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Background: Sport-related ankle sprains (SASs) are prevalent in adolescents (ages 10-19), increasing the risk of developing posttraumatic osteoarthritis (PTOA). Although early ankle osteoarthritis (OA) is not well defined, OA eventually includes alterations in bone mineral density (BMD), structural changes, and soft tissue pathology. This study examined the impact of SAS sustained in adolescent sport on bone and soft tissue structural outcomes 3-15 years postinjury., Methods: Participants (n = 10) with prior unilateral SAS in adolescent sport (HxAI) were compared to age- and sex-matched controls. To assess injury-related pathologies and BMD, 1.5-tesla (T) extremity magnetic resonance imaging (MRI) and computed tomography scans were used. Semiquantitative scores for injury patterns and OA features from MRI scans were summed and compared between groups. The talus, calcaneus, navicular, and 5% distal tibia were segmented, and BMD was measured for each bone., Results: All HxAI participants exhibited MRI injury pathology (median 2; IQR 1-6), whereas only 1 of 10 controls showed pathology (median 0; IQR 0-0), χ 2 (1, n = 20) = 16.36, P  < .001. Both the injured and uninjured ankles in HxAI displayed injury pattern pathology. Additionally, 3 of 10 injured ankles and 2 of 10 uninjured ankles in the HxAI group (median 0; IQR 0-3), but none of the controls (median 0; IQR 0-0), exhibited OA features. In the HxAI group, talus BMD was lower in the injured ankle (502.4 ± 67.9 g/cm 3 ) compared with the uninjured ankle (515.6 ± 70.1 g/cm 3 ) ( F  = 13.33, P  = .002), with no significant BMD differences at the calcaneus, navicular, or 5% distal tibia. No differences were observed between the ankles of the control group., Conclusion: The presence of injury pattern pathology, structural changes, and reduced talus BMD suggest that degenerative changes may occur in individuals as early as 3-15 years following ankle injury., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Michael T. Kuczynski, PhD, reports support for the present manuscript from NSERC, NSERC Doctoral Scholarship 2020-2023. Carolyn A. Emery, PhD, PT, reports support for the present manuscript from Canadian Institutes of Health Research Foundation Grant. Sarah L Manske, PhD, reports support for the present manuscript from Arthritis Society (Canada) and grants or contracts from Natural Sciences and Engineering Council (Canada); Canadian Institutes for Health Research. Jacob L. Jaremko, MD, PhD, is supported by CIFAR and Medical Imaging Consultants. The Sport Injury Prevention Research Centre is an International Olympic Committee Research Centre for Prevention of Injury and Protection of Athlete Health. Disclosure forms for all authors are available online.

Objective: To compare the number of new erosions in two metacarpophalangeal (MCP) joints over one year assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT) and conventional radiography (CR). Furthermore, to estimate the diagnostic accuracy of erosive progression by CR with HR-pQCT as the reference standard., Methods: Paired sets of image data were available from patients with RA (n=310), who underwent HR-pQCT and CR, including the 2 nd and 3 rd MCP joints only of the dominant hand at baseline and at the one-year follow-up. Erosion number was determined using HR-pQCT and CR. Erosive volume was estimated from segmented HR-pQCT images, and erosion scores were obtained by the Sharp/van der Heijde method from CR. Erosive progression was defined as an increase in total erosion number or a study-specified increase in total erosive volume or total erosion score., Results: At baseline, 250 erosions were identified by CR compared to 1864 erosions by HR-pQCT. After one year, 3 new erosions were detected by CR compared to 66 new erosions by HR-pQCT. Erosive progression was identified in 40 patients using HR-pQCT and in 3 patients using CR. With HR-pQCT as reference, CR had a sensitivity of 2.5% (95% CI: 0.1-13.2%) and a specificity of 99.3% (95% CI: 97.3-99.9%) for detecting erosive progression., Conclusion: HR-pQCT identified more than 20 times the number of new erosions, and more than 10 times as many patients with erosive progression than CR. HR-pQCT is a sensitive tool for monitoring new erosions and erosive progression over one year in RA., (Copyright © 2024. Published by Elsevier Masson SAS.)

High-Resolution peripheral quantitative CT (HR-pQCT) has become standard practice when quantifying volumetric bone mineral density (vBMD) in vivo. Yet, it is only accessible to peripheral sites, with small fields of view and lengthy scanning times. This limits general applicability in clinical workflows. The goal of this study was to assess the potential of Photon Counting CT (PCCT) in quantitative bone imaging. Using the European Forearm Phantom, PCCT was calibrated to hydroxy-apatite (HA) density. Eight cadaveric forearms were scanned twice with PCCT, and once with HR-pQCT. The dominant forearm of two volunteers was scanned twice with PCCT. In each scan the carpals were delineated. At bone-level, accuracy was assessed with a paired measurement of total vBMD (Tt.vBMD) calculated with PCCT and HR-pQCT. At voxel-level, repeatability was assessed by image registration and voxel-wise subtraction of the ex vivo PCCT scans. In an ideal scenario, this difference would be zero; any deviation was interpreted as falsely detected remodelling. For clinical usage, the least detectable remodelling was determined by finding a threshold in the PCCT difference image that resulted in a classification of bone formation and resorption below acceptable noise levels (<0.5%). The paired measurement of Tt.vBMD had a Pearson correlation of 0.986. Compared to HR-pQCT, PCCT showed a bias of 7.46 mgHA/cm3. At voxel-level, the repeated PCCT scans showed a bias of 17.66 mgHA/cm3 and standard error of 96.23 mgHA/cm3. Least detectable remodelling was found to be 250 mgHA/cm3, for which 0.37% of the voxels was incorrectly classified as newly added or resorbed bone. In vivo, this volume increased to 0.97%. Based on the cadaver data we conclude that PCCT can be used to quantify vBMD and bone turnover. We provided proof of principle that this technique is also accurate in vivo, hence, that it has high potential for clinical applications., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Background: Weight bearing computed tomography (WBCT) utilizes cone beam CT technology to provide assessments of lower limb joint structures while they are functionally loaded. Grey-scale values indicative of X-ray attenuation that are output from cone beam CT are challenging to calibrate, and their use for bone mineral density (BMD) measurement remains debatable. To determine whether WBCT can be reliably used for cortical and trabecular BMD assessment, we sought to establish the accuracy of BMD measurements at the knee using modern WBCT by comparing them to measurements from conventional CT., Methods: A hydroxyapatite phantom with three inserts of varying densities was used to systematically quantify signal uniformity and BMD accuracy across the acquisition volume. We evaluated BMD in vivo (n = 5, female) using synchronous and asynchronous calibration techniques in WBCT and CT. To account for variation in attenuation along the height (z-axis) of acquisition volumes, we tested a height-dependent calibration approach for both WBCT and CT images., Results: Phantom BMD measurement error in WBCT was as high as 15.3% and consistently larger than CT (up to 5.6%). Phantom BMD measures made under synchronous conditions in WBCT improved measurement accuracy by up to 3% but introduced more variability in measured BMD. We found strong correlations (R = 0.96) as well as wide limits of agreement (-324 mgHA/cm 3 to 183 mgHA/cm 3 ) from Bland-Altman analysis between WBCT and CT measures in vivo that were not improved by height-dependent calibration., Conclusion: Whilst BMD accuracy from WBCT was found to be dependent on apparent density, accuracy was independent of the calibration technique (synchronous or asynchronous) and the location of the measurement site within the field of view. Overall, we found strong correlations between BMD measures from WBCT and CT and in vivo measures to be more accurate in trabecular bone regions. Importantly, WBCT can be used to distinguish between anatomically relevant differences in BMD, however future work is necessary to determine the repeatability and sensitivity of BMD measures in WBCT., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Patient-initiated follow-up (PIFU) for rheumatoid arthritis (RA) is a model of care delivery wherein patients contact the clinic when needed instead of having regularly scheduled follow-up. Our objective was to investigate the influence of different patient eligibility characteristics on the number of potentially deferred visits to inform future implementation of a PIFU strategy., Methods: We conducted a retrospective chart review of 7 rheumatologists' practices at 2 university-based clinics between March 1, 2021, and February 28, 2022. Data extracted included the type and frequency of visits, disease management, comorbidities, and care complexities. Stable disease was defined as remission or low disease activity with no medication changes at all visits. The influence of patient characteristics on the number of deferrable visits in patients with stable disease was explored in 4 criteria sets that were based on early disease duration, medication prescribed, presence of care complexity elements, and comorbidity burden., Results: Records from 770 visits were reviewed from 365 patients with RA (71.5% female, 70% seropositive). Among all criteria sets, the proportion of visits that could be redirected varied between 2.5% and 20.9%. The highest proportion of deferrable visits was achieved when eligibility criteria included only stable disease activity and patients with RA on conventional synthetic disease-modifying antirheumatic drugs or no medications (n = 161, 20.9%)., Conclusion: PIFU may result in a more efficient use of specialist healthcare resources. However, the applicability of such models of care and the number of deferred visits is highly dependent on patient characteristics used to establish eligibility criteria for that model. These findings should be considered when planning implementation trials., (Copyright © 2024 by the Journal of Rheumatology.)

Objective: To conduct an environmental scan and appraisal of online patient resources to support rheumatoid arthritis (RA) flare self-management., Methods: We used the Google search engine (last search March 2023) using the terms "rheumatoid arthritis" and "flare management." Additional searches targeted major arthritis organizations, as well as regional, national, and international resources. Appraisal of the resources was conducted by 2 research team members and 1 patient partner to assess the understandability and actionability of the resource using the Patient Education Materials Assessment Tool (PEMAT). Resources rating ≥ 60% in both domains by either the research team or the patient partner were further considered for content review. During content review, resources were excluded if they contained product advertisements, inaccurate information, or use of noninclusive language. If content review criteria were met, resources were designated as "highly recommended" if both patient partners and researchers' PEMAT ratings were ≥ 60%. If PEMAT ratings were divergent and had a rating ≥ 60% from only 1 group of reviewers, the resource was designated "acceptable.", Results: We identified 44 resources; 12 were excluded as they did not pass the PEMAT assessment. Fourteen resources received ratings ≥ 60% on understandability and actionability from both researchers and patient partners; 10 of these were retained following content review as "highly recommended" flare resources. Of the 18 divergent PEMAT ratings, 8 resources were retained as "acceptable" following content review., Conclusion: There is high variability in the actionability and understandability of online RA flare materials; only 23% of resources were highly recommended by researchers and patient partners., (Copyright © 2024 by the Journal of Rheumatology.)

Objectives: To investigate the diagnostic accuracy of high-resolution peripheral quantitative computed tomography (HR-pQCT) to assess erosive progression during one year compared to conventional radiography (CR) in rheumatoid arthritis (RA)., Methods: This prospective study included 359 patients with RA (disease duration ≥ 5 years) between March 2018 and October 2020. HR-pQCT and CR were obtained at inclusion and after one year. Erosive assessment was performed at two metacarpophalangeal joints of the dominant hand using HR-pQCT and progression was defined as an increase in erosion number ≥ 1 or an increase in erosive volume > least significant change. CR of hands, wrists, and feet were evaluated using Sharp/van der Heijde scores and erosive progression was defined as a 1.1-point increase in erosion score according to the smallest detectable change., Results: In paired analyses (n = 310), erosive progression was identified in 30 patients using CR and in 40 patients using HR-pQCT. In the 40 patients with erosive progression on HR-pQCT, progression was not identified by CR in 33 patients. Adding HR-pQCT to CR doubled the proportion of patients identified with progression from 30 (10%) to 63 (20%) patients. Using CR as the reference, the sensitivity (% (95% CI)) of HR-pQCT for identifying erosive progression was 23.3 (9.9-42.3) and the specificity was 88.2 (83.8-91.7)., Conclusion: A substantial proportion of patients with erosive progression are overlooked using CR only to monitor erosive progression. Adding high-resolution peripheral CT to CR doubles the proportion of patients, who may benefit from individualised therapy targeting erosive progression in RA., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The intensity gradient is a new cutpoint-free metric that was developed to quantify physical activity (PA) measured using accelerometers. This metric was developed for use with the ENMO (Euclidean norm minus one) metric, derived from raw acceleration data, and has not been validated for use with count-based accelerometer data. In this study, we determined whether the intensity gradient could be reproduced using count-based accelerometer data. Twenty participants (aged 7-22 years) wore a GT1M, an ActiGraph (count-based), and a GT9X, ActiGraph (raw accelerations) accelerometer during both in-lab and at-home protocols. We found strong agreement between GT1M and GT9X counts during the combined in-lab activities (mean bias = 2 counts) and between minutes per day with different intensities of activity (e.g., sedentary, light, moderate, and vigorous) classified using cutpoints (mean bias < 5 min/d at all intensities). We generated bin sizes that could be used to generate IGs from the count data (mean bias = -0.15; 95% LOA [-0.65, 0.34]) compared with the original IG. Therefore, the intensity gradient could be used to analyze count data. The count-based intensity gradient metric will be valuable for re-analyzing historical datasets collected using older accelerometer models, such as the GT1M.

Introduction: Rheumatoid arthritis (RA) is commonly characterized by joint space narrowing. High-resolution peripheral quantitative computed tomography (HR-pQCT) provides unparalleled in vivo visualization and quantification of joint space in extremity joints commonly affected by RA, such as the 2nd and 3rd metacarpophalangeal joints. However, age, sex, and obesity can also influence joint space narrowing. Thus, this study aimed to determine whether HR-pQCT joint space metrics could distinguish between RA patients and controls, and determine the effects of age, sex and body mass index (BMI) on these joint space metrics., Methods: HR-pQCT joint space metrics (volume, width, standard deviation of width, maximum/minimum width, and asymmetry) were acquired from RA patients and age-and sex-matched healthy control participants 2nd and 3rd MCP joints. Joint health and functionality were assessed with ultrasound (i.e., effusion and inflammation), hand function tests, and questionnaires., Results: HR-pQCT-derived 3D joint space metrics were not significantly different between RA and control groups ( p  > 0.05), despite significant differences in inflammation and joint function ( p  < 0.05). Joint space volume, mean joint space width (JSW), maximum JSW, minimum JSW were larger in males than females ( p  < 0.05), while maximum JSW decreased with age. No significant association between joint space metrics and BMI were found., Conclusion: HR-pQCT did not detect group level differences between RA and age-and sex-matched controls. Further research is necessary to determine whether this is due to a true lack of group level differences due to well-controlled RA, or the inability of HR-pQCT to detect a difference., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Tse, Contreras, Salat, Barber, Hazlewood, Barnabe, Penney, Ibrahem, Mosher and Manske.)

Objective: To systematically review the published parameters for the assessment of subchondral bone in human osteoarthritis (OA) using computed tomography (CT) and gain an overview of current practices and standards., Design: A literature search of Medline, Embase and Cochrane Library databases was performed with search strategies tailored to each database (search from 2010 to January 2023). The search results were screened independently by two reviewers against pre-determined inclusion and exclusion criteria. Studies were deemed eligible if conducted in vivo/ex vivo in human adults (>18 years) using any type of CT to assess subchondral bone in OA. Extracted data from eligible studies were compiled in a qualitative summary and formal narrative synthesis., Results: This analysis included 202 studies. Four groups of CT modalities were identified to have been used for subchondral bone assessment in OA across nine anatomical locations. Subchondral bone parameters measuring similar features of OA were combined in six categories: (i) microstructure, (ii) bone adaptation, (iii) gross morphology (iv) mineralisation, (v) joint space, and (vi) mechanical properties., Conclusions: Clinically meaningful parameter categories were identified as well as categories with the potential to become relevant in the clinical field. Furthermore, we stress the importance of quantification of parameters to improve their sensitivity and reliability for the evaluation of OA disease progression and the need for standardised measurement methods to improve their clinical value., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Bone erosions are a pathological feature of several forms of inflammatory arthritis including rheumatoid arthritis (RA). The increased presence and size of erosions are associated with poor outcomes, joint function, and disease progression. High-resolution peripheral quantitative computed tomography (HR-pQCT) provides unparalleled in vivo visualization of bone erosions. However, at this resolution, discontinuities in the cortical shell (cortical breaks) that are associated with normal physiological processes and pathology are also visible. The Study grouP for xtrEme Computed Tomography in Rheumatoid Arthritis previously used a consensus process to develop a definition of pathological erosion in HR-pQCT: a cortical break detected in at least two consecutive slices, in at least two perpendicular planes, non-linear in shape, with underlying trabecular bone loss. However, despite the availability of a consensus definition, erosion identification is a demanding task with challenges in inter-rater variability. The purpose of this work is to introduce a training tool to provide users with guidance on identifying pathological cortical breaks on HR-pQCT images for erosion analysis. The protocol presented here uses a custom-built module (Bone Analysis Module (BAM) - Training), implemented as an extension to an open-source image processing software (3D Slicer). Using this module, users can practice identifying erosions and compare their results to erosions annotated by expert rheumatologists.

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.

Identification of bone erosions and quantification of erosion volume is important for rheumatoid arthritis diagnosis, and can add important information to evaluate disease progression and treatment effects. High-resolution peripheral quantitative computed tomography (HR-pQCT) is well suited for this purpose, however analysis methods are not widely available. The purpose of this study was to develop an open-source software tool for the identification and quantification of bone erosions using images acquired by HR-pQCT. The collection of modules, Bone Analysis Modules (BAM) - Erosion, implements previously published erosion analysis techniques as modules in 3D Slicer, an open-source image processing and visualization tool. BAM includes a module to automatically identify cortical interruptions, from which erosions are manually selected, and a hybrid module that combines morphological and level set operations to quantify the volume of bone erosions. HR-pQCT images of the second and third metacarpophalangeal (MCP) joints were acquired in patients with RA (XtremeCT, n = 14, XtremeCTII, n = 22). The number of cortical interruptions detected by BAM-Erosion agreed strongly with the previously published cortical interruption detection algorithm for both XtremeCT (r 2  = 0.85) and XtremeCTII (r 2  = 0.87). Erosion volume assessment by BAM-Erosion agreed strongly (r 2  = 0.95) with the Medical Image Analysis Framework. BAM-Erosion provides an open-source erosion analysis tool that produces comparable results to previously published algorithms, with improved options for visualization. The strength of the tool is that it implements multiple image processing algorithms for erosion analysis on a single, widely available, open-source platform that can accommodate future updates., Competing Interests: Declaration of competing interest Bert van Rietbergen is a consultant for Scanco Medical AG. All other authors have stated no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The trapeziometacarpal (TMC) joint is a mechanically complex joint and is commonly affected by musculoskeletal diseases such as osteoarthritis. Quantifying in vivo TMC joint biomechanics, such as joint angles, with traditional reflective marker-based methods can be difficult due to the joint's location in the hand. Dynamic computed tomography (CT) can facilitate the quantification of TMC joint motion by continuously capturing three-dimensional volumes over time. However, post-processing of dynamic CT datasets can be time intensive and automated methods are needed to reduce processing times to allow for application to larger clinical studies. The purpose of this work is to introduce a fast, semi-automated pipeline to quantify joint angles from dynamic CT scans of the TMC joint and evaluate the associated error in joint angle and translation computation by means of a reproducibility and repeatability study., Methods: Ten cadaveric hands were scanned with dynamic CT using a passive motion device to move thumbs in a radial abduction-adduction motion. Static CT scans and high-resolution peripheral quantitative CT scans were also acquired to generate high-resolution bone meshes. Abduction-adduction, flexion-extension, and axial rotation angles were computed using a joint coordinate system. Reproducibility and repeatability were assessed using intraclass correlation coefficients, Bland-Altman analysis, and root mean square errors. Target registration errors were computed to evaluate errors associated with image registration., Results: We found good repeatability for flexion-extension, abduction-adduction, and axial rotation angles. Reproducibility was moderate for all three angles. Joint translations exhibited greater repeatability than reproducibility. Specimens with greater joint degeneration had lower repeatability and reproducibility. We found that the difference in resulting joint angles and translations were likely due to differences in segment coordinate system definition between multiple raters, rather than due to registration errors., Conclusions: The proposed semi-automatic processing pipeline was fast, repeatable, and moderately reproducible when quantifying TMC joint angles and translations. This work provides a range of errors for TMC joint angles from dynamic CT scans using manually selected anatomical landmarks., (© 2022. The Author(s).)

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., Competing Interests: The authors have declared that no competing interests exist.

Femoral neck areal bone mineral density (FN aBMD) is a key determinant of fracture risk in older adults; however, the majority of individuals who have a hip fracture are not considered osteoporotic according to their FN aBMD. This study uses novel tools to investigate the characteristics of bone microarchitecture that underpin bone fragility. Recent hip fracture patients (n = 108, 77% female) were compared with sex- and age-matched controls (n = 216) using high-resolution peripheral quantitative computed tomography (HR-pQCT) imaging of the distal radius and tibia. Standard morphological analysis of bone microarchitecture, micro-finite element analysis, and recently developed techniques to identify void spaces in bone microarchitecture were performed to evaluate differences between hip fracture patients and controls. In addition, a new approach for phenotyping bone microarchitecture was implemented to evaluate whether hip fractures in males and females occur more often in certain bone phenotypes. Overall, hip fracture patients had notable deterioration of bone microarchitecture and reduced bone mineral density compared with controls, especially at weight-bearing sites (tibia and femoral neck). Hip fracture patients were more likely to have void spaces present at either site and had void spaces that were two to four times larger on average when compared with non-fractured controls (p < 0.01). Finally, bone phenotyping revealed that hip fractures were significantly associated with the low density phenotype (p < 0.01), with the majority of patients classified in this phenotype (69%). However, female and male hip fracture populations were distributed differently across the bone phenotype continuum. These findings highlight how HR-pQCT can provide insight into the underlying mechanisms of bone fragility by using information about bone phenotypes and identification of microarchitectural defects (void spaces). The added information suggests that HR-pQCT can have a beneficial role in assessing the severity of structural deterioration in bone that is associated with osteoporotic hip fractures. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)

Objectives: The aim of this study was to assess the accuracy and precision of a novel application of 3-material decomposition (3MD) with virtual monochromatic images (VMIs) in the dual-energy computed tomography (DECT) assessment of monosodium urate (MSU) and hydroxyapatite (HA) phantoms compared with a commercial 2-material decomposition (2MD) and dual-thresholding (DT) material decomposition methods., Materials and Methods: Monosodium urate (0.0, 3.4, 13.3, 28.3, and 65.2 mg/dL tubes) and HA (100, 400, and 800 mg/cm 3 tubes) phantoms were DECT scanned individually and together in the presence of the foot and ankle of 15 subjects. The raw data were decomposed with 3MD-VMI, 2MD, and DT to produce MSU-only and HA-only images. Mean values of 10 × 10 × 10-voxel volumes of interest (244 μm 3 ) placed in each MSU and HA phantom well were obtained and compared with their known concentrations and across measurements with subjects' extremities to obtain accuracy and precision measures. A statistical difference was considered significant if P < 0.05., Results: Compared with known phantom standards, 3MD-VMI was accurate for the detection of MSU concentrations as low as 3.4 mg/dL ( P = 0.75). In comparison, 2MD was limited to 13.3 mg/dL ( P = 0.06) and DT was unable to detect MSU concentrations below 65.2 mg/L ( P = 0.16). For the HA phantom, 3MD-VMI and 2MD were accurate for all concentrations including the lowest at 100 mg/cm 3 ( P = 0.63 and P = 0.55, respectively). Dual-thresholding was not useful for the decomposition of HA phantom. Precision was high for both 3MD-VMI and 2MD measurements for both MSU and HA phantoms. Qualitatively, 3MD-VMI MSU-only images demonstrated reduced beam-hardening artifact and voxel misclassification, compared with 2MD and DT., Conclusions: Three-material decomposition-VMI DECT is accurate for quantification of MSU and HA concentrations in phantoms and accurately detects a lower concentration of MSU than either 2MD or DT. For concentration measurements of both MSU and HA phantoms, 3MD-VMI and 2MD have high precision, but DT had limitations. Clinical implementation of 3MD-VMI DECT promises to improve the performance of this imaging modality for diagnosis and treatment monitoring of gout., Competing Interests: Conflicts of interest and sources of funding: J.J.T. is supported by a Canadian Institutes of Health Research (CIHR) Postdoctoral Fellowship; M.T.K. is supported by a doctoral Natural Sciences and Engineering Research Council (NSERC, Canada) fellowship. S.L.M.'s research is supported by The Arthritis Society (Stars Early Career Investigator Award), NSERC, and the American Society for Bone and Mineral Research. Portions of the DECT code were supported by D.W.H.'s Canadian Institutes for Health Research (Foundation Grant) FDN 14874., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: This study evaluated the ability of a custom dual-energy CT (DECT) post-processing material decomposition method to image bone marrow edema after acute knee injury. Using an independent validation cohort, the DECT method was compared to gold-standard, fluid-sensitive MRI. By including both quantitative voxel-by-voxel validation outcomes and semi-quantitative radiologist scoring-based assessment of diagnostic accuracy, we aimed to provide insight into the relationship between quantitative metrics and the clinical utility of imaging methods., Materials and Methods: Images from 35 participants with acute anterior cruciate ligament injuries were analyzed. DECT material composition was applied to identify bone marrow edema, and the DECT result was quantitatively compared to gold-standard, registered fluid-sensitive MRI on a per-voxel basis. In addition, two blinded readers rated edema presence in both DECT and fluid-sensitive MR images for evaluation of diagnostic accuracy., Results: Semi-quantitative assessment indicated sensitivity of 0.67 and 0.74 for the two readers, respectively, at the tibia and 0.55 and 0.57 at the femur, and specificity of 0.87 and 0.89 for the two readers at the tibia and 0.58 and 0.89 at the femur. Quantitative assessment of edema segmentation accuracy demonstrated mean dice coefficients of 0.40 and 0.16 at the tibia and femur, respectively., Conclusion: The custom post-processing-based DECT method showed similar diagnostic accuracy to a previous study that assessed edema associated with ligamentous knee injury using a CT manufacturer-provided, built-in edema imaging application. Quantitative outcome measures were more stringent than semi-quantitative scoring methods, accounting for the low mean dice coefficient scores., (© 2022. ISS.)

Musculoskeletal injuries often induce local accumulation of blood and/or fluid within the bone marrow, which is detected on medical imaging as edema-like marrow signal intensities (EMSI). In addition to its biological effects on post-injury recovery, the displacement of low-attenuating, largely adipocytic marrow by EMSI may introduce errors into quantitative computed tomography (QCT) measurements of bone mineral density (vBMD) and resulting bone stiffness estimates from image-based finite element (FE) analysis. We aimed to investigate the impact of post-injury changes in marrow soft tissue composition on CT-based bone measurements by applying CT imaging at multiple spatial resolutions. To do so, dual energy QCT (DECT) material decomposition was used to detect EMSI in the tibiae of nineteen participants with a recent anterior cruciate ligament tear. We then measured bone density and FE-based apparent modulus within the EMSI region and in a matched volume in the uninjured contralateral knee. Three measurement methods were applied: 1.) standard, QCT density calibration and density-based FEM; 2.) a DECT density calibration that provides density measurements adjusted for marrow soft tissues; and 3.) high-resolution peripheral QCT (HR-pQCT) density and microFE analyses. When measured using standard, single-energy QCT, vBMD and apparent modulus were elevated in the EMSI compared to the contralateral. After adjusting for marrow soft tissue composition using DECT, these measurements were no longer different between the two regions. By allowing for high-resolution, localized density analysis, HR-pQCT indicated that trabecular tissue mineral density was 9 mgHA/cm 3 lower, while density of marrow soft tissues was 18 mgHA/cm 3 higher, in the EMSI than the contralateral region, suggesting that EMSI have opposite effects on the measured density of trabecular bone and the underlying soft marrow. Thus, after an acute injury, altered composition of marrow soft tissues may artificially inflate overall measurements of bone density and apparent modulus obtained using standard QCT. This can be corrected by accounting for marrow soft tissue attenuation, either by using DECT-based density calibration or HR-pQCT microFE and measurements of local density of trabeculae., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: This study examined the association between youth sport-related ankle sprain injury and health-related outcomes, 3-15 years postinjury., Methods: A historical cohort study in which uninjured controls were cluster-matched with injured cases. The primary outcome was self-reported Foot and Ankle Outcome Score (FAOS). Secondary outcomes included measures of adiposity, validated questionnaires for physical activity, athletic identity, fear of pain, and tests of strength, balance, and function., Results: We recruited 86 participants (median age of 23 years; 77% female); 50 with a time-loss ankle sprain, median of 8 years postinjury, and 36 uninjured controls cluster-matched by sex and sport. Based on mixed effects multivariable regression models, previously injured participants demonstrated poorer outcomes than controls on all 5 FAOS subscales regardless of sex and time since injury, with the largest differences observed in symptoms (-20.9, 99% CI: -29.5 to -12.3) and ankle-related quality of life (-25.3, 99% CI: -34.7 to -15.9) subscales. Injured participants also had poorer unipedal dynamic balance (-1.9, 99% CI: 3.5 to -0.2) and greater fear of pain (7.2, 99% CI: 0.9-13.4) compared with controls. No statistically significant differences were found for other secondary outcomes., Conclusion: At 3-15 years following time-loss ankle sprain injury in youth sport, previously injured participants had more pain and symptoms, poorer self-reported function, ankle-related quality of life, reduced sport participation, balance, and greater fear of pain than controls. This underlines the need to promote the primary prevention of ankle sprains and secondary prevention of potential health consequences, including posttraumatic osteoarthritis., Level of Evidence: Level III, historical cohort study.

Purpose of Review: The purpose of this review is to inform researchers and clinicians with the most recent imaging techniques that are employed (1) to opportunistically screen for osteoporosis and (2) to provide a better understanding into the disease etiology of osteoporosis., Recent Findings: Phantomless calibration techniques for computed tomography (CT) may pave the way for better opportunistic osteoporosis screening and the retroactive analysis of imaging data. Additionally, hardware advances are enabling new applications of dual-energy CT and cone-beam CT to the study of bone. Advances in MRI sequences are also improving imaging evaluation of bone properties. Finally, the application of image registration techniques is enabling new uses of imaging to investigate soft tissue-bone interactions as well as bone turnover. While DXA remains the most prominent imaging tool for osteoporosis diagnosis, new imaging techniques are becoming more widely available and providing additional information to inform clinical decision-making., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Evidence for terrestriality in early tetrapods is fundamentally contradictory. Fossil trackways attributed to early terrestrial tetrapods long predate the first body fossils from the Late Devonian. However, the Devonian body fossils demonstrate an obligatorily aquatic lifestyle. Complicating our understanding of the transition from water to land is a pronounced gap in the fossil record between the aquatic Devonian taxa and presumably terrestrial tetrapods from the later Early Carboniferous. Recent work suggests that an obligatorily aquatic habit persists much higher in the tetrapod tree than previously recognized. Here, we present independent microanatomical data of locomotor capability from the earliest Carboniferous of Blue Beach, Nova Scotia. The site preserves limb bones from taxa representative of Late Devonian to mid-Carboniferous faunas as well as a rich trackway record. Given that bone remodels in response to functional stresses including gravity and ground reaction forces, we analysed both the midshaft compactness profiles and trabecular anisotropy, the latter using a new whole bone approach. Our findings suggest that early tetrapods retained an aquatic lifestyle despite varied limb morphologies, prior to their emergence onto land. These results suggest that trackways attributed to early tetrapods be closely scrutinized for additional information regarding their creation conditions, and demand an expansion of sampling to better identify the first terrestrial tetrapods., (© 2021 The Authors.)

Purpose: This study developed methods to quantify and improve the accuracy of dual-energy CT (DECT)-based bone marrow edema imaging using a clinical CT system. Objectives were: (a) to quantitatively compare DECT with gold-standard, fluid-sensitive MRI for imaging of edema-like marrow signal intensity (EMSI) and (b) to identify image analysis parameters that improve delineation of EMSI associated with acute knee injury on DECT images., Methods: DECT images from ten participants with acute knee injury were decomposed into estimated fractions of bone, healthy marrow, and edema based on energy-dependent differences in tissue attenuation. Fluid-sensitive MR images were registered to DECT for quantitative, voxel-by-voxel comparison between the two modalities. An optimization scheme was developed to find attenuation coefficients for healthy marrow and edema that improved EMSI delineation, compared to MRI. DECT method accuracy was evaluated by measuring dice coefficients, mutual information, and normalized cross correlation between the DECT result and registered MRI., Results: When applying the optimized three-material decomposition method, dice coefficients for EMSI identified through DECT vs MRI were 0.32 at the tibia and 0.13 at the femur. Optimization of attenuation coefficients improved dice coefficient, mutual information, and cross-correlation between DECT and gold-standard MRI by 48%-107% compared to three-material decomposition using non-optimized parameters, and improved mutual information and cross-correlation by 39%-58% compared to the manufacturer-provided two-material decomposition., Conclusions: This study quantitatively evaluated the performance of DECT in imaging knee injury-associated EMSI and identified a method to optimize DECT-based visualization of complex tissues (marrow and edema) whose attenuation parameters cannot be easily characterized. Further studies are needed to improve DECT-based EMSI imaging at the femur., (© 2021 American Association of Physicists in Medicine.)

Objective: The aim of this multireader exercise was to assess the reliability and change over time of erosion measurements in patients with rheumatoid arthritis (RA) using high-resolution peripheral quantitative computed tomography (HR-pQCT)., Methods: HR-pQCT scans of 23 patients with RA were assessed at baseline and 12 months. Four experienced readers examined the dorsal, palmar, radial, and ulnar surfaces of the metacarpal head (MH) and phalangeal base (PB) of the second and third digits, blinded to time order. In total, 368 surfaces (23 patients´ 16 surfaces) were evaluated per timepoint to characterize cortical breaks as pathological (erosion) or physiological, and to quantify erosion width and depth. Reliability was evaluated by intraclass correlation coefficients (ICC), percentage agreement, and Light k; change over time was defined by means ± SD of erosion numbers and dimensions., Results: ICC for the mean measurements of width and depth of the pathological breaks ranged between 0.819-0.883, and 0.771-0.907, respectively. Most physiological cortical breaks were found at the palmar PB, whereas most pathological cortical breaks were located at the radial MH. There was a significant increase in both the numbers and the dimensions of erosions between baseline and follow-up ( P = 0.0001 for erosion numbers, width, and depth in axial plane; P = 0.001 for depth in perpendicular plane)., Conclusion: This exercise confirmed good reliability of HR-pQCT erosion measurements and their ability to detect change over time., (Copyright © 2021 by the Journal of Rheumatology.)

Objectives: Erosion development is of crucial significance as it impacts prognosis and therapy decisions in patients with inflammatory joint diseases. Our study aimed to determine the sensitivity of high-resolution peripheral quantitative computed tomography (HR-pQCT) to detect change of bone surface over time and to identify erosion development in early inflammatory arthritis (EIA) patients. Moreover, the contribution of prognostic factors on periarticular bone damage in the first year of diagnosis assessed by HR-pQCT was explored., Methods: 46 patients with arthritic symptoms for less than one year, and a clinical diagnosis of inflammatory arthritis were prospectively imaged at baseline and 12-months. HR-pQCT scans of the 2nd and 3rd MCP joints and CR of the hands and feet were performed. Joint space width (JSW), total bone mineral density (Tt.BMD), erosion presence and volume were assessed with HR-pQCT. Scan-rescan precision was assessed to define an individual-level least significant change (LSC) criterion. Regression analyses explored prognostic factors for bone damage progression., Results: We observed no significant group-level changes in JSW, Tt.BMD or erosion volume. 20% or fewer joints demonstrated individual-level changes greater than the LSC criterion for mean JSW, Tt.BMD and erosion volume. HR-pQCT detected more erosions than CR in the 2nd and 3rd MCP. Increased symptom duration at diagnosis was weakly associated (P<0.10) with lower JSW minimum and higher JSW standard deviation., Conclusions: Gradual degradation of JSW, proportional to symptom duration, was detected by HR-pQCT. EIA patients need to be closely monitored for exacerbation of arthritis and progression of periarticular bone damage., (Copyright © 2020 Société française de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.)

Combining results from multiple imaging techniques (i.e., multi-modal imaging) through image registration can result in the better characterization of joint tissue characteristics. In the context of inflammatory arthritis conditions, high-resolution peripheral quantitative computed tomography (HR-pQCT) provides excellent bone contrast while magnetic resonance imaging (MRI) provides superior contrast and resolution of soft tissue and inflammatory characteristics. Superimposing these imaging results upon each other provides a robust characterization of the joint. In a preliminary study of nine rheumatoid arthritis (RA) participants in clinical remission, we acquired HR-pQCT and MR images of their 2nd and 3rd metacarpophalangeal (MCP) joints at two timepoints 6 months apart. We present the benefits of a multi-modal imaging approach, in which we demonstrate the ability to localize regions of inflammation with subtle changes in bone erosion volume. Using HR-pQCT and MRI to visualize bone damage and inflammation, respectively, will improve our understanding of the impact that subclinical inflammation has on bone damage progression, and demonstrating if bone repair occurs where inflammation is resolved. The presented multi-modal imaging technique has the potential to study the progression of bone damage in relation to inflammation that otherwise would not be possible with either imaging technique alone. The multi-modal image registration technique will be helpful to understanding the development and pathogenesis of RA-associated bone erosions. Additionally, multi-modal imaging may provide a technique to probe the tissue-level changes that occur as a result of treatment regimes., (Copyright © 2020 Tse, Brunet, Salat, Hazlewood, Barnabe and Manske.)

Background: Medical imaging plays an important role in determining the progression of joint damage in rheumatoid arthritis (RA). High resolution peripheral quantitative computed tomography (HR-pQCT) is a sensitive tool capable of evaluating bone microarchitecture and erosions, and 3D rigid image registration can be used to visualize and quantify bone remodeling over time. However, patient motion during image acquisition can cause a "stack shift" artifact resulting in loss of information and reducing the number of erosions that can be analyzed using HR-pQCT. The purpose of this study was to use image registration to improve the number of useable HR-pQCT scans and to apply image-based bone remodeling assessment to the metacarpophalangeal (MCP) joints of RA patients., Methods: Ten participants with RA completed HR-pQCT scans of the 2nd and 3rd MCP joints at enrolment to the study and at a 6-month follow-up interval. At 6-months, an additional repeat scan was acquired to evaluate reliability. HR-pQCT images were acquired in three individual 1 cm acquisitions (stacks) with a 25% overlap. We completed analysis first using standard evaluation methods, and second with multi-stack registration. We assessed whether additional erosions could be evaluated after multi-stack registration. Bone remodeling analysis was completed using registration and transformation of baseline and follow-up images. We calculated the bone formation and resorption volume fractions with 6-month follow-up, and same-day repositioning as a negative control., Results: 13/57 (23%) of erosions could not be analyzed from raw images due to a stack shift artifact. All erosions could be volumetrically assessed after multi-stack registration. We observed that there was a median bone formation fraction of 2.1% and resorption fraction of 3.8% in RA patients over the course of 6 months. In contrast to the same-day rescan negative control, we observed median bone formation and resorption fractions of 0%., Conclusions: Multi-stack image registration is a useful tool to improve the number of useable scans when analyzing erosions using HR-pQCT. Further, image registration can be used to longitudinally assess bone remodeling. These methods could be implemented in future studies to provide important pathophysiological information on the progression of bone damage.

Background: Joint space assessment for rheumatoid arthritis (RA) by ordinal conventional radiographic scales is susceptible to floor and ceiling effects. High-resolution peripheral quantitative computed tomography (HR-pQCT) provides superior resolution, and may detect earlier changes. The goal of this work was to compare existing 3D methods to calculate joint space width (JSW) metrics in human metacarpophalangeal (MCP) joints with HR-pQCT and reach consensus for future studies. Using the consensus method, we established reproducibility with repositioning as well as feasibility for use in second-generation HR-pQCT scanners., Methods: Three published JSW methods were compared using datasets from individuals with RA from three research centers. A SPECTRA consensus method was developed to take advantage of strengths of the individual methods. Using the SPECTRA method, reproducibility after repositioning was tested and agreement between scanner generations was also established., Results: When comparing existing JSW methods, excellent agreement was shown for JSW minimum and mean (ICC 0.987-0.996) but not maximum and volume (ICC 0.000-0.897). Differences were identified as variations in volume definitions and algorithmic differences that generated high sensitivity to boundary conditions. The SPECTRA consensus method reduced this sensitivity, demonstrating good scan-rescan reliability (ICC >0.911) except for minimum JSW (ICC 0.656). There was strong agreement between results from first- and second-generation HR-pQCT (ICC >0.833)., Conclusions: The SPECTRA consensus method combines unique strengths of three independently-developed algorithms and leverages underlying software updates to provide a mature analysis to measure 3D JSW. This method is robust with respect to repositioning and scanner generations, suggesting its suitability for detecting change., Competing Interests: Conflicts of Interest: KS Stok and V Stadelmann are former employees of Scanco Medical AG. N Vilayphiou is a current employee of Scanco Medical AG. The other authors have no conflicts of interest to declare., (2020 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

Musculoskeletal science has developed many overlapping branches, necessitating specialists from 1 area of focus to often require the expertise in others. In terms of imaging, this means obtaining a comprehensive illustration of bone, muscle, and fat tissues. There is currently a lack of a reliable resource for end users to learn about these tissues' imaging and quantification techniques together. An improved understanding of these tissues has been an important progression toward better prediction of disease outcomes and better elucidation of their interaction with frailty, aging, and metabolic disorders. Over the last decade, there have been major advances into the image acquisition and segmentation of bone, muscle, and fat features using computed tomography (CT), magnetic resonance imaging (MRI), and peripheral modules of these systems. Dedicated peripheral quantitative musculoskeletal imaging systems have paved the way for mobile research units, lower cost clinical research facilities, and improved resolution per unit cost paid. The purpose of this review was to detail the segmentation techniques available for each of these peripheral CT and MRI modalities and to describe advances in segmentation methods as applied to study longitudinal changes and treatment-related dynamics. Although the peripheral CT units described herein have established feasible standardized protocols that users have adopted globally, there remain challenges in standardizing MRI protocols for bone and muscle imaging., (Copyright © 2018 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

Anterior cruciate ligament (ACL) tears are common sports-related knee injuries that increase the risk of developing post-traumatic osteoarthritis. ACL tears are rarely an isolated injury but are often associated with traumatic bone marrow lesions (BMLs). While early loss of bone mass following the ACL injury has been previously described, to date, microarchitectural information has not been reported due to the limited resolution of clinical imaging systems. In this study, we provide the first evidence of detailed bone mass and microarchitectural changes in the first 10 months following an acute ACL tear, and localized to traumatic BMLs. Fifteen participants with an acute unilateral ACL tear were assessed at four-time points using dual-energy X-ray absorptiometry and high-resolution peripheral quantitative computed tomography, and traumatic BMLs were identified with magnetic resonance imaging. Loss of bone mass was localized to the injured knee (-4.6% to -15.8%, depending on bone and depth) and was accelerated immediately following the injury before suggesting a recovery phase. This loss of bone was accelerated even greater in traumatic BMLs (-18.2% to -20.6%, depending on bone). Bone loss was accompanied by microstructural degeneration of trabecular bone. For example, in the lateral femur of the injured knee, the subchondral bone plate decreased in thickness (-9.0%). This study confirmed loss of bone mass in the months following ACL tears and described the underlying bone microstructural changes. The presented bone changes were accelerated in regions of traumatic BMLs. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2325-2336, 2019., (© 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Objective: We assessed construct validity of high-resolution peripheral quantitative computed tomography (HR-pQCT) joint space outcomes by comparison with radiographs in patients with rheumatoid arthritis., Methods: In 43 patients, quantitative, volumetric, HR-pQCT measurements were compared with ordinal Sharp/van der Heijde scoring (SvdH) in the 2nd and 3rd metacarpophalangeal joints., Results: Generalized estimating equations showed that joint space minimum, SD, and asymmetry by HR-pQCT were associated with SvdH scores (p < 0.05). There was a considerable range in HR-pQCT measurements at SvdH equal to 0., Conclusion: HR-pQCT demonstrated construct validity outcomes and provides improved 3-D visualization of joint space.

Due to difficulty assessing healing of distal radius fractures using conventional radiography, there is interest in using high resolution peripheral quantitative computed tomography (HR-pQCT) to track healing at the microarchitectural level. Unfortunately, the plaster-of-Paris and fiberglass casts used to immobilize fractures affect HR-pQCT measurements due to beam hardening, and increased noise. The challenge is compounded because casts have variable thickness, and an individual patient will often have their cast changed 2-3 times during the course of treatment. This study quantifies the effect of casts within a clinically relevant range of thicknesses on measured bone parameters at the distal radius, and establishes conversion equations to correct for systematic error in due to cast presence. Eighteen nonfractured participants were scanned by HR-pQCT in three conditions: no cast, plaster-of-Paris cast, and fiberglass cast. Measured parameters were compared between the baseline scan (no cast) and each cast scan to evaluate if systematic error exists due to cast presence. A linear regression model was used to determine an appropriate conversion for parameters that were found to have systematic error. Plaster-of-Paris casts had a greater range of thicknesses (3.2-9.5 mm) than the fiberglass casts (3.0-5.4 mm), and induced a greater magnitude of systematic error overall. Key parameters of interest were bone mineral density (total, cortical, and trabecular) and trabecular bone volume fraction, all of which were found to have systematic error due to presence of either cast type. Linear correlations between baseline and cast scans for these parameters were excellent (R 2 > 0.98), and appropriate conversions could be determined within a margin of error less than a ±6% for the plaster-of-Paris cast, and ±4% for the fiberglass cast. We have demonstrated the effects of cast presence on bone microarchitecture measurements, and presented a method to correct for systematic error, in support of future use of HR-pQCT to study fracture healing., (Copyright © 2018. Published by Elsevier Inc.)

The finite element (FE) method based on high-resolution peripheral quantitative computed tomography (HR-pQCT) use a variety of tissue constitutive properties and boundary conditions at different laboratories making comparison of mechanical properties difficult. Furthermore, the advent of a second-generation HR-pQCT poses challenges due to improved resolution and a larger region of interest (ROI). This study addresses the need to harmonize results across FE models. The aims are to establish the relationship between FE results as a function of boundary conditions and a range of tissue properties for the first-generation HR-pQCT system, and to determine appropriate model parameters for the second-generation HR-pQCT system. We implemented common boundary conditions and tissue properties on a large cohort (N = 1371), and showed the relationships were highly linear (R 2  > 0.99) for yield strength and reaction force between FE models. Cadaver radii measured on both generation HR-pQCT with matched ROIs were used to back-calculate a tissue modulus that accounts for the increased resolution (61 µm versus 82 µm), resulting in a modulus of 8748 MPa for second-generation HR-pQCT to produce bone yield strength and reaction force equivalent to using 6829 MPa for first-generation HR-pQCT. Finally, in vivo scans (N = 61) conducted on both generations demonstrated that the larger ROI in the second-generation system results in stronger bone outcome measures, suggesting it is not advisable to convert FE results across HR-pQCT generations without matching ROIs. Together, these findings harmonize FE results by providing a means to compare findings with different boundary conditions and tissue properties, and across scanner generations., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Anterior cruciate ligament (ACL) tears increase the risk of developing knee osteoarthritis. This risk increases further with concurrent meniscus injury. The role of bone changes during knee osteoarthritis development are not well-understood, but may be important to its etiology., Purpose: To explore the effects of ACL tears on bone mineral density (BMD) and bone microarchitecture at five years post-op and their relationship to meniscal pathology, using high-resolution peripheral quantitative computed tomography (HR-pQCT)., Methods: Twenty-eight participants with unilateral ACL reconstructions five years prior and no evidence of clinical or radiographic osteoarthritis were recruited. All participants represented one of three meniscus statuses: meniscus intact, meniscus repair, or meniscectomy. BMD and bone microarchitecture of the subchondral bone plate and adjacent trabecular bone were assessed using HR-pQCT, and percent-differences between the injured and contralateral knee were determined., Results: Subchondral bone plate thickness in the lateral femoral condyle was higher in the reconstructed knee (9.0%, p = 0.002), driven by the meniscus repair and meniscectomy groups (15.2% to 15.4%, p < 0.05). Trabecular BMD was lower in the reconstructed knee in the medial femoral condyle (-4.8% to -7.6%, p < 0.05), driven by all meniscus statuses. In the lateral compartments, few differences in trabecular bone were found. However, accounting for meniscus status, the meniscus intact group had lower trabecular BMD throughout both femur and tibia., Conclusions: Five years post-op, reconstructed knees demonstrated detectable differences in BMD and bone microarchitecture, despite having normal radiographs. Meniscus damage affected primarily the lateral compartment, warranting further investigation to determine if these changes relate to osteoarthritis development., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: Anterior cruciate ligament (ACL) tears increase early onset osteoarthritis (OA) risk leading to cartilage and bone degradation. While the contribution of bone in OA development is unclear, evidence suggests that bone changes accompany cartilage degradation. This study aims to assess if regions with differences in subchondral bone plate thickness have differences in cartilage thickness when comparing ACL reconstructed (ACLR) knees of women ≥5 years post-injury to contralateral and controls with uninjured knees., Design: Magnetic resonance imaging (MRI) assessed cartilage and high resolution peripheral quantitative computed tomography (HR-pQCT) assessed subchondral bone in both knees. Multimodal 3D image registration aligned anatomy. Maps of the spatial distribution of thickness on the articular surfaces were generated to compare women with ACL reconstructions to contralateral and controls with uninjured knees., Results: ACLR knees had a thicker subchondral bone plate in the posterior and central lateral femur compared to contralateral knees (10.4% and 4.2% thicker, P = 0.032 and 0.032, W = 108 and 107, respectively) and in the posterior lateral femur compared to control knees (17.1% thicker, P = 0.014, W = 177). Cartilage differences were not detected (P > 0.05) in these regions., Conclusions: This study demonstrates that subchondral bone plate thickness differences are prominent following knee injury, as measured by HR-pQCT, but no statistically significant differences in cartilage morphology, measured by MRI, were found between ACLR knees compared to contralateral and control knees. These data provide novel insight into post-traumatic knee injuries that may be signs of early OA pathogenesis., (Copyright © 2018 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Anterior cruciate ligament (ACL) tears are a common sports-related knee injury that increases the risk of developing post-traumatic osteoarthritis (OA). During OA progression bone microarchitecture changes in the affected knee, however, little is known about bone microarchitecture in knees with early stage OA. The purpose of this study is to investigate in a cohort of females predisposed to develop OA how bone microarchitecture in ACL reconstructed knees differs from uninjured contralateral knees as well as healthy control knees and how this relates to early changes in OA. Bone microarchitecture was directly assessed in ACL reconstructed knees of injured female participants (n=15) with a median age of 25.4years (age range: 22.5-28.5) and compared to their uninjured contralateral knees, as well as to a healthy age-matched female control sample (n=14) with a median age of 25.2years (age range: 22.2-27.1). ACL reconstructed knees had lower trabecular bone mineral density (compared to contralateral: -7.7% to -10.4%, p<0.05; control knees: -7.1% to -13.9%, p<0.05) and altered trabecular bone microarchitecture in the medial femur compared to contralateral and control knees. The subchondral bone plate in the lateral femur was thicker in ACL reconstructed knees compared to contralateral (29.6%, p=0.009) and control knees (47.9% to 53.7%, p<0.05). Contralateral knees did not differ from control knees. Loss of trabecular bone and increased subchondral bone plate thickness in the ACL-reconstructed knees are consistent with changes associated with OA progression. Most differences in bone microarchitecture were found in the femur, with few differences in the tibia. The bone microarchitecture of contralateral knees did not differ from control knees in our participants, suggesting the potential to use them as control references in future longitudinal studies., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The aim of this prospective study was to use high-resolution peripheral quantitative computed tomography (HR-pQCT) to determine if baseline skeletal parameters can predict incident fragility fracture in women and, secondly, to establish if women that fracture lose bone at a faster rate than those who do not fracture. Women older than 60 years who experienced a fragility fracture during the 5-year follow-up period (incident fracture group, n = 22) were compared with those who did not experience a fragility fracture during the study (n = 127). After image registration between baseline and follow-up measures, standard and cortical morphological analyses were conducted. Odds ratios were calculated for baseline values and annualized percent change of HR-pQCT and finite element variables. At the radius, baseline HR-pQCT results show women who fractured had lower total bone mineral density (Tt.BMD; 19%), trabecular bone mineral density (Tb.BMD; 25%), and trabecular number (Tb.N; 14%), with higher trabecular separation (Tb.Sp; 19%) than women who did not fracture. At the tibia, women with incident fracture had lower Tt.BMD (15%), Tb.BMD (12%), cortical thickness (Ct.Th; 14%), cortical area (Ct.Ar; 12%), and failure load (10%) with higher total area (Tt.Ar; 7%) and trabecular area (Tb.Ar; 10%) than women who did not fracture. Odds ratios (ORs) at the radius revealed every SD decrease of Tt.BMD (OR = 2.1), Tb.BMD (OR = 2.0), and Tb.N (OR = 1.7) was associated with a significantly increased likelihood of fragility fracture. At the tibia, every SD decrease in Tt.BMD (OR = 2.1), Tb.BMD (OR = 1.7), Ct.Th (OR = 2.2), Ct.Ar (OR = 1.9), and failure load (OR = 1.7) were associated with a significantly increased likelihood of fragility fracture. Irrespective of scanning modality, the annualized percent rate of bone loss was not different between fracture groups. The results suggest baseline bone density, microarchitecture, and strength rather than change in these variables are associated with incident fragility fractures in women older than 60 years. Furthermore, irrespective of fragility fracture status, women experienced changes in skeletal health at a similar rate. © 2017 American Society for Bone and Mineral Research., (© 2017 American Society for Bone and Mineral Research.)

Bone strength is influenced by mineral density and macro- and microstructure. Research into factors that contribute to bone morphology and strength has focused on genetic, environmental and morphological factors (e.g., body mass index), but little is known regarding the impact of rates of skeletal elongation on adult skeletal morphology and strength. Using micro-CT, we examined the impact of rates of skeletal elongation on bone cortical and trabecular morphology, and on rates of estrogen-dependent bone loss in the tibia in CD-1 mice, and in mice with accelerated skeletal growth (Longshanks). Groups of adult mice (n = 7/group) were subjected to ovariectomy or sham surgeries, scanned for 6 weeks, and indices of bone morphology were collected. Results show that Longshanks mice had significantly less trabecular bone at skeletal maturity, characterized by fewer, thinner trabeculae, and furthermore lost trabecular bone more slowly in response to ovariectomy. Artificial selection for rapid skeletal growth relative to somatic growth thus had a significant impact on trabecular bone morphology in Longshanks. Our data do not unequivocally demonstrate a causal relationship between rapid bone growth and reduced trabecular bone quality, but suggest that rapid linear bone growth may influence the risk of cancellous bone fragility.

Second-generation high-resolution peripheral quantitative computed tomography (HR-pQCT) provides the highest resolution in vivo to assess bone density and microarchitecture in 3D. Although strong agreement of most outcomes measured with first- (XCTI) and second- (XCTII) generation HR-pQCT has been demonstrated, the ability to use the two systems interchangeably is unknown. From in vivo measurements, we determined the limits of estimating XCTII data from XCTI scans conducted in vivo and whether that estimation can be improved by linear cross-calibration equations. These data are crucial as the research field transitions to the new technology. Our study design established cross-calibration equations by scanning 62 individuals on both systems on the same day and then tested those cross-calibrations on the same cohort 6 months later so that estimated (denoted as XCTII*) and "true" XCTII parameters could be compared. We calculated the generalized least-significant change (GLSC) for those predictions. There was strong agreement between both systems for density (R 2  > 0.94), macroarchitecture (R 2  > 0.95), and most microarchitecture outcomes with the exception of trabecular thickness (Tb.Th, R 2  = 0.51 to 0.67). Linear regression equations largely eliminated the systematic error between XCTII and XCTII* and produced a good estimation of most outcomes, with individual error estimates between 0.2% and 3.4%, with the exception of Tt.BMD. Between-system GLSC was similar to within-XCTI LSC (eg, 8.3 to 41.9 mg HA/cm 3 for density outcomes). We found that differences between outcomes assessed with XCTI and XCTII can be largely eliminated by cross-calibration. Tb.Th is poorly estimated because it is measured more accurately by XCTII than XCTI. It may be possible to use cross-calibration for most outcomes when both scanner generations are used for multicenter and longitudinal studies. © 2017 American Society for Bone and Mineral Research., (© 2017 American Society for Bone and Mineral Research.)

Objective: High-resolution peripheral quantitative computed tomography (HR-pQCT) is a novel imaging modality capable of visualizing bone microarchitecture in vivo at human peripheral sites such as the distal radius and distal tibia. This research has extended the technology to provide a non-invasive assessment of bone microarchitecture at the human knee by establishing new hardware, imaging protocols and data analysis., Design: A custom leg holder was developed to stabilize a human knee centrally within a second generation HR-pQCT field of view. Five participants with anterior cruciate ligament reconstructions had their knee joint imaged in a continuous scan of 6cm axially. The nominal isotropic voxel size was 60.7μm. Bone mineral density and microarchitecture were assessed within the weight-bearing regions of medial and lateral compartments of the knee at three depths from the weight-bearing articular bone surface, including both the cortical and trabecular bone regions., Results: Scan duration was approximately 18min per knee and produced 5GB of projection data and 10GB of reconstructed image data (2304×2304 image matrix, 1008 slices). Motion during the scan was minimized by the leg holder and was similar in magnitude as a scan of the distal tibia. Bone mineral density and microarchitectural parameters were assessed for 16 volumes of interest in the tibiofemoral joint., Conclusions: This is a new non-invasive in vivo assessment tool for bone microarchitecture in the human knee that provides an opportunity to gain insight into normal, injured and surgically reconstructed human knee bone architecture in cross-sectional or longitudinal studies., (Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.)

Objective: The position-dependence of a method to measure the joint space of metacarpophalangeal (MCP) joints using high-resolution peripheral quantitative computed tomography (HR-pQCT) was studied., Methods: Cadaveric MCP were imaged at 7 flexion angles between 0 and 30 degrees. The variability in reproducibility for mean, minimum, and maximum joint space widths and volume measurements was calculated for increasing degrees of flexion., Results: Root mean square coefficient of variance values were < 5% under 20 degrees of flexion for mean, maximum, and volumetric joint spaces. Values for minimum joint space width were optimized under 10 degrees of flexion., Conclusion: MCP joint space measurements should be acquired at < 10 degrees of flexion in longitudinal studies.

Studies assessing bone health often select the dominant or nondominant limb to scan, but not both, for efficiency reasons. New scanning technology allows 3-dimensional (3D) visualization of the microarchitecture in bone, but it is not well understood whether there are differences between the dominant and nondominant limbs. Using 3D high-resolution peripheral quantitative computed tomography (HR-pQCT), the aim of this study is to investigate the effect of limb dominance on bone macroarchitecture and microarchitecture. Healthy male and female participants (N=100; 59 female, 41 male), mean age 30.7±12.1 years, were scanned at both radii and tibiae using HR-pQCT. Hand and foot dominance were determined by the participant's self-report. Most participants were right hand dominant (94.0%) and right foot dominant (91.0%). In the pooled cohort, the dominant radius had significantly greater cortical area (2.11%; p=0.002) and failure load (3.00%; p=0.001). At the tibia, the dominant foot had significantly lower bone mineral density (-0.77%; p=0.042), cortical area (-1.05%; p=0.031), and thickness (-1.51%; p=0.017). For females, there were no differences at the radius, but at the tibia, the dominant side had greater cross-sectional area (1.03%; p=0.044). Our data suggest that dominance has a small yet significant effect on macroarchitecture at both the ultradistal radius and tibia but not microarchitecture. This work emphasizes that it is important to be consistent in the selection of either dominant or nondominant limbs for HR-pQCT cohort studies; however, in the case where the opposite limb needs to be scanned, there would be small differences in macroarchitecture and no significant differences in microarchitecture anticipated., (Copyright © 2016 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

Purpose: Multiple exposures to unloading are overall more deleterious to the skeleton than is single exposure, although the rate of bone loss may diminish during multiple exposures. Here, we determined whether extending the reambulation (RA) period from 3 wk to 9 wk will mitigate bone loss during three distinct 3-wk hindlimb unloading (HLU) periods and enhance long-term recovery in skeletally mature, genetically heterogeneous mice., Methods: Female adult mice (4 months old) were subjected to three cycles of 3-wk unloading with 3-wk or 9-wk RA periods in between. Mice were terminated 46 wk after initiation of the study. Outcome measures for the distal femur were determined from multiple in vivo micro-computed tomography scans and finite-element modeling., Results: Tripling RA duration enhanced trabecular bone recovery in between HLU periods but also increased the rate of loss of bone volume fraction (bone volume/tissue volume) and metaphyseal stiffness during subsequent HLU periods. With shorter RA periods, the magnitude of bone loss decreased by the second HLU period, whereas this decrease was delayed with longer RA periods. RA duration did not affect long-term recovery 46 wk after the start of the experimental protocol, as both HLU groups had similar levels of bone volume/tissue volume, cortical area, and stiffness. Individual cage activity levels were unrelated to the magnitude of bone loss during HLU or bone recovery during RA., Conclusions: These data suggest that extending recovery duration between periods of unloading may provide temporary benefits but is an ineffective long-term strategy for combating the devastation of trabecular morphology and mechanics, as temporarily enhanced recovery is largely cancelled out by greater susceptibility to unloading. They also emphasize that cortical bone is more amenable to long-term recovery than is trabecular bone.

The second generation HR-pQCT scanner (XtremeCTII, Scanco Medical) can assess human bone microarchitecture of peripheral limbs with a 61 μm nominal isotropic voxel size. This is a marked improvement from the first generation HR-pQCT that had a nominal isotropic voxel size of 82 μm, which is at the limit to accurately determine the thickness of individual human trabeculae. We sought to determine the accuracy of a direct morphometric approach to measure trabecular bone microarchitecture with three-dimensional morphological techniques using second generation HR-pQCT, and to compare this with the approach currently applied by the first generation HR-pQCT scanner based on derived indices using ex vivo scans of human cadaveric radii. We also compared images acquired and resampled to mimic the first generation HR-pQCT with those obtained directly from the first generation HR-pQCT. We evaluated 20 human cadaveric radii and a micro-CT performance phantom using the first (XtremeCT, Scanco Medical) and second generation HR-pQCT scanner (XtremeCTII) and compared a patient evaluation (XCTII, 61 μm) with a high resolution ex vivo protocol (HR, 30μm). We generated 82 μm scans of the same specimens to mimic a first-generation HR-pQCT evaluation (XCTIM, 82 μm) and compared these with a first-generation patient evaluation (XCTI, 82 μm). A standard structural extraction approach was applied to both XCTII and HR evaluations for assessment of bone volume fraction (BV/TV), and a distance transform was used to assess trabecular number (Tb.N), trabecular thickness (Tb.Th) and trabecular separation (Tb.Sp). For XCTI and XCTIM evaluations we followed the manufacturer's standard procedure and assessed bone mineral density (BMD), Tb.N with a distance transform, and then derived bone volume ratio (BV/TV(d)), trabecular thickness (Tb.Th(d)) and separation (Tb.Sp(d)). The spatial resolution (10% MTF) was 142.2 μm for XCTI, 108.9 μm for XCTIM, 95.2μm for XCTII, and 55.9 μm for HR. XCTI and XCTIM provided strongly associated measurements of BMD and microarchitectural outcomes (R(2)>0.97), however there were systematic differences in all outcomes. The Tb.N was highly associated with HR by both XCTII (R(2)=0.93, mean error=-0.12 mm(-1)) and XCTIM (R(2)=0.98, mean error=0.25 mm(-1)). Also, both XCTII (R(2)=0.99, mean error=0.20mm) and XCTIM (R(2)=0.99, mean error=-0.18 mm) had Tb.Sp that were strongly related to HR. For Tb.Th, the XCTII was more closely related to HR (R(2)=0.94, mean error=0.04 mm) than the relatively weak XCTIM (R(2)=0.16, mean error=- 0.076 mm). We found that trabecular microarchitecture assessment following the XCTII direct morphometric approach accurately represented the HR data. In particular, the measure of Tb.Th was markedly improved for XCTII compared with the derived approach of XCTIM. These data support the application of analysis techniques in HR-pQCT that are analogous to those traditionally used for micro-CT to assess trabecular microarchitecture. The decreased dependence of structural outcomes on density provides a new, important opportunity to monitor human in vivo bone microarchitecture., (Copyright © 2015 Elsevier Inc. All rights reserved.)