Rapid bone microarchitecture decline in older men with high bone turnover-the prospective STRAMBO study.

Older men with high bone turnover have faster bone loss. We assessed the link between the baseline levels of bone turnover markers (BTMs) and the prospectively assessed bone microarchitecture decline in men. In 825 men aged 60-87 yr, we measured the serum osteocalcin (OC), bone alkaline phosphatase (BAP), N-terminal propeptide of type I procollagen (PINP), and C-terminal telopeptide of type I collagen (CTX-I), and urinary total deoxypyridinoline (tDPD). Bone microarchitecture and strength (distal radius and distal tibia) were estimated by high-resolution pQCT (XtremeCT, Scanco Medical) at baseline and then after 4 and 8 yr. Thirty-seven men took medications affecting bone metabolism. Statistical models were adjusted for age and BMI. At the distal radius, the decrease in the total bone mineral density (Tt.BMD), cortical BMD (Ct.BMD), cortical thickness (Ct.Thd), and cortical area (Ct.Ar) and failure load was faster in the highest vs the lowest CTX-I quartile (failure load: -0.94 vs -0.31% yr-1, P < .001). Patterns were similar for distal tibia. At the distal tibia, bone decline (Tt.BMD, Ct.Thd, Ct.Ar, Ct.BMD, and failure load) was faster in the highest vs the lowest tDPD quartile. At each skeletal site, the rate of decrease in Tb.BMD differed between the extreme OC quartiles (P < .001). Men in the highest BAP quartile had a faster loss of Tt.BMD, Tb.BMD, reaction force, and failure load vs the lowest quartile. The link between PINP and bone decline was poor. The BTM score is the sum of the nos. of the quartiles for each BTM. Men in the highest quartile of the score had a faster loss of cortical bone and bone strength vs the lowest quartile. Thus, in the older men followed prospectively for 8 yr, the rate of decline in bone microarchitecture and estimated bone strength was 50%-215% greater in men with high bone turnover (highest quartile, CTX-I above the median) compared to the men with low bone turnover (lowest quartile, CTX-I below the median).

Fracture risk based on HR-pQCT measures does not vary with age in older adults - the bone microarchitecture international consortium (BoMIC) prospective cohort study.

Fracture risk increases with lower areal BMD (aBMD); however, aBMD-related estimate of risk may decrease with age. This may depend on technical limitations of 2-dimensional (2D) DXA which are reduced with 3D high-resolution peripheral quantitative computed tomography (HR-pQCT). Our aim was to examine whether the predictive utility of HR-pQCT measures with fracture varies with age. We analyzed associations of HR-pQCT measures at the distal radius and distal tibia with two outcomes: incident fractures and major osteoporotic fractures. We censored follow-up time at first fracture, death, last contact or 8 years after baseline. We estimated hazard ratios (HR) and 95%CI for the association between bone traits and fracture incidence across age quintiles. Among 6835 men and women (ages 40-96) with at least one valid baseline HR-pQCT scan who were followed prospectively for a median of 48.3 months, 681 sustained fractures. After adjustment for confounders, bone parameters at both the radius and tibia were associated with higher fracture risk. The estimated HRs for fracture did not vary significantly across age quintiles for any HR-pQCT parameter measured at either the radius or tibia. In this large cohort, the homogeneity of the associations between the HR-pQCT measures and fracture risk across age groups persisted for all fractures and for major osteoporotic fractures. The patterns were similar regardless of the HR-pQCT measure, the type of fracture, or the statistical models. The stability of the associations between HR-pQCT measures and fracture over a broad age range shows that bone deficits or low volumetric density remain major determinants of fracture risk regardless of age group. The lower risk for fractures across measures of aBMD in older adults in other studies may be related to factors which interfere with DXA but not with HR-pQCT measures.

Transferability of bone phenotyping and fracture risk assessment by µFRAC from first-generation high-resolution peripheral quantitative computed tomography to second-generation scan data.

INTRODUCTION: The continued development of high-resolution peripheral quantitative computed tomography (HR-pQCT) has led to a second-generation scanner with higher resolution and longer scan region. However, large multi-center prospective cohorts were collected with first-generation HR-pQCT and have been used to develop bone phenotyping and fracture risk prediction (µFRAC) models. This study establishes whether there is sufficient universality of these first-generation trained models for use with second-generation scan data. METHODS: HR-pQCT data was collected for a cohort of 60 individuals, who had been scanned on both first- and second-generation scanners on the same day to establish the universality of the HR-pQCT models. These data were each used as input to first-generation trained bone microarchitecture models for bone phenotyping and fracture risk prediction, and their outputs were compared for each study participant. Reproducibility of the models were assessed using same-day repeat scans obtained from first-generation (n = 37) and second-generation (n = 74) scanners. RESULTS: Across scanner generations, the bone phenotyping model performed with an accuracy of 93.1%. Similarly, the five-year fracture risk assessment by µFRAC was well correlated with a Pearson's (r) correlation coefficient of r > 0.83 for the three variations of µFRAC (varying inclusion of clinical risk factors, finite element analysis, and dual X-ray absorptiometry). The first-generation reproducibility cohort performed with an accuracy for categorical assignment of 100% (bone phenotyping), and a correlation coefficient of 0.99 (µFRAC), the second-generation reproducibility cohort performed with an accuracy of 96.4% (bone phenotyping), and a correlation coefficient of 0.99 (µFRAC). CONCLUSION: We demonstrated that bone microarchitecture models trained using first-generation scan data generalize well to second-generation scans, performing with a high level of accuracy and reproducibility. Less than 4% of individuals' estimated fracture risk led to a change in treatment threshold, and in general these dissimilar outcomes using second-generation data tended to be more conservative.

Establishing error bounds for internal calibration of quantitative computed tomography.

Opportunistic computed tomography (CT) scans, which can assess relevant osteoporotic bones of interest, offer a potential solution for identifying osteoporotic individuals. CT scans usually do not contain calibration phantoms, so internal calibration methods have been developed to create a voxel-specific density calibration that can be used in opportunistic CT. It remains a challenge, however, to account for potential sources of error in internal calibration, such as beam hardening or heterogeneous internal reference tissues. The purpose of this work was to introduce our internal calibration method that accounts for these variations and to estimate error bounds for the bone mineral density (BMD) measurements taken from internally calibrated scans. The error bounds are derived by incorporating a combination of a Monte Carlo simulation and standard error propagation into our previously established internal calibration method. A cohort of 138 clinical abdominal CT scans were calibrated for BMD assessment with a phantom placed in the field of view and used as the ground truth. Our modified internal calibration method provided error bounds on the same images and was tested to contain the ground truth phantom-calibrated BMD. This was repeated using 10 different internal reference tissue combinations to explore how error bounds are affected by the choice of internal tissue referents. We found that the tissue combination of air, skeletal muscle, and cortical bone yielded the most accurate BMD estimates while maintaining error bounds that were sufficiently conservative to account for sources of error such as beam hardening and heterogeneous tissue samples. The mean difference between the phantom BMD and the BMD resulting from the tissue combination of air, skeletal muscle and cortical bone was 2.12 mg/cc (0.06% BMD error) and 1.13 mg/cc (0.02 % BMD error) for the left and right femur, respectively. Providing error bounds for internal calibration provides a method to explore the influence of internal reference tissues and confidence for BMD estimates.

Fixed and Relative Positioning of Scans for High Resolution Peripheral Quantitative Computed Tomography.

INTRODUCTION: High resolution peripheral quantitative computed tomography (HR-pQCT) imaging protocol requires defining where to position the ∼1 cm thick scan along the bone length. Discrepancies between the use of two positioning methods, the relative and fixed offset, may be problematic in the comparison between studies and participants. This study investigated how bone landmarks scale linearly with length and how this scaling affects both positioning methods aimed at providing a consistent anatomical location for scan acquisition. METHODS: Using CT images of the radius (N = 25) and tibia (N = 42), 10 anatomical landmarks were selected along the bone length. The location of these landmarks was converted to a percent length along the bone, and the variation in their location was evaluated across the dataset. The absolute location of the HR-pQCT scan position using both offset methods was identified for all bones and converted to a percent length position relative to the HR-pQCT reference line for comparison. A secondary analysis of the location of the scan region specifically within the metaphysis was explored at the tibia. RESULTS: The location of landmarks deviated from a linear relationship across the dataset, with a range of 3.6 % at the radius sites, and 4.5 % at the tibia sites. The consequent variation of the position of the scan at the radius was 0.6 % and 0.3 %, and at the tibia 2.4 % and 0.5 %, for the fixed and relative offset, respectively. The position of the metaphyseal junction with the epiphysis relative to the scan position was poorly correlated to bone length, with R2 = 0.06 and 0.37, for the fixed and relative offset respectively. CONCLUSION: The variation of the scan position by either method is negated by the intrinsic variation of the bone anatomy with respect both to total bone length as well as the metaphyseal region. Therefore, there is no clear benefit of either offset method. However, the lack of difference due to the inherent variation in the underlying anatomy implies that it is reasonable to compare studies even if they are using different positioning methods.

Bone Quality in Competitive Athletes: A Systematic Review.

The study objective was to assess bone quality measured by high resolution peripheral quantitative computed tomography (HR-pQCT) in competitive athletes. Medline, EMBASE and Sport Discus were searched through May 2022. Prior to submission, a follow-up database search was performed (January 2023). Studies of competitive athletes using HR-pQCT to assess bone quality were included. Athletes were aged between 14 and 45 years. Data extraction included study design and location (country), skeletal imaging modality and site, bone variables and any additional musculoskeletal-related outcome. Information identifying sports and athletes were also extracted. This review included 14 manuscripts and a total of 928 individuals (male: n=75; female: n=853). Athletes comprised 78% (n=722) of the included individuals and 93% of athletes were female. Assessment scores indicate the studies were good to fair quality. The athletes included in this review can be categorized into three groups: 1) healthy athletes, 2) athletes with compromised menstrual function (e.g., amenorrhoea), and 3) athletes with compromised bone health (e.g., bone stress injuries). When assessing bone quality using HR-pQCT, healthy competitive athletes had denser, stronger and larger bones with better microarchitecture, compared with controls. However, the same cannot be said for athletes with amenorrhoea or bone stress injuries.

Predicting Bone Adaptation in Astronauts during and after Spaceflight.

A method was previously developed to identify participant-specific parameters in a model of trabecular bone adaptation from longitudinal computed tomography (CT) imaging. In this study, we use these numerical methods to estimate changes in astronaut bone health during the distinct phases of spaceflight and recovery on Earth. Astronauts (N = 16) received high-resolution peripheral quantitative CT (HR-pQCT) scans of their distal tibia prior to launch (L), upon their return from an approximately six-month stay on the international space station (R+0), and after six (R+6) and 12 (R+12) months of recovery. To model trabecular bone adaptation, we determined participant-specific parameters at each time interval and estimated their bone structure at R+0, R+6, and R+12. To assess the fit of our model to this population, we compared static and dynamic bone morphometry as well as the Dice coefficient and symmetric distance at each measurement. In general, modeled and observed static morphometry were highly correlated (R2> 0.94) and statistically different (p < 0.0001) but with errors close to HR-pQCT precision limits. Dynamic morphometry, which captures rates of bone adaptation, was poorly estimated by our model (p < 0.0001). The Dice coefficient and symmetric distance indicated a reasonable local fit between observed and predicted bone volumes. This work applies a general and versatile computational framework to test bone adaptation models. Future work can explore and test increasingly sophisticated models (e.g., those including load or physiological factors) on a participant-specific basis.

Comparison of Bone Quality Among Winter Endurance Athletes with and Without Risk Factors for Relative Energy Deficiency in Sport (REDs): A Cross-Sectional Study.

Relative Energy Deficiency in Sport (REDs) is a syndrome describing the relationship between prolonged and/or severe low energy availability and negative health and performance outcomes. The high energy expenditures incurred during training and competition put endurance athletes at risk of REDs. The objective of this study was to investigate differences in bone quality in winter endurance athletes classified as either low-risk versus at-risk for REDs. Forty-four participants were recruited (M = 18; F = 26). Bone quality was assessed at the distal radius and tibia using high resolution peripheral quantitative computed tomography (HR-pQCT), and at the hip and spine using dual X-ray absorptiometry (DXA). Finite element analysis was used to estimate bone strength. Participants were grouped using modified criteria from the REDs Clinical Assessment Tool Version 1. Fourteen participants (M = 3; F = 11), were classified as at-risk of REDs (≥ 3 risk factors). Measured with HR-pQCT, cortical bone area (radius) and bone strength (radius and tibia) were 6.8%, 13.1% and 10.3% lower (p = 0.025, p = 0.033, p = 0.027) respectively, in at-risk compared with low-risk participants. Using DXA, femoral neck areal bone density was 9.4% lower in at-risk compared with low-risk participants (p = 0.005). At-risk male participants had 21.9% lower femoral neck areal bone density (via DXA) than low-risk males (p = 0.020) with no significant differences in females. Overall, 33.3% of athletes were at-risk for REDs and had lower bone quality than those at low-risk.

Addressing Challenges of Opportunistic Computed Tomography Bone Mineral Density Analysis.

Computed tomography (CT) offers advanced biomedical imaging of the body and is broadly utilized for clinical diagnosis. Traditionally, clinical CT scans have not been used for volumetric bone mineral density (vBMD) assessment; however, computational advances can now leverage clinically obtained CT data for the secondary analysis of bone, known as opportunistic CT analysis. Initial applications focused on using clinically acquired CT scans for secondary osteoporosis screening, but opportunistic CT analysis can also be applied to answer research questions related to vBMD changes in response to various disease states. There are several considerations for opportunistic CT analysis, including scan acquisition, contrast enhancement, the internal calibration technique, and bone segmentation, but there remains no consensus on applying these methods. These factors may influence vBMD measures and therefore the robustness of the opportunistic CT analysis. Further research and standardization efforts are needed to establish a consensus and optimize the application of opportunistic CT analysis for accurate and reliable assessment of vBMD in clinical and research settings. This review summarizes the current state of opportunistic CT analysis, highlighting its potential and addressing the associated challenges.

Measurements of the Vitamin D Metabolome in the Calgary Vitamin D Study: Relationship of Vitamin D Metabolites to Bone Loss.

In a 36-month randomized controlled trial examining the effect of high-dose vitamin D3 on radial and tibial total bone mineral density (TtBMD), measured by high-resolution peripheral quantitative tomography (HR-pQCT), participants (311 healthy males and females aged 55-70 years with dual-energy X-ray absorptiometry T-scores > -2.5 without vitamin D deficiency) were randomized to receive 400 IU (N = 109), 4000 IU (N = 100), or 10,000 IU (N = 102) daily. Participants had HR-pQCT radius and tibia scans and blood sampling at baseline, 6, 12, 24, and 36 months. This secondary analysis examined the effect of vitamin D dose on plasma measurements of the vitamin D metabolome by liquid chromatography-tandem mass spectrometry (LC-MS/MS), exploring whether the observed decline in TtBMD was associated with changes in four key metabolites [25-(OH)D3 ; 24,25-(OH)2 D3 ; 1,25-(OH)2 D3 ; and 1,24,25-(OH)3 D3 ]. The relationship between peak values in vitamin D metabolites and changes in TtBMD over 36 months was assessed using linear regression, controlling for sex. Increasing vitamin D dose was associated with a marked increase in 25-(OH)D3 , 24,25-(OH)2 D3 and 1,24,25-(OH)3 D3 , but no dose-related change in plasma 1,25-(OH)2 D3 was observed. There was a significant negative slope for radius TtBMD and 1,24,25-(OH)3 D3 (-0.05, 95% confidence interval [CI] -0.08, -0.03, p < 0.001) after controlling for sex. A significant interaction between TtBMD and sex was seen for 25-(OH)D3 (female: -0.01, 95% CI -0.12, -0.07; male: -0.04, 95% CI -0.06, -0.01, p = 0.001) and 24,25-(OH)2 D3 (female: -0.75, 95% CI -0.98, -0.52; male: -0.35, 95% CI -0.59, -0.11, p < 0.001). For the tibia there was a significant negative slope for 25-(OH)D3 (-0.03, 95% CI -0.05, -0.01, p < 0.001), 24,25-(OH)2 D3 (-0.30, 95% CI -0.44, -0.16, p < 0.001), and 1,24,25-(OH)3 D3 (-0.03, 95% CI -0.05, -0.01, p = 0.01) after controlling for sex. These results suggest vitamin D metabolites other than 1,25-(OH)2 D3 may be responsible for the bone loss seen in the Calgary Vitamin D Study. Although plasma 1,25-(OH)2 D3 did not change with vitamin D dose, it is possible rapid catabolism to 1,24,25-(OH)3 D3 prevented the detection of a dose-related rise in plasma 1,25-(OH)2 D3 . © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Bone-GAN: Generation of virtual bone microstructure of high resolution peripheral quantitative computed tomography.

BACKGROUND: Data-driven development of medical biomarkers of bone requires a large amount of image data but physical measurements are generally too restricted in size and quality to perform a robust training. PURPOSE: This study aims to provide a reliable in silico method for the generation of realistic bone microstructure with defined microarchitectural properties. Synthetic bone samples may improve training of neural networks and serve for the development of new diagnostic parameters of bone architecture and mineralization. METHODS: One hundred-fifty cadaveric lumbar vertebrae from 48 different male human spines were scanned with a high resolution peripheral quantitative CT. After prepocessing the scans, we extracted 10,795 purely spongeous bone patches, each with a side length of 32 voxels (5 mm) and isotropic voxel size of 164 µm. We trained a volumetric generative adversarial network (GAN) in a progressive manner to create synthetic microstructural bone samples. We then added a style transfer technique to allow the generation of synthetic samples with defined microstructure and gestalt by simultaneously optimizing two entangled loss functions. Reliability testing was performed by comparing real and synthetic bone samples on 10 well-understood microstructural parameters. RESULTS: The method was able to create synthetic bone samples with visual and quantitative properties that effectively matched with the real samples. The GAN contained a well-formed latent space allowing to smoothly morph bone samples by their microstructural parameters, visual appearance or both. Optimum performance has been obtained for bone samples with voxel size 32 × 32 × 32, but also samples of size 64 × 64 × 64 could be synthesized. CONCLUSIONS: Our two-step-approach combines a parameter-agnostic GAN with a parameter-specific style transfer technique. It allows to generate an unlimited anonymous database of microstructural bone samples with sufficient realism to be used for the development of new data-driven methods of bone-biomarkers. Particularly, the style transfer technique can generate datasets of bone samples with specific conditions to simulate certain bone pathologies.

A Fracture Risk Assessment Tool for High Resolution Peripheral Quantitative Computed Tomography.

Most fracture risk assessment tools use clinical risk factors combined with bone mineral density (BMD) to improve assessment of osteoporosis; however, stratifying fracture risk remains challenging. This study developed a fracture risk assessment tool that uses information about volumetric bone density and three-dimensional structure, obtained using high-resolution peripheral quantitative compute tomography (HR-pQCT), to provide an alternative approach for patient-specific assessment of fracture risk. Using an international prospective cohort of older adults (n = 6802) we developed a tool to predict osteoporotic fracture risk, called µFRAC. The model was constructed using random survival forests, and input predictors included HR-pQCT parameters summarizing BMD and microarchitecture alongside clinical risk factors (sex, age, height, weight, and prior adulthood fracture) and femoral neck areal BMD (FN aBMD). The performance of µFRAC was compared to the Fracture Risk Assessment Tool (FRAX) and a reference model built using FN aBMD and clinical covariates. µFRAC was predictive of osteoporotic fracture (c-index = 0.673, p < 0.001), modestly outperforming FRAX and FN aBMD models (c-index = 0.617 and 0.636, respectively). Removal of FN aBMD and all clinical risk factors, except age, from µFRAC did not significantly impact its performance when estimating 5-year and 10-year fracture risk. The performance of µFRAC improved when only major osteoporotic fractures were considered (c-index = 0.733, p < 0.001). We developed a personalized fracture risk assessment tool based on HR-pQCT that may provide an alternative approach to current clinical methods by leveraging direct measures of bone density and structure. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Rapid Cortical Bone Loss at the Distal Radius Is Associated With Higher Risk of Fracture in Older Men - The STRAMBO Study.

Rapid loss of areal bone mineral density (aBMD) is associated with higher fracture risk after adjustment for confounders including initial aBMD. However, the link between bone microarchitecture decline and fracture is not clear. We studied the association between bone microarchitecture deterioration assessed prospectively over 4 years and the subsequent fracture risk in older men. Bone microarchitecture at the distal radius and tibia was assessed by high-resolution peripheral QCT (HR-pQCT; XtremeCT, Scanco Medical) (baseline, 4 years) in 732 men aged 60-87 years. During the 8-year follow-up, 109 men had fragility fractures. Areal BMD was assessed by dual-energy X-ray absorptiometry. After adjustment for age, weight, prior falls and fractures, distal radius aBMD (baseline, slope), and baseline distal radius total volumetric BMD (Tt.BMD), a faster decrease in distal radius Tt.BMD was associated with higher fracture risk (hazard ratio [HR] = 1.54/SD, 95% confidence interval: 1.20-1.95, p < .005). Rapid cortical bone loss was associated with higher fracture risk (cortical thickness: HR = 1.48; 1.15-1.90, p < .01; cortical BMD: HR = 1.38; 1.11-1.72, p < .01). The rate of trabecular bone loss at the distal radius and the rate of bone microarchitecture decline at the distal tibia were not associated with fracture risk. After adjustment for aBMD and distal radius HR-pQCT measures assessed after 4 years, changes in Tt.BMD were associated with higher fracture risk (e.g., Tt.BMD: HR = 1.37; 1.11-1.69, p < .005). Compared with the reference model (age, weight, prior fractures and falls, baseline and slope of aBMD, baseline HR-pQCT value), further addition of the slope of the HR-pQCT measure did not improve the fracture prediction. Thus, rapid cortical bone loss at the distal radius is associated with higher fracture risk in the multivariable models including baseline values of the HR-pQCT measure. However, repeated HR-pQCT measurements did not improve the assessment of the fracture risk in older men (compared with the reference model defined earlier). © 2023 American Society for Bone and Mineral Research (ASBMR).

Automatic segmentation of trabecular and cortical compartments in HR-pQCT images using an embedding-predicting U-Net and morphological post-processing.

High-resolution peripheral quantitative computed tomography (HR-pQCT) is an emerging in vivo imaging modality for quantification of bone microarchitecture. However, extraction of quantitative microarchitectural parameters from HR-pQCT images requires an accurate segmentation of the image. The current standard protocol using semi-automated contouring for HR-pQCT image segmentation is laborious, introduces inter-operator biases into research data, and poses a barrier to streamlined clinical implementation. In this work, we propose and validate a fully automated algorithm for segmentation of HR-pQCT radius and tibia images. A multi-slice 2D U-Net produces initial segmentation predictions, which are post-processed via a sequence of traditional morphological image filters. The U-Net was trained on a large dataset containing 1822 images from 896 unique participants. Predicted segmentations were compared to reference segmentations on a disjoint dataset containing 386 images from 190 unique participants, and 156 pairs of repeated images were used to compare the precision of the novel and current protocols. The agreement of morphological parameters obtained using the predicted segmentation relative to the reference standard was excellent (R2 between 0.938 and > 0.999). Precision was significantly improved for several outputs, most notably cortical porosity. This novel and robust algorithm for automated segmentation will increase the feasibility of using HR-pQCT in research and clinical settings.

Twelve Months of Denosumab and/or Alendronate Is Associated With Improved Bone Fatigue Life, Microarchitecture, and Density in Ovariectomized Cynomolgus Monkeys.

Prolonged use of antiresorptives such as the bisphosphonate alendronate (ALN) and the RANKL inhibitor denosumab (DMAb) are associated with rare cases of atypical femoral fracture (AFF). The etiology of AFF is unclear, but it has been hypothesized that potent osteoclast inhibitors may reduce bone fatigue resistance. The purpose of this study was to quantify the relationship between antiresorptive treatment and fatigue life (cycles to failure) in bone from ovariectomized cynomolgus monkeys. We analyzed humeral bone from 30 animals across five treatment groups. Animals were treated for 12 months with subcutaneous (sc) vehicle (VEH), sc DMAb (25 mg/kg/month), or intravenous (iv) ALN (50 µg/kg/month). Another group received 6 months VEH followed by 6 months DMAb (VEH-DMAb), and the final group received 6 months ALN followed by 6 months DMAb (ALN-DMAb). A total of 240 cortical beam samples were cyclically tested in four-point bending at 80, 100, 120, or 140 MPa peak stress. High-resolution imaging and density measurements were performed to evaluate bone microstructure and composition. Samples from the ALN (p = 0.014), ALN-DMAb (p = 0.008), and DMAb (p < 0.001) groups illustrated higher fatigue-life measurements than VEH. For example, at 140 MPa the VEH group demonstrated a median ± interquartile range (IQR) fatigue life of 1987 ± 10593 cycles, while animals in the ALN, ALN-DMAb, and DMAb groups survived 9850 ± 13648 (+395% versus VEH), 10493 ± 16796 (+428%), and 14495 ± 49299 (+629%) cycles, respectively. All antiresorptive treatment groups demonstrated lower porosity, smaller pore size, greater pore spacing, and lower number of canals versus VEH (p < 0.001). Antiresorptive treatment was also associated with greater apparent density, dry density, and ash density (p ≤ 0.03). We did not detect detrimental changes following antiresorptive treatments that would explain their association with AFF. In contrast, 12 months of treatment may have a protective effect against fatigue fractures. © 2022 American Society for Bone and Mineral Research (ASBMR).

C-reactive protein predicts endocortical expansion but not fracture in older men: the prospective STRAMBO study.

In older men, higher high-sensitivity C-reactive protein (hsCRP) concentrations were associated with faster prospectively assessed endocortical expansion (distal radius, distal tibia) and slightly higher cortical bone loss at distal tibia, but not with the fracture risk. High hsCRP level has a limited impact on bone decline in older men. PURPOSE: Data on the link of the high-sensitivity C-reactive protein (hsCRP) with bone loss and fracture risk are discordant. We studied the association of the hsCRP with the prospectively assessed decrease in areal bone mineral density (aBMD), bone microarchitecture decline, and fracture risk in older men. METHODS: At baseline, hsCRP was measured in 823 men aged 60-88. Areal BMD and bone microarchitecture (distal radius, distal tibia) were assessed by dual-energy X-ray absorptiometry and high-resolution peripheral QCT, respectively, at baseline and after 4 and 8 years. Data on incident fractures were collected for 8 years. RESULTS: Higher hsCRP concentration was associated with faster increase in aBMD at the whole body and lumbar spine, but not other sites. Higher hsCRP levels were associated with faster decrease in cortical area and more rapid increase in trabecular area at the distal radius (0.048 mm2/year/SD, p < 0.05) and distal tibia (0.123 mm2/year/SD, p < 0.001). At the distal tibia, high hsCRP level was associated with greater decrease in total and cortical volumetric BMD (vBMD) and in failure load. The hsCRP levels were not associated with the fracture risk, even after accounting for competing risk of death. CONCLUSION: Higher hsCRP levels were associated with greater endocortical expansion at the distal radius and tibia. Higher hsCRP was associated with slightly faster decrease in total and cortical vBMD and failure load at distal tibia, but not with the fracture risk. Thus, high hsCRP levels are associated with faster cortical bone loss, but not with fracture risk in older men.

Internal calibration for opportunistic computed tomography muscle density analysis.

INTRODUCTION: Muscle weakness can lead to reduced physical function and quality of life. Computed tomography (CT) can be used to assess muscle health through measures of muscle cross-sectional area and density loss associated with fat infiltration. However, there are limited opportunities to measure muscle density in clinically acquired CT scans because a density calibration phantom, allowing for the conversion of CT Hounsfield units into density, is typically not included within the field-of-view. For bone density analysis, internal density calibration methods use regions of interest within the scan field-of-view to derive the relationship between Hounsfield units and bone density, but these methods have yet to be adapted for muscle density analysis. The objective of this study was to design and validate a CT internal calibration method for muscle density analysis. METHODOLOGY: We CT scanned 10 bovine muscle samples using two scan protocols and five scan positions within the scanner bore. The scans were calibrated using internal calibration and a reference phantom. We tested combinations of internal calibration regions of interest (e.g., air, blood, bone, muscle, adipose). RESULTS: We found that the internal calibration method using two regions of interest, air and adipose or blood, yielded accurate muscle density values (< 1% error) when compared with the reference phantom. The muscle density values derived from the internal and reference phantom calibration methods were highly correlated (R2 > 0.99). The coefficient of variation for muscle density across two scan protocols and five scan positions was significantly lower for internal calibration (mean = 0.33%) than for Hounsfield units (mean = 6.52%). There was no difference between coefficient of variation for the internal calibration and reference phantom methods. CONCLUSIONS: We have developed an internal calibration method to produce accurate and reliable muscle density measures from opportunistic computed tomography images without the need for calibration phantoms.

High performance multi-platform computing for large-scale image-based finite element modeling of bone.

BACKGROUND: Image-based finite element (FE) modeling of bone is a non-invasive method to estimate bone stiffness and strength. High-resolution imaging data as input allows for inclusion of bone microarchitecture but results in large amounts of data unsuitable for traditional FE solvers. Bone-specific mesh-free solvers have been developed over the past 20 years to improve on memory efficiency in simulated bone loading applications. The objective of this study was to provide linear performance benchmarking for a bone-specific, mesh-free solver (FAIM) using µCT and HR-pQCT image data on Mac, Linux, and Windows operating systems using both single- and multi-thread CPU and GPU processing. METHODS: The focus is on the linear gradient-descent solver using standardized uniaxial loading of bone models from µCT, and first- and second-generation HR-pQCT scans of the radius and tibia. Convergence, speedup, memory, and batch performance tests were completed using CPUs and GPUs on three laboratory-based systems with Windows, Linux, and Mac operating systems. RESULTS: Although varying by system and model size, time-per-iteration was as low as 0.03 s when an HR-pQCT-based radius model (6.45 million DOF) was solved with 3 GPUs. Strong scaling was achieved with GPU and CPU parallel processing, with strong parallel efficiencies when models were solved using 3 GPUs or ≤ 10 CPU threads. Errors in force, strain energy density, and Von Mises stress were as low as 0.1% when a convergence tolerance of 10-3 or smaller was used. CONCLUSION: The results of this study indicate that to maximize computational efficiency and minimize model solution times using FAIM software under the standardized tested conditions using µCT, XCT1 and XCT2 HR-pQCT image data, convergence tolerance set to 10-4, and 10 threads or 2 GPUs are sufficient for efficient solution times. Less strict convergence tolerances will improve solution times but will introduce more error in the outcome measures.

Denosumab treatment is associated with decreased cortical porosity and increased bone density and strength at the proximal humerus of ovariectomized cynomolgus monkeys.

Upper extremity fractures, including those at the humerus, are common among women with postmenopausal osteoporosis. Denosumab was shown to reduce humeral fractures in this population; however, no clinical or preclinical studies have quantified the effects of denosumab on humerus bone mineral density or bone microarchitecture changes. This study used micro-computed tomography (µCT) and computed tomography (CT), alongside image-based finite element (FE) models derived from both modalities, to quantify the effects of denosomab (DMAb) and alendronate (ALN) on humeral bone from acutely ovariectomized (OVX) cynomolgus monkeys. Animals were treated with 12 monthly injections of s.c. vehicle (VEH; n = 10), s.c. denosumab (DMAb; 25 mg/kg, n = 9), or i.v. alendronate (ALN; 50 µg/kg, n = 10). Two more groups received 6 months of VEH followed by 6 months of DMAb (VEH-DMAb; n = 7) or 6 months of ALN followed by 6 months of DMAb (ALN-DMAb; n = 9). After treatment, humeri were harvested and µCT was used to quantify tissue mineral density, trabecular morphology, and cortical porosity at the humeral head. Clinical CT imaging was also used to quantify trabecular and cortical bone mineral density (BMD) at the ultra-proximal, proximal, 1/5 proximal and midshaft of the bone. Finally, µCT-based FE models in compression, and CT-based FE models in compression, torsion, and bending, were developed to estimate differences in strength. Compared to VEH, groups that received DMAb at any time demonstrated lower cortical porosity and/or higher tissue mineral density via µCT; no effects on trabecular morphology were observed. FE estimated strength based on µCT was higher after 12-months DMAb (p = 0.020) and ALN-DMAb (p = 0.024) vs. VEH; respectively, FE predicted mean (SD) strength was 4649.88 (710.58) N, and 4621.10 (1050.16) N vs. 3309.4 (876.09) N. All antiresorptive treatments were associated with higher cortical BMD via CT at the 1/5 proximal and midshaft of the humerus; however, no differences in CT-based FE predicted strength were observed. Overall, these results help to explain the observed reductions in humeral fracture rate following DMAb treatment in women with postmenopausal osteoporosis.