Patients with cancer and bone metastases can have an increased risk of fracturing their femur. Treatment is based on the impending fracture risk: patients with a high fracture risk are considered for prophylactic surgery, whereas low fracture risk patients are treated conservatively with radiotherapy to decrease pain. Current clinical guidelines suggest to determine fracture risk based on axial cortical involvement of the lesion on conventional radiographs, but that appears to be difficult. Therefore, we developed a patient-specific finite element (FE) computer model that has shown to be able to predict fracture risk in an experimental setting and in patients. The goal of this study was to determine whether patient-specific finite element (FE) computer models are better at predicting fracture risk for femoral bone metastases compared to clinical assessments based on axial cortical involvement on conventional radiographs, as described in current clinical guidelines. 45 patients (50 affected femurs) affected with predominantly lytic bone metastases who were treated with palliative radiotherapy for pain were included. CT scans were made and patients were followed for six months to determine whether or not they fractured their femur. Non-linear isotropic FE models were created with the patient-specific geometry and bone density obtained from the CT scans. Subsequently, an axial load was simulated on the models mimicking stance. Failure loads normalized for bodyweight (BW) were calculated for each femur. High and low fracture risks were determined using a failure load of 7.5 × BW as a threshold. Experienced assessors measured axial cortical involvement on conventional radiographs. Following clinical guidelines, patients with lesions larger than 30 mm were identified as having a high fracture risk. FE predictions were compared to clinical assessments by means of diagnostic accuracy values (sensitivity, specificity and positive (PPV) and negative predictive values (NPV)). Seven femurs (14%) fractured during follow-up. Median time to fracture was 8 weeks. FE models were better at predicting fracture risk in comparison to clinical assessments based on axial cortical involvement (sensitivity 100% vs. 86%, specificity 74% vs. 42%, PPV 39% vs. 19%, and NPV 100% vs. 95%, for the FE computer model vs. axial cortical involvement, respectively). We concluded that patient-specific FE computer models improve fracture risk predictions of femoral bone metastases in advanced cancer patients compared to clinical assessments based on axial cortical involvement, which is currently used in clinical guidelines. Therefore, we are initiating a pilot for clinical implementation of the FE model

Introduction. Patients (2.7M in EU) with positive cancer prognosis frequently develop metastases (≈1M) in their remaining lifetime. In 30-70% cases, metastases affect the spine, reducing the strength of the affected vertebrae. Fractures occur in ≈30% patients. Clinicians must choose between leaving the patient exposed to a high fracture risk (with dramatic consequences) and operating to stabilise the spine (exposing patients to unnecessary surgeries). Currently, surgeons rely on their sole experience. This often results in to under- or over-treatment. The standard-of-care are scoring systems (e.g. Spine Instability Neoplastic Score) based on medical images, with little consideration of the spine biomechanics, and of the structure of the vertebrae involved. Such scoring systems fail to provide clear indications in ≈60% patients. Method. The HEU-funded METASTRA project is implemented by biomechanicians, modellers, clinicians, experts in verification, validation, uncertainty quantification and certification from 15 partners across Europe. METASTRA aims to improve the stratification of patients with vertebral metastases evaluating their risk of fracture by developing dedicated reliable computational models based on Explainable Artificial Intelligence (AI) and on personalised Physiology-based biomechanical (VPH) models. Result. The METASTRA-AI model is expected to be able to stratify most patients with limited effort end cost, based on parameters extracted semi-automatically from the medical files and images. The cases which are not reliably stratified through the AI model, are examined through a more detailed and personalised biomechanical VPH model. These METASTRA numerical tools are trained through an unprecedentedly large multicentric retrospective study (2000 cases) and validated against biomechanical ex vivo experiments (120 specimens). Conclusion. The METASTRA decision support system is tested in a multicentric prospective observational study (200 patients). The METASTRA approach is expected to cut down the indeterminate diagnoses from the current 60% down to 20% of cases. METASTRA project funded by the European Union, HEU topic HLTH-2022-12-01, grant 101080135

Prophylactic treatment is advised for metastatic bone disease patients with a high risk of fracture. Clinicians face the task of identifying these patients with high fracture risk and determining the optimal surgical treatment method. Subject-specific finite element (FE) models can aid in this decision process by predicting the mechanical effect of surgical treatment. In this study, we specifically evaluated the potential of FE models to simulate femoroplasty, as uncertainty remains whether this prophylactic procedure provides sufficient mechanical strengthening to the weight-bearing femur. In eight pairs of human cadaveric femurs artificial metastatic lesions were created. In each pair, an identical defect was milled in the left and right femur. Four pairs received a spherical lesion in the neck and the other four an ellipsoidal lesion in the intertrochanteric region, each at the medial, superior/lateral, anterior and posterior side, respectively. One femur of each pair was augmented with polymethylmethacrylate (5–10 ml), while the contralateral femur was left untreated. CT scans were made at three different time points: from the unaffected intact femurs, the defect femurs with lesion and the augmented femurs. Bone strength was measured by mechanical testing until failure in eight defect and eight augmented femurs. Nonlinear CT-based FE models were developed and validated against the experimentally measured bone strength. Subsequently, the validated FE model was applied to the available CT scans for the three different cases: intact (16 scans), defect (16) and augmented (8). The FE predicted strength was compared for the three different cases. The FE models predicted the experimental bone strength with a strong correspondence, both for the defect (R. 2. = 0.97, RMSE= 0.75 kN) and the augmented femurs (R. 2. = 0.90, RMSE = 0.98 kN). Although all lesions had a “moderate” to “high” risk for fracture according to the Mirels’ scoring system (score 7 or 8), three defect femurs did not fracture through the lesion (intertrochanteric anterior, lateral and posterior), indicating that these lesions did not act as a critical weak spot. In accordance with the experimental findings, the FE models indicated almost no reduction in strength between the intact and defect state for these femurs (0.02 ± 0.1%). For the remaining “critical” lesions, bone strength was reduced with 15.7% (± 14.9%) on average. The largest reduction was observed for lesions on the medial side (up to 43.1%). For the femurs with critical lesions, augmentation increased bone strength with 29.5% (± 29.7%) as compared to the defect cases, reaching strength values that were 2.5% (± 3.7%) higher than the intact bone strength. Our findings demonstrate that FE models can accurately predict the experimental bone strength before and after augmentation, thereby enabling to quantify the mechanical benefit of femoroplasty. This way FE models could aid in identifying suitable patients for whom femoroplasty provides sufficient increase in strength. For all lesions evaluated in this study, femoroplasty effectively restored the initial bone strength. Yet, additional studies on larger datasets with a wide variation of lesion types are required to confirm these results

Background. A large proportion of the expense incurred due to hip fractures arises due to secondary factors such as duration of hospital stay and additional theatre time due to surgical complications. Studies have shown that the use of intramedullary (IM) nail fixation presents a statistically higher risk of re-fracture than plating, which has been attributed to the stress riser at the end of the nail. It is not clear, however, if this situation also applies to unstable fractures, for which plating has a higher fixation failure rate. Moreover, biomechanical studies to date have not considered newer designs of IM nails which have been specifically designed to better distribute weight-bearing loads. This aim of this experimental study was to evaluate the re-fracture risk produced by a newer type of nailing system compared to an equivalent plate. Methods. Experimental testing was conducted using fourth generation Sawbones composite femurs and X-Bolt IM hip nail (n=4) and fracture plate (n=4) implants. An unstable pertrochanteric fracture pattern was used (AO classification: 31-A1 / 31-A2). Loading was applied along the peak loading vector experienced during walking, up to a maximum load of 500N. The risk of re-fracture was evaluated from equivalent strains measured using four rosette strain gauges on the surface of the bone at known stress riser locations. Results. Strain gauge readings determined that the equivalent strains in the femoral diaphysis were approximately 25% larger for the nail than the plate (p < 0.005). The strain levels at the location coinciding with the end of the plate were also larger for the nail, but not significantly (p > 0.26). Conclusions. Although the risk of re-fracture for displaced tronchantaric fractures was found to be larger for nailing than plating, measured strains were substantially lower than the failure strain of cortical bone (even when scaled for full weight-bearing loads of 1800N). This indicates that fracture risk is not present in either implant for bone of healthy quality, but may still become problematic in highly osteoporotic patients. Level of Evidence. IIb - Evidence from at least one well designed experimental trial

There is an established link between bone quality and fracture risk. It has been suggested that reduced bone quality will also reduce the toughening mechanisms displayed during loading at a high strain rate. We hypothesised that partially decalcified bone will not demonstrate an increase in force required to cause failure when comparing low and high strain rate loading. Mechanical properties were defined by the maximum force at failure. Bone quality was defined by the mineral content. This was altered by subjecting the bones to ultrasonically assisted decalcification in 10M EDTA to achieve an average 18% mineral reduction (A 70 yr old woman has approx 18% of her peak bone mass). 20 pairs of sheep femurs were harvested and split into four equal groups: normal bone quality, fast strain rate (NF); normal bone quality, slow strain rate (NS); low bone quality, fast strain rate (LF) and low bone quality, slow strain rate (LS). All mechanical testing was carried out by means of 3-point bending. Load representing the slow strain rate was applied by a mechanical testing machine (Zwick) at a rate resulting in a deflection of 1mm/s. The dynamic loading was applied by a custom designed pneumatic ram at a mean rate of deflection between the specimens of 2983 mm/s (±SD 1155), this equates to strain rates experienced in a road traffic accident. The following results for force at failure were found (mean ± SD). NF: Force 5503N (± 1012); NS: Force 3969N (± 572); LF: Force 3485N (± 772); LS: Force 3165N (± 605). Groups were compared using a Mann-Whitney U test. Significant results were found between the following groups: Normal bone quality, strain rate compared (NF-NS) p<0.002; Fast strain rate, bone quality compared (NF-LF) p=0.008; Slow strain rate, bone quality compared (NS-LS) p=0.02. No statistical significance was found when comparing low bone quality, strain rate compared (LF-LS) p=0.47. These results show that normal healthy bone has an ability to withstand higher strain rates which protects it against fracture. This ability to withstand high strain rates is lost in decalcified bone making it more susceptible to fracture. The results of this study indicate the importance of strain rate reduction as well as energy absorption in the design of hip protectors and in environmental modifications

Introduction. With an ageing population comes an increased prevalence of osteoporosis and associated fracture. Whilst treatment of the condition following such a fracture is partially effective, primary prevention through screening and appropriate follow-up is the ideal. In order to assess a population's risk of fracture, paper questionnaires would traditionally have to be sent, however this is an wasteful and costly. A more efficient method may be to have patients assess their own FRAX score through a modified computer application. Aim. To investigate the feasibility of patients self-reporting their FRAX score from the use of a touch screen application. Methods. A patient-friendly application based on the FRAX questionnaire was developed for use on iPad. This was then trialled on inpatients and outpatients at the RNOH, Stanmore and at 2 GP's surgeries. A paper questionnaire then was used to assess ease of use of the application. Results. 314 patients completed the iPad application with 68 patients over 55 completing the paper questionnaire. The mean useability score was 2.6 (1-easy, 10-hard). 75% of respondents preferred using a touch screen application than paper or phone surveys and 83% stated they would use the touch screen if it was offered in GP surgeries. Discussion and Conclusion. Touch screen applications are readily used to self-report fracture risk by the majority of the over 55 population. Applications such as these have the potential to collect large amounts of data quickly and cheaply, as well as engaging patients in becoming aware of the risks of osteoporosis

Total Hip Replacement (THR) is one of the most successful operations in all of medicine, however surgeons just rely on their experience and expertise when choosing between cemented or cementless stem, without having any quantitative guidelines. The aim of this project is to provide clinicians with some tools to support in their decision making. A novel method based on bone mineral density (BMD) measurements and assessments was developed 1) to estimate the periprosthetic fracture risk (FR) while press-fitting cementless stem; 2) to evaluate post-operative bone remodeling in terms of BMD changes after primary THR. Data for 5 out of over 70 patients (already involved in a previous study. 1. ) that underwent primary THA in Iceland were selected for developing novel methods to assess intra-operative FR and bone mineral density (BMD) changes after the operation. For each patient three CT images were acquired (Philips Brilliance 64 Spiral-CT, 120 kVp, slice thickness: 1 mm, slice increment: 0.5 mm): pre-op, 24 hours and 1 year post-operative. Pre-op CT scan was used to create 3D finite element model (Materialise Mimics) of the proximal femur. The material properties were assigned based on Hounsfield Units. Different strategies were analyzed for simulating the press-fitting operation, developing what has already been done in prior study. 1. In the finite element simulation (Ansys Workbench), a pressure (related to the implant hammering force of 9.25 kN. 2. ) was applied around the femur's hollow for the stem and the distribution of maximum principal elastic strain over the bone was calculated. Assuming a critical failure value. 3. of 7300 με, the percentage of fractured elements was calculated (i.e. FR). Post 24 hours and Post 1 year CT images were co-registrated and compared (Materialise Mimics) in order to assess BMD changes. Successively, volumes of bone lost and bone gained were calculated and represented in a 3D model. Age and gender should not be taken as unique indicators to choose between implants typologies, since also three dimensional BMD distribution along with volume of cortical bone influence the risk of periprosthetic fractures. Highest FR values were experienced in the calcar-femorale zone and in similar location on the posterior side. BMD loss volume fractions after 1 year were usually higher than BMD gain ones. Consistently with prior studies. 4. , BMD loss was mainly concentrated around the proximal end (lesser trochanter area, outer bone). If present, BMD gain occurred at the distal end (below stem's tip) or proximally (lesser trochanter area, interface contact with the stem). The use of clinical data for BMD assessments serves as an important tool to develop a quantitative method which will support surgeons in their decisions, guiding them to the optimal implant for the patient. Knowing the risk of fracture if choosing a cementless stem and being aware of how the bone will remodel around the stem in one year's time can eventually lead to reduction in revisions and increased quality of life for the patient. Further work will target analysis of a larger cohort of patients and validate FE models

Objectives

This study aims to assess the correlation of CT-based structural rigidity analysis with mechanically determined axial rigidity in normal and metabolically diseased rat bone.

Type-2 Diabetic (T2D) patients experience up to a 3-fold increase in bone fracture risk[1]. Paradoxically, T2D-patients have a normal or increased bone mineral density when compared to non-diabetic patients. This implies that T2D has a deleterious effect on bone quality, whereby the intrinsic material properties of the bone matrix are altered. Creating clinical challenges as current diagnostic techniques are unable to accurately predict the fracture probability in T2D-patients. To date, the relationship between cyclic fatigue loading, mechanical properties and microdamage accumulation of T2D-bone tissue has not yet been examined and thus our objective is to investigate this relationship. Ethically approved femoral heads were obtained from patients, with (n=8) and without (n=8) T2D. To obtain the mechanical properties of the sample, one core underwent a monotonic compression test to 10% strain, the other core underwent a cyclic compression test at a normalized stress ratio between 0.0035mm/mm and 0.016mm/mm to a maximum strain of 3%. Microdamage was evaluated by staining the tissue with barium sulfate precipitate [2] and conducting microcomputed tomography scanning with a voxel size of 10μm. The monotonically tested T2D-group showed no statistical difference in mechanical properties to the non-T2D-group, even when normalised against BV/TV. There was also no difference in BV/TV. For the cyclic test, the T2D-group had a significantly higher initial modulus (p<0.01) and final modulus (p<0.05). There was no difference in microdamage accumulation. Previous population-level studies have found that T2D-patients have been shown to have an increased fracture risk when compared to non-T2D-patients. This research indicates that T2D does not impair the mechanical properties of trabecular bone from the femoral heads of T2D-patients, suggesting that other mechanisms may be responsible for the increased fracture risk seen in T2D-patients

Osteoporosis is a worldwide disease resulting in the increase of bone fragility and enhanced fracture risk in adults. In the context of osteoporotic fractures, bone tissue engineering (BTE), i.e., the use of bone substitutes combining biomaterials, cells, and bone inducers, is a potential alternative to conventional treatments. Pre-clinical testing of innovative scaffolds relies on in vitro systems where the simultaneous presence of osteoblasts (OBs) and osteoclasts (OCs) is required to mimic their crosstalk and molecular cooperation for bone remodelling. To this aim, two composite materials based on type I collagen were developed, containing either strontium-enriched mesoporous bioactive glasses or rod-like hydroxyapatite nanoparticles. Following chemical crosslinking with genipin, the nanostructured materials were tested for 2–3 weeks with an indirect co-culture of human trabecular bone-derived OBs and buffy coat-derived OC precursors. The favourable structural and biological properties of the materials proved to successfully support the viability, adhesion, and differentiation of bone cells, encouraging a further investigation of the two bioactive systems as biomaterial inks for the 3D printing of more complex scaffolds for BTE

Stimulation of the mechanosensitive ion channel, Piezo1 promotes bone anabolism and SNPs in the Piezo1 locus are associated with changes in fracture risk. Osteocytes function as critical regulators of bone homeostasis by sensing mechanical signals. The current study used a human, cell-based physiological, 3D in vitro model of bone to determine whether loading of osteocytes in vitro results in upregulation of the Piezo1 pathway. Human Y201 MSCs, embedded in type I collagen gels and differentiated to osteocytes for 7-days, were subjected to pathophysiological load (5000 µstrain, 10Hz, 5 mins; n=6) with unloaded cells as controls (n=4). RNA was extracted 1-hr post load and assessed by RNAseq analysis. To mimic mechanical load and activate Piezo1, cells were differentiated to osteocytes for 13 days and treated ± Yoda1 (5µM, 2- and 24-hs, n=4); vehicle treated cells served as controls (n=4). RNA was subjected to RT-qPCR and data normalised to the housekeeping gene, YWHAZ. Media was analysed for IL6 release by ELISA. Mechanical load upregulated Piezo1 gene expression (16.5-fold, p<0.001) and expression of the transcription factor NFATc1, and matricellular protein CYR61, known regulators of Piezo1 mechanotransduction (3-fold; p= 5.0E-5 and 6.8-fold; p= 6.0E-5, respectively). After 2-hrs, Yoda1 increased the expression of the early mechanical response gene, cFOS (11-fold; p=0.021), mean Piezo1 expression (2.3-fold) and IL-6 expression (103-fold, p<0.001). Yoda1 increased the release of IL6 protein after 24 hours (7.5-fold, p=0.001). This study confirms Piezo1 as an important mechanosensor in osteocytes. Piezo1 activation mediated an increase in IL6, a cytokine that drives inflammation and bone resorption providing a direct link between mechanical activation of Piezo1, bone remodeling and inflammation, which may contribute to mechanically induced joint degeneration in diseases such as osteoarthritis. Mechanistically, we hypothesize this may occur through promoting Ca2+ influx and activation of the NFATc1 signaling pathway

Bone turnover and microdamage are impacted by skeletal metastases which can contribute to increased fracture risk. Treatments for metastatic disease may further impact bone quality. This study aimed to establish an understanding of microdamage accumulation and load to failure in healthy and osteolytic vertebrae following cancer treatment (stereotactic body radiotherapy (SBRT), zoledronic acid (ZA), or docetaxel (DTX)). Forty-two 6-week old athymic female rats (Hsd:RH-Foxn1rnu, Envigo) were studied; 22 were inoculated with HeLa cervical cancer cells through intracardiac injection (day 0). Animals were randomly assigned to four groups: untreated (healthy=5, osteolytic=6), SBRT on day 14 (healthy=6, osteolytic=6), ZA on day 7 (healthy=4, osteolytic=5), and DTX on day 14 (healthy=5, osteolytic=5). Animals were euthanized on day 21. L1-L3 motion segments were compression loaded to failure and force-displacement data recorded. T13 vertebrae were stained with BaSO. 4. and µCT imaged (90kVp, 44uA, 4.9µm) to visualize microdamage location and volume. Damage volume fraction (DV/BV) was calculated as the ratio of BaSO. 4. to bone volume. Differences in mean load-to-failure were compared using three-way ANOVA (disease status, treatment, cells injected). Differences in mean DV/BV between treatment groups were compared using one-way ANOVA. Treatment had a significant effect on load-to-failure (p=0.004) with ZA strengthening the healthy and osteolytic vertebrae. Reduced strength post SBRT seen in the metastatic (but not the healthy) group may be explained by greater tumor involvement secondary to higher cell injection concentrations. Untreated metastatic samples had higher DV/BV (16.25±2.54%) compared to all treatment groups (p<0.05) suggesting a benefit of treatment to bone quality. Focal and systemic cancer treatments were shown to effect load-to-failure and microdamage accumulation in healthy and osteolytic vertebrae. Developing a better understanding of how treatments effect bone quality and mechanical stability is critical for effective management of patients with spinal metastases

Osteoporosis is a common disorder characterized by low bone mass and reduced bone quality that affects the bone strength negatively and leads to increased risk of fracture. Bone mineral density (BMD) has been the standard instrument for the diagnosis of osteoporosis and the determination of fracture risk. Despite the approximation of the bone mass, BMD does not provide information about the bone structure. Trabecular bone score (TBS), which provides an indirect evaluation of skeletal microarchitecture, is calculated from dual X-ray absorptiometry and a simple and noninvasive method that may contribute to the prediction of osteoporotic fractures in addition to the measure of bone density. The goal of this study was to determine the mean TBS values in healthy postmenopausal women and the overall association between TBS and demographic features, bone mineral density of the lumbar spine and femoral neck and bone mineral density to body mass index ratio (BMD/BMI) of the lumbar spine. Fifty-three postmenopausal healthy women participated. The bone mineral density of the lumbar spine and femoral neck were measured dual X-ray absorptiometry. Anteroposterior lumbar spine acquisitions were used to calculate TBS for L1-L4. Age, height, weight, BMI and the ratio of BMD to BMI, which was considered to be a simple tool for assessing fracture risk in especially obese individuals, were calculated. The relationship between TBS and other variables was examined using Spearman's rank correlation coefficients. Mean BMD of the lumbar spine and the femoral neck were 0.945 ± 0.133 and 0.785 ± 0.112 g/cm2, respectively (Table 1). Mean TBS was 1.354 ± 0.107. There was a significant positive moderate correlation between TBS and total lumbar BMD/BMI ratio (r=0.595, pTBS values of postmenopausal women were negatively correlated with age and BMI and positively with bone mineral density and BMD/BMI ratio. The ratio between lumbar BMD and BMI presented a stronger correlation with TBS than that of BMD with TBS. Because of the better correlation, the BMD/BMI ratio may be used as a simple tool for the assessment of the risk of fractures. Further investigation may be needed to evaluate the factors influencing exercise intervention on TBS on this population of patients

Introduction and Objective. Type 2 diabetes mellitus (T2DM), and the often concurrent obesity, causes metabolic changes that affect many organs and tissues, including bone. Despite a normal or even higher bone mineral density (BMD), T2DM has often been associated with a higher fracture risk, indicating a compromised bone quality. In this work, we use a novel congenic leptin receptor-deficient BioBreeding Diabetes Resistant rat (BBDR.cg.lepr.cp) to investigate the impact of T2DM and obesity on bone morphology and architecture at the microscale. Materials and Methods. Two different anatomical locations, i.e., femur and cranium, were studied combining micro-computed X-ray tomography (micro-CT) with scanning electron microscopy (SEM). Micro-CT data were examined using advanced image analysis tools in three-dimensions (3D). Results. Both parietal bones and femurs were smaller, i.e., thinner and shorter, respectively, in diabetic animals compared to healthy controls. Image analysis of the sagittal suture revealed a reduced suture width and length in diabetic animals, suggesting an altered bone apposition rate. Histomorphometry analysis from micro-CT data highlighted differences in microstructure of both trabecular and cortical femur between diabetic and healthy rats. In particular, bone volume fraction (BV/TV) was lower in the T2DM group, while trabecular spacing (Tb.Sp) was increased, overall indicating a higher porosity in diabetic trabecular bone. SEM revealed the presence of extended portions of hyper-mineralized cartilage in the distal femur of the diabetic animals. Conclusions. Micro-CT analyses, combined with SEM imaging, suggest that T2DM impacts bone growth and remodelling, in turn leading to differences in the structural organization at the microscale

Fragility fractures are skeletal complications associated with type 2 diabetes (T2D) causing disability, hospitalization, impaired quality of life, and increased mortality. Increased circulating sclerostin and accumulation of advanced glycation end-products (AGEs) are two potential mechanisms underlying low bone turnover and increased fracture risk. We have recently shown that T2D affects the expression of genes controlling bone formation (SOST and RUNX2) and that accumulation of AGEs is associated with impaired bone formation in T2D. We hypothesized that Wnt/B- catenin target genes are down-regulated in bone of T2D subjects as a consequence of decreased SOST and AGEs accumulation. To this end, we studied gene expression in extracts of bone samples obtained from femoral heads of 14 subjects with relatively well-controlled T2D (HbA1c 6.5±1.7%) and 21 control, non-diabetic postmenopausal women (age >65 years) undergoing hip replacement. There were no differences in age (73.2± .8 vs. 75.2±8.5 years) or BMI (27.7±5.6 vs. 29.9±5.4 kg/m2) between control and T2D groups, respectively. Expression of LEF1 mRNA was significantly lower in T2D compared to non-diabetic subjects (p=0.002), while DKK1 was not different between groups (p=0.108). Correlation analysis showed that DKK1 (r2=0.038; p=0.043) and HbA1c (r2=0.503; p=0.048) increased with age in T2D. COL1A1 mRNA trended lower in T2D compared to controls (p=0.056). Bone volume (9,333 ± 1,443 vs. 15,53 ± 2,442 mm2; p=0.048), mineralized volume (9,278 ± 1,418 vs. 15,45 ± 2,444 mm. 2. ; p=0.048) and BV/TV (0,2125 ± 0,03114 vs. 0,3719 ± 0,03196 %; p=0.002) measured by bone histomorphometry were lower in T2D compared to controls. Our data show that even in patients with relatively good glycemic control, T2D decreases expression of Wnt/B-catenin target genes andCOL1A1, associated with decreased bone density. These results may help understand the mechanisms underlying bone fragility in T2D

Abstract. Objectives. Osteoporosis of the pelvis and femur is diagnosed in a high proportion of lower-limb amputees which carries an increased fracture risk and subsequently serious implications on mobility, physical dependency and morbidity. Through the development of biofidelic musculoskeletal and finite element (FE) models, we aim to determine the effect of lower-limb amputation on long-term bone remodelling in the hip and to understand the potential underpinning mechanisms for bone degradation in the younger amputee population. Methods. Our models are patient specific and anatomically accurate. Geometries are derived from MRI-scans of one bilateral, above-knee, amputee and one body-matched control subject. Musculoskeletal modelling enables comparison of muscle and joint reaction-forces throughout gait. This provides the loading scenario implemented in FE. FE modelling demonstrates the effect of loading on the amputated limb via a prosthetic socket by comparing bone mechanical stimulation in amputee and control cases. Results. Musculoskeletal modelling shows that the bilateral amputee has 25% higher peak hip-reaction force than controls but a 54% lower peak knee-reaction force. Compensation for missing muscles and joints cause large-scale changes to the muscle loading patterns of the residual limb. FE analysis shows a 32% reduction in bone stimulation within the proximal femur and an 81% reduction in the distal femoral shaft when compared to the healthy control. A shielding effect from weight-bearing through a prosthetic socket was observed that may offset any increases in joint and muscle loading at the amputated hip. Conclusions. Bone loss in the young amputee population could be driven by unloading osteopenia where altered joint and muscle loads cause altered mechanical stimulus in the femur. Over many cycles of remodelling, a net bone loss occurs. Importantly, this suggests that the issue is preventable, or even reversible, with the implementation of targeted loading regimes or changes to the design of the prosthetic socket. Declaration of Interest. (b) declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported:I declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project

Patients with advanced cancer can develop bone metastases in the femur which are often painful and increase the risk of pathological fracture. Accurate segmentation of bone metastases is, amongst others, important to improve patient-specific computer models which calculate fracture risk, and for radiotherapy planning to determine exact radiation fields. Deep learning algorithms have shown to be promising to improve segmentation accuracy for metastatic lesions, but require reliable segmentations as training input. The aim of this study was to investigate the inter- and intra-operator reliability of manual segmentation of femoral metastatic lesions and to define a set of lesions which can serve as a training dataset for deep learning algorithms. F. CT-scans of 60 advanced cancer patients with a femur affected with bone metastases (20 osteolytic, 20 osteoblastic and 20 mixed) were used in this study. Two operators were trained by an experienced radiologist and then segmented the metastatic lesions in all femurs twice with a four-week time interval. 3D and 2D Dice coefficients (DCs) were calculated to quantify the inter- and intra-operator reliability of the segmentations. We defined a DC>0.7 as good reliability, in line with a statistical image segmentation study. Mean first and second inter-operator 3D-DCs were 0.54 (±0.28) and 0.50 (±0.32), respectively. Mean intra-operator I and II 3D-DCs were 0.56 (±0.28) and 0.71 (±0.23), respectively. Larger lesions (>60 cm. 3. ) scored higher DCs in comparison with smaller lesions. This study reveals that manual segmentation of metastatic lesions is challenging and that the current manual segmentation approach resulted in dissatisfying outcomes, particularly for lesions with small volumes. However, segmentation of larger lesions resulted in a good inter- and intra-operator reliability. In addition, we were able to select 521 slices with good segmentation reliability that can be used to create a training dataset for deep learning algorithms. By using deep learning algorithms, we aim for more accurate automated lesion segmentations which might be used in computer modelling and radiotherapy planning

The ideal treatment method regarding various defect sizes after local aggressive tumor resection is unknown. We investigated the biomechanical properties of metaphyseal defect filling regarding different defect sizes and fixation methods. Ninety-one sheep tibias were divided into five groups as 21 tibias per four study groups and 7 tibias in the control group. Study groups were further divided into three subgroups according to 25%, 50% and 75% metaphyseal defect size. Control group tibias were left intact. In study group 1, a metaphyseal defect was created and no further process was applied. Metaphyseal defects were filled with cement without fixation in group 2. Cement filling and fixation with 2 screws were performed in group 3. In addition to cement filling, plate-screw fixation was performed in group 4. Axial loading test was applied to all tibias and the results were compared between study subgroups and control group. Plate-screw fixation was found to have the best biomechanical properties in all defect sizes. Load to failure for screw fixation was found to be significantly decreased between 25% and 50% defect size (P<0.05). However, load to failure for isolated cement filling was not affected from defect size (p>0.05). In conclusion, size of the defect predicts the fixation method in addition to filling with cement. Filling with cement in metaphyseal defects was found to be biomechanically insufficient. In addition to filling with cement, additional screw fixation in less than 25% defects and plate-screw fixation in more than 25% defects may decrease tibial plateau fracture or metaphyseal fracture risk after local aggressive tumor resection

Worldwide, osteoporosis, causes more than 8.9 million fractures annually, resulting in an osteoporotic fracture every 3 seconds, where 1 in every 3 women and 1 in every 5 men aged over 50 will experience osteoporotic fractures at least once in their lifetime. Vertebral fractures, estimated at 1.4 million/year are among the most common fractures, posing enormous health and socioeconomic challenges to the individual and society at large. Considering that the great majority of individuals at high risk (up to 80%), who have already had at least one osteoporotic fracture, are neither identified nor treated, prediction of the risk factors for vertebral fractures can be of great value for prevention/early diagnosis. Recent studies show that finite element analysis of computed tomography (CT) scans provides noninvasive means to assess fracture risk and has the potential to be clinically implemented upon proper validation. The objective of this study was to develop a voxel-based finite element model using quantitative computed tomography (QCT) images in conjunction with in-vitro experiments to evaluate the strength of the vertebral bodies and predict the fracture risk criteria. A total of 10 vertebrae were dissected from juvenile sheep lumbar spines. The attached soft tissues and posterior elements and facet joints were completely removed, and the upper and lower vertebral bodies were polished using glass paper to provide smooth surfaces. The specimens were wrapped in phosphate buffer saline (PBS) soaked gauze, sealed in plastic bags, and stored in a refrigerator at −22°C. QCT scans of the specimens were captured using a bone density calibration phantom (QRM Co., Moehrendorf, Germany) with three 18 mm cylindrical inserts, providing 0, 100 and 200 mg HA/ccm, respectively. All the specimens, preserved hydrated in PBS solution, were mechanically tested at room temperature using a mechanical testing apparatus (Zwick/Roell, Ulm-Germany). The QCT images were then used to reconstruct the voxel-based FE model employing a custom-developed heterogeneous material mapping code. Five different equations for the correlation of the density and the elastic modulus were used to validate the efficiency of the FE model as compared to the in-vitro experiments. The results of the voxel-based FE models matched well with the in-vitro experiments, with an average error of 11.38 (±4.09)% based on the power law equation. A failure criterion was embedded in the FE models and the initiation of fracture was successfully predicted for all specimens. Further, typical kyphoplasty treatment was simulated in the 5 models to evaluate the application of the validated algorithm in the estimation of the failure patterns. Our novel voxel-based FE model can be used in future studies to predict the outcome of different types of therapeutic modalities/surgeries and estimate fracture risk including postoperative fractures

Biomechanical analysis is important to evaluate the effect of orthopaedic surgeries. CT-image based finite element method (CT-FEM) is one of the most important techniques in the computational biomechanics field. We have been applied CT-FEM to evaluate resorptive bone remodeling, secondary to stress shielding, after total hip arthroplasty (THA). We compared the equivalent stress and strain energy density to postoperative BMD (bone mineral density) change in the femur after THA, and a significant correlation was observed between the rate of changes in BMD after THA and equivalent stress. For periacetabular osteotomy cases, we investigated mechanical stress in the hip joint before and after surgery. Mechanical stress in the hip joint decreased significantly after osteotomy and correlated with the degree of the acetabular coverage. For arthroscopic osteochondroplasty cases, we examined mechanical strength of the proximal femur after cam resection using CT-FEM. The results suggested that both the depth and area of the resection at the distal part of femoral head-neck junction correlated strongly with fracture risk after osteochondroplasty. This talk consists of our results of clinical application studies using CT-FEM, and importance of application of CT-FEM to biomechanical studies to assess the effect of orthopaedic surgeries