Publications by authors named "Thomas F Lang"

54 Publications

Heterogeneous Spatial and Strength Adaptation of the Proximal Femur to Physical Activity: A Within-Subject Controlled Cross-Sectional Study.

J Bone Miner Res 2020 04 30;35(4):681-690. Epub 2019 Dec 30.

Department of Physical Therapy, School of Health and Human Sciences, Indiana University, Indianapolis, IN, USA.

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.
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http://dx.doi.org/10.1002/jbmr.3939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145739PMC
April 2020

Greater Bone Marrow Adiposity Predicts Bone Loss in Older Women.

J Bone Miner Res 2020 02 14;35(2):326-332. Epub 2019 Nov 14.

Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA.

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 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 mg /cm /year greater loss of spine compressive strength index (p value = .003), a 0.9 mg/cm /year greater loss of spine trabecular BMD (p value = .02), and a 1.2 mg/cm /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.
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http://dx.doi.org/10.1002/jbmr.3895DOI Listing
February 2020

Use of Quantitative Computed Tomography to Assess for Clinically-relevant Skeletal Effects of Prolonged Spaceflight on Astronaut Hips.

J Clin Densitom 2020 Apr - Jun;23(2):155-164. Epub 2019 Aug 26.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA.

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.
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http://dx.doi.org/10.1016/j.jocd.2019.08.005DOI Listing
August 2019

Hip Fracture Discrimination Based on Statistical Multi-parametric Modeling (SMPM).

Ann Biomed Eng 2019 Nov 31;47(11):2199-2212. Epub 2019 May 31.

Department of Radiology, Beijing Jishuitan Hospital, Beijing, China.

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.
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http://dx.doi.org/10.1007/s10439-019-02298-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012369PMC
November 2019

Cigarette Smoking Is Associated With Lower Quadriceps Cross-sectional Area and Attenuation in Older Adults.

Nicotine Tob Res 2020 05;22(6):935-941

Laboratory of Epidemiology and Population Sciences, Intramural Research Program, National Institute on Aging, Bethesda, MD.

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.
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http://dx.doi.org/10.1093/ntr/ntz081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7249920PMC
May 2020

Hip load capacity cut-points for Astronaut Skeletal Health NASA Finite Element Strength Task Group Recommendations.

NPJ Microgravity 2019 14;5. Epub 2019 Mar 14.

18Division of Biomedical Research and Environmental Sciences, NASA Lyndon B. Johnson Space Center, Houston, TX USA.

Concerns raised at a 2010 Bone Summit held for National Aeronautics and Space Administration Johnson Space Center led experts in finite element (FE) modeling for hip fracture prediction to propose including hip load capacity in the standards for astronaut skeletal health. The current standards for bone are based upon areal bone mineral density (aBMD) measurements by dual X-ray absorptiometry (DXA) and an adaptation of aBMD cut-points for fragility fractures. Task Group members recommended (i) a minimum permissible outcome limit (POL) for post-mission hip bone load capacity, (ii) use of FE hip load capacity to further screen applicants to astronaut corps, (iii) a minimum pre-flight standard for a second long-duration mission, and (iv) a method for assessing which post-mission physical activities might increase an astronaut's risk for fracture after return. QCT-FE models of eight astronaut were analyzed using nonlinear single-limb stance (NLS) and posterolateral fall (NLF) loading configurations. QCT data from the Age Gene/Environment Susceptibility (AGES) Reykjavik cohort and the Rochester Epidemiology Project were analyzed using identical modeling procedures. The 75 percentile of NLS hip load capacity for fractured elderly males of the AGES cohort (9537N) was selected as a post-mission POL. The NLF model, in combination with a Probabilistic Risk Assessment tool, was used to assess the likelihood of exceeding the hip load capacity during post-flight activities. There was no recommendation to replace the current DXA-based standards. However, FE estimation of hip load capacity appeared more meaningful for younger, physically active astronauts and was recommended to supplement aBMD cut-points.
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http://dx.doi.org/10.1038/s41526-019-0066-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6418107PMC
March 2019

Chronic Kidney Disease Is Associated With Greater Bone Marrow Adiposity.

J Bone Miner Res 2018 12 27;33(12):2158-2164. Epub 2018 Aug 27.

Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA.

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 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 <45 (n = 58) using linear regression models. Participants had a mean age of 81.5 (SD 4.1) years, mean eGFR of 64.3 (SD 16.1) mL/min/1.734 cm , mean BMAT of 54.5% (SD 8.5); 48.2% were women. In unadjusted and adjusted models (age, visit window, gender, diabetes and visceral adipose tissue), BMAT was higher in those with eGFR <45 (adjusted mean 58.5%; 95% CI, 56.2 to 60.7) compared with those with 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 <45 versus >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.
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http://dx.doi.org/10.1002/jbmr.3562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702945PMC
December 2018

Sex hormones are negatively associated with vertebral bone marrow fat.

Bone 2018 03 11;108:20-24. Epub 2017 Dec 11.

Department of Epidemiology and Biostatistics, University of California San Francisco, CA 94158, USA. Electronic address:

Context: Higher bone marrow fat (BMF) is associated with osteoporosis and reduced hematopoiesis. Exogenous estradiol reduces BMF in older women, but effects of endogenous sex hormones are unknown.

Objective: To determine if endogenous sex hormones are associated with BMF in older men and women.

Design, Setting And Participants: Cross-sectional study in the Age Gene/Environment Susceptibility (AGES) Reykjavik cohort. Participants using medications that may affect BMF were excluded.

Main Outcome Measures: Vertebral 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.

Results: Analyses 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).

Conclusion: Higher 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.
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http://dx.doi.org/10.1016/j.bone.2017.12.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5803453PMC
March 2018

Osteocyte-Intrinsic TGF-β Signaling Regulates Bone Quality through Perilacunar/Canalicular Remodeling.

Cell Rep 2017 Nov;21(9):2585-2596

Department of Orthopaedic Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; UC Berkeley/UCSF Graduate Program in Bioengineering, San Francisco, CA 94143, USA. Electronic address:

Poor bone quality contributes to bone fragility in diabetes, aging, and osteogenesis imperfecta. However, the mechanisms controlling bone quality are not well understood, contributing to the current lack of strategies to diagnose or treat bone quality deficits. Transforming growth factor beta (TGF-β) signaling is a crucial mechanism known to regulate the material quality of bone, but its cellular target in this regulation is unknown. Studies showing that osteocytes directly remodel their perilacunar/canalicular matrix led us to hypothesize that TGF-β controls bone quality through perilacunar/canalicular remodeling (PLR). Using inhibitors and mice with an osteocyte-intrinsic defect in TGF-β signaling (TβRII), we show that TGF-β regulates PLR in a cell-intrinsic manner to control bone quality. Altogether, this study emphasizes that osteocytes are key in executing the biological control of bone quality through PLR, thereby highlighting the fundamental role of osteocyte-mediated PLR in bone homeostasis and fragility.
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http://dx.doi.org/10.1016/j.celrep.2017.10.115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6014615PMC
November 2017

Spatial Differences in the Distribution of Bone Between Femoral Neck and Trochanteric Fractures.

J Bone Miner Res 2017 Aug 5;32(8):1672-1680. Epub 2017 Jul 5.

Department of Radiology, Beijing Jishuitan Hospital, 4th Medical College of Peking University, Beijing, China.

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.
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http://dx.doi.org/10.1002/jbmr.3150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5550343PMC
August 2017

C-L-methyl methionine dynamic PET/CT of skeletal muscle: response to protein supplementation compared to L-[ring C] phenylalanine infusion with serial muscle biopsy.

Ann Nucl Med 2017 May 4;31(4):295-303. Epub 2017 Mar 4.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, Box 0946, San Francisco, CA, 94143-0946, USA.

Objective: The objective of this study was to determine if clinical dynamic PET/CT imaging with C-L-methyl-methionine (C-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 C] phenylalanine (C-Phe).

Methods: Healthy older women (73 ± 5 years) completed both dynamic PET/CT imaging with C-MET and a stable isotope infusion of C-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 K 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.

Results: Post-prandial values [mean ± standard error of the mean (SEM)] were higher than post-absorptive values for both K (0.0095 ± 0.001 vs. 0.00785 ± 0.001 min, p < 0.05) and FSR (0.083 ± 0.008 vs. 0.049 ± 0.006%/h, p < 0.001) in response to the whey protein supplement. The percent increase in K and FSR in response to the whey protein supplement was significantly correlated (r = 0.79, p = 0.015).

Conclusions: Dynamic PET/CT imaging with C-MET provides an estimate of the post-prandial anabolic response that is consistent with a traditional, invasive stable isotope, and muscle biopsy approach. These results support the potential future use of C-MET imaging as a non-invasive method for assessing conditions affecting skeletal muscle protein synthesis.
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http://dx.doi.org/10.1007/s12149-017-1157-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5397459PMC
May 2017

Statistical Parametric Mapping of HR-pQCT Images: A Tool for Population-Based Local Comparisons of Micro-Scale Bone Features.

Ann Biomed Eng 2017 04 9;45(4):949-962. Epub 2016 Nov 9.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA.

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.
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http://dx.doi.org/10.1007/s10439-016-1754-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811200PMC
April 2017

Muscle Quality and Myosteatosis: Novel Associations With Mortality Risk: The Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study.

Am J Epidemiol 2016 Jan 6;183(1):53-60. Epub 2015 Dec 6.

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.
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http://dx.doi.org/10.1093/aje/kwv153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5006223PMC
January 2016

Automatic multi-parametric quantification of the proximal femur with quantitative computed tomography.

Quant Imaging Med Surg 2015 Aug;5(4):552-68

1 Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA ; 2 Department of Endocrinology, Creighton University, Omaha, NE, USA ; 3 Department of Radiological Sciences, Department of Mechanical and Aerospace Engineering, Department of Biomedical Engineering, and Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, CA, USA ; 4 Intramural Research Program, National Institute on Aging, Bethesda, Maryland, USA ; 5 Division of Endocrinology, Diabetes, Metabolism and Nutrition, Department of Internal Medicine, College of Medicine, Mayo Clinic, Rochester, MN, USA.

Background: Quantitative computed tomography (QCT) imaging is the basis for multiple assessments of bone quality in the proximal femur, including volumetric bone mineral density (vBMD), tissue volume, estimation of bone strength using finite element modeling (FEM), cortical bone thickness, and computational-anatomy-based morphometry assessments.

Methods: Here, we present an automatic framework to perform a multi-parametric QCT quantification of the proximal femur. In this framework, the proximal femur is cropped from the bilateral hip scans, segmented using a multi-atlas based segmentation approach, and then assigned volumes of interest through the registration of a proximal femoral template. The proximal femur is then subjected to compartmental vBMD, compartmental tissue volume, FEM bone strength, compartmental surface-based cortical bone thickness, compartmental surface-based vBMD, local surface-based cortical bone thickness, and local surface-based cortical vBMD computations. Consequently, the template registrations together with vBMD and surface-based cortical bone parametric maps enable computational anatomy studies. The accuracy of the segmentation was validated against manual segmentations of 80 scans from two clinical facilities, while the multi-parametric reproducibility was evaluated using repeat scans with repositioning from 22 subjects obtained on CT imaging systems from two manufacturers.

Results: Accuracy results yielded a mean dice similarity coefficient of 0.976±0.006, and a modified Haussdorf distance of 0.219±0.071 mm. Reproducibility of QCT-derived parameters yielded root mean square coefficients of variation (CVRMS) between 0.89-1.66% for compartmental vBMD; 0.20-1.82% for compartmental tissue volume; 3.51-3.59% for FEM bone strength; 1.89-2.69% for compartmental surface-based cortical bone thickness; and 1.08-2.19% for compartmental surface-based cortical vBMD. For local surface-based assessments, mean CVRMS were between 3.45-3.91% and 2.74-3.15% for cortical bone thickness and vBMD, respectively.

Conclusions: The automatic framework presented here enables accurate and reproducible QCT multi-parametric analyses of the proximal femur. Our subjects were elderly, with scans obtained across multiple clinical sites and manufacturers, thus documenting its value for clinical trials and other multi-site studies.
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http://dx.doi.org/10.3978/j.issn.2223-4292.2015.08.02DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4559986PMC
August 2015

Plasma phospholipid fatty acids and fish-oil consumption in relation to osteoporotic fracture risk in older adults: the Age, Gene/Environment Susceptibility Study.

Am J Clin Nutr 2015 May 18;101(5):947-55. Epub 2015 Mar 18.

From the Laboratory of Epidemiology, and Population Sciences, National Institute on Aging, Bethesda, MD (TBH, IR, MEG, and RAM); the Biomarker Laboratory, Fred Hutchinson Cancer Research Center, Seattle, WA (XS); the Department of Health Sciences and the EMGO+ Institute for Health and Care Research, VU University, Amsterdam, The Netherlands (IR and IAB); the Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA (TFL); the Icelandic Heart Association, Kopavogur, Iceland (KS, SS, VG, GE, GS, and TA); and the University of Iceland, Reykjavik, Iceland (VG, GS, and LS).

Background: Polyunsaturated fatty acids (PUFAs) may play a role in fracture, but studies have been largely confined to estimates of dietary intake.

Objective: We 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.

Design: Osteoporotic 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.

Results: In 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).

Conclusions: Greater 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.
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http://dx.doi.org/10.3945/ajcn.114.087502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4409686PMC
May 2015

Fat distribution and mortality: the AGES-Reykjavik Study.

Obesity (Silver Spring) 2015 Apr 9;23(4):893-7. Epub 2015 Mar 9.

Department of Social Medicine, CAPHRI School for Public Health and Primary Care, Maastricht University, Maastricht, The Netherlands; Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, Maryland, USA.

Objective: This study examined associations of regional fat depots with all-cause mortality over 11 years of follow-up.

Methods: Data were from 2,187 men and 2,900 women, aged 66-96 years in the AGES-Reykjavik Study. Abdominal visceral fat and subcutaneous fat and thigh intermuscular fat and subcutaneous fat were measured by CT.

Results: In men, every standard deviation (SD) increment in thigh intermuscular fat was related to a significantly greater mortality risk (HR: 1.17, 95% CI: 1.08-1.26) after adjustment for age, education, smoking, physical activity, alcohol, BMI, type 2 diabetes, and coronary heart disease. In women, visceral fat (per SD increment) significantly increased mortality risk (HR: 1.13, 95% CI: 1.03-1.25) while abdominal subcutaneous fat (per SD increment) was associated with a lower mortality risk (HR: 0.70, 95% CI: 0.61-0.80). Significant interactions with BMI were found in women, indicating that visceral fat was a strong predictor of mortality in obese women while abdominal and thigh subcutaneous fat were associated with a lower mortality risk in normal-weight and overweight women.

Conclusions: Fat distribution is associated with mortality over 11 years of follow-up independent of overall fatness. The divergent mortality risks for visceral fat and subcutaneous fat in women suggest complex relationships between overall fatness and mortality.
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http://dx.doi.org/10.1002/oby.21028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4758353PMC
April 2015

Circulating sclerostin associated with vertebral bone marrow fat in older men but not women.

J Clin Endocrinol Metab 2014 Dec;99(12):E2584-90

University of California, San Francisco (Y.-H.V.M., A.V.S., T.F.H., T.F.L., E.V., L.P., X.L.), San Francisco, California 94107; Icelandic Heart Association (S.S., G.E., A.M.H., K.S., D.O., V.G.), IS-201 Kopavogur, Iceland; Laboratory of Epidemiology, Demography, and Biometry (T.B.H.), Intramural Research Program, National Institute on Aging, Bethesda, Maryland 20892; Maine Medical Center Research Institute (C.J.R.), Scarborough, Maine 04074; Faculty of Medicine (G.S., D.O., V.G.), University of Iceland, IS-101 Reykjavik, Iceland; Department of Endocrinology and Metabolism (G.S.), Landspitali University Hospital, IS-101 Reykjavik, Iceland; and Universita Campus Bio-Medico (N.N.), 00128 Rome, Italy.

Context: Osteocyte 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.

Objective: Our 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 Participants: We conducted a cross-sectional study in the Age Gene/Environment Susceptibility-Reykjavik cohort.

Main Outcome Measures: Outcome measures included vertebral MF (L1-L4) measured with magnetic resonance spectroscopy and vBMD (spine and hip) and abdominal fat measured with quantitative computed tomography.

Results: After 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 <.01) in models adjusted for age, body mass index, and diabetes. Sclerostin was positively associated with cortical and trabecular total hip vBMD, weight in men and women, and total fat mass in men but was not associated with total lean mass or abdominal fat depots.

Conclusion: Circulating sclerostin levels are associated with higher vertebral marrow fat in men, suggesting a relationship between osteocyte function and marrow adipogenesis.
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http://dx.doi.org/10.1210/jc.2013-4493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4255105PMC
December 2014

Inter-scanner differences in in vivo QCT measurements of the density and strength of the proximal femur remain after correction with anthropomorphic standardization phantoms.

Med Eng Phys 2014 Oct 4;36(10):1225-32. Epub 2014 Jul 4.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, United States.

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.
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http://dx.doi.org/10.1016/j.medengphy.2014.06.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4589175PMC
October 2014

Axial QCT: clinical applications and new developments.

J Clin Densitom 2014 Oct-Dec;17(4):438-48. Epub 2014 May 28.

Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, USA.

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.
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http://dx.doi.org/10.1016/j.jocd.2014.04.119DOI Listing
January 2015

The effect of metal artefact reduction on CT-based attenuation correction for PET imaging in the vicinity of metallic hip implants: a phantom study.

Ann Nucl Med 2014 Jul 8;28(6):540-50. Epub 2014 Apr 8.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, Box 0946, San Francisco, CA, 94143-0946, USA,

Background: To determine if metal artefact reduction (MAR) combined with a priori knowledge of prosthesis material composition can be applied to obtain CT-based attenuation maps with sufficient accuracy for quantitative assessment of (18)F-fluorodeoxyglucose uptake in lesions near metallic prostheses.

Methods: A custom hip prosthesis phantom with a lesion-sized cavity filled with 0.2 ml (18)F-FDG solution having an activity of 3.367 MBq adjacent to a prosthesis bore was imaged twice with a chrome-cobalt steel hip prosthesis and a plastic replica, respectively. Scanning was performed on a clinical hybrid PET/CT system equipped with an additional external (137)Cs transmission source. PET emission images were reconstructed from both phantom configurations with CT-based attenuation correction (CTAC) and with CT-based attenuation correction using MAR (MARCTAC). To compare results with the attenuation-correction method extant prior to the advent of PET/CT, we also carried out attenuation correction with (137)Cs transmission-based attenuation correction (TXAC). CTAC and MARCTAC images were scaled to attenuation coefficients at 511 keV using a trilinear function that mapped the highest CT values to the prosthesis alloy attenuation coefficient. Accuracy and spatial distribution of the lesion activity was compared between the three reconstruction schemes.

Results: Compared to the reference activity of 3.37 MBq, the estimated activity quantified from the PET image corrected by TXAC was 3.41 MBq. The activity estimated from PET images corrected by MARCTAC was similar in accuracy at 3.32 MBq. CTAC corrected PET images resulted in nearly 40 % overestimation of lesion activity at 4.70 MBq. Comparison of PET images obtained with the plastic and metal prostheses in place showed that CTAC resulted in a marked distortion of the (18)F-FDG distribution within the lesion, whereas application of MARCTAC and TXAC resulted in lesion distributions similar to those observed with the plastic replica.

Conclusions: MAR combined with a trilinear CT number mapping for PET attenuation correction resulted in estimates of lesion activity comparable in accuracy to that obtained with (137)Cs transmission-based attenuation correction, and far superior to estimates made without attenuation correction or with a standard CT attenuation map. The ability to use CT images for attenuation correction is a potentially important development because it obviates the need for a (137)Cs transmission source, which entails extra scan time, logistical complexity and expense.
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http://dx.doi.org/10.1007/s12149-014-0844-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4101148PMC
July 2014

Spatial heterogeneity in the response of the proximal femur to two lower-body resistance exercise regimens.

J Bone Miner Res 2014 Jun;29(6):1337-45

Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA.

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.
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http://dx.doi.org/10.1002/jbmr.2155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4029859PMC
June 2014

Structural patterns of the proximal femur in relation to age and hip fracture risk in women.

Bone 2013 Nov 25;57(1):290-9. Epub 2013 Aug 25.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA.

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.
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http://dx.doi.org/10.1016/j.bone.2013.08.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3809121PMC
November 2013

Adipose tissue density, a novel biomarker predicting mortality risk in older adults.

J Gerontol A Biol Sci Med Sci 2014 Jan 24;69(1):109-17. Epub 2013 May 24.

Laboratory of Population Science, National Institute on Aging, 7201 Wisconsin Ave, 3C-309 Bethesda, MD 20814.

Background: Knowledge 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.

Methods: VAT 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.

Results: Higher 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.

Conclusion: VAT and SAT density provide a unique marker of mortality risk that does not appear to be inflammation related.
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http://dx.doi.org/10.1093/gerona/glt070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3859360PMC
January 2014

Fracture risk assessment in older adults using a combination of selected quantitative computed tomography bone measures: a subanalysis of the Age, Gene/Environment Susceptibility-Reykjavik Study.

J Clin Densitom 2014 Jan-Mar;17(1):25-31. Epub 2013 Apr 2.

LEDB, National Institute on Aging, Bethesda, MD, USA.

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.
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http://dx.doi.org/10.1016/j.jocd.2013.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4948945PMC
April 2014

Vertebral bone marrow fat associated with lower trabecular BMD and prevalent vertebral fracture in older adults.

J Clin Endocrinol Metab 2013 Jun 3;98(6):2294-300. Epub 2013 Apr 3.

University of California, San Francisco, San Francisco, California 94107, USA.

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.
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http://dx.doi.org/10.1210/jc.2012-3949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3667265PMC
June 2013

Proximal femoral density distribution and structure in relation to age and hip fracture risk in women.

J Bone Miner Res 2013 Mar;28(3):537-46

Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA.

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.
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http://dx.doi.org/10.1002/jbmr.1802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3578081PMC
March 2013

Central QCT reveals lower volumetric BMD and stiffness in premenopausal women with idiopathic osteoporosis, regardless of fracture history.

J Clin Endocrinol Metab 2012 Nov 7;97(11):4244-52. Epub 2012 Sep 7.

Department of Medicine, PH8-864, Columbia University, College of Physicians and Surgeons, 630 West 168th Street, New York, New York 10032, USA.

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.
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http://dx.doi.org/10.1210/jc.2012-2099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3485589PMC
November 2012

Mid-thigh cortical bone structural parameters, muscle mass and strength, and association with lower limb fractures in older men and women (AGES-Reykjavik Study).

Calcif Tissue Int 2012 May 27;90(5):354-64. Epub 2012 Mar 27.

University of Iceland, Reykjavik, Iceland.

In a cross-sectional study we investigated the relationship between muscle and bone parameters in the mid-thigh in older people using data from a single axial computed tomographic section through the mid-thigh. Additionally, we studied the association of these variables with incident low-trauma lower limb fractures. A total of 3,762 older individuals (1,838 men and 1,924 women), aged 66-96 years, participants in the AGES-Reykjavik study, were studied. The total cross-sectional muscular area and knee extensor strength declined with age similarly in both sexes. Muscle parameters correlated most strongly with cortical area and total shaft area (adjusted for age, height, and weight) but explained <10 % of variability in those bone parameters. The increment in medullary area (MA) and buckling ratio (BR) with age was almost fourfold greater in women than men. The association between MA and muscle parameters was nonsignificant. During a median follow-up of 5.3 years, 113 women and 66 men sustained incident lower limb fractures. Small muscular area, low knee extensor strength, large MA, low cortical thickness, and high BR were significantly associated with fractures in both sexes. Our results show that bone and muscle loss proceed at different rates and with different gender patterns.
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http://dx.doi.org/10.1007/s00223-012-9585-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5111551PMC
May 2012

Heritability of prevalent vertebral fracture and volumetric bone mineral density and geometry at the lumbar spine in three generations of the Framingham study.

J Bone Miner Res 2012 Apr;27(4):954-8

Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.

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.
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http://dx.doi.org/10.1002/jbmr.1537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3375687PMC
April 2012

The bone-muscle relationship in men and women.

Authors:
Thomas F Lang

J Osteoporos 2011 5;2011:702735. Epub 2011 Oct 5.

Department of Radiology and Biomedical Imaging, School of Medicine, University of California, San Francisco, San Francisco, CA 94143-0946, USA.

Muscle forces are a strong determinant of bone structure, particularly during the process of growth and development. The gender divergence in the bone-muscle relationship becomes strongly evident during adolescence. In females, growth is characterized by increased estrogen levels and increased mass and strength of bone relative to that of muscle, whereas in men, increases in testosterone fuel large increases in muscle, resulting in muscle forces that coincide with a large growth in bone dimensions and strength. In adulthood, significant age-related losses are observed for both bone and muscle tissues. Large decrease in estrogen levels in women appears to diminish the skeleton's responsiveness to exercise more than in men. In contrast, the aging of the muscle-bone axis in men is a function of age related declines in both hormones. In addition to the well-known age related changes in the mechanical loading of bone by muscle, newer studies appear to provide evidence of age- and gender-related variations in molecular signaling between bone and muscle that are independent of purely mechanical interactions. In summary, gender differences in the acquisition and age-related loss in bone and muscle tissues may be important for developing gender-specific strategies for using exercise to reduce bone loss with aging.
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http://dx.doi.org/10.4061/2011/702735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3189615PMC
November 2011