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Introduction: Metastases increase the risk of fracture when affecting the femur. Consequently, clinicians need to know if the patient's femur can withstand the stress of daily activities. The current tools used in clinics are not sufficiently precise. A new method, the CT-scan-based finite element analysis, gives good predictive results. However, none of the existing models were tested for reproducibility. This is a critical issue to address in order to apply the technique on a large cohort around the world to help evaluate bone metastatic fracture risk in patients. The aim of this study is then to evaluate 1) the reproducibility 2) the transposition of the reproduced model to another dataset and 3) the global sensitivity of one of the most promising models of the literature (original model)., Methods: The model was reproduced based on the paper describing it and discussion with authors to avoid reproduction errors. The reproducibility was evaluated by comparing the results given in the original model by the original first team (Leuven, Belgium) and the reproduced model made by another team (Lyon, France) on the same dataset of CT-scans of ex vivo femurs. The transposition of the model was evaluated by comparing the results of the reproduced model on two different datasets. The global sensitivity analysis was done by using the Morris method and evaluates the influence of the density calibration coefficient, the segmentation, the orientations and the length of the femur., Results: The original and reproduced models are highly correlated (r 2  = 0.95), even though the reproduced model gives systematically higher failure loads. When using the reproduced model on another dataset, predictions are less accurate (r 2 with the experimental failure load decreases, errors increase). The global sensitivity analysis showed high influence of the density calibration coefficient (mean variation of failure load of 84 %) and non-negligible influence of the segmentation, orientation and length of the femur (mean variation of failure load between 7 and 10 %)., Conclusion: This study showed that, although being validated, the reproduced model underperformed when using another dataset. The difference in performance depending on the dataset is commonly the cause of overfitting when creating the model. However, the dataset used in the original paper (Sas et al., 2020a) and the Leuven's dataset gave similar performance, which indicates a lesser probability for the overfitting cause. Also, the model is highly sensitive to density parameters and automation of measurement may minimize the uncertainty on failure load. An uncertainty propagation analysis would give the actual precision of such model and improve our understanding of its behavior and is part of future work., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Marc GARDEGARONT reports financial support was provided by LabEx PRIMES. Marc GARDEGARONT reports financial support was provided by MSD Avenir. If there are other authors, they 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 Authors. Published by Elsevier Ltd.. All rights reserved.)

As far as their mechanical properties are concerned, cancerous lesions can be confused with healthy surrounding tissues in elastography protocols if only the magnitude of moduli is considered. We show that the frequency dependence of the tissue's mechanical properties allows for discriminating the tumor from other tissues, obtaining a good contrast even when healthy and tumor tissues have shear moduli of comparable magnitude. We measured the shear modulus G * (ω) of xenograft subcutaneous tumors developed in mice using breast human cancer cells, compared with that of fat, skin and muscle harvested from the same mice. As the absolute shear modulus |G * (ω)| of tumors increases by 42% (from 5.2 to 7.4 kPa) between 0.25 and 63 Hz, it varies over the same frequency range by 77% (from 0.53 to 0.94 kPa) for the fat, by 103% (from 3.4 to 6.9 kPa) for the skin and by 120% (from 4.4 to 9.7 kPa) for the muscle. These measurements fit well to the fractional model G * (ω)=K(iω) n , yielding a coefficient K and a power-law exponent n for each sample. Tumor, skin and muscle have comparable K parameter values, that of fat being significantly lower; the p-values given by a Mann-Whitney test are above 0.14 when comparing tumor, skin and muscle between themselves, but below 0.001 when comparing fat with tumor, skin or muscle. With regards the n parameter, tumor and fat are comparable, with p-values above 0.43, whereas tumor differs from both skin and muscle, with p-values below 0.001. Tumor tissues thus significantly differs from fat, skin and muscle on account of either the K or the n parameter, i.e. of either the magnitude or the frequency-dependence of the shear modulus., 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 Elsevier Ltd. All rights reserved.)

A theoretical numerical model is proposed to predict patient dependent osteoporotic bone degradation. The model parameters are identified through a particle swarm optimization algorithm and based on individual patient high resolution peripherical quantitative computer tomography (HRpQCT) scan data. The degradation model is based on cellular activity initiated by the elastic strain energy developed in the bone microstructure through patient's body weight. The macro (organ scale) and meso (trabecular scale) scale analyses are carried out and predicted bone volume fraction and microstructure evolution are compared with in-vivo experimental bone degradation for four elderly women over a period of 10 years. A significant correlation (r > 0.9) is observed between the model predictions and in-vivo experiments in all cases with an average deviation error of 1.46%. The model can easily be extended to other patients and provide good predictions for different population categories such as ethnicity, gender, age, etc., 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 Elsevier Ltd. All rights reserved.)

Fragility fractures that occur after a fall from a standing height or less are almost always due to osteoporosis, which remains underdiagnosed and untreated. Patient-specific finite element (FE) models have been introduced to predict bone strength and strain. This approach, based on structure mechanics, is derived from Quantitative Computed Tomography (QCT), and element mechanical properties are computed from bone mineral densities. In this study, we developed a credible finite element model of the radius to discriminate low-trauma-fractured radii from non-fractured radii obtained experimentally. Thirty cadaveric radii were impacted with the same loading condition at 2 m/s, and experimental surface strain was retrieved by stereo-correlation in addition to failure loads in fracture cases. Finite element models of the distal radius were created from clinical computed tomography. Different density-elasticity relationships and failure criteria were tested. The strongest agreement (simulations-experiments) for average strain showed a Spearman's rank correlation (ρ) between 0.75 and 0.82, p < 0.0001, with a root mean square error between 0.14 and 0.19%. The experimental mean strain was 0.55%. Predicted failure load error (23%) was minimized for derived Pistoia's failure criterion. Numerical failure demonstrated area under the receiver operating characteristic (ROC) curves of 0.76 when classifying radius fractures with an accuracy of 82%. These results suggest that a credible FE modelling method in a large region of interest (distal radius) is a suitable technique to predict radius fractures after a forward fall., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Viscoelasticity is an essential property of bone related to fragility, which is altered in aging and bone disease. Bone viscoelastic behavior is attributed to several mechanisms involving collagen and mineral properties, porosities, and bone hierarchical tissue organization. We aimed to assess the relationships between cortical bone viscoelastic damping measured with Resonant Ultrasound Spectroscopy (RUS), microstructural and compositional characteristics. We measured 52 bone specimens from the femur of 26 elderly human donors. RUS provided a shear damping coefficient at a frequency of the order of 150 kHz. The characteristics of the structure of the vascular pore network and tissue mineral density were measured using synchrotron radiation high-resolution computed tomography (SR-μCT). Fourier transformed infrared microspectroscopy (FTIRM) was used to quantify mineral-to-organic phase ratio, mineral maturity, crystallinity, and collagen maturity. Cross-links were quantified from biochemistry. Viscoelastic damping was found to increase with vascular porosity (r=0.68), to decrease with the degree of mineralization of the extravascular matrix (r=-0.68), and was marginally affected by collagen. We built a multilinear model suggesting that when porosity is controlled, the variation of mineral content explains a small additional part of the variability of damping. The work supports the consideration of viscoelasticity measurement as a potential biomarker of fragility and provides a documentation of bone viscoelastic behavior and its determinants in a frequency range rarely investigated., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Lysphosphatidic acid (LPA) is a major natural bioactive lipid mediator whose biological functions affect multiple organs. These include bone as demonstrated by global Lpar1-knockout mice (Lpar1 -/- ) which present a bone growth defect. LPA acts on all bone cells including osteoblasts, that are responsible for bone formation, and osteoclasts, which are specialized cells that resorb bone. LPA appears as a potential new coupling molecule during bone remodeling. LPA 1 is the most ubiquitous LPA receptor among the six LPA receptor family members (LPA 1 - 6 ). To better understand the specific role of LPA via its receptor LPA 1 in osteoblastic cell lineage we generated osteoblast-specific Lpar1 knockout mice (Lpar1-∆Ob) by crossing Lpar1 flox/flox and Osx:Cre + mouse lines. Lpar1-∆Ob mice do not recapitulate the bone defects of Lpar1 -/- mice but revealed reduced bone mineralization and decreased cortical thickness, as well as increased bone porosity associated with an augmentation in the lacunae areas of osteocyte and their apoptotic yield. In vitro, primary Lpar1-∆Ob and immortalized cl1-Ob-Lpar1 -/- osteoblasts revealed a remarkable premature expression of alkaline phosphatase, reduced cell proliferation associated with decreased YAP-P nuclear accumulation, and reduced mineralization activity. Osteocyte specification is markedly impaired as demonstrated by reduced expression of early (E11) and late (DMP1, DKK1, SOST) osteocyte markers ex vivo in enriched osteocytic fractions of Lpar1-∆Ob mouse bone explants. In addition, E11 expression and dendrite formation induced by FGF2 are markedly impaired in both primary Lpar1-∆Ob and immortalized cl1-Ob-Lpar1 -/- osteoblasts. Taken together these results suggest a new role for LPA in bone mass control via bone mineralization and osteocyte function., 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 © 2020. Published by Elsevier B.V.)

The strong dependence between cortical bone elasticity at the millimetre-scale (mesoscale) and cortical porosity has been evidenced by previous studies. However, bone is an anisotropic composite material made by mineral, proteins and water assembled in a hierarchical structure. Whether the variations of structural and compositional properties of bone affect the different elastic coefficients at the mesoscale is not clear. Aiming to understand the relationships between bone elastic properties and compositions and microstructure, we applied state-of-the-art experimental modalities to assess these aspects of bone characteristics. All elastic coefficients (stiffness tensor of the transverse isotropic bone material), structure of the vascular pore network, collagen and mineral properties were measured in 52 specimens from the femoral diaphysis of 26 elderly donors. Statistical analyses and micromechanical modeling showed that vascular pore volume fraction and the degree of mineralization of bone are the most important determinants of cortical bone anisotropic mesoscopic elasticity. Though significant correlations were observed between collagen properties and elasticity, their effects in bone mesoscopic elasticity were minor in our data. This work also provides a unique set of data exhibiting a range of variations of compositional and microstructural cortical bone properties in the elderly and gives strong experimental evidence and basis for further development of biomechanical models for human cortical bone. STATEMENT OF SIGNIFICANCE: This study reports the relationships between microstructure, composition and the mesoscale anisotropic elastic properties of human femoral cortical bone in elderly. For the first time, we provide data covering the complete anisotropic elastic tensor, the microstructure of cortical vascular porosity, mineral and collagen characteristics obtained from the same or adjacent samples in each donor. The results revealed that cortical vascular porosity and degree of mineralization of bone are the most important determinants of bone anisotropic stiffness at the mesoscale. The presented data gives strong experimental evidence and basis for further development of biomechanical models for human cortical bone., (Copyright © 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Bone fracture is a major health issue worldwide and consequently there have been extensive investigations into the fracture behavior of human cortical bone. However, the fracture properties of human cortical bone under fall-like loading conditions remains poorly documented. Further, most published research has been performed on femoral diaphyseal bone, whereas it is known that the femoral neck and the radius are the most vulnerable sites to fracture. Hence, the aim of this study is to provide information on human cortical bone fracture behavior by comparing different anatomical sites including the radius and the femoral neck acquired from 32 elderly subjects (50 - 98 y.o.). In order to investigate the intrinsic fracture behavior of human cortical bone, toughness experiments were performed at two different strain rates: standard quasi-static conditions, and a higher strain rate representative of a fall from a standing position. The tests were performed on paired femoral neck, femoral, tibial and radius diaphyseal samples. Linear elastic fracture toughness and the non-linear J-integral method were used to take into account both the elastic and non-elastic behavior of cortical bone. Under quasi-static conditions, the radius presents a significantly higher toughness than the other sites. At the higher strain rate, all sites showed a significantly lower toughness. Also, at the high strain rate, there is no significant difference in fracture properties between the four anatomical sites. These results suggest that regardless of the anatomical site (femur, femoral neck, tibia and radius), the bone has the same fracture properties under fall loading conditions. This should be considered in biomechanical models under fall-like loading conditions., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Cortical porosity is a major determinant of bone strength. Haversian and Volkmann׳s canals are׳seen' as pores in 2D cross-section but fashion a dynamic network of interconnected channels in 3D, a quantifiable footprint of intracortical remodeling. Given the changes in bone remodeling across life, we hypothesized that the 3D microarchitecture of the cortical pore network influences its stiffness during growth and ageing. Cubes of cortical bone of 2 mm side-length were harvested in the distal 1/3 of the fibula in 13 growing children (mean age±SD: 13±4 yrs) and 16 adults (age: 75±13 yrs). The cubes were imaged using desktop micro-CT (8.14µm isotropic voxel size). Pores were segmented as a solid to assess pore volume fraction, number, diameter, separation, connectivity and structure model index. Elastic coefficients were derived from measurements of ultrasonic bulk compression and shear wave velocities and apparent mass density. The pore volume fraction did not significantly differ between children and adults but originates from different microarchitectural patterns. Compared to children, adults had 42% (p=0.033) higher pore number that were more connected (Connective Density: +205%, p=0.001) with a 18% (p=0.007) lower pore separation. After accounting for the contribution of pore volume fraction, axial elasticity in traction-compression mode was significantly correlated with better connectivity in growing children and with pore separation among adults. The changes in intracortical remodeling across life alter the distribution, size and connectedness of the channels from which cortical void fraction originates. These alterations in pore network microarchitecture participate in changes in compressive and shear mechanical behavior, partly in a porosity-independent manner. The assessment of pore volume fraction (i.e., porosity) provides only a limited understanding of the role of cortical void volume fraction in its mechanical properties., (Copyright © 2016. Published by Elsevier Ltd.)

Child cortical bone tissue is rarely studied because of the difficulty of obtaining samples. Yet the preparation and ultrasonic characterization of the small samples available, while challenging, is one of the most promising ways of obtaining information on the mechanical behavior of non-pathological children׳s bone. We investigated children׳s cortical bone obtained from chirurgical waste. 22 fibula or femur samples from 21 children (1-18 years old, mean age: 9.7±5.8 years old) were compared to 16 fibula samples from 16 elderly patients (50-95 years old, mean age: 76.2±13.5 years old). Stiffness coefficients were evaluated via an ultrasonic method and anisotropy ratios were calculated as the ratio of C33/C11, C33/C22 and C11/C22. Stiffness coefficients were highly correlated with age in children (R>0.56, p<0.01). No significant difference was found between C11 and C22 for either adult or child bone (p>0.5), nor between C44 and C55 (p>0.5). We observe a transverse isotropy with C33>C22=C11>C44C55>C66. For both groups, we found no correlation between age and anisotropy ratios. This study offers the first complete analysis of stiffness coefficients in the three orthogonal bone axes in children, giving some indication of how bone anisotropy is related to age. Future perspectives include studying the effect of the structure and composition of bone on its mechanical behavior., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Numerical simulation using finite element models (FEM) has become more and more suitable to estimate the mechanical properties of trabecular bone. The size and kind of elements involved in the models, however, may influence the results. The purpose of this study is to analyze the influence of hexahedral elements formulation on the evaluation of mechanical stress applied to trabeculae bone during a compression test simulation. Trabecular bone cores were extracted from 18 L2 vertebrae (12 women and 6 men, mean age: 76 ± 11, BV/TV=7.5 ± 1.9%). Samples were micro-CT scanned at 20 μm isotropic voxel size. Micro-CT images have been sub-sampled (20, 40 and 80 μm) to create 5.6 mm cubic FEM. For each sample, a compression test FEM has been created, using either 8-nodes linear hexahedral elements with full or reduced integration or 20-nodes quadratic hexahedral elements fully integrated, resulting in nine models per samples. Bone mechanical properties have been assumed isotropic, homogenous and to follow a linear elastic behavior law (Young modulus: 8 GPa, Poisson ratio: 0.3). Despite micro-architecture modifications (loss of connectivity, trabeculae thickening) due to voxel size increase, apparent mechanical properties calculated with low resolution models are significantly correlated with high resolution results, no matter the element formulation. However, stress distributions are more sensitive to both resolution and element formulation modifications. With linear elements, increasing voxel size leads to an alteration of stress concentration areas due to stiffening errors. On the opposite, the use of reduced integration induces severe smoothing and underestimation of stress fields resulting in stress raisers loss. Notwithstanding their high computational cost, quadratic elements are most appropriate for stress prediction in low resolution trabecular bone FEM. These observations are dependent on trabecular bone micro-architecture, and are more significant for low density sample displaying low trabecular thickness. In conclusion, we found that element formulation is almost important as element size when evaluating trabecular bone mechanical behavior at trabeculae scale. Therefore, element type should be chosen carefully when evaluating trabecular bone behavior using FEM., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Bone is a multiscale composite material made of both a type I collagen matrix and a poorly crystalline apatite mineral phase. Due to remodeling activity, cortical bone is made of Bone Structural Units (BSUs) called osteons. Since osteon represents a fundamental level of structural hierarchy, it is important to investigate the relationship between mechanical behavior and tissue composition at this scale for a better understanding of the mechanisms of bone fragility. The aim of this study is to analyze the links between ultrastructural properties and the mechanical behavior of bone tissue at the scale of osteon. Iliac bone biopsies were taken from untreated postmenopausal osteoporotic women, embedded, sectioned and microradiographed to assess the degree of mineralization of bone (DMB). On each section, BSUs of known DMB were indented with relatively high load (~500 mN) to determine local elastic modulus (E), contact hardness (H(c)) and true hardness (H) of several bone lamellae. Crystallinity and collagen maturity were measured by Fourier Transform InfraRed Microspectroscopy (FTIRM) on the same BSUs. Inter-relationships between mechanical properties and ultrastructural components were analyzed using multiple regression analysis. This study showed that elastic deformation was only explained by DMB whereas plastic deformation was more correlated with collagen maturity. Contact hardness, reflecting both elastic and plastic behaviors, was correlated with both DMB and collagen maturity. No relationship was found between crystallinity and mechanical properties at the osteon level., (Copyright © 2011 Elsevier Ltd. All rights reserved.)