Clinical observation of diminished bone quality and quantity through longitudinal HR-pQCT-derived remodeling and mechanoregulation.

High resolution peripheral quantitative computed tomography (HR-pQCT) provides methods for quantifying volumetric bone mineral density and microarchitecture necessary for early diagnosis of bone disease. When combined with a longitudinal imaging protocol and finite element analysis, HR-pQCT can be used to assess bone formation and resorption (i.e., remodeling) and the relationship between this remodeling and mechanical loading (i.e., mechanoregulation) at the tissue level. Herein, 25 patients with a contralateral distal radius fracture were imaged with HR-pQCT at baseline and 9-12 months follow-up: 16 patients were prescribed vitamin D3 with/without calcium supplement based on a blood biomarker measures of bone metabolism and dual-energy X-ray absorptiometry image-based measures of normative bone quantity which indicated diminishing (n = 9) or poor (n = 7) bone quantity and 9 were not. To evaluate the sensitivity of this imaging protocol to microstructural changes, HR-pQCT images were registered for quantification of bone remodeling and image-based micro-finite element analysis was then used to predict local bone strains and derive rules for mechanoregulation. Remodeling volume fractions were predicted by both average values of trabecular and cortical thickness and bone mineral density (R2 > 0.8), whereas mechanoregulation was affected by dominance of the arm and group classification (p < 0.05). Overall, longitudinal, extended HR-pQCT analysis enabled the identification of changes in bone quantity and quality too subtle for traditional measures.

Bone Mechanoregulation Allows Subject-Specific Load Estimation Based on Time-Lapsed Micro-CT and HR-pQCT in Vivo.

Patients at high risk of fracture due to metabolic diseases frequently undergo long-term antiresorptive therapy. However, in some patients, treatment is unsuccessful in preventing fractures or causes severe adverse health outcomes. Understanding load-driven bone remodelling, i.e., mechanoregulation, is critical to understand which patients are at risk for progressive bone degeneration and may enable better patient selection or adaptive therapeutic intervention strategies. Bone microarchitecture assessment using high-resolution peripheral quantitative computed tomography (HR-pQCT) combined with computed mechanical loads has successfully been used to investigate bone mechanoregulation at the trabecular level. To obtain the required mechanical loads that induce local variances in mechanical strain and cause bone remodelling, estimation of physiological loading is essential. Current models homogenise strain patterns throughout the bone to estimate load distribution in vivo, assuming that the bone structure is in biomechanical homoeostasis. Yet, this assumption may be flawed for investigating alterations in bone mechanoregulation. By further utilising available spatiotemporal information of time-lapsed bone imaging studies, we developed a mechanoregulation-based load estimation (MR) algorithm. MR calculates organ-scale loads by scaling and superimposing a set of predefined independent unit loads to optimise measured bone formation in high-, quiescence in medium-, and resorption in low-strain regions. We benchmarked our algorithm against a previously published load history (LH) algorithm using synthetic data, micro-CT images of murine vertebrae under defined experimental in vivo loadings, and HR-pQCT images from seven patients. Our algorithm consistently outperformed LH in all three datasets. In silico-generated time evolutions of distal radius geometries (n = 5) indicated significantly higher sensitivity, specificity, and accuracy for MR than LH (p < 0.01). This increased performance led to substantially better discrimination between physiological and extra-physiological loading in mice (n = 8). Moreover, a significantly (p < 0.01) higher association between remodelling events and computed local mechanical signals was found using MR [correct classification rate (CCR) = 0.42] than LH (CCR = 0.38) to estimate human distal radius loading. Future applications of MR may enable clinicians to link subtle changes in bone strength to changes in day-to-day loading, identifying weak spots in the bone microstructure for local intervention and personalised treatment approaches.

Formation Dominates Resorption With Increasing Mineralized Density and Time Postfracture in Cortical but Not Trabecular Bone: A Longitudinal HRpQCT Imaging Study in the Distal Radius.

Clinical evaluation of fracture healing is often limited to an assessment of fracture bridging from radiographic images, without consideration for other aspects of bone quality. However, recent advances in HRpQCT offer methods to accurately monitor microstructural bone remodeling throughout the healing process. In this study, local bone formation and resorption were investigated during the first year post fracture in both the fractured (n = 22) and contralateral (n = 19) radii of 34 conservatively treated patients (24 female, 10 male) who presented with a unilateral radius fracture at the Innsbruck University Hospital, Austria. HRpQCT images and clinical metrics were acquired at six time points for each patient. The standard HRpQCT image acquisition was captured for all radii, with additional distal and proximal image acquisitions for the fractured radii. Measured radial bone densities were isolated with a voxel-based mask and images were rigidly registered to images from the previous imaging session using a pyramid-based approach. From the registered images, bone formation and resorption volume fractions were quantified for multiple density-based thresholds and compared between the fractured and contralateral radius and relative to demographics, bone morphometrics, and fracture metrics using regression. Compared with the contralateral radius, both bone formation and resorption were significantly increased in the fractured radius throughout the study for nearly all evaluated thresholds. Higher density cortical bone formation continually increased throughout the duration of the study and was significantly greater than resorption during late-stage healing in both the fractured and intact regions of the radius. With the small and diverse study population, only weak relationships between fracture remodeling and patient-specific parameters were unveiled. However this study provides methods for the analysis of local bone remodeling during fracture healing and highlights relevant considerations for future studies, specifically that remodeling postfracture is likely to continue beyond 12-months postfracture. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Automated segmentation of fractured distal radii by 3D geodesic active contouring of in vivo HR-pQCT images.

Radius fractures are among the most common fracture types; however, there is limited consensus on the standard of care. A better understanding of the fracture healing process could help to shape future treatment protocols and thus improve functional outcomes of patients. High-resolution peripheral quantitative computed tomography (HR-pQCT) allows monitoring and evaluation of the radius on the micro-structural level, which is crucial to our understanding of fracture healing. However, current radius fracture studies using HR-pQCT are limited by the lack of automated contouring routines, hence only including small number of patients due to the prohibitively time-consuming task of manually contouring HR-pQCT images. In the present study, a new method to automatically contour images of distal radius fractures based on 3D morphological geodesic active contours (3D-GAC) is presented. Contours of 60 HR-pQCT images of fractured and conservatively treated radii spanning the healing process up to one year post-fracture are compared to the current gold standard, hand-drawn 2D contours, to assess the accuracy of the algorithm. Furthermore, robustness was established by applying the algorithm to HR-pQCT images of intact radii of 73 patients and comparing the resulting morphometric indices to the gold standard patient evaluation including a threshold- and dilation-based contouring approach. Reproducibility was evaluated using repeat scans of intact radii of 19 patients. The new 3D-GAC approach offers contours within inter-operator variability for images of fractured distal radii (mean Dice score of 0.992 ± 0.005 versus median operator Dice score of 0.992 ± 0.006). The generated contours for images of intact radii yielded morphometric indices within the in vivo reproducibility limits compared to the current gold standard. Additionally, the 3D-GAC approach shows an improved robustness against failure (n = 5) when dealing with cortical interruptions, fracture fragments, etc. compared with the automatic, default manufacturer pipeline (n = 40). Using the 3D-GAC approach assures consistent results, while reducing the need for time-consuming hand-contouring.

Nonlinear voxel-based finite element model for strength assessment of healthy and metastatic proximal femurs.

Nonlinear finite element (FE) models can accurately quantify bone strength in healthy and metastatic femurs. However, their use in clinical practice is limited since state-of-the-art implementations using tetrahedral meshes involve a lot of manual work for which specific modelling software and engineering knowledge are required. Voxel-based meshes could enable the transition since they are robust and can be highly automated. Therefore, the aim of this work was to bridge the modelling gap between the tetrahedral and voxel-based approach. Specifically, we validated a nonlinear voxel-based FE method relative to experimental data from 20 femurs with and without artificial metastases that had been mechanically loaded until failure. CT scans of the femurs were segmented and automatically converted into a voxel-based mesh with hexahedral elements. Nonlinear material properties were implemented in an open-source linear voxel-based FE solver by adding an additional loop to the routine such that the material properties could be adapted after each increment. Bone strength, quantified as the maximum force in the force-displacement curve, was evaluated. The results were compared to a previously established nonlinear tetrahedral FE approach as well as to the experimentally measured bone strength. The voxel-based FE model predicted the experimental bone strength very well both for healthy (R2 = 0.90, RMSE = 0.88 kN) and metastatic femurs (R2 = 0.93, RMSE = 0.64 kN). The model precision and accuracy were very similar to the ones obtained with the tetrahedral model (R2 = 0.90/0.93, RMSE = 0.90/0.64 kN for intact/metastatic respectively). The more intuitive voxel-based meshes thus quantified macroscale femoral strength equally well as state-of-the-art tetrahedral models. The robustness, high level of automation and time-efficiency (< 30 min) of the implemented workflow offer great potential for developing FE models to improve fracture risk prediction in clinical practice.

Validation of HR-pQCT against micro-CT for morphometric and biomechanical analyses: A review.

High-resolution peripheral quantitative computed-tomography (HR-pQCT) has the potential to become a powerful clinical assessment and diagnostic tool. Given the recent improvements in image resolution, from 82 to 61 µm, this technology may be used to accurately quantify in vivo bone microarchitecture, a key biomarker of degenerative bone diseases. However, computational methods to assess bone microarchitecture were developed for micro computed tomography (micro-CT), a higher-resolution technology only available for ex vivo studies, and validation of these computational analysis techniques against the gold-standard micro-CT has been inconsistent and incomplete. Herein, we review methods for segmentation of bone compartments and microstructure, quantification of bone morphology, and estimation of mechanical strength using finite-element analysis, highlighting the need throughout for improved standardization across the field. Studies have relied on homogenous datasets for validation, which does not allow for robust comparisons between methods. Consequently, the adaptation and validation of novel segmentation approaches has been slow to non-existent, with most studies still using the manufacturer's segmentation for morphometric analysis despite the existence of better performing alternative approaches. The promising accuracy of HR-pQCT for capturing morphometric indices is overshadowed by considerable variability in outcomes between studies. For finite element analysis (FEA) methods, the use of disparate material models and FEA tools has led to a fragmented ability to assess mechanical bone strength with HR-pQCT. Further, the scarcity of studies comparing 62 µm HR-pQCT to the gold standard micro-CT leaves the validation of this imaging modality incomplete. This review revealed that without standardization, the capabilities of HR-pQCT cannot be adequately assessed. The need for a public, extendable, heterogeneous dataset of HR-pQCT and corresponding gold-standard micro-CT images, which would allow HR-pQCT users to benchmark existing and novel methods and select optimal methods depending on the scientific question and data at hand, is now evident. With more recent advancements in HR-pQCT, the community must learn from its past and provide properly validated technologies to ensure that HR-pQCT can truly provide value in patient diagnosis and care.