Evaluation of bone density and microarchitecture in adult patients with X-linked hypophosphatemic rickets: A pilot longitudinal study.

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.

The BMP7-Derived Peptide p[63-82] Reduces Cartilage Degeneration in the Rat ACLT-pMMx Model for Posttraumatic Osteoarthritis.

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.

Incorporating strontium enriched amorphous calcium phosphate granules in collagen/collagen-magnesium-hydroxyapatite osteochondral scaffolds improves subchondral bone repair.

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.

Prediction of the Proximal Humerus Morphology Based on a Statistical Shape Model with Two Parameters: Comparison to Contralateral Registration Method.

(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.

Micro finite element analysis of continuously loaded mini-implants - A micro-CT study in the rat tail model.

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 nickel­titanium 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.

Automatic generation of subject-specific finite element models of the spine from magnetic resonance images.

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.

Knee instability caused by altered graft mechanical properties after anterior cruciate ligament reconstruction: the early onset of osteoarthritis?

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.

Biomechanical evaluation of different semi-rigid junctional fixation techniques using finite element analysis.

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.

The contribution of lower-mineralized tissue to the healing of distal radius fractures assessed using HR-pQCT.

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 (Msingle) included only higher-mineralized tissue (>320 mg HA/cm3), and one series (Mdual) differentiated between lower-mineralized tissue (200-320 mg HA/cm3) 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 Sdual/Ssingle. 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. Sdual and Ssingle gradually increased during healing to a significantly higher value than BL at 12 weeks post-fracture (both p < 0.0001). In contrast, Sdual/Ssingle 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.

Development and validation of a clinical tool to semi-automatic measure three-dimensional TAR alignment on two-dimensional radiographs.

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.

Characterization of three-dimensional bone-like tissue growth and organization under influence of directional fluid flow.

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.

Effectiveness of BMP-2 and PDGF-BB Adsorption onto a Collagen/Collagen-Magnesium-Hydroxyapatite Scaffold in Weight-Bearing and Non-Weight-Bearing Osteochondral Defect Bone Repair: In Vitro, Ex Vivo and In Vivo Evaluation.

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.

What Is the Diagnostic Performance of Conventional Radiographs and Clinical Reassessment Compared With HR-pQCT Scaphoid Fracture Diagnosis?

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.

Open-source image analysis tool for the identification and quantification of cortical interruptions and bone erosions in high-resolution peripheral quantitative computed tomography images of patients with rheumatoid arthritis.

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 (r2 = 0.85) and XtremeCTII (r2 = 0.87). Erosion volume assessment by BAM-Erosion agreed strongly (r2 = 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.

Malalignment of the total ankle replacement increases peak contact stresses on the bone-implant interface: a finite element analysis.

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.

Effect of Denosumab Compared With Risedronate on Bone Strength in Patients Initiating or Continuing Glucocorticoid Treatment.

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).

Peptide Enhanced Bone Graft Substitute Presents Improved Short-Term Increase in Bone Volume and Construct Stiffness Compared to Iliac Crest Autologous Bone in an Ovine Lumbar Interbody Fusion Model.

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.

Early bone ingrowth and segmental stability of a trussed titanium cage versus a polyether ether ketone cage in an ovine lumbar interbody fusion model.

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.

Combining phosphate binder therapy with vitamin K2 inhibits vascular calcification in an experimental animal model of kidney failure.

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.

Bone Phenotyping Approaches in Human, Mice and Zebrafish - Expert Overview of the EU Cost Action GEMSTONE ("GEnomics of MusculoSkeletal traits TranslatiOnal NEtwork").

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".