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Abstract: For many years, pharmaceutical therapies for osteoarthritis (OA) were focused on cartilage. However, it has been theorized that bone changes such as increased bone volume fraction and decreased bone matrix mineralization may play an important role in the initiation and pathogenesis of OA as well. The mechanisms behind the bone changes are subject of debate, and a better understanding may help in the development of bone-targeting OA therapies. In the literature, the increase in bone volume fraction has been hypothesized to result from mechanoregulated bone adaptation in response to decreased mineralization. Furthermore, both changes in bone volume fraction and mineralization have been reported to be highest close to the cartilage, and bone volume fraction has been reported to be correlated with cartilage degeneration. These data indicate that cartilage degeneration, bone volume fraction, and bone matrix mineralization may be related in OA. In the current study, we aimed to investigate the relationships between cartilage degeneration, bone matrix mineralization and bone volume fraction at a local level. With microCT, we determined bone matrix mineralization and bone volume fraction as a function of distance from the cartilage in osteochondral plugs from human OA tibia plateaus with varying degrees of cartilage degeneration. In addition, we evaluated whether mechanoregulated bone adaptation in response to decreased bone matrix mineralization may be responsible for the increase in bone volume fraction observed in OA. For this purpose, we used the experimentally obtained mineralization data as input for bone adaptation simulations. We simulated the effect of mechanoregulated bone adaptation in response to different degrees of mineralization, and compared the simulation results to the experimental data. We found that local changes in subchondral bone mineralization and bone volume fraction only occurred underneath severely degenerated cartilage, indicating that bone mineralization and volume fraction are related to cartilage degeneration at a local level. In addition, both the experimental data and the simulations indicated that a depth-dependent increase in bone volume fraction could be caused by decreased bone matrix mineralization. However, a quantitative comparison showed that decreased mineralization can only explain part of the subchondral sclerosis observed in OA. [Copyright &y& Elsevier]

Improving the clinical outcome of scaphoid fractures may benefit from adequate monitoring of their healing in order to for example identify complications such as scaphoid nonunion at an early stage and to adjust the treatment strategy accordingly. However, quantitative assessment of the healing process is limited with current imaging modalities. In this study, high-resolution peripheral quantitative computed tomography (HR-pQCT) was used for the first time to assess the changes in bone density, microarchitecture, and strength during the healing of conservatively-treated scaphoid fractures. Thirteen patients with a scaphoid fracture (all confirmed on HR-pQCT and eleven on CT) received an HR-pQCT scan at baseline and three, six, twelve, and 26 weeks after first presentation at the emergency department. Bone mineral density (BMD) and trabecular microarchitecture of the scaphoid bone were quantified, and failure load (FL) was estimated using micro-finite element analysis. Longitudinal changes were evaluated with linear mixed-effects models. Data of two patients were excluded due to surgical intervention after the twelve-week follow-up visit. In the eleven fully evaluable patients, the fracture line became more apparent at 3 weeks. At 6 weeks, individual trabeculae at the fracture region became more difficult to identify and distinguish from neighboring trabeculae, and this phenomenon concerned a larger region around the fracture line at 12 weeks. Quantitative assessment showed that BMD and FL were significantly lower than baseline at all follow-up visits with the largest change from baseline at 6 weeks (−13.6% and − 23.7%, respectively). BMD remained unchanged thereafter, while FL increased. Trabecular thickness decreased significantly from baseline at three (−3.9%), six (−6.7%), and twelve (−4.4%) weeks and trabecular number at six (−4.5%), twelve (−7.3%), and 26 (−7.9%) weeks. Trabecular separation was significantly higher than baseline at six (+13.3%), twelve (+19.7%), and 26 (+16.3%) weeks. To conclude, this explorative HR-pQCT study showed a substantial decrease in scaphoid BMD, Tb.Th, and FL during the first 6 weeks of healing of conservatively-treated scaphoid fractures, followed by stabilization or increase in these parameters. At 26 weeks, BMD, trabecular microarchitecture, and FL were not returned to baseline values. • HR-pQCT can be used to assess the healing process of scaphoid fractures. • Density and failure load significantly decreased until 6 weeks post-fracture. • Density and failure load were not returned to baseline 26 weeks post-fracture. • The healing of scaphoid fractures seems slower than that of distal radius fractures. [ABSTRACT FROM AUTHOR]

Abstract: From a mechanical point of view, the most relevant components of articular cartilage are the tight and highly organized collagen network together with the charged proteoglycans. Due to the fixed charges of the proteoglycans, the cation concentration inside the tissue is higher than in the surrounding synovial fluid. This excess of ion particles leads to an osmotic pressure difference, which causes swelling of the tissue. The fibrillar collagen network resists straining and swelling pressures. This combination makes cartilage a unique, highly hydrated and pressurized tissue, enforced with a strained collagen network. Many theories to explain articular cartilage behavior under loading, expressed in computational models that either include the swelling behavior or the properties of the anisotropic collagen structure, can be found in the literature. The most common tests used to determine the mechanical quality of articular cartilage are those of confined compression, unconfined compression, indentation and swelling. All theories currently available in the literature can explain the cartilage response occurring in some of the above tests, but none of them can explain these for all of the tests. We hypothesized that a model including simultaneous mathematical descriptions of (1) the swelling properties due to the fixed-change densities of the proteoglycans and (2) the anisotropic viscoelastic collagen structure, can explain all these test simultaneously. To study this hypothesis we extended our fibril-reinforced poroviscoelastic finite element model with our biphasic swelling model. We have shown that the newly developed fibril-reinforced poroviscoelastic swelling (FPVES) model for articular cartilage can simultaneously account for the reaction force during swelling, confined compression, indentation and unconfined compression as well as the lateral deformation during unconfined compression. Using this theory it is possible to analyze the link between the collagen network and the swelling properties of articular cartilage. [Copyright &y& Elsevier]

It is assumed that density and morphology of trabecular bone is partially controlled by mechanical forces. How these effects are expressed in the local metabolic functions of osteoclast resorption and osteoblast formation is not known. In order to investigate possible mechano-biological pathways for these mechanisms we have proposed a mathematical theory (Nature 405 (2000) 704). This theory is based on hypothetical osteocyte stimulation of osteoblast bone formation, as an effect of elevated strain in the bone matrix, and a role for microcracks and disuse in promoting osteoclast resorption. Applied in a 2-D Finite Element Analysis model, the theory explained the formation of trabecular patterns. In this article we present a 3-D FEA model based on the same theory and investigated its potential morphological predictability of metabolic reactions to mechanical loads. The computations simulated the development of trabecular morphological details during growth, relative to measurements in growing pigs, reasonably realistic. They confirmed that the proposed mechanisms also inherently lead to optimal stress transfer. Alternative loading directions produced new trabecular orientations. Reduction of load reduced trabecular thickness, connectivity and mass in the simulation, as is seen in disuse osteoporosis. Simulating the effects of estrogen deficiency through increased osteoclast resorption frequencies produced osteoporotic morphologies as well, as seen in post-menopausal osteoporosis. We conclude that the theory provides a suitable computational framework to investigate hypothetical relationships between bone loading and metabolic expressions. [Copyright &y& Elsevier]

Osteoarthritis (OA) is a multifactorial disease, resulting in diarthrodial joint wear and eventually destruction. Swelling of cartilage, which is proportional to the amount of collagen damage, is an initial event of cartilage degeneration, so damage to the collagen fibril network is likely to be one of the earliest signs of OA cartilage degeneration. We propose that the local stresses and strains in the collagen fibrils, which cause the damage, cannot be determined dependably without taking the local arcade-like collagen-fibril structure into account. We investigate this using a poroviscoelastic fibril-reinforced FEA model. The constitutive fibril properties were determined by fitting numerical data to experimental results of unconfined compression and indentation tests on samples of bovine patellar articular cartilage. It was demonstrated that with this model the stresses and strains in the collagen fibrils can be calculated. It was also exhibited that fibrils with different orientations at the same location can be loaded differently, depending on the local architecture of the collagen network. To the best of our knowledge, the present model is the first that can account for these features. We conclude that the local stresses and strains in the articular cartilage are highly influenced by the local morphology of the collagen-fibril network. [Copyright &y& Elsevier]

Introduction: The aim of this study was to investigate the associations of patient characteristics, bone mineral density (BMD), bone microarchitecture and calculated bone strength with secondary displacement of a DRF based on radiographic alignment parameters.Materials and Methods: Dorsal angulation, radial inclination and ulnar variance were assessed on conventional radiographs of a cohort of 251 patients, 38 men and 213 women, to determine the anatomic position of the DRF at presentation (primary position) and during follow-up. Secondary fracture displacement was assessed in the non-operatively treated patients (N = 154) with an acceptable position, preceded (N = 97) or not preceded (N = 57) by primary reduction (baseline position). Additionally, bone microarchitecture and calculated bone strength at the contralateral distal radius and tibia were assessed by HR-pQCT in a subset of, respectively, 63 and 71 patients.Outcome: Characteristics of patients with and without secondary fracture displacement did not differ. In the model with adjustment for primary reduction [OR 22.00 (2.27-212.86), p = 0.008], total [OR 0.16 (95% CI 0.04-0.68), p = 0.013] and cortical [OR 0.19 (95% CI 0.05-0.80], p = 0.024] volumetric BMD (vBMD) and cortical thickness [OR 0.13 (95% CI 0.02-0.74), p = 0.021] at the distal radius were associated with secondary DRF displacement. No associations were found for other patient characteristics, such as age gender, BMD or prevalent vertebral fractures.Conclusions: In conclusion, our study indicates that besides primary reduction, cortical bone quality may be important for the risk of secondary displacement of DRFs. [ABSTRACT FROM AUTHOR]

Summary: Vertebral fracture (VF) locations are bimodally distributed in the spine. The association between VF and bone attenuation (BA) measured on chest CT scans varied according to the location of VFs, indicating that other factors than only BA play a role in the bimodal distribution of VFs. Introduction: Vertebral fractures (VFs) are associated with low bone mineral density but are not equally distributed throughout the spine and occur most commonly at T7–T8 and T11–T12 ("cVFs") and less commonly at T4–T6 and T9–T10 ("lcVF"). We aimed to determine whether associations between bone attenuation (BA) and VFs vary between subjects with cVFs only, with lcVFs only and with both cVFs and lcVFs. Methods: Chest CT images of T4–T12 in 1237 smokers with and without COPD were analysed for prevalent VFs according to the method described by Genant (11,133 vertebrae). BA (expressed in Hounsfield units) was measured in all non-fractured vertebrae (available for 10,489 vertebrae). Linear regression was used to compare mean BA, and logistic regression was used to estimate the association of BA with prevalent VFs (adjusted for age and sex). Results: On vertebral level, the proportion of cVFs was significantly higher than of lcVF (5.6% vs 2.0%). Compared to subjects without VFs, BA was 15% lower in subjects with cVFs (p < 0.0001), 25% lower in subjects with lcVFs (p < 0.0001) and lowest in subjects with cVFs and lcVFs (− 32%, p < 0.0001). The highest ORs for presence of VFs per − 1SD BA per vertebra were found in subjects with both cVFs and lcVFs (3.8 to 4.6). Conclusions: The association between VFs and BA differed according to VF location. ORs increased from subjects with cVFs to subjects with lcVFs and were highest in subjects with cVFs and lcVFs, indicating that other factors than only BA play a role in the bimodal VF distribution. Trial registration: Clinicaltrials.gov identifier: NCT00292552 [ABSTRACT FROM AUTHOR]

Background: Computed tomography (CT), magnetic resonance imaging, and bone scintigraphy are second-line imaging techniques that are frequently used for the evaluation of patients with a clinically suspected scaphoid fracture. However, as a result of varying diagnostic performance results, no true reference standard exists for scaphoid fracture diagnosis. We hypothesized that the use of high-resolution peripheral quantitative CT (HR-pQCT) in patients with a clinically suspected scaphoid fracture could improve scaphoid fracture detection compared with conventional CT in the clinical setting.Methods: The present study included 91 consecutive patients (≥18 years of age) who presented to the emergency department with a clinically suspected scaphoid fracture between December 2017 and October 2018. All patients were clinically reassessed within 14 days after first presentation, followed by CT and HR-pQCT. If a scaphoid fracture was present, the fracture type was determined according to the Herbert classification system and correlation between CT and HR-pQCT was estimated with use of the Kendall W statistic or coefficient of concordance (W) (the closer to 1, the higher the correlation).Results: The cohort included 45 men and 46 women with a median age of 52 years (interquartile range, 29 to 67 years). HR-pQCT revealed a scaphoid fracture in 24 patients (26%), whereas CT revealed a scaphoid fracture in 15 patients (16%). Patients with a scaphoid fracture were younger and more often male. The correlation between CT and HR-pQCT was high for scaphoid fracture type according to the Herbert classification system (W = 0.793; 95% confidence interval [CI], 0.57 to 0.91; p < 0.001) and very high for scaphoid fracture location (W = 0.955; 95%, CI 0.90 to 0.98; p < 0.001).Conclusions: In the present study, the number of patients diagnosed with a scaphoid fracture was 60% higher when using HR-pQCT as compared with CT. These findings imply that a substantial proportion of fractures-in this study, more than one-third-will be missed by the current application of CT scanning in patients with a clinically suspected scaphoid fracture.Level Of Evidence: Diagnostic Level II. See Instructions for Authors for a complete description of levels of evidence. [ABSTRACT FROM AUTHOR]

Purpose: As yet, there are no studies describing a relationship between radiographic subsidence after lumbar total disc replacement (TDR) and patient symptoms. To investigate if subsidence, in terms of penetrated bone volume or angular rotation over time (ΔPBV and ΔAR), is related to clinical outcome. To assess if subsidence can be predicted by position implant asymmetry (IA) or relative size of the TDR, areal undersizing index (AUI) on direct post-operative radiographs.Methods: Retrospective cohort study consists of 209 consecutive patients with lumbar TDR for degenerative disc disease. A three-dimensional graphical representation of the implant in relation to the bony endplates was created on conventional radiographs. Consequently, the PBV, AR, IA and AUI were calculated, direct post-operative (DPO) and at last follow-up (LFU). For clinical evaluation, patients with substantial pain (VAS ≥ 50) and malfunction (ODI ≥ 40) were considered failures.Results: At a mean follow-up of 16.7 years, 152 patients (73%) were available for analysis. In 32 patients, revision by spinal fusion had been performed. Both ΔAR (4.33° vs. 1.83°, p = 0.019) and ΔPBV (1448.4 mm3 vs. 747.3 mm3, p = 0.003) were significantly higher in the failure-compared to the success-group. Using ROC curves, thresholds for symptomatic subsidence were defined as ΔPBV ≥ 829 mm3 or PBV-LFU ≥ 1223 mm3 [area under the curve (AUC) 0.723, p = 0.003 and 0.724, p = 0.005, respectively]. Associations between symptomatic subsidence and AUI-DPO ≥ 0.50 (AUC 0.750, p = 0.002) and AR-DPO ≥ 3.95° (AUC 0.690, p = 0.022) were found.Conclusion: Subsidence of a TDR is associated with a worse clinical outcome. The occurrence of subsidence is higher in case of incorrect placement or shape mismatch. [ABSTRACT FROM AUTHOR]

Identifying determinants of long-term functional outcome after a distal radius fracture is challenging. Previously, we reported on the association between early HR-pQCT measurements and clinical outcome 12 weeks after a conservatively treated distal radius fracture. We extended the follow-up and assessed functional outcome after two years in relation to early HR-pQCT derived bone parameters. HR-pQCT scans of the fracture region were performed in 15 postmenopausal women with a distal radius fracture at 1–2 (baseline), 3–4 weeks and 26 months post-fracture. Additionally, the contralateral distal radius was scanned at baseline. Bone density, micro-architecture parameters and bone stiffness using micro-finite element analysis (μFEA) were evaluated. During all visits, wrist pain and function were assessed using the patient-rated wrist evaluation questionnaire (PRWE), quantifying functional outcome with a score between 0 and 100. Two-year PRWE was associated with torsional and bending stiffness 3–4 weeks post-fracture (R2: 0.49, p = 0.006 and R2: 0.54, p = 0.003, respectively). In contrast, early micro-architecture parameters of the fracture region or contralateral bone parameters did not show any association with long-term outcome. This exploratory study indicates that HR-pQCT with μFEA performed within four weeks after a distal radius fracture captures biomechanical fracture characteristics that are associated with long-term functional outcome and therefore could be a valuable early outcome measure in clinical trials and clinical practice. • HR-pQCT scans can be used to assess the healing process of distal radius fractures. • μFEA-derived stiffness is associated with functional outcome 2 years post-fracture. • Early torsional/bending stiffness may be most important for functional recovery. • Fracture region micro-architecture is not associated with long-term function. [ABSTRACT FROM AUTHOR]

Summary: This study developed a well-standardized and reproducible approach for micro-finite element (mFE) and homogenized-FE (hFE) analyses that can accurately predict the distal radius failure load using either mFE or hFE models when using the approaches and parameters developed in this study. Introduction: Micro-FE analyses based on high-resolution peripheral quantitative CT (HR-pQCT) images are frequently used to predict distal radius failure load. With the introduction of a second-generation HR-pQCT device, however, the default modelling approach no longer provides accurate results. The aim of this study was to develop a well-standardized and reproducible approach for mFE and hFE analyses that can provide precise and accurate results for distal radius failure load predictions based on second-generation HR-pQCT images. Methods: Second-generation HR-pQCT was used to scan the distal 20-mm section of 22 cadaver radii. The sections were excised and mechanically tested afterwards. For these sections, mFE and hFE models were made that were used to identify required material parameters by comparing predicted and measured results. Using these parameters, the models were cropped to represent the 10-mm region recommended for clinical studies to test their performance for failure load prediction. Results: After identification of material parameters, the measured failure load of the 20-mm segments was in good agreement with the results of mFE models (R2 = 0.969, slope = 1.035) and hFE models (R2 = 0.966, slope = 0.890). When the models were restricted to the clinical region, mFE still accurately predicted the measured failure load (R2 = 0.955, slope = 1.021), while hFE predictions were precise but tended to overpredict the failure load (R2 = 0.952, slope = 0.780). Conclusions: It was concluded that it is possible to accurately predict the distal radius failure load using either mFE or hFE models when using the approaches and parameters developed in this study. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of the study was to prospectively investigate change (repair or progression) in the number, surface area and volume of cortical interruptions, bone density (vBMD) and micro-structural parameters assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT) in finger joints of patients with rheumatoid arthritis (RA) treated with synthetic disease modifying anti-rheumatic drugs (sDMARDs) and/or biologic DMARDs (bDMARDs) over a 1-year follow-up period, and in comparison with healthy subjects (HS).Methods: Thirty-two patients with RA (221 joints, 53% on bDMARDs) and 32 HS (117 joints) were assessed at baseline and after 1 year using semi-automatic analysis of HR-pQCT images. Mean changes (group level) and the proportion of joints (joint level) with changes beyond the least significant change were calculated.Results: At baseline, 530 interruptions were identified in patients, and 136 in HS. The mean of the interruption parameters did not significantly change in either group Mean vBMD decreased more in patients than in HS (- 4.4 versus - 1.1 mgHA/cm3, respectively). In patients versus HS, proportionally more joints showed repair in interruption volume (6.6% versus 1.7%, respectively) and loss of vBMD (26.7% versus 12.9%, respectively). In patients on sDMARDs versus patients on bDMARDs, proportionally more joints showed progression in the number of interruptions and loss of vBMD (6.1% versus 1.8% and 31.3% versus 17.2%, respectively).Conclusions: HR-pQCT is able to quantify bone repair and progression. Cortical interruption-, vBMD-, and micro-structure were impaired in RA, of which vBMD and micro-structure further deteriorated, particularly in patients on sDMARDs. [ABSTRACT FROM AUTHOR]

Summary: A longitudinal analysis of bone microstructure in postmenopausal women of the Geneva Retirees Cohort indicates that age-related cortical bone loss is attenuated at non-bearing bone sites in fermented dairy products consumers, not in milk or ripened cheese consumers, independently of total energy, calcium, or protein intakes.Introduction: Fermented dairy products (FDP), including yogurts, provide calcium, phosphorus, and proteins together with prebiotics and probiotics, all being potentially beneficial for bone. In this prospective cohort study, we investigated whether FDP, milk, or ripened cheese consumptions influence age-related changes of bone mineral density (BMD) and microstructure.Methods: Dietary intakes were assessed at baseline and after 3.0 ± 0.5 years with a food frequency questionnaire in 482 postmenopausal women enrolled in the Geneva Retirees Cohort. Cortical (Ct) and trabecular (Tb) volumetric (v) BMD and microstructure at the distal radius and tibia were assessed by high-resolution peripheral quantitative computerized tomography, in addition to areal (a) BMD and body composition by dual-energy X-ray absorptiometry, at the same time points.Results: At baseline, FDP consumers had lower abdominal fat mass and larger bone size at the radius and tibia. Parathyroid hormone and β-carboxyterminal cross-linked telopeptide of type I collagen levels were inversely correlated with FDP consumption. In the longitudinal analysis, FDP consumption (mean of the two assessments) was associated with attenuated loss of radius total vBMD and of Ct vBMD, area, and thickness. There was no difference in aBMD and at the tibia. These associations were independent of total energy, calcium, or protein intakes. For other dairy products categories, only milk consumption was associated with lower decrease of aBMD and of failure load at the radius.Conclusion: In this prospective cohort of healthy postmenopausal women, age-related Ct bone loss was attenuated at non-bearing bone sites in FDP consumers, not in milk or ripened cheese consumers, independently of total energy, calcium, or protein intakes.Study registration: ISRCTN11865958 (http://www.isrctn.com) [ABSTRACT FROM AUTHOR]

We developed a semi-automated algorithm for the detection of cortical interruptions in finger joints using high-resolution peripheral quantitative computed tomography (HR-pQCT). Here, we tested its reliability compared to microCT (µCT) as gold standard. Nineteen joints of 10 female anatomic index fingers were imaged by HR-pQCT and µCT (82 and 18 µm isotropic voxel sizes, respectively). The algorithm was applied for detection of cortical interruptions of different minimum diameters (range >0.16 to >0.50 mm). Reliability was tested at the joint level with intra-class correlation coefficient (ICC) for the number of interruptions and interruption surface, and at the level of a single interruption for matching between HR-pQCT and µCT with a fixed interruption diameter (>0.10 mm) on µCT. The positive predictive value (PPV0.10mm) and sensitivity0.10mm were evaluated. The mean number of interruptions per joint depended on the diameter cut-off and ranged from 3.4 to 53.5 on HR-pQCT and from 1.8 to 45.1 on µCT for interruptions >0.50 to >0.16 mm, respectively. Reliability at the joint level was almost perfect (ICC ≥0.81) for both the number and surface of interruptions >0.16 and >0.33 mm. As expected, the PPV0.10mm increased with increasing interruption diameter from 84.9 to 100%, for interruptions >0.16 and >0.50 mm, respectively. However, the sensitivity0.10mm decreased with increasing interruption diameter from 62.4 to 4.7%. This semi-automated algorithm for HR-pQCT in finger joints performed best for the detection of cortical interruptions with a minimum diameter of >0.16 or >0.33 mm, showing almost perfect reliability at the joint level and interruptions matched with those on µCT. [ABSTRACT FROM AUTHOR]

Bioactive Glass (BAG) granules are osteoconductive and possess unique antibacterial properties for a synthetic biomaterial. To assess the applicability of BAG granules in load-bearing defects, the aim was to compare mechanical behaviour of graft layers consisting of BAG granules and morselized cancellous bone allograft in different volume mixtures under clinically relevant conditions. The graft layers were mechanically tested, using two mechanical testing modalities with simulated physiological loading conditions: highly controllable confined compression tests (CCT) and more clinically realistic in situ compression tests (ISCT) in cadaveric porcine bone defects. Graft layer impaction strain, residual strain, aggregate modulus, and creep strain were determined in CCT. Graft layer porosity was determined using micro computed tomography. The ISCT was used to determine graft layer subsidence in bone environment. ANOVA showed significant differences ( p <0.001) between different graft layer compositions. True strains absolutely decreased for increasing BAG content: impaction strain −0.92 (allograft) to −0.39 (BAG), residual strain −0.12 to −0.01, and creep strain −0.09 to 0.00 respectively. Aggregate modulus increased with increasing BAG content from 116 to 653 MPa. Porosity ranged from 66% (pure allograft) to 15% (pure BAG). Subsidence was highest for allograft, and remarkably low for a 1:1 BAG-allograft volume mixture. Both BAG granules and allograft morsels as stand-alone materials exhibit suboptimal mechanical behaviour for load-bearing purpose. BAG granules are difficult to handle and less porous, whereas allograft subsides and creeps. A 1:1 volume mixture of BAG and allograft is therefore proposed as the best graft material in load-bearing defects. [ABSTRACT FROM AUTHOR]

Abstract: Pressurized fluid has been proposed to play an important role in subchondral bone cyst development. However, the exact mechanism remains speculative. We used an established computational mechanoregulated bone adaptation model to investigate two hypotheses: 1) pressurized fluid causes cyst growth through altered bone tissue loading conditions, 2) pressurized fluid causes cyst growth through osteocyte death. In a 2D finite element model of bone microarchitecture, a marrow cavity was filled with fluid to resemble a cyst. Subsequently, the fluid was pressurized, or osteocyte death was simulated, or both. Rather than increasing the load, which was the prevailing hypothesis, pressurized fluid decreased the load on the surrounding bone, thereby leading to net bone resorption and growth of the cavity. In this scenario an irregularly shaped cavity developed which became rounded and obtained a rim of sclerotic bone after removal of the pressurized fluid. This indicates that cyst development may occur in a step-wise manner. In the simulations of osteocyte death, cavity growth also occurred, and the cavity immediately obtained a rounded shape and a sclerotic rim. Combining both mechanisms increased the growth rate of the cavity. In conclusion, both stress-shielding by pressurized fluid, and osteocyte death may cause cyst growth. In vivo observations of pressurized cyst fluid, dead osteocytes, and different appearances of cysts similar to our simulation results support the idea that both mechanisms can simultaneously play a role in the development and growth of subchondral bone cysts. [Copyright &y& Elsevier]

We recruited a population-based sample of 58 males and 74 females aged 20–79 from a primary care medical practice to provide normative and descriptive data for high-resolution peripheral quantitative computed tomography (pQCT) parameters. Important effects of ageing and contrasts in the effects of sex on the micro-architecture and strength of upper and lower limb bones were revealed. The advent of high-resolution pQCT scanners has permitted non-invasive assessment of structural data on cortical and trabecular bone. We investigated age-related changes in pQCT and finite element (FE) modelling parameters at the distal radius and distal tibia in a population-based cross-sectional study of 58 males and 74 females aged 20–79 years. Linear regression models including quadratic terms for age were used for inference. Age-related changes and sex differences were generally similar for pQCT parameters at the radius and tibia. At each site, mean values for bone density, cortical thickness and trabecular micro-architecture (number, separation and thickness) were lower (trabecular separation higher) in women than men. Changes with age were most apparent for bone density and cortical thickness, which declined with age, in contrast to trabecular micro-architecture parameters which were not significantly associated with age ( p > 0.05) in either sex. Cortical bone density and thickness declined faster in women than men after age 50 and trabecular bone density was consistently lower in women. FE-analysis predicted failure load decreased with age and percentage of load carried by trabecular bone increased ( p < 0.05). These data show contrasts in the effects of sex on the micro-architecture and strength of upper and lower limb bones with ageing. The faster decline in cortical bone thickness and density in women than men after age 50 and consistently lower trabecular bone density in women have implications for the excess risks of wrist and hip fractures in women. [ABSTRACT FROM AUTHOR]

Abstract: Osteoporosis (OP) is characterized by low bone mass and weak bone structure, which results in increased fracture risk. It has been suggested that osteoporotic bone is strongly adapted to the main loading direction and less adapted to the other directions. In this study, we hypothesized that osteoporotic femoral heads have 1) an increased anisotropy; 2) a more heterogenic distribution of bone volume fraction (BV/TV) throughout the femoral head; and, 3) a more heterogenic distribution of the trabecular thickness (Tb.Th.) throughout the femoral head, as compared to non-osteoporotic bone. To test these hypotheses, we used 7 osteoporotic femoral heads from patients who fractured their femoral neck and 7 non-fractured femoral heads from patients with osteoarthrosis (OA). Bone structural parameters from the entire trabecular region were analyzed using microCT. We found that the degree of anisotropy was higher in the fractured femoral heads, i.e. 1.72, compared to a value of 1.61 in the non-fractured femoral heads. The BV/TV and Tb.Th. and their variations throughout the femoral head, however, were all significantly lower in the fractured group. Hence, the first hypothesis was confirmed, whereas the other two were rejected. Interestingly, the variation of Tb.Th. throughout the femoral head provided a 100% discrimination between the OP and OA groups, i.e. for the same BV/TV, all fractured cases had a less heterogenic distribution. In conclusion, our results suggest that bone loss in OP takes place uniformly throughout the femoral head, leading to an overall decrease in bone mass and trabecular thickness. Furthermore, the variation of Tb.Th. in the femoral head could be an interesting parameter to improve the prediction of fracture risk in the proximal femur. [Copyright &y& Elsevier]

In recent decades, an increasing number of tissue engineered bone grafts have been developed. However, expensive and laborious screenings in vivo are necessary to assess the safety and efficacy of their formulations. Rodents are the first choice for initial in vivo screens but their size limits the dimensions and number of the bone grafts that can be tested in orthotopic locations. Here, we report the development of a refined murine subcutaneous model for semi-orthotopic bone formation that allows the testing of up to four grafts per mouse one order of magnitude greater in volume than currently possible in mice. Crucially, these defects are also "critical size" and unable to heal within the timeframe of the study without intervention. The model is based on four bovine bone implants, ring-shaped, where the bone healing potential of distinct grafts can be evaluated in vivo. In this study we demonstrate that promotion and prevention of ossification can be assessed in our model. For this, we used a semi-automatic algorithm for longitudinal micro-CT image registration followed by histological analyses. Taken together, our data supports that this model is suitable as a platform for the real-time screening of bone formation, and provides the possibility to study bone resorption, osseointegration and vascularisation. [Display omitted] [ABSTRACT FROM AUTHOR]

Bisphosphonates are antiresorptive drugs commonly used to treat osteoporosis. It is not clear, however, what the influence of the time point of treatment is. Recently developed in vivo micro-computed tomographic (CT) scanners offer the possibility to study such effects on bone microstructure in rats. The aim of this study was to determine the influence of early and late zoledronic acid treatment on bone in ovariectomized rats, using in vivo micro-CT. Twenty-nine female Wistar rats were divided into the following groups: ovariectomy (OVX, n = 5), OVX and zoledronic acid (ZOL) at week 0 (n = 8), OVX and ZOL at week 8 (n = 7), and sham (n = 9). CT scans were made of the proximal tibia at weeks 0, 2, 4, 8, 12, and 16; and bone structural parameters were determined in the metaphysis. Two fluorescent labels were administered to calculate dynamic histomorphometric parameters. At week 16, all groups were significantly different from each other in bone volume fraction (BV/TV), connectivity density, and trabecular number (Tb.N), except for the early ZOL and control groups which were not significantly different for any structural parameter. After ZOL treatment at week 8, BV/TV, structure model index, Tb.N, and trabecular thickness significantly improved in the late ZOL group. The OVX and ZOL groups showed, respectively, higher and lower bone formation rates than the control group. Early ZOL treatment inhibited all bone microstructural changes seen after OVX. Late ZOL treatment significantly improved bone microstructure, although the structure did not recover to original levels. Early ZOL treatment resulted in a significantly better microstructure than late treatment. However, late treatment was still significantly better than no treatment. [ABSTRACT FROM AUTHOR]

X-linked Hypophosphatemia (XLH) is the most common type of inherited rickets. Although the clinical features are well characterized, bone structure, mineralization, and biomechanical properties are poorly known. Our aim was to analyze bone properties in the appendicular and axial skeleton of adults with XLH. In this observational case-control study, each affected patient (N = 14; 9 females; age 50 ± 15 years) was matched by sex, age and body mass index to a minimum of two healthy controls (N = 34). Dual-energy X-ray Absorptiometry (DXA) analyses revealed that areal bone mineral density (aBMD) was higher in XLH patients at the lumbar spine (Z score mean difference = +2.47 SD, P value = 1.4 × 10 -3 ). Trabecular Bone Score was also higher at the lumbar spine (P value = 1.0 × 10 -4 ). High Resolution peripheral Quantitative Computed Tomography (HRpQCT) demonstrated that bone cross-sectional area was larger at the distal radius (P value = 6 × 10 -3 ). Total and trabecular volumetric BMD were lower at both sites. Trabecular bone volume fraction was also lower with fewer trabecular numbers at both sites. However, bone strength evaluated by micro-finite element analyzes revealed unaffected bone stiffness and maximum failure load. Evaluation of bone mineralization with aBMD by DXA at the distal radius correlated with vBMD by HRpQCT measurements at both sites. PTH levels were inversely correlated with trabecular vBMD and BV/TV at the tibia. We then followed a subset of nine patients (median follow-up of 4 years) and reassessed HRpQCT. At the tibia, we observed a greater decrease than expected from an age and sex standardized normal population in total and cortical vBMD as well as a trabecularization of the cortical compartment. In conclusion, in adult patients with XLH, bone mineral density is high at the axial skeleton but low at the appendicular skeleton. With time, microarchitectural alterations worsen. We propose that noninvasive evaluation methods of bone mineralization such as DXA including the radius should be part of the management of XLH patients. Larger studies are needed to evaluate the clinical significance of BMD changes in XLH patients under conventional or targeted therapies., Competing Interests: Declaration of competing interest TFB and MCS disclose their participation in a sponsored symposium by Kyowa Kirin. MCS received a research grant by Kyowa Kirin., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Accurate measurements of trabecular bone microarchitecture are required for a proper assessment of bone fragility. Photon-counting detector CT (PCD-CT) has different technical properties than conventional CT, resulting in higher resolution and thereby potentially enabling in-vivo measurement of trabecular microarchitecture. The purpose of this study was to quantify trabecular bone microarchitectural parameters with PCD-CT at varying radiation doses and compare this to µCT as gold standard., Method: Both distal radii, distal tibiae, femoral heads, and two vertebrae were dissected from one human. All specimens were scanned ex-vivo on a PCD-CT system (slice increment 0.1 mm; pixel size 0.1042-0.127 mm) and a µCT system (isotropic voxel size 49-68.4 µm). The radiation doses of the PCD-CT scans were varied from 2.5 to 120 mGy based on the volume CT dose index (CTDI vol32 ). For the PCD-CT scans, contrast-to-noise ratio and trabecular sharpness were calculated and compared between radiation doses. µCT and PCD-CT scans were registered. The trabecular bone was then segmented from all PCD-CT and µCT scans and split into cubes with 6-mm edge length. For each cube, bone volume over total volume, trabecular thickness, trabecular number, and trabecular heterogeneity were calculated and compared between corresponding PCD-CT and µCT cubes., Results: With increasing dose, contrast-to-noise ratio and trabecular sharpness values increased for the PCD-CT images. Already at the lowest dose, high correlations between the trabecular microarchitectural parameters between µCT and PCD-CT were found (R 2  = 0.55-0.95), which improved with increasing radiation dose (R 2  = 0.76-0.96 at 20 mGy)., Conclusions: PCD-CT can be used to quantify trabecular bone microarchitecture, with accuracy comparable to µCT and at clinically relevant radiation doses., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Musculoskeletal research should synergistically investigate bone and muscle to inform approaches for maintaining mobility and to avoid bone fractures. The relationship between sarcopenia and osteoporosis, integrated in the term 'osteosarcopenia', is underscored by the close association shown between these two conditions in many studies, whereby one entity emerges as a predictor of the other. In a recent workshop of Working Group (WG) 2 of the EU Cooperation in Science and Technology (COST) Action 'Genomics of MusculoSkeletal traits Translational Network' (GEMSTONE) consortium (CA18139), muscle characterization was highlighted as being important, but currently under-recognized in the musculoskeletal field. Here, we summarize the opinions of the Consortium and research questions around translational and clinical musculoskeletal research, discussing muscle phenotyping in human experimental research and in two animal models: zebrafish and mouse., Competing Interests: Declaration of interests No interests are declared., (Crown Copyright © 2024. Published by Elsevier Ltd. All rights reserved.)

Data on bone microarchitecture in osteogenesis imperfecta (OI) are scarce. The aim of this cross-sectional study was to assess bone microarchitecture and strength in a large cohort of adults with OI using high-resolution peripheral quantitative computed tomography (HR-pQCT) and to evaluate challenges of using HR-pQCT in this cohort. Second-generation HR-pQCT scans were obtained at the distal radius and tibia in 118 men and women with Sillence OI type I, III, or IV using an extremity-length-dependent scan protocol. In total, 102 radius and 105 tibia scans of sufficient quality could be obtained, of which 11 radius scans (11%) and 14 tibia scans (13%) had a deviated axial scan angle as compared with axial angle data of 13 young women. In the scans without a deviated axial angle and compared with normative HR-pQCT data, Z-scores at the radius for trabecular bone mineral density (BMD), number, and separation were -1.6 ± 1.3, -2.5 ± 1.4, and -2.7 (IQR: 2.7), respectively. They were -1.4 ± 1.5 and -1.1 ± 1.2 for stiffness and failure load and between ±1 for trabecular thickness and cortical bone parameters. Z-scores were significantly lower for total and trabecular BMD, stiffness, failure load, and cortical area and thickness at the tibia. Additionally, local microarchitectural inhomogeneities were observed, most pronounced being trabecular void volumes. In the scans with a deviated axial angle, the proportion of Z-scores <-4 or >4 was significantly higher for trabecular BMD and separation (radius) or most total and trabecular bone parameters (tibia). To conclude, especially trabecular bone microarchitecture and bone strength were impaired in adults with OI. HR-pQCT may be used without challenges in most adults with OI, but approximately 12% of the scans may have a deviated axial angle in OI due to bone deformities or scan positioning limitations. Furthermore, standard HR-pQCT parameters may not always be reliable due to microarchitectural inhomogeneities nor fully reflect all inhomogeneities., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Osteoarthritis (OA) is characterized by articular cartilage erosion, pathological subchondral bone changes, and signs of synovial inflammation and pain. We previously identified p[63-82], a bone morphogenetic protein 7 (BMP7)-derived bioactive peptide that attenuates structural cartilage degeneration in the rat medial meniscal tear-model for posttraumatic OA. This study aimed to evaluate the cartilage erosion-attenuating activity of p[63-82] in a different preclinical model for OA (anterior cruciate ligament transection-partial medial meniscectomy [anterior cruciate ligament transection (ACLT)-pMMx]). The disease-modifying action of the p[63-82] was followed-up in this model for 5 and 10 weeks., Design: Skeletally mature male Lewis rats underwent ACLT-pMMx surgery. Rats received weekly intra-articular injections with either saline or 500 ng p[63-82]. Five and 10 weeks postsurgery, rats were sacrificed, and subchondral bone characteristics were determined using microcomputed tomography (µCT). Histopathological evaluation of cartilage degradation and Osteoarthritis Research Society International (OARSI)-scoring was performed following Safranin-O/Fast Green staining. Pain-related behavior was measured by incapacitance testing and footprint analysis., Results: Histopathological evaluation at 5 and 10 weeks postsurgery showed reduced cartilage degeneration and a significantly reduced OARSI score, whereas no significant changes in subchondral bone characteristics were found in the p[63-82]-treated rats compared to the saline-treated rats. ACLT-pMMx-induced imbalance of static weightbearing capacity in the p[63-82] group was significantly improved compared to the saline-treated rats at weeks 5 postsurgery. Footprint analysis scores in the p[63-82]-treated rats demonstrated improvement at week 10 postsurgery., Conclusions: Weekly intra-articular injections of p[63-82] in the rat ACLT-pMMx posttraumatic OA model resulted in reduced degenerative cartilage changes and induced functional improvement in static weightbearing capacity during follow-up., 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: MC and TW are listed as the inventor on filed patents: WO2017178251 and WO2017178253. TW, PE, and LR have shares in Chondropeptix BV.

Osteochondral defect repair with a collagen/collagen-magnesium-hydroxyapatite (Col/Col-Mg-HAp) scaffold has demonstrated good clinical results. However, subchondral bone repair remained suboptimal, potentially leading to damage to the regenerated overlying neocartilage. This study aimed to improve the bone repair potential of this scaffold by incorporating newly developed strontium (Sr) ion enriched amorphous calcium phosphate (Sr-ACP) granules (100-150 μm). Sr concentration of Sr-ACP was determined with ICP-MS at 2.49 ± 0.04 wt%. Then 30 wt% ACP or Sr-ACP granules were integrated into the scaffold prototypes. The ACP or Sr-ACP granules were well embedded and distributed in the collagen matrix demonstrated by micro-CT and scanning electron microscopy/energy dispersive x-ray spectrometry. Good cytocompatibility of ACP/Sr-ACP granules and ACP/Sr-ACP enriched scaffolds was confirmed with in vitro cytotoxicity assays. An overall promising early tissue response and good biocompatibility of ACP and Sr-ACP enriched scaffolds were demonstrated in a subcutaneous mouse model. In a goat osteochondral defect model, significantly more bone was observed at 6 months with the treatment of Sr-ACP enriched scaffolds compared to scaffold-only, in particular in the weight-bearing femoral condyle subchondral bone defect. Overall, the incorporation of osteogenic Sr-ACP granules in Col/Col-Mg-HAp scaffolds showed to be a feasible and promising strategy to improve subchondral bone repair., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:M. Maraglino Misciagna and L. Dolcini work at Fin-Ceramica Faenza S. p.A, a company that develops, manufactures, and markets collagen/collagen-magnesium-hydroxyapatite scaffolds for orthopaedic and spinal applications., (© 2024 The Authors.)

Implant migration has been described as a minor displacement of orthodontic mini-implants (OMIs) when subjected to constant forces. Aim of this study was to evaluate the impact of local stresses on implant migration and bone remodelling around constantly loaded OMIs. Two mini-implants were placed in one caudal vertebra of 61 rats, connected by a nickel‑titanium contraction spring, and loaded with different forces (0.0, 0.5, 1.0, 1.5 N). In vivo micro-CT scans were taken immediately and 1, 2 (n = 61), 4, 6 and 8 (n = 31) weeks post-op. Nine volumes of interest (VOIs) around each implant were defined. To analyse stress values, micro-finite element models were created. Bone remodelling was analysed by calculating the bone volume change between scans performed at consecutive time points. Statistical analysis was performed using a linear mixed model and likelihood-ratio-tests, followed by Tuckey post hoc tests when indicated. The highest stresses were observed in the proximal top VOI. In all VOIs, stress values tended to reach their maximum after two weeks and decreased thereafter. Bone remodelling analysis revealed initial bone loss within the first two weeks and bone gain up to week eight, which was noted especially in the highest loading group. The magnitude of local stresses influenced bone remodelling and it can be speculated that the stress related bone resorption favoured implant migration. After a first healing phase with a high degree of bone resorption, net bone gain representing consolidation was observed., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Bert van Rietbergen is a consultant for Scanco Medical AG. All other authors declare that they have no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

(1) Background: Complex proximal humerus fractures often result in complications following surgical treatment. A better understanding of the full 3D displacement would provide insight into the fracture morphology. Repositioning of fracture elements is often conducted by using the contralateral side as a reconstruction template. However, this requires healthy contralateral anatomy. The purpose of this study was to create a Statistical Shape Model (SSM) and compare its effectiveness to the contralateral registration method for the prediction of the humeral proximal segment; (2) Methods: An SSM was created from 137 healthy humeri. A prediction for the proximal segment of the left humeri from eight healthy patients was made by combining the SSM with parameters. The predicted proximal segment was compared to the left proximal segment of the patients. Their left humerus was also compared to the contralateral (right) humerus; (3) Results: Eight modes explained 95% of the variation. Most deviations of the SSM prediction and the contralateral registration method were below the clinically relevant 2 mm distance threshold.; (4) Conclusions: An SSM combined with parameters is a suitable method to predict the proximal humeral segment when the contralateral CT scan is unavailable or the contralateral humerus is unhealthy, provided that the fracture pattern allows measurements of these parameters.

High-resolution peripheral quantitative CT (HR-pQCT) enables quantitative assessment of distal radius fracture healing. In previous studies, lower-mineralized tissue formation was observed on HR-pQCT scans, starting early during healing, but the contribution of this tissue to the stiffness of distal radius fractures is unknown. Therefore, the aim of this study was to investigate the contribution of lower-mineralized tissue to the stiffness of fractured distal radii during the first twelve weeks of healing. We did so by combining the results from two series of micro-finite element (μFE-) models obtained using different density thresholds for bone segmentation. Forty-five postmenopausal women with a conservatively-treated distal radius fracture had HR-pQCT scans of their fractured radius at baseline (BL; 1-2 weeks post-fracture), 3-4 weeks, 6-8 weeks, and 12 weeks post-fracture. Compression stiffness (S) was computed using two series of μFE-models from the scans: one series (M single ) included only higher-mineralized tissue (>320 mg HA/cm 3 ), and one series (M dual ) differentiated between lower-mineralized tissue (200-320 mg HA/cm 3 ) and higher-mineralized tissue. μFE-elements were assigned a Young's Modulus of 10 GPa (higher-mineralized tissue) or 5 GPa (lower-mineralized tissue), and an axial compression test to 1 % strain was simulated. The contribution of the lower-mineralized tissue to S was quantified as the ratio S dual /S single . Changes during healing were quantified using linear mixed effects models and expressed as estimated marginal means (EMMs) with 95 %-confidence intervals (95 %-CI). Median time to cast removal was 5.0 (IQR: 1.1) weeks. S dual and S single gradually increased during healing to a significantly higher value than BL at 12 weeks post-fracture (both p < 0.0001). In contrast, S dual /S single was significantly higher than BL at 3-4 weeks post-fracture (p = 0.0010), remained significantly higher at 6-8 weeks post-fracture (p < 0.0001), and then decreased to BL-values at the 12-week visit. EMMs ranged between 1.05 (95 %-CI: 1.04-1.06) and 1.08 (95 %-CI: 1.07-1.10). To conclude, combining stiffness results from two series of μFE-models obtained using single- and dual-threshold segmentation enables quantification of the contribution of lower-mineralized tissue to the stiffness of distal radius fractures during healing. This contribution is minor but changes significantly around the time of cast removal. Its course and timing during healing may be clinically relevant. Quantification of the contribution of lower-mineralized tissue to stiffness gives a more complete impression of strength recovery post-fracture than the evaluation of stiffness using a single series of μFE-models., Competing Interests: Declaration of competing interest B. van Rietbergen is a consultant for Scanco Medical AG. J.P. van den Bergh is a consultant for Porous GmbH. All other authors declare that they have no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The generation of subject-specific finite element models of the spine is generally a time-consuming process based on computed tomography (CT) images, where scanning exposes subjects to harmful radiation. In this study, a method is presented for the automatic generation of spine finite element models using images from a single magnetic resonance (MR) sequence. The thoracic and lumbar spine of eight adult volunteers was imaged using a 3D multi-echo-gradient-echo sagittal MR sequence. A deep-learning method was used to generate synthetic CT images from the MR images. A pre-trained deep-learning network was used for the automatic segmentation of vertebrae from the synthetic CT images. Another deep-learning network was trained for the automatic segmentation of intervertebral discs from the MR images. The automatic segmentations were validated against manual segmentations for two subjects, one with scoliosis, and another with a spine implant. A template mesh of the spine was registered to the segmentations in three steps using a Bayesian coherent point drift algorithm. First, rigid registration was applied on the complete spine. Second, non-rigid registration was used for the individual discs and vertebrae. Third, the complete spine was non-rigidly registered to the individually registered discs and vertebrae. Comparison of the automatic and manual segmentations led to dice-scores of 0.93-0.96 for all vertebrae and discs. The lowest dice-score was in the disc at the height of the implant where artifacts led to under-segmentation. The mean distance between the morphed meshes and the segmentations was below 1 mm. In conclusion, the presented method can be used to automatically generate accurate subject-specific spine models., Competing Interests: Authors PS and TV were employed by the company MRIguidance BV. The remaining 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 © 2023 Kok, Shcherbakova, Schlösser, Seevinck, van der Velden, Castelein, Ito and van Rietbergen.)

Anterior cruciate ligament (ACL) rupture is a very common knee joint injury. Torn ACLs are currently reconstructed using tendon autografts. However, half of the patients develop osteoarthritis (OA) within 10 to 14 years postoperatively. Proposedly, this is caused by altered knee kine(ma)tics originating from changes in graft mechanical properties during the in vivo remodeling response. Therefore, the main aim was to use subject-specific finite element knee models and investigate the influence of decreasing graft stiffness and/or increasing graft laxity on knee kine(ma)tics and cartilage loading. In this research, 4 subject-specific knee geometries were used, and the material properties of the ACL were altered to either match currently used grafts or mimic in vivo graft remodeling, i.e., decreasing graft stiffness and/or increasing graft laxity. The results confirm that the in vivo graft remodeling process increases the knee range of motion, up to >300 percent, and relocates the cartilage contact pressures, up to 4.3 mm. The effect of remodeling-induced graft mechanical properties on knee stability exceeded that of graft mechanical properties at the time of surgery. This indicates that altered mechanical properties of ACL grafts, caused by in vivo remodeling, can initiate the early onset of osteoarthritis, as observed in many patients clinically., 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 © 2023 Spierings, Van den Hengel, Janssen, Van Rietbergen, Ito and Foolen.)

Background: Proximal junctional failure is a common complication attributed to the rigidity of long pedicle screw fixation constructs used for surgical correction of adult spinal deformity. Semi-rigid junctional fixation achieves a gradual transition in range of motion at the ends of spinal instrumentation, which could lead to reduced junctional stresses, and ultimately reduce the incidence of proximal junctional failure. This study investigates the biomechanical effect of different semi-rigid junctional fixation techniques in a T8-L3 finite element spine segment model., Methods: First, degeneration of the intervertebral disc was successfully implemented by altering the height. Second, transverse process hooks, one- and two-level clamped tapes, and one- and two-level knotted tapes instrumented proximally to three-level pedicle screw fixation were validated against ex vivo range of motion data of a previous study. Finally, the posterior ligament complex forces and nucleus pulposus stresses were quantified., Findings: Simulated range of motions demonstrated the fidelity of the general model and modelling of semi-rigid junctional fixation techniques. All semi-rigid junctional fixation techniques reduced the posterior ligament complex forces at the junctional zone compared to pedicle screw fixation. Transverse process hooks and knotted tapes reduced nucleus pulposus stresses, whereas clamped tapes increased nucleus pulposus stresses at the junctional zone., Interpretation: The relationship between the range of motion transition and the reductions in posterior ligament complex and nucleus pulposus stresses was complex and dependent on the fixation techniques. Clinical trials are required to compare the effectiveness of semi-rigid junctional fixation techniques in terms of reducing proximal junctional failure incidence rates., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The transition in the field of bone tissue engineering from bone regeneration to in vitro models has come with the challenge of recreating a dense and anisotropic bone-like extracellular matrix (ECM). Although the mechanism by which bone ECM gains its structure is not fully understood, mechanical loading and curvature have been identified as potential contributors. Here, guided by computational simulations, we evaluated cell and bone-like tissue growth and organization in a concave channel with and without directional fluid flow stimulation. Human mesenchymal stromal cells were seeded on donut-shaped silk fibroin scaffolds and osteogenically stimulated for 42 days statically or in a flow perfusion bioreactor. After 14, 28, and 42 days, constructs were investigated for cell and tissue growth and organization. As a result, directional fluid flow was able to improve organic tissue growth but not organization. Cells tended to orient in the tangential direction of the channel, possibly attributed to its curvature. Based on our results, we suggest that organic ECM production but not anisotropy can be stimulated through the application of fluid flow. With this study, an initial attempt in three-dimensions was made to improve the resemblance of in vitro produced bone-like ECM to the physiological bone ECM., (© 2023 The Authors. Biotechnology and Bioengineering published by Wiley Periodicals LLC.)

Background: Malalignment is often postulated as an important reason for the high failure rate of total ankle replacements (TARs). The correlation between TAR malalignment and clinical outcome, however, is not fully understood. Improving and expanding radiographic TAR alignment measurements in the clinic might lead to a better insight into the correlation between malalignment and the clinical outcome. This study aims to develop and validate a tool to semi-automatic measure TAR alignment, and to improve alignment measurements on radiographs in the clinic., Methods: A tool to semi-automatically measure TAR alignment on anteroposterior and lateral radiographs was developed in MATLAB. Using the principle of edge contouring and the perpendicular relationship between the anteroposterior and lateral radiographs, the exact configuration of the TAR components can be found. Two observers validated the tool by measuring TAR alignment of ten patients using the tool. The Intraclass Coefficient (ICC) was calculated to assess the reliability of the developed method. The results obtained by the tool were compared to clinical results during radiographic follow-up in the past, and the accuracy of both methods was calculated using three-dimensional CT data., Results: The tool showed an accuracy of 76% compared to 71% for the method used during follow-up. ICC values were 0.94 (p < 0.01) and higher for both inter-and intra-observer reliability., Conclusions: The tool presents a reproducible method to measure TAR alignment parameters. Three-dimensional alignment parameters are obtained from two-dimensional radiographs, and as the tool can be applied to most TAR designs, it offers a valuable addition in the clinic and for research purposes., (© 2023. The Author(s).)

Despite promising clinical results in osteochondral defect repair, a recently developed bi-layered collagen/collagen-magnesium-hydroxyapatite scaffold has demonstrated less optimal subchondral bone repair. This study aimed to improve the bone repair potential of this scaffold by adsorbing bone morphogenetic protein 2 (BMP-2) and/or platelet-derived growth factor-BB (PDGF-BB) onto said scaffold. The in vitro release kinetics of BMP-2/PDGF-BB demonstrated that PDGF-BB was burst released from the collagen-only layer, whereas BMP-2 was largely retained in both layers. Cell ingrowth was enhanced by BMP-2/PDFG-BB in a bovine osteochondral defect ex vivo model. In an in vivo semi-orthotopic athymic mouse model, adding BMP-2 or PDGF-BB increased tissue repair after four weeks. After eight weeks, most defects were filled with bone tissue. To further investigate the promising effect of BMP-2, a caprine bilateral stifle osteochondral defect model was used where defects were created in weight-bearing femoral condyle and non-weight-bearing trochlear groove locations. After six months, the adsorption of BMP-2 resulted in significantly less bone repair compared with scaffold-only in the femoral condyle defects and a trend to more bone repair in the trochlear groove. Overall, the adsorption of BMP-2 onto a Col/Col-Mg-HAp scaffold reduced bone formation in weight-bearing osteochondral defects, but not in non-weight-bearing osteochondral defects.

Background: Conventional radiographs and clinical reassessment are considered guides in managing clinically suspected scaphoid fractures. This is a unique study as it assessed the value of conventional radiographs and clinical reassessment in a cohort of patients, all of whom underwent additional imaging, regardless of the outcome of conventional radiographs and clinical reassessment., Questions/purposes: (1) What is the diagnostic performance of conventional radiographs in patients with a clinically suspected scaphoid fracture compared with high-resolution peripheral quantitative CT (HR-pQCT)? (2) What is the diagnostic performance of clinical reassessment in patients with a clinically suspected scaphoid fracture compared with HR-pQCT? (3) What is the diagnostic performance of conventional radiographs and clinical reassessment combined compared with HR-pQCT?, Methods: Between December 2017 and October 2018, 162 patients with a clinically suspected scaphoid fracture presented to the emergency department (ED). Forty-six patients were excluded and another 25 were not willing or able to participate, which resulted in 91 included patients. All patients underwent conventional radiography in the ED and clinical reassessment 7 to 14 days later, together with CT and HR-pQCT. The diagnostic performance characteristics and accuracy of conventional radiographs and clinical reassessment were compared with those of HR-pQCT for the diagnosis of fractures since this was proven to be superior to CT scaphoid fracture detection. The cohort included 45 men and 46 women with a median (IQR) age of 52 years (29 to 67). Twenty-four patients with a median age of 44 years (35 to 65) were diagnosed with a scaphoid fracture on HR-pQCT., Results: When compared with HR-pQCT, conventional radiographs alone had a sensitivity of 67% (95% CI 45% to 84%), specificity of 85% (95% CI 74% to 93%), positive predictive value (PPV) of 62% (95% CI 46% to 75%), negative predictive value (NPV) of 88% (95% CI 80% to 93%), and a positive and negative likelihood ratio (LR) of 4.5 (95% CI 2.4 to 8.5) and 0.4 (95% CI 0.2 to 0.7), respectively. Compared with HR-pQCT, clinical reassessment alone resulted in a sensitivity of 58% (95% CI 37% to 78%), specificity of 42% (95% CI 30% to 54%), PPV of 26% (95% CI 19% to 35%), NPV of 74% (95% CI 62% to 83%), as well as a positive and negative LR of 1.0 (95% CI 0.7 to 1.5) and 1.0 (95% CI 0.6 to 1.7), respectively. Combining clinical examination with conventional radiography produced a sensitivity of 50% (95% CI 29% to 71%), specificity of 91% (95% CI 82% to 97%), PPV of 67% (95% CI 46% to 83%), NPV of 84% (95% CI 77% to 88%), as well as a positive and negative LR of 5.6 (95% CI 2.4 to 13.2) and 0.6 (95% CI 0.4 to 0.8), respectively., Conclusion: The accuracy of conventional radiographs (80% compared with HR-pQCT) and clinical reassessment (46% compared with HR-pQCT) indicate that the value of clinical reassessment is limited in diagnosing scaphoid fractures and cannot be considered directive in managing scaphoid fractures. The combination of conventional radiographs and clinical reassessment does not increase the accuracy of these diagnostic tests compared with the accuracy of conventional radiographs alone and is therefore also limited in diagnosing scaphoid fractures., Level of Evidence: Level II, diagnostic study., Competing Interests: All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request., (Copyright © 2022 by the Association of Bone and Joint Surgeons.)

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.)

Study Design: Preclinical ovine model., Objective: To assess the in vivo efficacy and safety of the P-15 L bone graft substitute and compare its performance to autologous iliac crest bone graft (ICBG) for lumbar interbody fusion indications., Methods: Thirty skeletally mature sheep underwent lumbar interbody fusion surgery. Half of the sheep received autologous ICBG and the other half the peptide enhanced bone graft substitute (P-15 L). Following termination at 1, 3, and 6 months after surgery, the operated segments were analyzed using micro computed tomography (µCT), histology, and destructive mechanical testing. Additional systemic health monitoring was performed for the P-15 L group., Results: One month after surgery, there was only minor evidence of bone remodeling and residual graft material could be clearly observed within the cage. There was active bone remodeling between 1 and 3 months after surgery. At 3 months after surgery significantly denser and stiffer bone was found in the P-15 L group, whereas at 6 months, P-15 L and ICBG gave similar fusion results. The P-15 L bone graft substitute did not have any adverse effects on systemic health., Conclusions: The drug device combination P-15 L was demonstrated to be effective and save for lumbar interbody fusion as evidenced by this ovine model. Compared to autologous ICBG, P-15 L seems to expedite bone formation and remodeling but in the longer-term fusion results were similar.

In a randomized clinical trial in patients initiating glucocorticoid therapy (GC-I) or on long-term therapy (GC-C), denosumab every 6 months increased spine and hip bone mineral density at 12 and 24 months significantly more than daily risedronate. The aim of this study was to evaluate the effects of denosumab compared with risedronate on bone strength and microarchitecture measured by high-resolution peripheral quantitative computed tomography (HR-pQCT) in GC-I and GC-C. A subset of 110 patients had high-resolution peripheral quantitative computed tomography (HR-pQCT) scans of the distal radius and tibia at baseline and at 12 and 24 months. Cortical and trabecular microarchitecture were assessed with standard analyses and failure load (FL) with micro-finite element analysis. At the radius at 24 months, FL remained unchanged with denosumab and significantly decreased with risedronate in GC-I (-4.1%, 95% confidence interval [CI] -6.4, -1.8) and, in GC-C, it significantly increased with denosumab (4.3%, 95% CI 2.1, 6.4) and remained unchanged with risedronate. Consequently, FL was significantly higher with denosumab than with risedronate in GC-I (5.6%, 95% CI 2.4, 8.7, p < 0.001) and in GC-C (4.1%, 95% CI 1.1, 7.2, p = 0.011). We also found significant differences between denosumab and risedronate in percentage changes in cortical and trabecular microarchitectural parameters in GC-I and GC-C. Similar results were found at the tibia. To conclude, this HR-pQCT study shows that denosumab is superior to risedronate in terms of preventing FL loss at the distal radius and tibia in GC-I and in increasing FL at the radius in GC-C, based on significant differences in changes in the cortical and trabecular bone compartments between treatment groups in GC-I and GC-C. These results suggest that denosumab could be a useful therapeutic option in patients initiating GC therapy or on long-term GC therapy and may contribute to treatment decisions in this patient population. © 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).)

Introduction: Malalignment of the Total Ankle Replacement (TAR) has often been postulated as the main reason for the high incidence of TAR failure. As the ankle joint has a small contact area, stresses are typically high, and malalignment may lead to non-homogeneous stress distributions, including stress peaks that may initiate failure. This study aims to elucidate the effect of TAR malalignment on the contact stresses on the bone-implant interface, thereby gaining more understanding of the potential role of malalignment in TAR failure., Methods: Finite Element (FE) models of the neutrally aligned as well as malaligned CCI (Ceramic Coated Implant) Evolution TAR implant (Van Straten Medical) were developed. The CCI components were virtually inserted in a generic three-dimensional (3D) reconstruction of the tibia and talus. The tibial and talar TAR components were placed in neutral alignment and in 5° and 10° varus, valgus, anterior and posterior malalignment. Loading conditions of the terminal stance phase of the gait cycle were applied. Peak contact pressure and shear stress at the bone-implant interface were simulated and stress distributions on the bone-implant interface were visualized., Results: In the neutral position, a peak contact pressure and shear stress of respectively 98.4 MPa and 31.9 MPa were found on the tibial bone-implant interface. For the talar bone-implant interface, this was respectively 68.2 MPa and 39.0 MPa. TAR malalignment increases peak contact pressure and shear stress on the bone-implant interface. The highest peak contact pressure of 177 MPa was found for the 10° valgus malaligned tibial component, and the highest shear stress of 98.5 MPa was found for the 10° posterior malaligned talar model. High contact stresses were mainly located at the edges of the bone-implant interface and the fixation pegs of the talar component., Conclusions: The current study demonstrates that TAR malalignment leads to increased peak stresses. High peak stresses could contribute to bone damage and subsequently reduced implant fixation, micromotion, and loosening. Further research is needed to investigate the relationship between increased contact stresses at the bone-implant interface and TAR failure., (© 2022. The Author(s).)

Background: Hyperphosphataemia is strongly associated with cardiovascular disease and mortality. Recently, phosphate binders (PBs), which are used to bind intestinal phosphate, have been shown to bind vitamin K, thereby potentially aggravating vitamin K deficiency. This vitamin K binding by PBs may offset the beneficial effects of phosphate reduction in reducing vascular calcification (VC). Here we assessed whether combining PBs with vitamin K2 supplementation inhibits VC., Methods: We performed 3/4 nephrectomy in rats, after which warfarin was given for 3 weeks to induce vitamin K deficiency. Next, animals were fed a high phosphate diet in the presence of low or high vitamin K2 and were randomized to either control or one of four different PBs for 8 weeks. The primary outcome was the amount of thoracic and abdominal aorta VC measured by high-resolution micro-computed tomography (µCT). Vitamin K status was measured by plasma MK7 levels and immunohistochemically analysed in vasculature using uncarboxylated matrix Gla protein (ucMGP) specific antibodies., Results: The combination of a high vitamin K2 diet and PB treatment significantly reduced VC as measured by µCT for both the thoracic (P = 0.026) and abdominal aorta (P = 0.023), compared with MK7 or PB treatment alone. UcMGP stain was significantly more present in the low vitamin K2-treated groups in both the thoracic (P < 0.01) and abdominal aorta (P < 0.01) as compared with high vitamin K2-treated groups. Moreover, a high vitamin K diet and PBs led to reduced vascular oxidative stress., Conclusion: In an animal model of kidney failure with vitamin K deficiency, neither PB therapy nor vitamin K2 supplementation alone prevented VC. However, the combination of high vitamin K2 with PB treatment significantly attenuated VC., (© The Author(s) 2021. Published by Oxford University Press on behalf of the ERA.)

Introduction: 3D printed trussed titanium interbody cages may deliver bone stimulating mechanobiological strains to cells attached at their surface. The exact size and distribution of these strains may depend on patient-specific factors, but the influence of these factors remains unknown. Therefore, this study aimed to determine patient-specific variations in local strain patterns on the surface of a trussed titanium interbody fusion cage. Materials and Methods: Four patients eligible for spinal fusion surgery with the same cage size were selected from a larger database. For these cases, patient-specific finite element models of the lumbar spine including the same trussed titanium cage were made. Functional dynamics of the non-operated lumbar spinal segments, as well as local cage strains and caudal endplate stresses at the operated segment, were evaluated under physiological extension/flexion movement of the lumbar spine. Results: All patient-specific models revealed physiologically realistic functional dynamics of the operated spine. In all patients, approximately 30% of the total cage surface experienced strain values relevant for preserving bone homeostasis and stimulating bone formation. Mean caudal endplate contact pressures varied up to 10 MPa. Both surface strains and endplate contact pressures varied more between loading conditions than between patients. Conclusions: This study demonstrates the applicability of patient-specific finite element models to quantify the impact of patient-specific factors such as bone density, degenerative state of the spine, and spinal curvature on interbody cage loading. In the future, the same framework might be further developed in order to establish a pipeline for interbody cage design optimizations., Competing Interests: AL reports investigator salary from 4WEB EU funded in parts by the Prosperos project, Interreg VA Flanders – In Netherlands program, CCI grant no. 2014TC16RFCB046. The remaining 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 © 2022 Loenen, Noailly, Ito, Willems, Arts and van Rietbergen.)

Background Context: Lumbar interbody fusion is an effective treatment for unstable spinal segments. However, the time needed to establish a solid bony interbody fusion between the two vertebrae may be longer than twelve months after surgery. During this time window, the instrumented spinal segment is assumed to be at increased risk for instability related complications such as cage migration or subsidence. It is hypothesized that the design of new interbody cages that enable direct osseointegration of the cage at the vertebral endplates, without requiring full bony fusion between the two vertebral endplates, might shorten the time window that the instrumented spinal segment is susceptible to failure., Purpose: To quantify the bone ingrowth and resulting segmental stability during consolidation of lumbar interbody fusion using two different cage types., Study Design: Preclinical ovine model., Methods: Seven skeletally mature sheep underwent bi-segmental lumbar interbody fusion surgery with one conventional polyether ether ketone (PEEK) cage, and one newly developed trussed titanium (TT) cage. After a postoperative time period of 13 weeks, non-destructive range of motion testing, and histologic analysis was performed. Additionally, sample specific finite element (FE) analysis was performed to predict the stability of the interbody fusion region alone., Results: Physiological movement of complete spinal motion segments did not reveal significant differences between the segments operated with PEEK and TT cages. The onset of creeping substitution within the cage seemed to be sooner for PEEK cages, which led to significantly higher bone volume over total volume (BV/TV) compared with the TT cages. TT cages showed significantly more direct bone to implant contact (BIC). Although the mean stability of the interbody fusion region alone was not statistically different between the PEEK and TT cages, the variation within the cage types illustrated an all-or-nothing response for the PEEK cages while a more gradual increase in stability was found for the TT cages., Conclusions: Spinal segments operated with conventional PEEK cages were not different from those operated with newly developed TT cages in terms of segmental stability but did show a different mechanism of bone ingrowth and attachment. Based on the differences in development of bony fusion, we hypothesize that TT cages might facilitate increased early segmental stability by direct osseointegration of the cage at the vertebral endplates without requiring complete bony bridging through the cage., Clinical Significance: Interbody cage type affects the consolidation process of spinal interbody fusion. Whether different consolidation processes of spinal interbody fusion result in clinically significant differences requires further investigation., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

A synoptic overview of scientific methods applied in bone and associated research fields across species has yet to be published. Experts from the EU Cost Action GEMSTONE ("GEnomics of MusculoSkeletal Traits translational Network") Working Group 2 present an overview of the routine techniques as well as clinical and research approaches employed to characterize bone phenotypes in humans and selected animal models (mice and zebrafish) of health and disease. The goal is consolidation of knowledge and a map for future research. This expert paper provides a comprehensive overview of state-of-the-art technologies to investigate bone properties in humans and animals - including their strengths and weaknesses. New research methodologies are outlined and future strategies are discussed to combine phenotypic with rapidly developing -omics data in order to advance musculoskeletal research and move towards "personalised medicine"., 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 © 2021 Foessl, Bassett, Bjørnerem, Busse, Calado, Chavassieux, Christou, Douni, Fiedler, Fonseca, Hassler, Högler, Kague, Karasik, Khashayar, Langdahl, Leitch, Lopes, Markozannes, McGuigan, Medina-Gomez, Ntzani, Oei, Ohlsson, Szulc, Tobias, Trajanoska, Tuzun, Valjevac, van Rietbergen, Williams, Zekic, Rivadeneira and Obermayer-Pietsch.)

Scaphoid fractures are difficult to diagnose with current imaging modalities. It is unknown whether the shape of the scaphoid bone, assessed by statistical shape modeling, can be used to differentiate between fractured and non-fractured bones. Therefore, the aim of this study was to investigate whether the presence of a scaphoid fracture is associated with shape modes of a statistical shape model (SSM). Forty-one high-resolution peripheral quantitative computed tomography (HR-pQCT) scans were available from patients with a clinically suspected scaphoid fracture of whom 15 patients had a scaphoid fracture. The scans showed no motion artefacts affecting bone shape. The scaphoid bones were semi-automatically contoured, and the contours were converted to triangular meshes. The meshes were registered, followed by principal component analysis to determine mean shape and shape modes describing shape variance. The first five out of the forty shape modes cumulatively explained 87.8% of the shape variance. Logistic regression analysis was used to study the association between shape modes and fracture presence. The regression models were used to classify the 41 scaphoid bones as fractured or non-fractured using a cut-off value that maximized the sum of sensitivity and specificity. The classification of the models was compared with fracture diagnosis on HR-pQCT. A regression model with four shape modes had an area under the ROC-curve of 72.3% and correctly classified 75.6% of the scaphoid bones (fractured: 60.0%, non-fractured: 84.6%). To conclude, fracture presence in patients with a clinically suspected scaphoid fracture appears to be associated with the shape of the scaphoid bone., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Mechanobiology research is for understanding the role of mechanics in cell physiology and pathology. It will have implications for studying bone physiology and pathology and to guide the strategy for regenerating both the structural and functional features of bone. Mechanobiological studies in vitro apply a dynamic micro-mechanical environment to cells via bioreactors. Porous scaffolds are commonly used for housing the cells in a three-dimensional (3D) culturing environment. Such scaffolds usually have different pore geometries (e.g. with different pore shapes, pore dimensions and porosities). These pore geometries can affect the internal micro-mechanical environment that the cells experience when loaded in the bioreactor. Therefore, to adjust the applied micro-mechanical environment on cells, researchers can tune either the applied load and/or the design of the scaffold pore geometries. This review will provide information on how the micro-mechanical environment (e.g. fluid-induced wall shear stress and mechanical strain) is affected by various scaffold pore geometries within different bioreactors. It shall allow researchers to estimate/quantify the micro-mechanical environment according to the already known pore geometry information, or to find a suitable pore geometry according to the desirable micro-mechanical environment to be applied. Finally, as future work, artificial intelligent - assisted techniques, which can achieve an automatic design of solid porous scaffold geometry for tuning/optimising the micro-mechanical environment are suggested., 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 © 2021 Zhao, Xiong, Ito, van Rietbergen and Hofmann.)