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Context: FSH may have independent actions on bone remodeling and body fat regulation. Cross-sectionally, we have shown that serum FSH is associated with bone mineral density (BMD) and body fat in older postmenopausal women, but it remains unknown whether FSH predicts bone and fat changes., Objective: We examined whether baseline FSH level is associated with subsequent bone loss or body composition changes in older adults., Setting, Design, Participants: We studied 162 women and 158 men (mean age 82 ± 4 years) from the Age, Gene/Environment Susceptibility (AGES)-Bone Marrow Adiposity cohort, a substudy of the AGES-Reykjavik Study of community-dwelling older adults. Skeletal health and body composition were characterized at baseline and 3 years later., Main Outcomes: Annualized change in BMD and body composition by dual-energy X-ray absorptiometry (DXA) and quantitative computed tomography (QCT). Models were adjusted for serum estradiol and testosterone levels., Results: There was no evidence for an association between baseline FSH level and change in BMD or body composition by DXA or QCT. For femoral neck areal BMD, adjusted mean difference (95% CI) per SD increase in FSH was 1.3 (-0.7 to 3.3) mg/cm2/y in women, and -0.2 (-2.6 to 2.2) mg/cm2/y in men. For visceral fat, adjusted mean difference (95% CI) per SD increase in FSH was 1.80 (-0.03 to 3.62) cm2/y in women, and -0.33 (-3.73 to 3.06) cm2/y in men., Conclusions: Although cross-sectional studies and studies in perimenopausal women have demonstrated associations between FSH and BMD and body composition, in older adults, FSH level is not associated with bone mass or body composition changes., (Published by Oxford University Press on behalf of the Endocrine Society 2021.)

Introduction: In 2010, experts in osteoporosis and bone densitometry were convened by the Space Life Sciences Directorate at NASA Johnson Space Center to identify a skeletal outcome in astronauts after spaceflight that would require a clinical response to address fracture risk. After reviewing astronaut data, experts expressed concern over discordant patterns in loss and recovery of bone mineral density (BMD) after spaceflight as monitored by dual-energy X-ray absorptiometry (DXA) and quantitative computed tomography (QCT). The pilot study described herein demonstrates the use of QCT to evaluate absence of recovery in hip trabecular BMD by QCT as an indicator of a clinically actionable response., Methodology: QCT and DXA scans of both hips were performed on 10 astronauts: once preflight and twice postflight about 1 wk and 1 yr after return. If trabecular BMD had not returned to baseline (i.e., within QCT measurement error) in 1 or both hips 1 yr after flight, then another QCT hip scan was obtained at 2 yr after flight., Results: Areal BMD by DXA recovered in 9 of 10 astronauts at 1 yr postflight while incomplete recovery of trabecular BMD by QCT was evident in 5 of 10 astronauts and persisted in 4 of the 5 astronauts 2 yr postflight., Conclusion: As an adjunct to DXA, QCT is needed to detect changes to hip trabecular BMD after spaceflight and to confirm complete recovery. Incomplete recovery at 2 yr should trigger the need for further evaluation and possible intervention to mitigate premature fragility and fractures in astronauts following long-duration spaceflight., (Copyright © 2019 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2018. Published by Elsevier Inc.)

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., (Published by Elsevier Inc.)

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., (© 2017 American Society for Bone and Mineral Research.)

Background: Although 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., Objectives: This study aimed to examine the association of 24-hour sleep duration with mid-thigh muscle composition and proximal femur volumetric bone mineral density (vBMD)., Methods: 2438 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., Results: We 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., Conclusion: Long 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., (Published by Elsevier Inc.)

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., (© 2017 American Society for Bone and Mineral Research.)

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.

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., (© 2016 American Society for Bone and Mineral Research.)

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., (© 2015 American Society for Bone and Mineral Research.)

Quantitative computed tomography (QCT) is currently undergoing a renaissance, with an increasing number of studies being published and the definition of both QCT-specific osteoporosis thresholds and treatment criteria. Compared with dual-energy X-ray absorptiometry, the current standard bone mineral density technique, QCT has a number of pertinent advantages, including volumetric measurements, less susceptibility to degenerative spine changes, and higher sensitivity to changes in bone mass. Disadvantages include the higher radiation doses and less experience with fracture prediction and therapy monitoring. Over the last 10 yr, a number of novel applications have been described allowing assessment of bone mineral density and bone quality in larger patient populations, developments that may substantially improve patient care., (Copyright © 2014 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

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<0.05) inter-scanner differences were detected in all measurements except My and FEfall, and no ASP-based correction was able to reduce inter-scanner variability to corresponding levels of intra-scanner precision. Inter-scanner variability was considerably higher than intra-scanner precision, even in cases where the mean inter-scanner difference was statistically insignificant. A significant (p<0.01) effect of body size on inter-scanner differences in BMD was detected, demonstrating a need to address the effects of body size on QCT measurements. The results of this study show that significant inter-scanner differences in QCT-based measurements of BMD and bone strength can remain even when using an ASP., (Copyright © 2014 IPEM. All rights reserved.)

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 < 0.05) associations with fractures. Results remained the same in stratified models for participants not taking bone-promoting medication. In women on bone-promoting medication, greater femur neck cortical thickness and trabecular BMD were significantly associated with fracture status. However, the association between fracture and combined bone score was not stronger than the associations between fracture and individual measures or total femur BMD. Thus, the selected measures did not all similarly associate with fracture status and did not appear to have an additive effect on fracture status., (Copyright © 2014 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

Context: The 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., Objective: The objective of the study was to evaluate bone microarchitecture and remodeling in healthy premenopausal women of varying weights., Design: We 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., Results: Body 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., Conclusions: At 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.

Context: Bone 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., Objective: Our objective was to assess the relationships between vertebral BMF, BMD by quantitative computed tomography, and fracture in older adults., Design, Setting, and Participants: We conducted a cross-sectional study in the Age Gene/Environment Susceptibility-Reykjavik cohort., Main Outcome Measures: Outcomes 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., Results: In 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., Conclusion: Higher 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.

Context: Idiopathic 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., Objective: The 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., Design: We 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., Results: Subjects 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., Conclusion: Women 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.

Genetic factors likely contribute to the risk for vertebral fractures; however, there are few studies on the genetic contributions to vertebral fracture (VFrx), vertebral volumetric bone mineral density (vBMD), and geometry. Also, the heritability (h(2)) for VFrx and its genetic correlation with phenotypes contributing to VFrx risk have not been established. This study aims to estimate the h(2) of vertebral fracture, vBMD, and cross-sectional area (CSA) derived from quantitative computed tomography (QCT) scans and to estimate the extent to which they share common genetic association in adults of European ancestry from three generations of Framingham Heart Study (FHS) families. Members of the FHS families were assessed for VFrx by lateral radiographs or QCT lateral scout views at 13 vertebral levels (T(4) to L(4)) using Genant's semiquantitative (SQ) scale (grades 0 to 3). Vertebral fracture was defined as having at least 25% reduction in height of any vertebra. We also analyzed QCT scans at the L(3) level for integral (In.BMD) and trabecular (Tb.BMD) vBMD and CSA. Heritability estimates were calculated, and bivariate genetic correlation analysis was performed, adjusting for various covariates. For VFrx, we analyzed 4099 individuals (148 VFrx cases) including 2082 women and 2017 men from three generations. Estimates of crude and multivariable-adjusted h(2) were 0.43 to 0.69 (p < 1.1 × 10(-2)). A total of 3333 individuals including 1737 men and 1596 women from two generations had VFrx status and QCT-derived vBMD and CSA information. Estimates of crude and multivariable-adjusted h(2) for vBMD and CSA ranged from 0.27 to 0.51. In a bivariate analysis, there was a moderate genetic correlation between VFrx and multivariable-adjusted In.BMD (-0.22) and Tb.BMD (-0.29). Our study suggests vertebral fracture, vertebral vBMD, and CSA in adults of European ancestry are heritable, underscoring the importance of further work to identify the specific variants underlying genetic susceptibility to vertebral fracture, bone density, and geometry., (Copyright © 2012 American Society for Bone and Mineral Research.)

The mechanism whereby poor intrauterine growth increases risk of adult hip fracture is unclear. We report the association between birth weight and proximal femoral geometry and density in community-dwelling elderly men. We used self-reported birth weight, measured adult height and weight and proximal femoral quantitative computed tomography (QCT) measurements of femoral neck axis length, cross-sectional area, and volumetric BMD (vBMD) among the participants in the Osteoporotic Fractures in Men (MrOS), a cohort study of community-dwelling US men aged 65 and older. We compared men with birth weight <7 pounds (lower birth weight [LBW]; n = 501) and ≥ 9 pounds (higher birth weight [HBW]; n = 262) with those weighing 7-8.9 pounds (medium birth weight [MBW], referent group; n = 1068) using linear regression adjusting for current age, height, and BMI. The mean age of the 1831 men who had both birth weight and QCT measurements was 73 years (SD 5.9). Compared with the referent MBW, HBW men had concordantly longer femoral neck (+0.16 SD; p = .028) and cross-sectional area (+0.24 SD, p = .001). LBW men had a smaller cross-sectional (-0.26 SD, p < .001) but longer femoral neck for their height (+0.11 SD, p = .05). Neither cortical nor trabecular vBMD at the femoral neck was associated with birth weight. These findings support the hypothesis that the skeletal envelope, but not density, is set, in part, at birth. Further research exploring the association between early developmental factors and lifetime fracture risk is needed and may inform primary preventative strategies for fracture prevention., (Copyright © 2011 American Society for Bone and Mineral Research.)

Context: Older adults with type 2 diabetes are at higher risk for fracture compared with nondiabetic adults after adjustment for their higher bone mineral density. Infiltration of muscle by fat predicts increased risk of hip fracture., Objective: We investigated whether fat infiltration of muscle, which is greater in diabetic adults, is associated with all clinical fracture and whether it accounts for the increased fracture risk in those with diabetes., Design, Setting, and Participants: Data were analyzed from the Health, Aging, and Body Composition Study, a cohort of community-dwelling adults aged 70-79 yr. Glucose metabolism status and x-ray attenuation of thigh muscle were determined at baseline for 2762 participants., Main Outcome Measures: During a mean 8.2 ± 2.3 yr follow-up, 331 participants reported at least one clinical fracture., Results: Fat infiltration of muscle was higher in those with diabetes or impaired glucose metabolism than in those with normal glucose metabolism (P < 0.001). Fat infiltration of muscle was independently associated with a 19% increased risk of incident clinical fracture (multivariate hazard ratio = 1.19; 95% confidence interval = 1.04-1.36); this association did not differ across glucose metabolism groups (P for interaction = 0.65). As previously reported, diabetes was associated with a greater fracture risk compared with normal glucose metabolism (hazard ratio = 1.42; 95% confidence interval = 1.07-1.89) after adjustment for bone mineral density, but further adjustment for fat infiltration of muscle did not attenuate this association., Conclusions: Fat infiltration of muscle predicts clinical fracture in older adults. Although fat infiltration of muscle is higher among those with diabetes, it does not account for their increased fracture risk.

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., (Copyright 2010 American Society for Bone and Mineral Research.)

Genetics is a well-established but poorly understood determinant of BMD. Whereas some genetic variants may influence BMD throughout the body, others may be skeletal site specific. We initially screened for associations between 4608 tagging and potentially functional single nucleotide polymorphisms (SNPs) in 383 candidate genes and femoral neck and lumbar spine volumetric BMD (vBMD) measured from QCT scans among 862 community-dwelling white men >or=65 yr of age in the Osteoporotic Fractures in Men Study (MrOS). The most promising SNP associations (p < 0.01) were validated by genotyping an additional 1156 white men from MrOS. This analysis identified 8 SNPs in 6 genes (APC, DMP1, FGFR2, FLT1, HOXA, and PTN) that were associated with femoral neck vBMD and 13 SNPs in 7 genes (APC, BMPR1B, FOXC2, HOXA, IGFBP2, NFATC1, and SOST) that were associated with lumbar spine vBMD in both genotyping samples (p < 0.05). Although most associations were specific to one skeletal site, SNPs in the APC and HOXA gene regions were associated with both femoral neck and lumbar spine BMD. This analysis identifies several novel and robust genetic associations for volumetric BMD, and these findings in combination with other data suggest the presence of genetic loci for volumetric BMD that are at least to some extent skeletal-site specific.

We propose a fracture risk estimation technique based on image similarity. We employ image similarity indices to determine how images are similar to each other in their 3D bone mineral density distributions. Our premise for fracture risk estimation is that if a given scan is more similar to scans of subjects known to have fractures than to scans of control subjects, this subject is likely to have a higher degree of fracture risk. To test this hypothesis, we analyzed hip QCT scans of 37 patients with hip fractures and 38 age-matched controls. We divided the scans randomly into two groups: the Model Group and the Test Group. For each scan in the Test Group, the difference between the mean value of its image similarities to the Model fracture group and the mean value of its image similarities to the Model control group was used as index of fracture risk. We then used the estimated fracture risk indices to discriminate the fractured patients and controls in the Test Group. A test scan with a larger mean value of image similarities with respect to the Model fracture group was classified as a scan from a fractured patient, otherwise it was classified as a scan from a control subject. Based on ROC analysis, we compared the discrimination performances using image similarity measures with that obtained by using bone mineral density (BMD). When using BMD measured in the femoral neck, with the optimal BMD cutoff, the sensitivity and specificity were 86.5% and 73.7%. For the image similarity measures, the sensitivity ranged between 86.5% and 100%, and specificity ranged between 63.2% and 76.3%. By combining BMD with image similarity measures, the sensitivity and specificity reached 94.6% and 76.3% using linear discriminant analysis (LDA) algorithm, or 91.9% and 81.6% using recursive partitioning and regression trees (RPART) algorithm. In the RPART approach, the AUC value of the ROC curve was 0.923, higher than the AUC value of 0.835 when using BMD alone (p-value: 0.0046). Our results showed that combining BMD with image similarity measures resulted in improved hip fracture risk estimation.

To examine the effects of race and sex on bone density and geometry at specific sites within the proximal femur and lumbar spine, we used quantitative computed tomography to image 30 Caucasian American (CA) men, 25 African American (AA) men, 30 CA women, and 17 AA women aged 35-45 yr. Volumetric integral bone mineral density (BMD), trabecular BMD (tBMD), and cross sectional area were measured in the femoral neck, trochanter, total femur, and L1/L2 vertebrae. Volumetric cortical BMD (cBMD) was also measured in the femur regions of interest. Differences were ascertained using a multivariate regression model. Overall, AA subjects had denser bones than CA subjects, but there were no racial differences in bone size. Men had larger femoral necks but not larger vertebrae than women. The AA men had higher tBMD and cBMD in the femur than CA men, whereas AA women had higher femoral tBMD but not higher femoral cBMD than CA women. These data support the idea that higher hip fracture rates in women compared with men are associated with smaller bone size. Lower fracture rates in AA elderly compared with CA elderly are consistent with higher peak bone density, particularly in the trabecular compartment, and potentially lower rates of age-related bone loss rather than larger bone size.

Atherosclerosis and osteoporosis share many risk factors, but their independent association is unclear. The authors investigated the independent associations between volumetric trabecular bone mineral density (vBMD) of the lumbar spine and coronary artery calcium (CAC) and abdominal aortic calcium (AAC). During 2002-2005, they used quantitative computed tomography to assess vBMD and the presence and extent of CAC and AAC among 946 women (mean age = 65.5 years) and 963 men (mean age = 64.1 years) in a substudy of the Multi-Ethnic Study of Atherosclerosis. Prevalences of CAC were 47% and 68% in women and men, respectively, and AAC prevalences were 70% and 73%. Sequential, sex-specific regression models included adjustment for age, ethnicity, body mass index, hypertension, dyslipidemia, diabetes mellitus, smoking, alcohol consumption, physical activity, interleukin-6, C-reactive protein, homocysteine, and sex hormones. After full adjustment, lower vBMD was associated with greater CAC score among women (P < 0.002) and greater AAC score among women (P = 0.004) and men (P < 0.001). After adjustment, vBMD quartile was inversely associated with CAC prevalence (P-trend = 0.05) in women and AAC prevalence (P-trend < 0.01) in men. Partially and fully adjusted models showed similar results. Though modest, these significant, independent associations suggest that atherosclerosis and bone loss may be related.

Unlabelled: In a prospective study of 1446 black and white adults 70-79 yr of age (average follow-up, 6.4 yr), vertebral TrvBMD from QCT predicted non-spine fracture in black and white women and black men, but it was not a stronger predictor than total hip aBMD from DXA. Hip aBMD predicted non-spine fracture in black men., Introduction: Areal BMD (aBMD) at multiple skeletal sites predicts clinical non-spine fractures in white and black women and white men. The predictive ability of vertebral trabecular volumetric BMD (TrvBMD) for all types of clinical non-spine fractures has never been tested or compared with hip aBMD. Also, the predictive accuracy of hip aBMD has never been tested prospectively for black men., Materials and Methods: We measured vertebral TrvBMD with QCT and hip aBMD with DXA in 1446 elderly black and white adults (70-79 yr) in the Health, Aging, and Body Composition Study. One hundred fifty-two clinical non-spine fractures were confirmed during an average of 6.4 yr of >95% complete follow-up. We used Cox proportional hazards regression to determine the hazard ratio (HR) and 95% CIs of non-spine fracture per SD reduction in hip aBMD and vertebral TrvBMD., Results: Vertebral TrvBMD and hip aBMD were both associated with risk of non-spine fracture in black and white women and black men. The age-adjusted HR of fracture per SD decrease in BMD was highest in black men (hip aBMD: HR = 2.04, 95% CI = 1.03, 4.04; vertebral TrvBMD: HR = 3.00, 95% CI = 1.29, 7.00) and lowest in white men (hip aBMD: HR = 1.23, 95% CI = 0.85, 1.78; vertebral TrvBMD: HR = 1.06, 95% CI = 0.73, 1.54). Adjusted for age, sex, and race, each SD decrease in hip aBMD was associated with a 1.67-fold (95% CI = 1.36, 2.07) greater risk of fracture, and each SD decrease in vertebral TrvBMD was associated with a 1.47-fold (95% CI = 1.18, 1.82) greater risk. Combining measurements of hip aBMD and vertebral TrvBMD did not improve fracture prediction., Conclusions: Low BMD measured by either spine QCT or hip DXA predicts non-spine fracture in older black and white women and black men. Vertebral TrvBMD is not a stronger predictor than hip aBMD of non-spine fracture.

Unlabelled: We measured femoral neck and shaft dimensions and volumetric BMD with QCT. Relations of these measures to age were quantified in a cross-sectional study among 3358 men 65-100 years old. Relations of femoral neck dimensions and vBMD to age differed from those in the shaft, indicating that patterns of bone modeling and remodeling in the neck and shaft are distinct., Introduction: Little is known about population variation in dimensions and volumetric BMD of the proximal femur or the relation of these measures to age among older men., Materials and Methods: In a cross-sectional study, dimensions and volumetric BMD (vBMD) in the femoral neck and shaft were obtained from QCT scans among 3358 men 65-100 years of age in the Osteoporotic Fractures in Men cohort. Total bone size and size of the cortical and medullary compartments were measured with volumes in the femoral neck and with areas in the shaft. We quantified distributions of these measures and examined their relations to age with multivariable linear regression., Results: Population variation in femoral neck and shaft dimensions and vBMD was substantial. In the femoral neck, total volume was minimally related to age, whereas cortical volume was 5% smaller and medullary volume was 10% larger (both p < 0.0001) in the oldest (85+ years) compared with the youngest (65-69 years) men. Across these ages, the percent of cortical bone declined from 46% to 42% (p < 0.0001). Integral and trabecular vBMD were 9% and 22% lower, whereas DXA femoral neck BMD was 4% lower, in the older men. Neck cortical vBMD was unrelated to age. In the shaft, cross-sectional area and medullary area were 9% and 22% larger, respectively, in the oldest men (both p < 0.0001), but cortical area was unchanged with age. The percent of cortical bone declined from 69% to 65% across these ages (p < 0.0001). Shaft cortical BMD was 4% lower in the older men (p < 0.0001)., Conclusions: There is substantial diversity of femoral morphology and vBMD among older U.S. men. Patterns indicative of modeling and remodeling in the femoral neck were distinct from those in the shaft. Notably, changes in periosteal and endosteal dimensions that underlie cortical thinning appear to differ in the neck and shaft.

To eliminate user interaction in longitudinal quantitative computed tomography (QCT) measurements of bone mineral density (BMD) and geometry, we have developed and optimized an automated registration algorithm for QCT images of the hip and spine and integrated it with a previously developed 3D densitometric and structural analysis program. With registration, the follow-up images are automatically aligned with respect to the baseline scans, and the bone quantification of the aligned follow-up scan is initiated based on the bone morphometric features defined on the baseline scan. To validate the algorithm, we analyzed 20 pairs of repeat QCT images (10 hip pairs and 10 spine pairs) acquired on a modern multi-slice CT scanner, with repositioning between each scan pair to simulate repeat visits. Bone measurements obtained with automatic registration achieved comparable or improved precision errors compared to those obtained by careful manual analysis of the follow-up scans. The algorithm we have developed was based on the mutual information approach, with simplex optimization under a multi-resolution scheme. The average registration time was 2.3 min for a hip pair and 1.1 min for a vertebra pair using a standard desktop computer. Based on the reduced user interaction, high degree of precision, and short execution time, this is a promising technique for monitoring therapy in patients and clinical trials.

Background: Since the use of parathyroid hormone as a treatment for osteoporosis is limited to two years or less, the question of whether antiresorptive therapy should follow parathyroid hormone therapy is important. We previously reported results after the first year of this randomized trial comparing the use of full-length parathyroid hormone (1-84) alone, alendronate alone, or both combined. In the continuation of this trial, we asked whether antiresorptive therapy is required to maintain gains in bone mineral density after one year of therapy with parathyroid hormone (1-84)., Methods: In the data reported here, women who had received parathyroid hormone (1-84) monotherapy (100 microg daily) in year 1 were randomly reassigned to one additional year with either placebo (60 subjects) or alendronate (59 subjects). Subjects who had received combination therapy in year 1 received alendronate in year 2; those who had received alendronate monotherapy in year 1 continued with alendronate in year 2. Bone mineral density at the spine and hip was assessed with the use of dual-energy x-ray absorptiometry and quantitative computed tomography (CT)., Results: Over two years, alendronate therapy after parathyroid hormone therapy led to significant increases in bone mineral density in comparison with the results for placebo after parathyroid hormone therapy, a difference particularly evident for bone mineral density in trabecular bone at the spine on quantitative CT (an increase of 31 percent in the parathyroid hormone-alendronate group as compared with 14 percent in the parathyroid hormone-placebo group). During year 2, subjects receiving placebo lost substantial bone mineral density., Conclusions: After one year of parathyroid hormone (1-84), densitometric gains appear to be maintained or increased with alendronate but lost if parathyroid hormone is not followed by an antiresorptive agent. These results have clinical implications for therapeutic choices after the discontinuation of parathyroid hormone., (Copyright 2005 Massachusetts Medical Society.)

We sought to evaluate serum concentrations of cathepsin K in peripheral blood and to determine whether they correlated with bone-mineral density (BMD) and the incidence of nontraumatic fractures. We took blood samples from 162 patients (101 with osteoporosis, 48 with osteopenia) and 13 healthy controls, then conducted quantitative measurements of cathepsin K using a commercially available enzyme-linked immunosorbent assay. Cathepsin K concentrations were correlated with the incidence of nontraumatic fracture, BMD, markers of bone turnover (alkaline phosphatase, bone-specific alkaline phosphatase, osteocalcin, parathyroid hormone, and C-telopeptide). The correlations between cathepsin K concentrations in subjects without fractures and in those with multiple nontraumatic fractures were statistically significant ( t = -2.1, degrees of freedom = 107, P = .036). The cathepsin K levels of controls and patients with osteoporosis were significantly different ( t = -3.7, degrees of freedom = 58.9, p>0.0001) These results suggest that the serum level of cathepsin K could serve as a marker for fracture prediction and BMD.

Unlabelled: Chronic treatment with glucocorticoids (GCs) leads to significant bone loss and increased risk of fractures. In chronically GC-treated patients, hip fracture risk is nearly 50%. The purpose of this investigation was to determine if there are differences in the quantities of trabecular and cortical bone and bone strength of the hip between GC-treated osteoporotic patients and controls., Methods: Study subjects were GC-treated osteoporotic postmenopausal women, and controls were postmenopausal women, recruited for separate clinical trials. Quantitative computed tomography (QCT) and dual-energy X-ray absorptiometry (DXA) of the hip were obtained from all subjects. QCT outcome variables measured included total, cortical, and trabecular BMD of hip subregions (femoral neck and trochanter) and total hip. In addition, finite element modeling (FEM) was performed on a subset of 19 cases and 38 controls, matched on age (+/- 5 years), weight (+/- 5 kg), and history of hormone replacement (> 1 year use) to assess failure load in stance and fall loading conditions. Generalized linear models were used to adjust the QCT variables for covariates between groups. Multiple regression was performed to identify independent predictors of bone strength from the QCT variables., Results: Compared with controls, GC-treated subjects were significantly (p < 0.05) younger, weighed less, and had more years of hormone replacement. QCT of the hip in GC-treated subjects for total femoral integral, cortical, and trabecular BMD averaged 4.9-23.2% (p < 0.002) less than controls, and similar results were seen by hip subregion including the trochanter and femoral neck. DXA of the total hip was 17% lower in GC subjects than controls (p < 0.05). Compared with controls, FEM failure load in GC subjects was 15% (p<0.05) and 16% (p = 0.07) lower for stance and fall loading conditions, respectively. Multiple regression analysis demonstrated that a combination of QCT measures was correlated with bone strength as measured by FEM., Conclusions: Chronic GC treatment in postmenopausal women resulted in significantly decreased BMD of the hip, measured by QCT, with loss of both trabecular and cortical bone. In addition, GC treatment decreased bone strength as determined by FEM. The reduced cortical and trabecular bone mass in the hip may contribute to the disproportionately high hip fracture rates observed in GC-treated subjects.

Volumetric quantitative computed tomography (vQCT), using multiple thin-slice acquisition, measures three-dimensional volumetric bone mineral density (BMD, mg/cm3). vQCT is often used to measure BMD of lumbar vertebrae and may detect early changes in trabecular, cortical, or integral BMD that extend beyond the technical limits of areal dual X-ray absorptiometry (DXA) BMD measurements. The objective of this study was to determine the effect of 2 years of raloxifene (RLX) treatment on several volumetric BMD measures in a subset of postmenopausal women (n=58) enrolled in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial. Patients in this study were randomized to one of three treatment groups: placebo (n=21), RLX 60 mg/day (n=17), or RLX 120 mg/day (n=20), and all patients received daily calcium (500 mg) and vitamin D (400-600 IU) supplementation. Data from the raloxifene treatment groups were pooled for each analysis. Following 2 years of raloxifene treatment, there was a significant percent change from baseline in the vQCT regions of interest (ROIs) of midintegral BMD, total trabecular BMD, and total integral BMD (P<0.05) compared to placebo, while there was no significant change in the spinal DXA BMD measurement. These data provide the first longitudinal assessment by vQCT of changes in vertebral bone density after 2 years of treatment with raloxifene. vQCT appears to be a valuable technique for measuring the effects of raloxifene treatment in this population of postmenopausal women with osteoporosis.

Unlabelled: We measured cortical and trabecular bone loss using QCT of the spine and hip in 14 crewmembers making 4- to 6-month flights on the International Space Station. There was no compartment-specific loss of bone in the spine. Cortical bone mineral loss in the hip occurred primarily by endocortical thinning., Introduction: In an earlier study, areal BMD (aBMD) measurements by DXA showed that cosmonauts making flights of 4- to 12-month duration on the Soviet/Russian MIR spacecraft lost bone at an average rate of 1%/month from the spine and 1.5%/month from the hip. However, because DXA measurements represent the sum of the cortical and trabecular compartments, there is no direct information on how these bone envelopes are affected by spaceflight., Materials and Methods: To address this, we performed a study of crewmembers (13 males and 1 female; age range, 40-55 years) on long-duration missions (4-6 months) on the International Space Station (ISS). We used DXA to obtain aBMD of the hip and spine and volumetric QCT (vQCT) to assess integral, cortical, and trabecular volumetric BMD (vBMD) in the hip and spine. In the heel, DXA was used to measure aBMD, and quantitative ultrasound (QUS) was used to measure speed of sound (SOS) and broadband ultrasound attenuation (BUA)., Results and Conclusions: aBMD was lost at rates of 0.9%/month at the spine (p < 0.001) and 1.4-1.5%/month at the hip (p < 0.001). Spinal integral vBMD was lost at a rate of 0.9%/month (p < 0.001), and trabecular vBMD was lost at 0.7%/month (p < 0.05). In contrast to earlier reports, these changes were generalized across the vertebrae and not focused in the posterior elements. In the hip, integral, cortical, and trabecular vBMD was lost at rates of 1.2-1.5%/month (p < 0.0001), 0.4-0.5%/month (p < 0.01), and 2.2-2.7%/month (p < 0.001), respectively. The cortical bone loss in the hip occurred primarily by cortical thinning. Calcaneal aBMD measurements by DXA showed smaller mean losses (0.4%/month) than hip or spine measurements, with SOS and BUA showing no change. In summary, our results show that ISS crewmembers, on average, experience substantial loss of both trabecular and cortical bone in the hip and somewhat smaller losses in the spine. These results do not support the use of calcaneal aBMD or QUS measurements as surrogate measures to estimate changes in the central skeleton., (Copyright 2004 American Society for Bone and Mineral Research)

Unlabelled: BMD was examined in users of NSAIDs (by COX selectivity) and aspirin in the Health ABC cohort (n = 2853). Significantly higher BMD was found in users of relative COX-2 selective NSAIDs with aspirin (COX-2/ASA) compared with nonusers. This suggests a role for COX-2/ASA in osteoporosis., Introduction: The purpose of this study was to determine the relationship of nonsteroidal anti-inflammatory drug (NSAID) use, by cyclo-oxygenase selectivity (COX), and aspirin use on bone mineral density (BMD) in participants from the Health, Aging, and Body Composition (Health ABC) population-based cohort. It is known that NSAIDs inhibit the COX enzyme and decrease production of prostaglandins, which are involved in regulation of bone turnover. COX has two isoforms, COX-1 and COX-2. Production of prostaglandins associated with bone loss is primarily mediated through the COX-2 pathway. In addition, aspirin may have effects on bone independent of the prostaglandin pathway., Materials and Methods: NSAID (by COX selectivity) and aspirin use and BMD were assessed in 2853 adults (49.5% women, 50.5% men: 43.1% black, 56.9% white; mean age: 73.6 years) from the Health ABC cohort. For the purposes of this analysis, relative COX-1 selective NSAIDs were defined as having a ratio of COX-1 IC50 to COX-2 IC50 of > 1 in whole blood, and relative COX-2 selective NSAIDs were defined as having a ratio of COX-1 IC50 to COX-2 IC50 of < 1 in whole blood. Analysis of covariance was used to compare BMD across each NSAID use and aspirin use category adjusting for age, race, gender, weight, height, study site, calcium and vitamin D supplementation, Womac score, history of rheumatoid arthritis, history of arthritis other than rheumatoid, and smoking status., Results: After adjustment for possible confounders, current use of relative COX-2 selective NSAIDs with aspirin was associated with higher BMD at the whole body (4.2%, 1.2-7.3 CI) and total hip (4.6%, 0.5-8.8 CI) by DXA and at both trabecular (34.1%, 15.4-52.7 CI) and cortical spine (12.8%, 2.3-23.3 CI) by quantitative computed tomography., Conclusions: Our data suggest that the combination of relative COX-2 selective NSAIDs and aspirin is associated with higher BMD at multiple skeletal sites in men and women.

Background and Aims: Hip fracture is a devastating event in terms of outcome in the elderly, and the best predictor of hip fracture risk is hip bone density, usually measured by dual X-ray absorptiometry (DXA). However, bone density can also be ascertained from computerized tomography (CT) scans, and mid-thigh scans are frequently employed to assess the muscle and fat composition of the lower limb. Therefore, we examined if it was possible to predict hip bone density using mid-femoral bone density., Methods: Subjects were 803 ambulatory white and black women and men, aged 70-79 years, participating in the Health, Aging and Body Composition (Health ABC) Study. Bone mineral content (BMC, g) and volumetric bone mineral density (vBMD, mg/cm3) of the mid-femur were obtained by CT, whereas BMC and areal bone mineral density (aBMD, g/cm2) of the hip (femoral neck and trochanter) were derived from DXA., Results: In regression analyses stratified by race and sex, the coefficient of determination was low with mid-femoral BMC, explaining 6-27% of the variance in hip BMC, with a standard error of estimate (SEE) ranging from 16 to 22% of the mean. For mid-femur vBMD, the variance explained in hip aBMD was 2-17% with a SEE ranging from 15 to 18%. Adjusting aBMD to approximate volumetric density did not improve the relationships. In addition, the utility of fracture prediction was examined. Forty-eight subjects had one or more fractures (various sites) during a mean follow-up of 4.07 years. In logistic regression analysis, there was no association between mid-femoral vBMD and fracture (all fractures), whereas a 1 SD increase in hip BMD was associated with reduced odds for fracture of approximately approximately 60%., Conclusions: These results do not support the use of CT-derived mid-femoral vBMD or BMC to predict DXA-measured hip bone mineral status, irrespective of race or sex in older adults. Further, in contrast to femoral neck and trochanter BMD, mid-femur vBMD was not able to predict fracture (all fractures).

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

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.

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.

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.

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.

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.

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

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.

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.

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.

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.