Bone marrow fat composition as a novel imaging biomarker in postmenopausal women with prevalent fragility fractures

The goal of this magnetic resonance (MR) imaging study was to quantify vertebral bone marrow fat content and composition in diabetic and nondiabetic postmenopausal women with fragility fractures and to compare them with nonfracture controls with and without type 2 diabetes mellitus. Sixty‐nine postmenopausal women (mean age 63 ± 5 years) were recruited. Thirty‐six patients (47.8%) had spinal and/or peripheral fragility fractures. Seventeen fracture patients were diabetic. Thirty‐three women (52.2%) were nonfracture controls. Sixteen women were diabetic nonfracture controls. To quantify vertebral bone marrow fat content and composition, patients underwent MR spectroscopy (MRS) of the lumbar spine at 3 Tesla. Bone mineral density (BMD) was determined by dual‐energy X‐ray absorptiometry (DXA) of the hip and lumbar spine (LS) and quantitative computed tomography (QCT) of the LS. To evaluate associations of vertebral marrow fat content and composition with spinal and/or peripheral fragility fractures and diabetes, we used linear regression models adjusted for age, race, and spine volumetric bone mineral density (vBMD) by QCT. At the LS, nondiabetic and diabetic fracture patients had lower vBMD than controls and diabetics without fractures (p = 0.018; p = 0.005). However, areal bone mineral density (aBMD) by DXA did not differ between fracture and nonfracture patients. After adjustment for age, race, and spinal vBMD, the prevalence of fragility fractures was associated with ?1.7% lower unsaturation levels (confidence interval [CI] ?2.8% to ?0.5%, p = 0.005) and +2.9% higher saturation levels (CI 0.5% to 5.3%, p = 0.017). Diabetes was associated with ?1.3% (CI –2.3% to ?0.2%, p = 0.018) lower unsaturation and +3.3% (CI 1.1% to 5.4%, p = 0.004) higher saturation levels. Diabetics with fractures had the lowest marrow unsaturation and highest saturation. There were no associations of marrow fat content with diabetes or fracture. Our results suggest that altered bone marrow fat composition is linked with fragility fractures and diabetes. MRS of spinal bone marrow fat may therefore serve as a novel tool for BMD‐independent fracture risk assessment.     

Explicit Finite Element Models Accurately Predict Subject-Specific and Velocity-Dependent Kinetics of Sideways Fall Impact

The majority of hip fractures in the elderly are the result of a fall from standing or from a lower height. Current injury models focus mostly on femur strength while neglecting subject-specific loading. This article presents an injury modeling strategy for hip fractures related to sideways falls that takes subject-specific impact loading into account. Finite element models (FEMs) of the human body were used to predict the experienced load and the femoral strength in a single model. We validated these models for their predicted peak force, effective pelvic stiffness, and fracture status against matching ex vivo sideways fall impacts (n = 11) with a trochanter velocity of 3.1 m/s. Furthermore, they were compared to sideways impacts of volunteers with lower impact velocities that were previously conducted by other groups. Good agreement was found between the ex vivo experiments and the FEMs with respect to peak force (root mean square error [RMSE] = 10.7%, R² = 0.85) and effective pelvic stiffness (R² = 0.92, RMSE = 12.9%). The FEMs were predictive of the fracture status for 10 out of 11 specimens. Compared to the volunteer experiments from low height, the FEMs overestimated the peak force by 25% for low BMI subjects and 8% for high BMI subjects. The effective pelvic stiffness values that were derived from the FEMs were comparable to those derived from impacts with volunteers. The force attenuation from the impact surface to the femur ranged between 27% and 54% and was highly dependent on soft tissue thickness (R² = 0.86). The energy balance in the FEMS showed that at the time of peak force 79% to 93% of the total energy is either kinetic or was transformed to soft tissue deformation. The presented FEMs allow for direct discrimination between fracture and nonfracture outcome for sideways falls and bridge the gap between impact testing with volunteers and impact conditions representative of real life falls. © 2019 American Society for Bone and Mineral Research.     

Association of QCT Bone Mineral Density and Bone Structure With Vertebral Fractures in Patients With Multiple Myeloma

Computed tomography (CT) is used for staging osteolytic lesions and detecting fractures in patients with multiple myeloma (MM). In the OsteoLysis of Metastases and Plasmacell‐infiltration Computed Tomography 2 study (OLyMP‐CT) study we investigated whether patients with and without vertebral fractures show differences in bone mineral density (BMD) or microstructure that could be used to identify patients at risk for fracture. We evaluated whole‐body CT scans in a group of 104 MM patients without visible osteolytic lesions using an underlying lightweight calibration phantom (Image Analysis Inc., Columbia, KY, USA). QCT software (StructuralInsight) was used for the assessment of BMD and bone structure of the T₁₁ or T₁₂ vertebral body. Age‐adjusted standardized odds ratios (sORs) per SD change were derived from logistic regression analyses, and areas under the receiver operating characteristics (ROC) curve (AUCs) analyses were calculated. Forty‐six of the 104 patients had prevalent vertebral fractures (24/60 men, 22/44 women). Patients with fractures were not significantly older than patients without fractures (mean ± SD, 64 ± 9.2 versus 62 ± 12.3 years; p = 0.4). Trabecular BMD in patients with fractures versus without fractures was 169 ± 41 versus 192 ± 51 mg/cc (AUC = 0.62 ± 0.06, sOR = 1.6 [1.1 to 2.5], p = 0.02). Microstructural variables achieved optimal discriminatory power at bone thresholds of 150 mg/cc. Best fracture discrimination for single microstructural variables was observed for trabecular separation (Tb.Sp) (AUC = 0.72 ± 0.05, sOR = 2.4 (1.5 to 3.9), p < 0.0001). In multivariate models AUCs improved to 0.77 ± 0.05 for BMD and Tb.Sp, and 0.79 ± 0.05 for Tb.Sp and trabecular thickness (Tb.Th). Compared to BMD values, these improvements of AUC values were statistically significant (p < 0.0001). In MM patients, QCT‐based analyses of bone structure derived from routine CT scans permit discrimination of patients with and without vertebral fractures. Rarefaction of the trabecular network due to plasma cell infiltration and osteoporosis can be measured. Deterioration of microstructural measures appear to be of value for vertebral fracture risk assessment and may indicate early stages of osteolytic processes not yet visible. © 2014 American Society for Bone and Mineral Research.     

Trabecular Bone Structure Analysis in the Osteoporotic Spine Using a Clinical In Vivo Setup for 64‐Slice MDCT Imaging: Comparison to μCT Imaging and μFE Modeling

Assessment of trabecular microarchitecture may improve estimation of biomechanical strength, but visualization of trabecular bone structure in vivo is challenging. We tested the feasibility of assessing trabecular microarchitecture in the spine using multidetector CT (MDCT) on intact human cadavers in an experimental in vivo–like setup. BMD, bone structure (e.g., bone volume/total volume = BV/TV; trabecular thickness = Tb.Th; structure model index = SMI) and bone texture parameters were evaluated in 45 lumbar vertebral bodies using MDCT (mean in‐plane pixel size, 274 μm²; slice thickness, 500 μm). These measures were correlated with structure measures assessed with μCT at an isotropic spatial resolution of 16 μm and to microfinite element models (μFE) of apparent modulus and stiffness. MDCT‐derived BMD and structure measures showed significant correlations to the density and structure obtained by μCT (BMD, R² = 0.86, p < 0.0001; BV/TV, R² = 0.64, p < 0.0001; Tb.Th, R² = 0.36, p < 0.01). When comparing μCT‐derived measures with μFE models, the following correlations (p < 0.001) were found for apparent modulus and stiffness, respectively: BMD (R² = 0.58 and 0.66), BV/TV (R² = 0.44 and 0.58), and SMI (R² = 0.44 and 0.49). However, the overall highest correlation (p < 0.001) with μFE app. modulus (R² = 0.75) and stiffness (R² = 0.76) was achieved by the combination of QCT‐derived BMD with the bone texture measure Minkowski Dimension. In summary, although still limited by its spatial resolution, trabecular bone structure assessment using MDCT is overall feasible. However, when comparing with μFE‐derived bone properties, BMD is superior compared with single parameters for microarchitecture, and correlations further improve when combining with texture measures.     

Vertebral Strength and Estimated Fracture Risk Across the BMI Spectrum in Women

Somewhat paradoxically, fracture risk, which depends on applied loads and bone strength, is elevated in both anorexia nervosa and obesity at certain skeletal sites. Factor‐of‐risk (Φ), the ratio of applied load to bone strength, is a biomechanically based method to estimate fracture risk; theoretically, higher Φ reflects increased fracture risk. We estimated vertebral strength (linear combination of integral volumetric bone mineral density [Int.vBMD] and cross‐sectional area from quantitative computed tomography [QCT]), vertebral compressive loads, and Φ at L₄ in 176 women (65 anorexia nervosa, 45 lean controls, and 66 obese). Using biomechanical models, applied loads were estimated for: 1) standing; 2) arms flexed 90°, holding 5 kg in each hand (holding); 3) 45° trunk flexion, 5 kg in each hand (lifting); 4) 20° trunk right lateral bend, 10 kg in right hand (bending). We also investigated associations of Int.vBMD and vertebral strength with lean mass (from dual‐energy X‐ray absorptiometry [DXA]) and visceral adipose tissue (VAT, from QCT). Women with anorexia nervosa had lower, whereas obese women had similar, Int.vBMD and estimated vertebral strength compared with controls. Vertebral loads were highest in obesity and lowest in anorexia nervosa for standing, holding, and lifting (p < 0.0001) but were highest in anorexia nervosa for bending (p < 0.02). Obese women had highest Φ for standing and lifting, whereas women with anorexia nervosa had highest Φ for bending (p < 0.0001). Obese and anorexia nervosa subjects had higher Φ for holding than controls (p < 0.03). Int.vBMD and estimated vertebral strength were associated positively with lean mass (R = 0.28 to 0.45, p ≤ 0.0001) in all groups combined and negatively with VAT (R = –[0.36 to 0.38], p < 0.003) within the obese group. Therefore, women with anorexia nervosa had higher estimated vertebral fracture risk (Φ) for holding and bending because of inferior vertebral strength. Despite similar vertebral strength as controls, obese women had higher vertebral fracture risk for standing, holding, and lifting because of higher applied loads from higher body weight. Examining the load‐to‐strength ratio helps explain increased fracture risk in both low‐weight and obese women. © 2015 American Society for Bone and Mineral Research.     

Novel Genetic Variants Associated With Increased Vertebral Volumetric BMD,Reduced Vertebral Fracture Risk,and Increased Expression of SLC1A3 and EPHB2

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.     

Naturally Occurring Stable Calcium Isotope Ratios in Body Compartments Provide a Novel Biomarker of Bone Mineral Balance in Children and Young Adults

Serum calcium (Ca), bone biomarkers, and radiological imaging do not allow accurate evaluation of bone mineral balance (BMB), a key determinant of bone mineral density (BMD) and fracture risk. We studied naturally occurring stable (non-radioactive) Ca isotopes in different body pools as a potential biomarker of BMB. ⁴²Ca and ⁴⁴Ca are absorbed from our diet and sequestered into different body compartments following kinetic principles of isotope fractionation; isotopically light ⁴²Ca is preferentially incorporated into bone, whereas heavier ⁴⁴Ca preferentially remains in blood and is excreted in urine and feces. Their ratio (δ^44/42Ca) in serum and urine increases during bone formation and decreases with bone resorption. In 117 healthy participants, we measured Ca isotopes, biomarkers, and BMD by dual-energy X-ray absorptiometry (DXA) and tibial peripheral quantitative CT (pQCT). ⁴⁴Ca and ⁴²Ca were measured by multi-collector ionization-coupled plasma mass-spectrometry in serum, urine, and feces. The relationship between bone Ca gain and loss was calculated using a compartment model. δ^44/42Ca_serum and δ^44/42Ca_urine were higher in children (n = 66, median age 13 years) compared with adults (n = 51, median age 28 years; p < 0.0001 and p = 0.008, respectively). δ^44/42Ca_serum increased with height in boys (p < 0.001, R² = 0.65) and was greatest at Tanner stage 4. δ^44/42Ca_serum correlated positively with biomarkers of bone formation (25-hydroxyvitaminD [p < 0.0001, R² = 0.37] and alkaline phosphatase [p = 0.009, R² = 0.18]) and negatively with bone resorption marker parathyroid hormone (PTH; p = 0.03, R² = 0.13). δ^44/42Ca_serum strongly positively correlated with tibial cortical BMD Z-score (n = 62; p < 0.001, R² = 0.39) but not DXA. Independent predictors of tibial cortical BMD Z-score were δ^44/42Ca_serum (p = 0.004, β = 0.37), 25-hydroxyvitaminD (p = 0.04, β = 0.19) and PTH (p = 0.03, β = −0.13), together predicting 76% of variability. In conclusion, naturally occurring Ca isotope ratios in different body compartments may provide a novel, non-invasive method of assessing bone mineralization. Defining an accurate biomarker of BMB could form the basis of future studies investigating Ca dynamics in disease states and the impact of treatments that affect bone homeostasis. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

Improved Fracture Risk Assessment Based on Nonlinear Micro‐Finite Element Simulations From HRpQCT Images at the Distal Radius

More accurate techniques to estimate fracture risk could help reduce the burden of fractures in postmenopausal women. Although micro‐finite element (µFE) simulations allow a direct assessment of bone mechanical performance, in this first clinical study we investigated whether the additional information obtained using geometrically and materially nonlinear µFE simulations allows a better discrimination between fracture cases and controls. We used patient data and high‐resolution peripheral quantitative computed tomography (HRpQCT) measurements from our previous clinical study on fracture risk, which compared 100 postmenopausal women with a distal forearm fracture to 105 controls. Analyzing these data with the nonlinear µFE simulations, the odds ratio (OR) for the factor‐of‐risk (yield load divided by the expected fall load) was marginally higher (1.99; 95% confidence interval [CI], 1.41–2.77) than for the factor‐of‐risk computed from linear µFE (1.89; 95% CI, 1.37–2.69). The yield load and the energy absorbed up to the yield point as computed from nonlinear µFE were highly correlated with the initial stiffness (R² = 0.97 and 0.94, respectively) and could therefore be derived from linear simulations with little loss in precision. However, yield deformation was not related to any other measurement performed and was itself a good predictor of fracture risk (OR, 1.89; 95% CI, 1.39–2.63). Moreover, a combined risk score integrating information on relative bone strength (yield load‐based factor‐of‐risk), bone ductility (yield deformation), and the structural integrity of the bone under critical loads (cortical plastic volume) improved the separation of cases and controls by one‐third (OR, 2.66; 95% CI, 1.84–4.02). We therefore conclude that nonlinear µFE simulations provide important additional information on the risk of distal forearm fractures not accessible from linear µFE nor from other techniques assessing bone microstructure, density, or mass. © 2013 American Society for Bone and Mineral Research.     

Influence of vertical trabeculae on the compressive strength of the human vertebra

Vertebral strength, a key etiologic factor of osteoporotic fracture, may be affected by the relative amount of vertically oriented trabeculae. To better understand this issue, we performed experimental compression testing, high‐resolution micro–computed tomography (µCT), and micro–finite‐element analysis on 16 elderly human thoracic ninth (T₉) whole vertebral bodies (ages 77.5 ± 10.1 years). Individual trabeculae segmentation of the µCT images was used to classify the trabeculae by their orientation. We found that the bone volume fraction (BV/TV) of just the vertical trabeculae accounted for substantially more of the observed variation in measured vertebral strength than did the bone volume fraction of all trabeculae (r² = 0.83 versus 0.59, p < .005). The bone volume fraction of the oblique or horizontal trabeculae was not associated with vertebral strength. Finite‐element analysis indicated that removal of the cortical shell did not appreciably alter these trends; it also revealed that the major load paths occur through parallel columns of vertically oriented bone. Taken together, these findings suggest that variation in vertebral strength across individuals is due primarily to variations in the bone volume fraction of vertical trabeculae. The vertical tissue fraction, a new bone quality parameter that we introduced to reflect these findings, was both a significant predictor of vertebral strength alone (r² = 0.81) and after accounting for variations in total bone volume fraction in multiple regression (total R² = 0.93). We conclude that the vertical tissue fraction is a potentially powerful microarchitectural determinant of vertebral strength. © 2011 American Society for Bone and Mineral Research.     

Serum uric acid is associated with bone health in older men: A cross‐sectional population‐based study

Serum uric acid (UA) is a strong endogenous antioxidant. Since oxidative stress has been linked to osteoporosis, we examined the association between serum UA levels and bone mineral density (BMD), prevalent vertebral and nonvertebral fractures, and laboratory measures such as calcitropic hormones and bone turnover marker levels. This cross‐sectional analysis consisted of 1705 community‐dwelling men aged 70 years or over who participated in the baseline part of the Concord Health and Ageing in Men Project (CHAMP), a population‐based study of older men in Sydney, Australia. BMD at all sites was significantly higher among men with serum UA levels above the group median than among men with UA levels below the median. In multiple regression analyses adjusted for potential confounders, serum UA remained associated with BMD at all sites (β = 0.12 to 0.14, p < .001), serum calcium (β = 0.11, p = .001), parathyroid hormone (β = 0.09, p = .002), 25‐hydroxyvitamin D (β = 0.09, p = .005), and was negatively associated with urinary excretion amino‐terminal cross‐linked telopeptide of type 1 collagen (β = –0.09, p = .006). Overall, serum UA accounted for 1.0% to 1.44% of the variances in BMD (R² = 0.10 to 0.22). In multiple logistic regression analyses, above‐median serum UA levels were associated with a lower prevalence of osteoporosis at the femoral neck [odds ratio (OR) = 0.42, 95% confidence interval (CI) 0.22–0.81, p = .010) and lumbar spine (OR = 0.44, 95% CI 0.23–0.86, p = .016) and a lower prevalence of vertebral (OR = 0.62, 95% CI 0.43–0.91, p = .015) and nonvertebral (OR = 0.51, 95% CI 0.29–0.89, p = .018) fractures. In conclusion, higher serum UA levels are associated with higher BMD at all skeletal sites and with a lower prevalence of vertebral and nonvertebral fractures in older men. © 2011 American Society for Bone and Mineral Research.     

Heterogeneity and Spatial Distribution of Intravertebral Trabecular Bone Mineral Density in the Lumbar Spine Is Associated With Prevalent Vertebral Fracture

The spatial heterogeneity in trabecular bone density within the vertebral centrum is associated with vertebral strength and could explain why volumetric bone mineral density (vBMD) exhibits low sensitivity in identifying fracture risk. This study evaluated whether the heterogeneity and spatial distribution of trabecular vBMD are associated with prevalent vertebral fracture. We examined the volumetric quantitative computed tomography (QCT) scans of the L₃ vertebra in 148 participants in the Framingham Heart Study Multidetector CT study. Of these individuals, 37 were identified as cases of prevalent fracture, and 111 were controls, matched on sex and age with three controls per case. vBMD was calculated within 5-mm contiguous cubic regions of the centrum. Two measures of heterogeneity were calculated: (i) interquartile range (IQR); and (ii) quartile coefficient of variation (QCV). Ratios in the spatial distributions of the trabecular vBMD were also calculated: anterior/posterior, central/outer, superior/mid-transverse, and inferior/mid-transverse. Heterogeneity and spatial distributions were compared between cases and controls using Wilcoxon rank sum tests and t tests and tested for association with prevalent fractures with conditional logistic regressions independent of integral vBMD. Prevalent fracture cases had lower mean ± SD integral vBMD (134 ± 38 versus165 ± 42 mg/cm³, p < .001), higher QCV (0.22 ± 0.13 versus 0.17 ± 0.09, p = .003), and lower anterior/posterior rBMD (0.65 ± 0.13 versus 0.78 ± 0.16, p < .001) than controls. QCV was positively associated with increased odds of prevalent fracture (OR 1.61; 95% CI, 1.04 to 2.49; p = .034), but this association was not independent of integral vBMD (p = .598). Increased anterior/posterior trabecular vBMD ratio was associated with decreased odds of prevalent fracture independent of integral vBMD (OR 0.38; 95% CI, 0.20 to 0.71; p = .003). In conclusion, increased trabecular vBMD in the anterior versus posterior centrum, but not trabecular vBMD heterogeneity, was associated with decreased risk of prevalent fracture independent of integral vBMD. Regional measurements of trabecular vBMD could aid in determining the risk and underlying mechanisms of vertebral fracture. © 2019 American Society for Bone and Mineral Research.     

Cartilage Damage Is Related to ACL Stiffness in a Porcine Model of ACL Repair

Inferior anterior cruciate ligament (ACL) structural properties may inadequately restrain tibiofemoral joint motion following surgery, contributing to the increased risk of post‐traumatic osteoarthritis. Using both a direct measure of ACL linear stiffness and an in vivo magnetic resonance imaging (MRI) T₂*‐based prediction model, we hypothesized that cartilage damage and ACL stiffness would increase over time, and that an inverse relationship between cartilage damage and ACL stiffness would emerge at a later stage of healing. After either 6, 12, or 24 weeks (w) of healing after ACL repair, ACL linear stiffness was determined from the force–displacement relationship during tensile testing ex vivo and predicted in vivo from the MRI T₂*‐based multiple linear regression model in 24 Yucatan minipigs. Tibiofemoral cartilage was graded postmortem. There was no relationship between cartilage damage and ACL stiffness at 6 w (R² = 0.04; p = 0.65), 12 w (R² = 0.02; p = 0.77), or when the data from all animals were pooled (R² = 0.02; p = 0.47). A significant inverse relationship between cartilage damage and ACL stiffness based on both ex vivo measurement (R² = 0.90; p < 0.001) and in vivo MRI prediction (R² = 0.78; p = 0.004) of ACL stiffness emerged at 24 w. This result suggests that 90% of the variability in gross cartilage changes is associated with the repaired ACL linear stiffness at 6 months of healing. Clinical Significance: Techniques that provide a higher stiffness to the repaired ACL may be required to mitigate the post‐traumatic osteoarthritis commonly seen after ACL injury, and MRI T₂* can be used as a noninvasive estimation of ligament stiffness. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2249–2257, 2019     

Early Changes in Bone Density,Microarchitecture, Bone Resorption,and Inflammation Predict the Clinical Outcome 12 Weeks After Conservatively Treated Distal Radius Fractures: An Exploratory Study

Fracture healing is an active process with early changes in bone and inflammation. We performed an exploratory study evaluating the association between early changes in densitometric, structural, biomechanical, and biochemical bone parameters during the first weeks of fracture healing and wrist‐specific pain and disability at 12 weeks in postmenopausal women with a conservatively treated distal radius fracture. Eighteen patients (aged 64 ± 8 years) were evaluated at 1 to 2 and 3 to 4 weeks postfracture, using high‐resolution peripheral quantitative computed tomography (HR‐pQCT), micro‐finite element analysis, serum procollagen type‐I N‐terminal propeptide (P1NP), carboxy‐terminal telopeptide of type I collagen (ICTP), and high‐sensitive C‐reactive protein (hsCRP). After 12 weeks, patients rated their pain and disability using Patient Rated Wrist Evaluation (PRWE) questionnaire. Additionally, Quick Disability of the Arm Shoulder and Hand (QuickDASH) questionnaire and active wrist range of motion was evaluated. Linear regression models were used to study the relationship between changes in bone parameters and in hsCRP from visit 1 to 2 and PRWE score after 12 weeks. A lower PRWE outcome, indicating better outcome, was significantly related to an early increase in trabecular bone mineral density (BMD) (β ?0.96 [95% CI ?1.75 to ?0.16], R² = 0.37), in torsional stiffness (?0.14 [?0.28 to ?0.004], R² = 0.31), and to an early decrease in trabecular separation (209 [15 to 402], R² = 0.33) and in ICTP (12.1 [0.0 to 24.1], R² = 0.34). Similar results were found for QuickDASH. Higher total dorsal and palmar flexion range of motion was significantly related to early increase in hsCRP (9.62 [3.90 to 15.34], R² = 0.52). This exploratory study indicates that the assessment of early changes in trabecular BMD, trabecular separation, calculated torsional stiffness, bone resorption marker ICTP, and hsCRP after a distal radius fracture provides valuable information regarding the 12‐week clinical outcome in terms of pain, disability, and range of motion and validates its use in studies on the process of early fracture healing. © 2014 American Society for Bone and Mineral Research.     

Use of DXA‐based finite element analysis of the proximal femur in a longitudinal study of hip fracture

Bone mineral density (BMD) measured by dual‐energy X‐ray absorptiometry (DXA) is used for clinical assessment of fracture risk; however, measurements that incorporate bone strength could improve predictive ability. The aim of this study was to determine whether bone strength derived from finite element (FE) analysis was associated with hip fracture risk in a longitudinal study. We studied 728 women (mean age 82 years), 182 with subsequent hip fracture. FE models were generated from baseline DXA scans of the hip to determine femoral bone strength and load‐to‐strength ratio (LSR). The baseline LSR was significantly higher in fracture cases (median 1.1) compared with controls (0.7, p < 0.0001). Femoral strength and BMD were also significantly lower in cases (median 1820 N, 0.557 g/cm²) compared with controls (2614 N, 0.618 g/cm²) both p < 0.0001. Fracture risk increased per standard deviation decrease in femoral strength (odds ratio [OR] = 2.2, 95% confidence interval [CI] 1.8–2.8); femoral neck (FN) BMD (OR = 2.1, 95% CI 1.7–2.6); total hip BMD (OR = 1.8, 95% CI 1.5–2.1); and per SD increase in LSR (OR = 1.8, 95% CI 1.5–2.1). After adjusting for FN BMD, the odds ratio for femoral strength (OR = 1.7, 95% CI 1.2–2.4) and LSR (OR = 1.4, 95% CI 1.1–1.7) remained significantly greater than 1. The area under the curve (AUC) for LSR combined with FN BMD (AUC 0.69, 95% CI 0.64–0.73) was significantly greater than FN BMD alone (AUC 0.66, 95% CI 0.62–0.71, p = 0.004). Strength and LSR remained significant when adjusted for prevalent fragility fracture, VFA, and FRAX score. In conclusion, the DXA‐based FE model was able to discriminate incident hip fracture cases from controls in this longitudinal study independently from FN BMD, prior fracture, VFA, and FRAX score. Such an approach may provide a useful tool for better assessment of bone strength to identify patients at high risk of hip fracture who may benefit from treatment to reduce fracture risk. © 2013 American Society for Bone and Mineral Research.     

Bone Volume Fraction and Fabric Anisotropy Are Better Determinants of Trabecular Bone Stiffness Than Other Morphological Variables

As our population ages, more individuals suffer from osteoporosis. This disease leads to impaired trabecular architecture and increased fracture risk. It is essential to understand how morphological and mechanical properties of the cancellous bone are related. Morphology‐elasticity relationships based on bone volume fraction (BV/TV) and fabric anisotropy explain up to 98% of the variation in elastic properties. Yet, other morphological variables such as individual trabeculae segmentation (ITS) and trabecular bone score (TBS) could improve the stiffness predictions. A total of 743 micro–computed tomography (μCT) reconstructions of cubic trabecular bone samples extracted from femur, radius, vertebrae, and iliac crest were analyzed. Their morphology was assessed via 25 variables and their stiffness tensor () was computed from six independent load cases using micro finite element (μFE) analyses. Variance inflation factors were calculated to evaluate collinearity between morphological variables and decide upon their inclusion in morphology‐elasticity relationships. The statistically admissible morphological variables were included in a multiple linear regression model of the dependent variable . The contribution of each independent variable was evaluated (ANOVA). Our results show that BV/TV is the best determinant of (r²_adj = 0.889), especially in combination with fabric anisotropy (r²_adj = 0.968). Including the other independent predictors hardly affected the amount of variance explained by the model (r²_adj = 0.975). Across all anatomical sites, BV/TV explained 87% of the variance of the bone elastic properties. Fabric anisotropy further described 10% of the bone stiffness, but the improvement in variance explanation by adding other independent factors was marginal (<1%). These findings confirm that BV/TV and fabric anisotropy are the best determinants of trabecular bone stiffness and show, against common belief, that other morphological variables do not bring any further contribution. These overall conclusions remain to be confirmed for specific bone diseases and postelastic properties. © 2015 American Society for Bone and Mineral Research.     

The Initial Slope of the Variogram,Foundation of the Trabecular Bone Score,Is Not or Is Poorly Associated With Vertebral Strength

Trabecular bone score (TBS) rests on the textural analysis of dual‐energy X‐ray absorptiometry (DXA) to reflect the decay in trabecular structure characterizing osteoporosis. Yet, its discriminative power in fracture studies remains incomprehensible because prior biomechanical tests found no correlation with vertebral strength. To verify this result possibly owing to an unrealistic setup and to cover a wide range of loading scenarios, the data from three previous biomechanical studies using different experimental settings were used. They involved the compressive failure of 62 human lumbar vertebrae loaded 1) via intervertebral discs to mimic the in vivo situation (“full vertebra”); 2) via the classical endplate embedding (“vertebral body”); or 3) via a ball joint to induce anterior wedge failure (“vertebral section”). High‐resolution peripheral quantitative computed tomography (HR‐pQCT) scans acquired from prior testing were used to simulate anterior‐posterior DXA from which areal bone mineral density (aBMD) and the initial slope of the variogram (ISV), the early definition of TBS, were evaluated. Finally, the relation of aBMD and ISV with failure load (F_exp) and apparent failure stress (σ_exp) was assessed, and their relative contribution to a multilinear model was quantified via ANOVA. We found that, unlike aBMD, ISV did not significantly correlate with F_exp and σ_exp, except for the “vertebral body” case (r² = 0.396, p = 0.028). Aside from the “vertebra section” setup where it explained only 6.4% of σ_exp (p = 0.037), it brought no significant improvement to aBMD. These results indicate that ISV, a replica of TBS, is a poor surrogate for vertebral strength no matter the testing setup, which supports the prior observations and raises a fortiori the question of the deterministic factors underlying the statistical relationship between TBS and vertebral fracture risk. © 2015 American Society for Bone and Mineral Research.     

Structural Factors Associated With Femoral Neck Fractures and its Prediction in Chinese Males

We have recently proposed a new approach to evaluate 2D femoral neck (FN) structure, named the Minimal Model (MM), that comprised FN areal bone mineral density (FNaBMD) and FNWidth and 2 new internal structural measures; (1) the standard deviation of normalized mineral mass projection profile distribution (FNSigma), and (2) the displacement between center-of-mineral mass and geometric center of mineral mass projection profile (FNDelta). The contralateral hip of 67 FN fracture Chinese male patients had a QCT scan shortly after fracture and was compared to 156 community participants without hip fracture. The QCT scans were analyzed using Mindways software to enable DXA-equivalent 2D images to be obtained; MM variables were calculated from these images. In FN fracture and nonfracture participants, the 4 MM variables as well as age, weight and height were compared. Compared to nonfracture, fracture participants were older, weighed less and were taller. After adjustment for these differences FN fracture participants compared to nonfracture had mean ± SD lower FNaBMD 0.54 ± 0.11 vs 0.70 ± 0.11 g/cm² (p < 0.001); larger FNSigma 1.05 ± 0.11 vs 0.98 ± 0.10 cm (p < 0.001); larger FNDelta 0.43 ± 0.09 vs 0.33 ± 0.09 cm (p < 0.001), however FNWidth did not differ 2.96 ± 0.35 vs 2.92 ± 0.34 cm. All variables except FNaBMD and FNWidth were correlated; however logistic regression identified increased age and height, reduced FNaBMD and increased FNSigma as independent contributors to differentiating participants with FN fracture from nonfracture. Area under ROC analysis identified significant improvement in discrimination with addition of FNSigma to the base model of Age and FNaBMD (C statistic 0.88 and 0.91, p = 0.019). These analyses identified important internal structural information available from 2D DXA imaging that contributes to discrimination of FN fracture in addition to low bone mass. This analytical approach may contribute to improved clinical FN fracture prediction, extending value of widely available DXA technology.     

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

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 (h²) for VFrx and its genetic correlation with phenotypes contributing to VFrx risk have not been established. This study aims to estimate the h² 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 (T₄ to L₄) 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 L₃ 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 h² 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 h² 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. © 2012 American Society for Bone and Mineral Research.     

Reduction in Torsional Stiffness and Strength at the Proximal Tibia as a Function of Time Since Spinal Cord Injury

Spinal cord injury (SCI) is characterized by marked bone loss and a high rate of low‐energy fracture around regions of the knee. Changes in the mechanical integrity of bone after SCI are poorly defined, and a better understanding may inform approaches to prevent fractures. The purpose of this study was to quantify reductions in torsional stiffness and strength at the proximal tibia as a function of time since SCI. Sixty adults with SCI ranging from 0 to 50 years of duration and a reference group of 10 able‐bodied controls received a CT scan of the proximal tibia. Measures of integral bone mineral were calculated for the total proximal tibia, and localized measures of cortical and trabecular bone mineral were calculated for the epiphysis, metaphysis, and diaphysis. Torsional stiffness (K) and strength (T_ult) for the total proximal tibia were quantified using validated subject‐specific finite element models. Total proximal tibia measures of integral bone mineral, K, and T_ult decreased exponentially (r² = 0.52 to 0.70) and reached a new steady state within 2.1 to 2.7 years after SCI. Whereas new steady‐state values for integral bone mineral and K were 52% to 56% (p < 0.001) lower than the reference group, the new steady state for T_ult was 69% (p < 0.001) lower than the reference group. Reductions in total proximal tibia measures occurred through a combination of trabecular and endocortical resorption, leaving a bone comprised primarily of marrow fat rather than hydroxyapatite. These findings illustrate that a short therapeutic window exists early (ie, 2 years) after SCI, during which bone‐specific intervention may attenuate reductions in mechanical integrity and ultimately prevent SCI‐related fragility fracture. © 2015 American Society for Bone and Mineral Research.     

A Surrogate Measure of Cortical Bone Matrix Density by Long T2‐Suppressed MRI

Magnetic resonance has the potential to image and quantify two pools of water within bone: free water within the Haversian pore system (transverse relaxation time, T₂> 1 ms), and water hydrogen‐bonded to matrix collagen (T₂ ～ 300 to 400 μs). Although total bone water concentration quantified by MRI has been shown to scale with porosity, greater insight into bone matrix density and porosity may be gained by relaxation‐based separation of bound and pore water fractions. The objective of this study was to evaluate a recently developed surrogate measurement for matrix density, single adiabatic inversion recovery (SIR) zero echo‐time (ZTE) MRI, in human bone. Specimens of tibial cortical bone from 15 donors (aged 27 to 97 years; 8 female and 7 male) were examined at 9.4T field strength using two methods: (1) ¹H ZTE MRI, to capture total ¹H signal, and (2) ¹H SIR‐ZTE MRI, to selectively image matrix‐associated ¹H signal. Total water, bone matrix, and bone mineral densities were also quantified gravimetrically, and porosity was measured by micro‐CT. ZTE apparent total water ¹H concentration was 32.7 ± 3.2 M (range 28.5 to 40.3 M), and was correlated positively with porosity (R² = 0.80) and negatively with matrix and mineral densities (R² = 0.90 and 0.82, respectively). SIR‐ZTE apparent bound water ¹H concentration was 32.9 ± 3.9 M (range 24.4 to 39.8 M), and its correlations were opposite to those of apparent total water: negative with porosity (R² = 0.73) and positive with matrix density (R² = 0.74) and mineral density (R² = 0.72). Porosity was strongly correlated with gravimetric matrix density (R² = 0.91, negative) and total water density (R² = 0.92, positive). The strong correlations of SIR‐ZTE‐derived apparent bound water ¹H concentration with ground‐truth measurements suggest that this quantitative solid‐state MRI method provides a nondestructive surrogate measure of bone matrix density. © 2015 American Society for Bone and Mineral Research.