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.

Association of higher bone turnover with risk of curve progression in adolescent idiopathic scoliosis.

OBJECTIVE: Emerging evidence suggest abnormal bone metabolism and defective bone qualities are associated to etipathogenesis of Adolescent Idiopathic Scoliosis (AIS). Systemic low bone mass is important prognosticator to predict risk of curve progression in AIS. The underlying mechanism is still unclear. We hypothesize that aberrant bone turnover correlates with bone qualities in AIS and associates to risk of curve progression. SUBJECTS AND METHODS: Two cohorts were included in this study. The case-control study recruited 161 AIS girls and 161 ethnic/age-matched healthy girls. The longitudinal cohort recruited 128 AIS girls with two-year follow-up. Areal bone mineral density (BMD) at femoral necks were measured with dual-energy x-ray absorptiometry (DXA), and bone qualities of distal radius by high-resolution peripheral quantitative computed tomography (HR-pQCT). Time-lapse analysis of registered HR-pQCT images estimated local bone remodeling quantitatively. Serum levels of CTX and P1NP were measured with ELISA kits. RESULTS: AIS presented significantly higher serum level of P1NP. In both AIS and control, the negative correlations were consistently observed between serum CTX/P1NP levels and most cortical bone quality parameters after adjustment to age. Significant correlation between serum bone turnover markers and trabecular bone parameters have been observed only in control. Progressive AIS has significant increase of serum P1NP level at first clinic visit. Time lapse register analysis showed high bone resorption and low net bone gain was associated with risk of progression in AIS. CONCLUSIONS: Our study characterized AIS with higher serum bone turnover markers, which may contribute to defective bone qualities in AIS. For the first time, we showed that progressive AIS had higher systemic bone turnover markers level and local bone remodeling. This fresh evidence indicated association between disrupted bone turnover and risk of progression of AIS, which set the foundation of new prognostic method and of novel treatment target to curve progression. This study demonstrated the importance of bone metabolism in developing disease management of AIS to achieve goal of early prediction and non-surgical modulation.

A new musculoskeletal AnyBody™ detailed hand model.

Musculoskeletal research questions regarding the prevention or rehabilitation of the hand can be addressed using inverse dynamics simulations when experiments are not possible. To date, no complete human hand model implemented in a holistic human body model has been fully developed. The aim of this work was to develop, implement, and validate a fully detailed hand model using the AnyBody Modelling System (AMS) (AnyBody, Aalborg, Denmark). To achieve this, a consistent multiple cadaver dataset, including all extrinsic and intrinsic muscles, served as a basis. Various obstacle methods were implemented to obtain with the correct alignment of the muscle paths together with the full range of motion of the fingers. These included tori, cylinders, and spherical ellipsoids. The origin points of the lumbrical muscles within the tendon of the flexor digitorum profundus added a unique feature to the model. Furthermore, the possibility of an entire patient-specific scaling based on the hand length and width were implemented in the model. For model validation, experimental datasets from the literature were used, which included the comparison of numerically calculated moment arms of the wrist, thumb, and index finger muscles. In general, the results displayed good comparability of the model and experimental data. However, the extrinsic muscles showed higher accordance than the intrinsic ones. Nevertheless, the results showed, that the proposed developed inverse dynamics hand model offers opportunities in a broad field of applications, where the muscles and joint forces of the forearm play a crucial role.

The association between mineralised tissue formation and the mechanical local in vivo environment: Time-lapsed quantification of a mouse defect healing model.

An improved understanding of how local mechanical stimuli guide the fracture healing process has the potential to enhance clinical treatment of bone injury. Recent preclinical studies of bone defect in animal models have used cross-sectional data to examine this phenomenon indirectly. In this study, a direct time-lapsed imaging approach was used to investigate the local mechanical strains that precede the formation of mineralised tissue at the tissue scale. The goal was to test two hypotheses: 1) the local mechanical signal that precedes the onset of tissue mineralisation is higher in areas which mineralise, and 2) this local mechanical signal is independent of the magnitude of global mechanical loading of the tissue in the defect. Two groups of mice with femoral defects of length 0.85 mm (n = 10) and 1.45 mm (n = 9) were studied, allowing for distinct distributions of tissue scale strains in the defects. The regeneration and (re)modelling of mineralised tissue was observed weekly using in vivo micro-computed tomography (micro-CT), which served as a ground truth for resolving areas of mineralised tissue formation. The mechanical environment was determined using micro-finite element analysis (micro-FE) on baseline images. The formation of mineralised tissue showed strong association with areas of higher mechanical strain (area-under-the-curve: 0.91 ± 0.04, true positive rate: 0.85 ± 0.05) while surface based strains could correctly classify 43% of remodelling events. These findings support our hypotheses by showing a direct association between the local mechanical strains and the formation of mineralised tissue.

Virtual supersampling as post-processing step preserves the trabecular bone morphometry in human peripheral quantitative computed tomography scans.

In the clinical field of diagnosis and monitoring of bone diseases, high-resolution peripheral quantitative computed tomography (HR-pQCT) is an important imaging modality. It provides a resolution where quantitative bone morphometry can be extracted in vivo on patients. It is known that HR-pQCT provides slight differences in morphometric indices compared to the current standard approach micro-computed tomography (micro-CT). The most obvious reason for this is the restriction of the radiation dose and with this a lower image resolution. With advances in micro-CT evaluation techniques such as patient-specific remodeling simulations or dynamic bone morphometry, a higher image resolution would potentially also allow the application of such novel evaluation techniques to clinical HR-pQCT measurements. Virtual supersampling as post-processing step was considered to increase the image resolution of HR-pQCT scans. The hypothesis was that this technique preserves the structural bone morphometry. Supersampling from 82 µm to virtual 41 µm by trilinear interpolation of the grayscale values of 42 human cadaveric forearms resulted in strong correlations of structural parameters (R2: 0.96-1.00). BV/TV was slightly overestimated (4.3%, R2: 1.00) compared to the HR-pQCT resolution. Tb.N was overestimated (7.47%; R2: 0.99) and Tb.Th was slightly underestimated (-4.20%; R2: 0.98). The technique was reproducible with PE%CV between 1.96% (SMI) and 7.88% (Conn.D). In a clinical setting with 205 human forearms with or without fracture measured at 82 µm resolution HR-pQCT, the technique was sensitive to changes between groups in all parameters (p < 0.05) except trabecular thickness. In conclusion, we demonstrated that supersampling preserves the bone morphometry from HR-pQCT scans and is reproducible and sensitive to changes between groups. Supersampling can be used to investigate on the resolution dependency of HR-pQCT images and gain more insight into this imaging modality.

Least-detectable and age-related local in vivo bone remodelling assessed by time-lapse HR-pQCT.

We previously developed an image analysis approach for the determination of local sites of bone remodelling using time-lapse in vivo HR-pQCT. The involved image filtering for removing noise was chosen rather aggressively, and also removed some effects of the bone remodelling. In this paper, we quantify these filtering settings using ex vivo reproducibility HR-pQCT images, and determine the least-detectable bone remodelling using in vivo reproducibility HR-pQCT images, as well as testing whether the approach is capable of capturing age-related bone remodelling by use of in vivo long-term HR-pQCT images. We found that a threshold value of 225 mg HA/cm3 for the filtering led to acceptable results with falsely determined bone remodelling of less than 0.5%, and that the least-detectable bone formation and bone resorption are 2.0 ± 1.0% and 2.2 ± 0.7% respectively. We also found that age-related local bone remodelling can be captured satisfactorily in postmenopausal women. The latter revealed new insights into the effect of ageing on bone remodelling, and showed that bone remodelling seems to take place through a few small formation packets and many large resorption volumes leading to a net bone loss. We conclude that local in vivo bone remodelling can be successfully assessed with time-lapse in vivo HR-pQCT capable of assessing age-related changes in bone remodelling.

Patient-specific in silico models can quantify primary implant stability in elderly human bone.

Secure implant fixation is challenging in osteoporotic bone. Due to the high variability in inter- and intra-patient bone quality, ex vivo mechanical testing of implants in bone is very material- and time-consuming. Alternatively, in silico models could substantially reduce costs and speed up the design of novel implants if they had the capability to capture the intricate bone microstructure. Therefore, the aim of this study was to validate a micro-finite element model of a multi-screw fracture fixation system. Eight human cadaveric humerii were scanned using micro-CT and mechanically tested to quantify bone stiffness. Osteotomy and fracture fixation were performed, followed by mechanical testing to quantify displacements at 12 different locations on the instrumented bone. For each experimental case, a micro-finite element model was created. From the micro-finite element analyses of the intact model, the patient-specific bone tissue modulus was determined such that the simulated apparent stiffness matched the measured stiffness of the intact bone. Similarly, the tissue modulus of a small damage region around each screw was determined for the instrumented bone. For validation, all in silico models were rerun using averaged material properties, resulting in an average coefficient of determination of 0.89 ± 0.04 with a slope of 0.93 ± 0.19 and a mean absolute error of 43 ± 10 µm when correlating in silico marker displacements with the ex vivo test. In conclusion, we validated a patient-specific computer model of an entire organ bone-implant system at the tissue-level at high resolution with excellent overall accuracy. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:954-962, 2018.

Feasibility of rigid 3D image registration of high-resolution peripheral quantitative computed tomography images of healing distal radius fractures.

For accurate analysis of bone formation and resorption during fracture healing, correct registration of follow-up onto baseline image is required. A per-fragment approach could improve alignment compared to standard registration based on the whole fractured region. In this exploratory study, we tested the effect of fragment size and displacement on a per-fragment registration, and compared the results of this per-fragment registration to the results of the standard registration in two stable fractures and one unstable fracture. To test the effect of fragment size and displacement, high-resolution peripheral quantitative computed tomography (HR-pQCT) scans of three unfractured radii were divided into subvolumes. Different displacements in x-, y, or z-direction or rotations around each axis were applied, and each subvolume was registered onto the initial volume to realign it. Next, registration of follow-up onto baseline scan was performed in two stable and one unstable fracture. After coarsely aligning the follow-up onto the baseline scan, a more accurate registration was performed of the whole fracture, i.e. the standard registration, and of each fracture fragment separately, i.e. per-fragment registration. Alignment was checked using overlay images showing baseline, follow-up and overlap between these scans, and by comparing correlation coefficients between the standard and per-fragment registration. Generally, subvolumes as small as 300 mm3 that were displaced up to 0.82 mm in x- or y-, or up to 1.64 mm in z-direction could be realigned correctly. For the fragments of all fractures, correlation coefficients were higher after per-fragment registration compared to standard registration. Most improvement was found in the unstable fracture and one fragment of the unstable fracture did not align correctly. This exploratory study showed that image registration of individual subvolumes, such as fracture fragments, is feasible in both stable and unstable fractures, and leads to better alignment of these fragments compared to an approach that is based on registration using the whole fractured region. This result is promising for additional analysis of bone formation and resorption in HR-pQCT studies on fracture healing.

In vivo Visualisation and Quantification of Bone Resorption and Bone Formation from Time-Lapse Imaging.

PURPOSE OF REVIEW: Mechanoregulation of bone cells was proposed over a century ago, but only now can we visualise and quantify bone resorption and bone formation and its mechanoregulation. In this review, we show how the newest advances in imaging and computational methods paved the way for this breakthrough. RECENT FINDINGS: Non-invasive in vivo assessment of bone resorption and bone formation was demonstrated by time-lapse micro-computed tomography in animals, and by high-resolution peripheral quantitative computed tomography in humans. Coupled with micro-finite element analysis, the relationships between sites of bone resorption and bone formation and low and high tissue loading, respectively, were shown. Time-lapse in vivo imaging and computational methods enabled visualising and quantifying bone resorption and bone formation as well as its mechanoregulation. Future research includes visualising and quantifying mechanoregulation of bone resorption and bone formation from molecular to organ scales, and translating the findings into medicine using personalised bone health prognosis.

Computational modeling of long-term effects of prophylactic vertebroplasty on bone adaptation.

Cement augmentation in vertebrae (vertebroplasty) is usually used to restore mechanical strength after spinal fracture but could also be used as a prophylactic treatment. So far, the mechanical competence has been determined immediately post-treatment, without considering long-term effects of bone adaptation. In this work, we investigated such long-term effects of vertebroplasty on the stiffness of the augmented bone by means of computational simulation of bone adaptation. Using micro-finite element analysis, we determined sites of increased mechanical stress (stress raisers) and stress shielding and, based on the simulations, regions with increased or decreased bone loss due to augmentation. Cement volumes connecting the end plates led to increased stress shielding and bone loss. The increased stiffness due to the augmentation, however, remained constant over the simulation time of 30 years. If the intervention was performed at an earlier time point, it did lead to more bone loss, but again, it did not affect long-term stability as this loss was compensated by bone gains in other areas. In particular, around the augmentation cement, bone structures were preserved, suggesting a long-term integration of the cement in the augmented bone. We conclude that, from a biomechanical perspective, the impact of vertebroplasty on the bone at the microstructural level is less detrimental than previously thought.

A novel in silico method to quantify primary stability of screws in trabecular bone.

Insufficient primary stability of screws in bone leads to screw loosening and failure. Unlike conventional continuum finite-element models, micro-CT based finite-element analysis (micro-FE) is capable of capturing the patient-specific bone micro-architecture, providing accurate estimates of bone stiffness. However, such in silico models for screws in bone highly overestimate the apparent stiffness. We hypothesized that a more accurate prediction of primary implant stability of screws in bone is possible by considering insertion-related bone damage. We assessed two different screw types and loading scenarios in 20 trabecular bone specimens extracted from 12 cadaveric human femoral heads (N = 5 for each case). In the micro-FE model, we predicted specimen-specific Young's moduli of the peri-implant bone damage region based on morphometric parameters such that the apparent stiffness of each in silico model matched the experimentally measured stiffness of the corresponding in vitro specimen as closely as possible. The standard micro-FE models assuming perfectly intact peri-implant bone overestimated the stiffness by over 330%. The consideration of insertion related damaged peri-implant bone corrected the mean absolute percentage error down to 11.4% for both loading scenarios and screw types. Cross-validation revealed a mean absolute percentage error of 14.2%. We present the validation of a novel micro-FE modeling technique to quantify the apparent stiffness of screws in trabecular bone. While the standard micro-FE model overestimated the bone-implant stiffness, the consideration of insertion-related bone damage was crucial for an accurate stiffness prediction. This approach provides an important step toward more accurate specimen-specific micro-FE models. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2415-2424, 2017.

Load-adaptive bone remodeling simulations reveal osteoporotic microstructural and mechanical changes in whole human vertebrae.

Osteoporosis is a major medical burden and its impact is expected to increase in our aging society. It is associated with low bone density and microstructural deterioration. Treatments are available, but the critical factor is to define individuals at risk from osteoporotic fractures. Computational simulations investigating not only changes in net bone tissue volume, but also changes in its microstructure where osteoporotic deterioration occur might help to better predict the risk of fractures. In this study, bone remodeling simulations with a mechanical feedback loop were used to predict microstructural changes due to osteoporosis and their impact on bone fragility from 50 to 80 years of age. Starting from homeostatic bone remodeling of a group of seven, mixed sex whole vertebrae, five mechanostat models mimicking different biological alterations associated with osteoporosis were developed, leading to imbalanced bone formation and resorption with a total net loss of bone tissue. A model with reduced bone formation rate and cell sensitivity led to the best match of morphometric indices compared to literature data and was chosen to predict postmenopausal osteoporotic bone loss in the whole group. Thirty years of osteoporotic bone loss were predicted with changes in morphometric indices in agreement with experimental measurements, and only showing major deviations in trabecular number and trabecular separation. In particular, although being optimized to match to the morphometric indices alone, the predicted bone loss revealed realistic changes on the organ level and on biomechanical competence. While the osteoporotic bone was able to maintain the mechanical stability to a great extent, higher fragility towards error loads was found for the osteoporotic bones.

Voxel size dependency, reproducibility and sensitivity of an in vivo bone loading estimation algorithm.

A bone loading estimation algorithm was previously developed that provides in vivo loading conditions required for in vivo bone remodelling simulations. The algorithm derives a bone's loading history from its microstructure as assessed by high-resolution (HR) computed tomography (CT). This reverse engineering approach showed accurate and realistic results based on micro-CT and HR-peripheral quantitative CT images. However, its voxel size dependency, reproducibility and sensitivity still need to be investigated, which is the purpose of this study. Voxel size dependency was tested on cadaveric distal radii with micro-CT images scanned at 25 µm and downscaled to 50, 61, 75, 82, 100, 125 and 150 µm. Reproducibility was calculated with repeated in vitro as well as in vivo HR-pQCT measurements at 82 µm. Sensitivity was defined using HR-pQCT images from women with fracture versus non-fracture, and low versus high bone volume fraction, expecting similar and different loading histories, respectively. Our results indicate that the algorithm is voxel size independent within an average (maximum) error of 8.2% (32.9%) at 61 µm, but that the dependency increases considerably at voxel sizes bigger than 82 µm. In vitro and in vivo reproducibility are up to 4.5% and 10.2%, respectively, which is comparable to other in vitro studies and slightly higher than in other in vivo studies. Subjects with different bone volume fraction were clearly distinguished but not subjects with and without fracture. This is in agreement with bone adapting to customary loading but not to fall loads. We conclude that the in vivo bone loading estimation algorithm provides reproducible, sensitive and fairly voxel size independent results at up to 82 µm, but that smaller voxel sizes would be advantageous.

Large-scale microstructural simulation of load-adaptive bone remodeling in whole human vertebrae.

Identification of individuals at risk of bone fractures remains challenging despite recent advances in bone strength assessment. In particular, the future degradation of the microstructure and load adaptation has been disregarded. Bone remodeling simulations have so far been restricted to small-volume samples. Here, we present a large-scale framework for predicting microstructural adaptation in whole human vertebrae. The load-adaptive bone remodeling simulations include estimations of appropriate bone loading of three load cases as boundary conditions with microfinite element analysis. Homeostatic adaptation of whole human vertebrae over a simulated period of 10 years is achieved with changes in bone volume fraction (BV/TV) of less than 5%. Evaluation on subvolumes shows that simplifying boundary conditions reduces the ability of the system to maintain trabecular structures when keeping remodeling parameters unchanged. By rotating the loading direction, adaptation toward new loading conditions could be induced. This framework shows the possibility of using large-scale bone remodeling simulations toward a more accurate prediction of microstructural changes in whole human bones.

A potential mechanism for allometric trabecular bone scaling in terrestrial mammals.

Trabecular bone microstructural parameters, including trabecular thickness, spacing, and number, have been reported to scale with animal size with negative allometry, whereas bone volume fraction is animal size-invariant in terrestrial mammals. As for the majority of scaling patterns described in animals, its underlying mechanism is unknown. However, it has also been found that osteocyte density is inversely related to animal size, possibly adapted to metabolic rate, which shows a negative relationship as well. In addition, the signalling reach of osteocytes is limited by the extent of the lacuno-canalicular network, depending on trabecular dimensions and thus also on animal size. Here we propose animal size-dependent variations in osteocyte density and their signalling influence distance as a potential mechanism for negative allometric trabecular bone scaling in terrestrial mammals. Using an established and tested computational model of bone modelling and remodelling, we run simulations with different osteocyte densities and influence distances mimicking six terrestrial mammals covering a large range of body masses. Simulated trabecular structures revealed negative allometric scaling for trabecular thickness, spacing, and number, constant bone volume fraction, and bone turnover rates inversely related to animal size. These results are in agreement with previous observations supporting our proposal of osteocyte density and influence distance variation as a potential mechanism for negative allometric trabecular bone scaling in terrestrial mammals. The inverse relationship between bone turnover rates and animal size further indicates that trabecular bone scaling may be linked to metabolic rather than mechanical adaptations.

Determination of hip-joint loading patterns of living and extinct mammals using an inverse Wolff's law approach.

It is well known that bone adapts its microstructure in response to loading. Based on this form-follows-function relationship, we previously developed a reverse approach to derive joint loads from bone microstructure as acquired with micro-computed tomography. Here, we challenge this approach by calculating hip-joint loading patterns for human and dog, two species exhibiting different locomotion, and comparing them to in vivo measurements. As a proof of concept to use the approach also for extinct taxa, we applied it to a cave lion fossil bone. Calculations were in close agreement with in vivo measurements during walking for extant species, showing distinguished patterns for bipedalism and quadrupedalism. The cave lion calculations clearly revealed its quadrupedal locomotion and suggested a more diverse behaviour compared to the dog, which is in agreement with extant felids. This indicates that our novel approach is potentially useful for making inferences about locomotion in living as well as extinct mammals and to study evolutionary joint development.

Bone remodelling in humans is load-driven but not lazy.

During bone remodelling, bone cells are thought to add and remove tissue at sites with high and low loading, respectively. To predict remodelling, it was proposed that bone is removed below and added above certain thresholds of tissue loading and within these thresholds, called a 'lazy zone', no net change in bone mass occurs. Animal experiments linking mechanical loading with changes in bone density or microstructure support load-adaptive bone remodelling, while in humans the evidence for this relationship at the micro-scale is still lacking. Using new high-resolution CT imaging techniques and computational methods, we quantify microstructural changes and physiological tissue loading in humans. Here, we show that bone remodelling sites in healthy postmenopausal women strongly correlate with tissue loading following a linear relationship without a 'lazy zone' providing unbiased evidence for load-driven remodelling in humans. This suggests that human and animal bones both react to loading induced remodelling in a similar fashion.

Challenges in longitudinal measurements with HR-pQCT: evaluation of a 3D registration method to improve bone microarchitecture and strength measurement reproducibility.

Definition of identical regions between repeated computed tomography (CT) scans is a key factor to monitor changes in bone microarchitecture. In longitudinal studies, accurate determination of the volume of interest (VOI), using three dimensional (3D) registration may improve precision. Therefore, the aim of our study was to investigate the short-term reproducibility of bone geometry, density, microstructure and biomechanical parameters assessed by HR-pQCT and micro-finite element (µFE) derived analyses, using the cross-sectional area (CSA) registration method in comparison with the use of 3D registration, to find overlapping regions between scans. Fifteen healthy individuals (aged 21-47 years) underwent 3 separate scans at the distal radius and tibia, within a one-month interval. Reproducibility was assessed after double contouring the cortical compartment and after applying three different methods to determine the common region between repeated scans: (i) the VOI was determined with no registration, i.e., on 110 slices, (ii) the VOI was determined after CSA-based registration, and (iii) the VOI was determined after 3D registration. Both pre- and post-registration short-term reproducibility for each subject was determined. With no registration, CVrms of geometry parameters ranged from 0.5 to 3.7%, showing a slight variation in the CSA between scans. When the CSA registration method was employed, the variability of geometry (CVrms<1.8%) and density parameters (CVrms<1.8%), was better than that obtained without registration. By removing the effect of repositioning, the 3D registration further improved the reproducibility of cortical bone measurements compared to other methods. Indeed, significant improvements were found for cortical geometry and microstructure measurements (CVrms ranged from 0.4% to 10.7% at both sites; p<0.05), whereas the impact on trabecular bone measurements was restricted to its geometry parameter. The repositioning error was significantly reduced, most markedly at the radius compared to the tibia. For µFE measures, the impact of 3D registration on whole bone stiffness was negligible, indicating adequate assessment of longitudinal changes in estimated biomechanical properties, even without registration. In conclusion, we have shown that the 3D registration improved the identification of the common region retained for longitudinal analysis, contributing to improve the reproducibility of cortical bone parameter measurements. We also quantified the minimally detectable bone changes to help designing future studies with HR-pQCT.