RR/SD = 1.42; 95% CI 1.03-1.97). Decreased thigh muscle HU, a measure of fatty infiltration of muscle, is associated with increased risk of hip fracture and appears to account for the association between reduced muscle strength, physical performance, and muscle mass and risk of hip fracture. This characteristic captures a physical characteristic of muscle tissue that may have importance in hip fracture etiology.

In contrast to conventional dual-energy X-ray absorptiometry, quantitative computed tomography separately measures trabecular and cortical volumetric bone mineral density (vBMD). Little is known about the genetic variants associated with trabecular and cortical vBMD in humans, although both may be important for determining bone strength and osteoporotic risk. In the current analysis, we tested the hypothesis that there are genetic variants associated with trabecular and cortical vBMD at the femoral neck by genotyping 4608 tagging and potentially functional single-nucleotide polymorphisms (SNPs) in 383 bone metabolism candidate genes in 822 Caucasian men aged 65 years or older from the Osteoporotic Fractures in Men Study (MrOS). Promising SNP associations then were tested for replication in an additional 1155 men from the same study. We identified SNPs in five genes (IFNAR2, NFATC1, SMAD1, HOXA, and KLF10) that were robustly associated with cortical vBMD and SNPs in nine genes (APC, ATF2, BMP3, BMP7, FGF18, FLT1, TGFB3, THRB, and RUNX1) that were robustly associated with trabecular vBMD. There was no overlap between genes associated with cortical vBMD and trabecular vBMD. These findings identify novel genetic variants for cortical and trabecular vBMD and raise the possibility that some genetic loci may be unique for each bone compartment.