Objectives. Bisphosphonates (BP) are the first-line treatment for preventing fragility fractures. However, concern regarding their efficacy is growing because bisphosphonate is associated with over-suppression of remodelling and accumulation of microcracks. While dual-energy X-ray absorptiometry (DXA) scanning may show a gain in bone density, the impact of this class of drug on mechanical properties remains unclear. We therefore sought to quantify the mechanical strength of bone treated with BP (oral alendronate), and correlate data with the microarchitecture and density of microcracks in comparison with untreated controls. Methods. Trabecular bone from hip fracture patients treated with BP (n = 10) was compared with naïve fractured (n = 14) and non-fractured controls (n = 6). Trabecular cores were synchrotron scanned and micro-CT scanned for microstructural analysis, including quantification of bone volume fraction, microarchitecture and microcracks. The specimens were then mechanically tested in compression. Results. BP bone was 28% lower in strength than untreated hip fracture bone, and 48% lower in strength than non-fractured control bone (4.6 MPa vs 6.4 MPa vs 8.9 MPa). BP-treated bone had 24% more microcracks than naïve fractured bone and 51% more than non-fractured control (8.12/cm. 2. vs 6.55/cm. 2. vs 5.25/cm. 2. ). BP and naïve fracture bone exhibited similar trabecular microarchitecture, with significantly lower bone volume fraction and connectivity than non-fractured controls. Conclusion. BP therapy had no detectable mechanical benefit in the specimens examined. Instead, its use was associated with substantially reduced bone strength. This low strength may be due to the greater accumulation of microcracks and a lack of any discernible improvement in bone volume or microarchitecture. This preliminary study suggests that the clinical impact of BP-induced microcrack accumulation may be significant. Cite this article: A. Jin, J. Cobb, U. Hansen, R. Bhattacharya, C. Reinhard, N. Vo, R. Atwood, J. Li, A. Karunaratne, C. Wiles, R. Abel. The effect of long-term bisphosphonate therapy on trabecular bone strength and microcrack density. Bone Joint Res 2017;6:602–609. DOI: 10.1302/2046-3758.610.BJR-2016-0321.R1

Bone strength is influenced by bone quality besides its density. This study aimed to evaluate the effects of teriparatide on changes of bone strength as well as trabecular and cortical bone microstructures at femoral neck in female ovariectomized (OVX) rats. Eighteen female Wister rats were divided into three groups: the sham control, OVX and treatment (Tx) groups. All of them were sacrificed after 3-month intermittent teriparatide intervention in Tx group. All left femurs were removed and scanned using micro-CT and followed by mechanical test for each femoral neck. Regarding micro-CT, four trabecular parameters including bone volume fraction (BV/TV), trabecular thickness (TbTh), trabecular separation (TbSp), and trabecular number (TbN) and three cortical parameters including volumetric bone mineral density (vBMD), cortical cross-sectional area (CtAr) and cortical thickness (CtTh) were measured at femoral neck region. All data were analyzed and was presented as median ± SEM. The mean bone strength of femoral neck significantly decreased in OVX group when compared to the control group (p < 0.05) and was significantly restored in Tx group (p < 0.01). Regarding the trabecular parameters, the BV/TV and TbTh significantly decreased in OVX group while compare to Tx group. However, no significant difference was observed in TbSp and TbN between the groups. Regarding the cortical parameters, CtTh was significantly greater in Tx group than that in OVX group (p<0.01). As our findings, intermittent teriparatide can improve the deteriorated bone strength of femoral neck due to ovarian deficiency via changing both trabecular microarchitecture and cortical morphology

Summary Statement. In a retrospective study, FE-based bone strength from CT data showed a greater ability than aBMD to discriminate proximal femur fractures versus controls. Introduction. Personalised Finite Element (FE) models from Computed Tomography (CT) data are superior to bone mineral density (BMD) in predicting proximal femoral strength in vitro [Cody, 1999]. However, results similar to BMD were obtained in vivo, in retrospective classification of generic prevalent fractures [Amin, 2011] and in prospective classification of femoral fractures [Orwoll, 2009]. The aim of this work is to test, in a case-control retrospective study, the ability of a different, validated FE modelling procedure [Schileo, 2008] to: (i) discriminate between groups of proximal femoral fractures and controls; (ii) individually classify fractures and controls. Patients & Methods. 55 women (22 incident low-trauma proximal femur fractures and 33 controls) were enrolled in 3 clinical centres in Emilia Romagna region, Italy. All received a full femoral CT and DXA exams (in acute conditions for fractured cases) with a standardised protocol. Femoral neck aBMD was measured from DXA. FE models were built from CT (right femur for controls, intact for fractured) [Schileo, 2008]. Differently from existing works, FE strength was calculated for a range of 12 physiological directions of hip joint reactions [Bergmann, 2001] and 10 fall directions [Grassi, 2012]. Bone strength (in stance and fall) was the minimum load inducing on the femoral neck surface an elastic principal strain value greater than the yield limit [Bayraktar, 2004]. Fracture classification was analysed through logistic regressions and AUC of ROC curves. Results. Mean FE strength and aBMD were significantly lower in the fractured than in the control group (33%, p<0.0001 for strength; 12% p=0.01 for aBMD). Logistic regression on single variables. All classifiers were significant (p<0.001, AUC=0.88 for both stance and fall FE strength, p=0.02, AUC=0.72 for aBMD). The statistical power of the logistic regressions [Vaeth, 2004] was >0.9 for FE strength, 0.86 for aBMD. Logistic regressions on multiple variables. Only FE strength was retained significant (p<0.001, AUC=0.88) when including aBMD in the regression. Adding age to the logistic regression, FE strength and age (but not aBMD) remained significant, with AUC=0.95. Discussion. FE strength could discriminate the fractured group better than aBMD and than [Keyak, 2011]. FE strength was a better fracture classifier than aBMD, and obtained AUC values slightly higher than [Amin, 2011; Orwoll, 2009]. The high statistical power mildens the small sample numerosity. Cases and controls were not age matched, but FE strength and age were found to be independent classifiers. In conclusion the proposed FE method was superior to aBMD in the classification of proximal femoral fractures

There have been conflicting reports on the effects of gamma irradiation on the material properties of cortical allograft bone. To investigate changes which result from the method of preparation, test samples must be produced with similar mechanical properties to minimise variations other than those resulting from treatment. We describe a new method for the comparative measurement of bone strength using standard bone samples. We used 233 samples from six cadavers to study the effects of irradiation at a standard dose (28 kGy) alone and combined with deep freezing. We also investigated the effects of varying the dose from 6.8 to 60 kGy (n = 132). None of the treatments had any effect on the elastic behaviour of the samples, but there was a reduction in strength to 64% of control values (p < 0.01) after irradiation with 28 kGy. There was also a dose-dependent reduction in strength and in the ability of the samples to absorb work before failure. We suggest that irradiation may cause an alteration in the bone matrix of allograft bone, but provided it is used in situations in which loading is within its elastic region, then failure should not occur

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

Introduction. Patient-specific biomechanical modeling using Finite Element Analysis (FEA) is pivotal for understanding the structural health of bones, optimizing surgical procedures, assessing outcomes, and validating medical devices, aligning with guidance issued by standards and regulatory bodies. Accurate mapping of image-to-mesh-material is crucial given bone's heterogeneous composition. This study aims to rigorously assess mesh convergence and evaluate the sensitivity of material grouping strategies in quantifying bone strength. Method. Subject-specific geometry and nonlinear material properties were derived from computed tomography (CT) scan data of one cadaveric human vertebral body. Linear tetrahedral elements with varying edge lengths between 2mm and 0.9mm were then generated to study the mesh convergence. To compare the effectiveness of different grouping strategies, three approaches were used: Modulus Gaping (a user-defined absolute threshold of Young's modulus ranging from 500 MPa to 1 MPa), Percentual Thresholding (relative parameter thresholds ranging from 50% to 1%), and Adaptive clustering (unsupervised k-means-based clustering ranging from 10 to 200 clusters). Adaptive clustering enables a constant number of unique material properties in cross-specimen studies, improving the validity of results. Result. Mesh convergence was evaluated via fracture load and reached at a 1mm mesh size across grouping strategies. All strategies exhibit minimal deviation (within 5%) from individually assigned material parameters, except Modulus Gaping, with a 500 MPa threshold (32% difference). Computational efficiency, measured by runtime, significantly improved with grouping strategies, reducing computational cost by 82 to 94% and unique material count by up to 99%. Conclusion. Different grouping strategies offer comparable mesh convergence, highlighting their potential to reduce computational complexity while maintaining accuracy in the biomechanical modeling of bones and suggesting a more efficient approach than individual element materials. The higher efficiency of FEA may increase its applicability in clinical settings with limited computational resources. Further studies are needed to refine grouping parameters and assess their suitability across different subjects

Among the advanced technology developed and tested for orthopaedic surgery, the Rizzoli (IOR) has a long experience on custom-made design and implant of devices for joint and bone replacements. This follows the recent advancements in additive manufacturing, which now allows to obtain products also in metal alloy by deposition of material layer-by-layer according to a digital model. The process starts from medical image, goes through anatomical modelling, prosthesis design, prototyping, and final production in 3D printers and in case post-production. These devices have demonstrated already to be accurate enough to address properly the specific needs and conditions of the patient and of his/her physician. These guarantee also minimum removal of the tissues, partial replacements, no size related issues, minimal invasiveness, limited instrumentation. The thorough preparation of the treatment results also in a considerable shortening of the surgical and of recovery time. The necessary additional efforts and costs of custom-made implants seem to be well balanced by these advantages and savings, which shall include the lower failures and revision surgery rates. This also allows thoughtful optimization of the component-to-bone interfaces, by advanced lattice structures, with topologies mimicking the trabecular bone, possibly to promote osteointegration and to prevent infection. IOR's experience comprises all sub-disciplines and anatomical areas, here mentioned in historical order. Originally, several systems of Patient-Specific instrumentation have been exploited in total knee and total ankle replacements. A few massive osteoarticular reconstructions in the shank and foot for severe bone fractures were performed, starting from mirroring the contralateral area. Something very similar was performed also for pelvic surgery in the Oncology department, where massive skeletal reconstructions for bone tumours are necessary. To this aim, in addition to the standard anatomical modelling, prosthesis design, technical/technological refinements, and manufacturing, surgical guides for the correct execution of the osteotomies are also designed and 3D printed. Another original experience is about en-block replacement of vertebral bodies for severe bone loss, in particular for tumours. In this project, technological and biological aspects have also been addressed, to enhance osteointegration and to diminish the risk of infection. In our series there is also a case of successful custom reconstruction of the anterior chest wall. Initial experiences are in progress also for shoulder and elbow surgery, in particular for pre-op planning and surgical guide design in complex re-alignment osteotomies for severe bone deformities. Also in complex flat-foot deformities, in preparation of surgical corrections, 3D digital reconstruction and 3D printing in cheap ABS filaments have been valuable, for indication, planning of surgery and patient communication; with special materials mimicking bone strength, these 3D physical models are precious also for training and preparation of the surgery. In Paediatric surgery severe multi planar & multifocal deformities in children are addressed with personalized pre-op planning and custom cutting-guides for the necessary osteotomies, most of which require custom allografts. A number of complex hip revision surgeries have been performed, where 3D reconstruction for possible final solutions with exact implants on the remaining bone were developed. Elective surgery has been addressed as well, in particular the customization of an original total ankle replacement designed at IOR. Also a novel system with a high-tibial-osteotomy, including a custom cutting jig and the fixation plate was tested. An initial experience for the design and test of custom ankle & foot orthotics is also in progress, starting with 3D surface scanning of the shank and foot including the plantar aspect. Clearly, for achieving these results, multi-disciplinary teams have been formed, including physicians, radiologists, bioengineers and technologists, working together for the same goal

Abstract. Objectives. Osteocytes function as critical regulators of bone homeostasis by sensing mechanical signals. Stimulation of the mechanosensitive ion channel, Piezo1 promotes bone anabolism and deletion of Piezo1 in osteoblasts and osteocytes decreases bone mass and bone strength in mice. This study determined whether loading of osteocytes in vitro results in upregulation of the Piezo1 pathway. Methods. Human MSC cells (Y201), embedded in type I collagen gels and differentiated to osteocytes in osteogenic media 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 Piezo1 activation assessed by RNAseq analysis (NovaSeq S1 flow cell 2 × 100bp PE reads). To mimic mechanical load and activate Piezo1, Y201s were differentiated to osteocytes in 3D gels for 13 days and treated, with Yoda1 (5µM, 2 hours, n=4); vehicle treated cells served as controls (n=4). Extracted RNA was subjected to RT-qPCR and data analysed by Minitab. Results. Low mRNA expression of PIEZO1 in unloaded cells was upregulated 5-fold following 1-hr of mechanical load (p=0.003). In addition, the transcription factor NFATc1, a known regulator of Piezo1 mechanotransduction, was also upregulated by load (2.4-fold; p=0.03). Y201 cells differentiated in gels expressed the osteocyte marker, SOST. Yoda1 upregulated PIEZO1 (1.7-fold; p=0.057), the early mechanical response gene, cFOS (4-fold; p=0.006), COL1A1 (3.9-fold; p=0.052), and IL-6 expression (7.7-fold; p=0.001). Discussion. This study reveals PIEZO1 as an important mechanosenser in osteocytes. Piezo 1 mediated increases in the bone matrix protein, type I collagen, and IL-6, a cytokine that drives inflammation and bone resorption. This provides a direct link between mechanical activation of Piezo 1, bone remodelling and inflammation, which may contribute to mechanically-induced joint degeneration in osteoarthritis. Mechanistically, we hypothesise this may occur through promoting Ca2+ influx and activation of the NFAT1 signalling pathway

Most of researches related to osteoporosis emphasized on trabecular bone loss. However, cortical bone has a prominent role on bone strength determined by bone quality, such as 2D or 3D geometry and microstructure of bone, not only density.[1] The focal thinning of cortical bone associated with aging in post-menopausal osteoporotic bone in the proximal femur may predispose a hip to fracture.[2, 3] As the trabecular bone is lost with progression of osteoporosis, the remaining cortical bone take more predominant role on bone strength.[4] To date, no effective osteoporotic agent was demonstrated to enhance both cortical geometric change and bone strength. Herein, we investigate the effect of Teriparatide (rhPTH(1–34)) on cortical bone at femoral diaphysis in OVX rat model. Twenty 12-week-old, female Sprague Dawley rats were used in this study. Bilateral ovariectomies were performed in 16 animals and randomly divided to three groups as control (N=6), OVX (N=6) and treatment group after OVX (OVX+F) by teriparatide (N=8). After twelve weeks of intervention, all rats were euthanized and right femurs and L5 vertebrae were extracted for further tests. All bone specimens were subjected to dual-energy X-ray absorptiometer (DXA) to evaluate areal bone mineral density (aBMD) of L5 vertebrae and femurs, micro-computed tomography (micro-CT) to analyze cortical bone parameters of femoral diaphysis, including cortical cross section area (CSA), cortical thickness and cross-sectional moment of inertia (CSMI). A three-point bending test was applied to determine fracture load of each femurs. Compare to OVX group, increase of aBMD by 14.6 % at L5 vertebrae and 13.3% at femoral diahpysis in treatment group. The cortical parameters of femoral diaphysis, CSA and cortical thickness, analyzed by micro-CT were significantly increased but the increasing tendency of CSMI did not have significant changes statistically after teriparatide intervention for 3 months duration. The increase of cortical bone strength (OVX vs OVX+F group, 120.72±2.72 vs 137.93±5.02, p < 0.05) at femoral diaphysis after treatment were also noticed. This study has point out a deeper look at geometric change of cortical bone after teriparatide treatment. This finding imply teirparatide has the ability to change the geometry of cortical bone and increase bone strength at femoral diaphysis

Introduction and Objective. Individuals with type 2 diabetes (T2D) have a 3-fold increased risk of bone fracture compared to non-diabetics, with the majority of fractures occurring in the hip, vertebrae and wrists. However, unlike osteoporosis, in T2D, increased bone fragility is generally not accompanied by a reduction in bone mineral density (BMD). This implies that T2D is explained by poorer bone quality, whereby the intrinsic properties of the bone tissue itself are impaired, rather than bone mass. Yet, the mechanics remain unclear. The objective of this study is to (1) assess the fracture mechanics of bone at the structural and tissue level; and (2) investigate for changes in the composition of bone tissue along with measuring total fluorescent advanced glycation end products (fAGEs) from the skin, as T2D progresses with age in Zucker diabetic fatty (ZDF (fa/fa)) and lean Zucker (ZL (fa/+)) rats. Materials and Methods. Right ulnae and skin sections were harvested from ZDF (fa/fa) (T2D) and ZL (fa/+) (Control) rats at 12 and 46 weeks (wks) of age (n = 8, per strain and age) and frozen. Right ulnae were thawed for 12 hrs before micro-CT (μCT) scanning to assess the microstructure and measure BMD. After scanning, ulnae were loaded until failure via three-point bending. Fourier transform-infrared microspectroscopy (FTIR) was used to measure various bone mineral- and collagen-related parameters such as, mineral-to-matrix ratio and nonenzymatic cross-link ratio. Finally, fAGEs were measured from skin sections using fluorescence spectrometry and an absorbance assay, reported in units of ng quinine/ mg collagen. Results. At 12 and 46 wks bone size was significantly smaller in length (p < 0.01), cortical area (p < 0.001) and cross-sectional moment of inertia (p < 0.001) in T2D rats compared to age-matched controls. A slight reduction in BMD was observed in T2D rats compared to controls at both ages, however, this was not significant. Structural properties of T2D bone were significantly altered at 12 and 46 wks, with bending rigidity increasing approximately 2.5-fold and 1.5-fold in control and T2D rats with age, respectively (p < 0.0001). Similarly, yield and ultimate moment significantly reduced in T2D rats with age in comparison to controls (p < 0.0001). Energy absorbed to failure was significantly reduced in T2D rats at 46 weeks of age compared to controls (p < 0.01). The amount of energy absorbed to failure increased approximately 1.4-fold from 12 to 46 wks in control rats, however, in T2D rats a reduction was seen with age, although not significant. At 12 wks, there was no significant deficits in tissue material properties, whereas, at 46 wks a significant reduction in yield stress, yield strain and ultimate stress was observed for T2D rats in comparison to controls (p < 0.05). Conclusions. These findings show that longitudinal growth is impaired as early as 12 wks of age and by 46 wks bone size is significantly reduced in T2D rats compared to controls. The reduction in T2D structural properties is likely attributed to the bone geometry deficits. At 12 wks of age, the tissue material properties are not altered in T2D bone versus controls. However, at 46 wks, bone strength is reduced in T2D, leading to the conclusion that tissue properties are altered as the disease progresses

Bone healing especially in elderly patients is a complex process with limited therapeutic options. In recent years the use of BMP2 for fracture healing is investigated extensively. However, for many applications superficial amounts of BMP2 were required for efficacy due to the absence of sustained release carriers and severe side effects have reported thereby limiting the use of BMP2. Here we present an alternative method based on the use of a combination of low molecular weight compounds, testosterone and alendronate, with established safety profiles in men. Moreover, in contrast to BMP2 which activates both osteoblasts and osteoclasts, this combination of drugs enhances osteoblast activity but simultaneously inhibits osteoclast activity resulting in a net effect of bone growth. Human primary osteoblasts were obtained from bone of patients requiring knee prostheses and cultured in the presence of various concentrations testosterone with and without alendronate. Optimal concentrations were selected and used to stimulate 5×8 mm porcine bone biopsies for 4 weeks. Medium was exchanged regularly and ALP activity was determined. At endpoint biopsies were analyzed in a MicroCT (Bruker Skyscan 1076) to analyze bone volume (BV), trabecular thickness (Tb.Th) and tissue volume (TV). Bone strength was measured using Hounsfield (H10KT) test equipment. The data obtained showed a significant and dose dependent increase in ALP activity of primary osteoblasts (day 7–10) indicating robust activation of osteoblast activity. Optimal and synergistic ALP activation was observed when treating cells with 15–375 nM testosterone in combination with 2 μM alendronate. Significant inhibition (75%) of osteoclast activity was observed by alendronate (2–10 μM) which was further enhanced by high testosterone levels. This concept was further tested in bovine bone biopsies cultured for 4 weeks in the presence of 75 nM testosterone and 2 μM alendronate. MicroCT analysis of the biopsies revealed a ± 40% increase in both bone volume (trabecular and cortical bone) and bone strength. Moreover bone mineral density was increased by 20% indicating increased mineralization of bone tissue. Treatment of human primary osteoblasts or human or bovine bone explants with a combination of an androgen (testosterone) and a bisphosphonate (alendronate) significantly enhance bone growth and bone mineral density. Moreover, bone strength was increased indicating the formation of high quality bone tissue. These findings are the basis for the development of sustained release materials to be applied locally at the bone fracture site, which would allow for low amounts of the drugs and no systemic exposure. By encapsulating testosterone and alendronate in a biodegradable polymer coating, a sustained release up to 5 weeks can be achieved, and the loaded coating can be applied in combination with collagen membranes to improve bone healing or as a coating onto implants to improve osseo-integration

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

Summary. A retrospective study on 98 patients shows that FE-based bone strength from CT data (using validated FE models) is a suitable candidate to discriminate fractured versus controls within a clinical cohort. Introduction. Subject-specific Finite element models (FEM) from CT data are a promising tool to non-invasively assess the bone strength and the risk of fracture of bones in vivo in individual patients. The current clinical indicators, based on the epidemiological models like the FRAX tool, give limitation estimation of the risk of femoral neck fracture and they do not account for the mechanical determinants of the fracture. Aim of the present study is to prove the better predictive accuracy of individualised computer models based a CT-FEM protocol, with the accuracy of a widely used standard of care, the FRAX risk indicator. Patients and Methods. This retrospective cohort is individually-matched case control study composed by 98 Caucasian women who were at least 5 years post menopause. The case group consisted of 49 patients who had sustained a hip fracture (36 intra-capsular and 13 extra-capsular fractures) within the previous 90 days due to low-energy trauma. The CT datasets were segmented (using the ITK-Snap software) in order to extract the periosteal bone surface. Unstructured meshes (10-node tetrahedral elements) were generated using ANSYS mesh morphing software. Each CT dataset was calibrated using the European Spine Phantom. The inhomogeneous material properties were mapped from CT datasets into the FEM with the BoneMat_V3 software. Bone strength was evaluated in quasi-axial loading conditions, for a set of 12 different configurations sampling the cone of recorded in vivo hip joint reactions, and was defined as the minimum load inducing on the femoral neck surface an elastic principal strain value greater than a limit value. Results. There were no statistically significant difference between the fracture and the control groups for age, height and weight (p<0.05). All indices of areal bone mineral density (aBMD) and the volumetric mineral density (vBMD) between fractured and controls showed on average a lower value for fractured respect of the controls, with similar mean difference (14% for aBMD and 13% for the vBMD). FEM-predicted strength differed between fractured and non-fractured on average for 20%. To evaluate its ability to identify patients at risk of hip fracture, FEM-based strength was compared to the FRAX predictor by computing for each predictor the Receiver Operating Characteristic (ROC) curve, and the Area Under the Curve (AUC). The individualised risk predictor based on FEM bone strength was found to perform significantly better (AUC=0.76) than FRAX (AUC=0.66). When the FEM-based strength indicator was combined with available clinical information in a logistic regression, the resulting predictor achieved in this retrospective study an excellent accuracy (AUC=0.82). Discussion. This study confirms that individualised, CT- FEM, when generated using to the state-of-the-art protocols, can provide a predictor of the risk of hip fracture more accurate than those based on clinical data alone. In the integrated workflow developed in the VPHOP Project (FP7-ICT-223865) CT-based risk prediction is requested only for those patients for whom the clinical decision is uncertain

Aims

This study intended to investigate the effect of vericiguat (VIT) on titanium rod osseointegration in aged rats with iron overload, and also explore the role of VIT in osteoblast and osteoclast differentiation.

Femoroplasty is the process of injecting cement (cement augmentation) into the proximal femur to prevent osteoporotic hip fractures. Femoroplasty increases the strength and energy to failure of the femur and can be performed in a minimally-invasively manner with lower hospitalization costs and reduced recovery. Our hypothesis was that efficient cement augmentation strategies can be identified via computational optimization. Therefore, using patient-specific planning we can minimize cement volume while increasing bone strength and reducing the risk of fracture. We proposed an in-silico methodology that was validated with in vitro experiments. A discrete particle model for cement infiltration was used to determine the optimum volume and filling pattern of the cement such that the best outcome was achieved. Several artificial bones were scanned before and after cement augmentation to applied previous in silico methodology. Then those femurs were mechanically tested (non-augmented and augmented). Therefore, in silico methodology was validated. Cement augmentation significantly increased the yield load. Predicted yield loads correlated well with the experiments. Results suggest that patient-specific planning of femoroplasty reduces the risk of hip fracture while minimizing the amount of cement required

Osteoporosis is a worldwide disease with a high prevalence in elderly population; it results in bone loss and decreased bone strength that lead to low-energy fractures. Since antiresorptive treatments could lead to long-term adverse effects, the ERC BOOST project aims to propose a biomimetic 3D-printed scaffold reproducing the architecture and chemistry of healthy bone. In this study, the structural parameters of healthy bone were studied in order to reproduce them through 3D printing; furthermore, structural and mechanical differences between healthy and osteoporotic (OP) bones were assessed. Healthy and OP humeral heads discarded during surgical interventions (following ethical approval by Istituto Ortopedico Rizzoli-Italy) were tomographically analysed to obtain bone structural parameters. Successively, 8 mm diameter biopsies were harvested from the heads and underwent compression and nanoindentation tests to investigate macroscopic and microscopic mechanical properties, respectively. XRD measurements were performed on bone fragments. OP bone samples exhibited inferior mechanical properties to their less interconnected and more anisotropic structure, with thinner trabeculae and larger pores. On the other hand, nanoindentations performed on OP trabeculae showed increased Young Modulus compared to healthy samples probably due to their increased hydroxyapatite crystal size, as revealed by XRD. Osteoporosis causes the weakening of the trabecular structure that leads to a decrease of bone mechanical properties. However, OP trabeculae are stiffer due to increased dimensions of hydroxyapatite crystals

Previously, we have demonstrated reduced biomechanical bone strength and matrix quality in Tachykinin (Tac)1-deficient mice lacking the sensory neuropeptide substance P (SP). A similar distortion of bone microarchitecture was described for α-calcitonin gene-related pepide (α-CGRP)-deficient mice. In previous studies we observed alterations in cell survival and differentiation capacity of bone cells isolated from wildtype mice when stimulated with SP and α-CGRP. We assume that changes in sensory neurotransmitter balance modulate bone cell metabolism thereby possibly contributing to inferior bone quality. In order to explore this hypothesis, we investigated and compared metabolic parameters in osteoblasts and osteoclasts isolated from SP- and α-CGRP-deficient mice and wildtype (WT) controls. Bone marrow-derived macrophages (BMMs) and osteoblast-like cells from female C57Bl/6J (WT-control), Tac1-deficient (Tac1-/−) and α-CGRP-deficient (α-CGRP-/−) mice were isolated and differentiated according to established protocols (Niedermair et al., 2014). Cell metabolism studies were performed for enzyme activity and cell survival. We observed reduced numbers of BMM from Tac1-/− and α-CGRP-/− mice after initial seeding compared to WT but no changes in viability. Osteoblast-like cells from Tac1-/− mice tend to migrate out faster from bone chips compared to WT-controls whereas migration of osteoblast-like cells from α-CGRP-/− mice was not affected. Osteoblasts and osteoclast/BMM cultures from WT mice endogenously synthesize and secrete SP as well as α-CGRP at a picomolar range. We found no changes regarding BMM or osteoblast proliferation from both, Tac1-/− and α-CGRP-/− mice when compared to WT-controls. Caspase 3/7-activity was reduced by trend in osteoclast/BMM cultures of α-CGRP-/− mice and significantly reduced in osteoclast/BMM cultures of Tac1-/− mice compared to WT-controls. We found significantly higher Caspase 3/7-activity in osteoblasts of Tac1-/− mice after 14 days of osteogenic culture conditions when compared to WT-controls whereas osteoblasts of α-CGRP-/− mice were unaffected. Cathepsin K enzyme activity was significantly reduced in osteoclast/BMM cultures of Tac1-/− and α-CGRP-/− mice compared to WT-controls. ALP activity of Tac1-/− osteoblasts was higher after 7 days and reduced after 21 days of osteogenic culture compared to WT-controls whereas ALP activity of osteoblasts of α-CGRP-/− mice was unchanged. Acccording to our in vitro observations, we suggest some reduction in bone resorption rate but concomitantly a reduction in bone formation rate in Tac1-/− mice compared to WT-controls resulting in a net bone loss in these mice as bone resorption is faster than bone formation. Furthermore, we assume that bone resorption rate is slightly reduced in α-CGRP-/− mice but bone formation rate seems to be unchanged. Therefore we hypothesize that additional conditions present in vivo might contribute to the inferior bone properties of α-CGRP-/− mice

Multiple myeloma (MM) is a chronic, malignant B-cell disorder, with a less than 50% 5-year survival rate [1]. This disease is responsible for vertebral compression fractures (VCFs) in 34 to 64% of diagnosed patients [1], and at least 80% of MM patients experience pathological fractures [3]. Even though reduced DXA-derived bone mineral density (BMD) has been observed in MM patients with vertebral fractures [4], the current quantitative standard method is insufficient in MM due to the osteo-destructive bone changes. Finite-element (FE) analysis is a computational and non-destructive modeling and testing approach to determine bone strength using 3D bone models from CT images. Thus, this study aimed to assess the differences in FE-predicted critical fracture load in MM patients with and without VCFs in the thoracic and lumbar segments of the spine. Multi-detector CT (MDCT) images of two radiologically assessed MM patients (1 with VCFs and 1 without VCFs) were used to generate three-dimensional (3D) models of the whole spine. For each subject, the thoracic segments, 1 to 12 (T1-T12) and lumbar segments, 1 to 5 (L1-L5) were segmented and meshed. Heterogeneous, non-linear anisotropic material properties were applied by discretizing each vertebral segment into 10 distinct sets of materials. A compressive load was simulated by constraining the surface nodes on the inferior endplate in all directions, and a displacement load was applied on the surface nods on the superior endplate [2]. This analysis was performed using ABAQUS version 6.10 (Hibbitt, Karlsson, and Sorensen, Inc., Pawtucket, RI, USA). The MM subject with VCFs had originally experienced fractures in the T4, T5, T12, L1, and L5 segments whereas the MM subject without VCFs experienced none. The former displayed large and abrupt differences in fracture loads between adjacent vertebrae segments, unlike the latter, which exhibited progressive differences instead (no abrupt changes between adjacent vertebrae segments observed). Results from this preliminary study suggest that segments at high risk of fracture are collectively involved in an unstable network, which place the vertebral segments with high values of fracture loads (peaks) as well as the adjacent segments at risk of VCF. For instance, the high fracture load at T11 places T10, T11 and T12 at risk of fracture. Accordingly, T12 has already fractured, and T10 and T11 remain at risk. The relative changes between adjacent vertebrae segments that indicate instability (extremely high fracture load values) enables ease of identification of segments at high fracture risk. Clinicians would be able to work with pre-emptive treatment strategies in future as they can focus on more targeted therapy options at the high-risk vertebrae segments [3]

The effect of bisphosphonates on the mechanical properties of the uninjured contra-lateral cortical bone during fracture healing is poorly reported. There remains conflicting evidence with regards the effect of bisphosphonate therapy on cortical bone strength. We assessed the effect of nine weeks of Ibandronate therapy, in a dose known to preserve cancellous bone BMD and strength, on the mechanical properties of the uninjured rat tibial diaphyses using a standardised model of tibial osteotomy and plate fixation. Skeletally mature ex-breeder rats were used. Stress at failure of the tibial diaphyses was measured by a four-point bending test using a custom made jig for rat tibiae. The mechanical strength was compared with radiographic measurements of bone density. Animals received daily subcutaneous injections. 11 rats received 1μg/kg Ibandronate (IBAN) daily and 17 rats received 1ml 0.9% Sodium Chloride (CONTROL) daily. The IBAN group had a statistically significant, p=0.024, higher stress at failure 212.7 (±42.04) MPa compared to the CONTROL group 171.7 (±46.13)MPa. There was a positive correlation between the mechanical strength of bone and the radiological measure of bone density. Osteopenia is known to occur following a fracture even in the contra-lateral limb. This study demonstrates that ibandronate therapy has no detrimental effect and may even increase the strength of uninjured cortical bone during the fracture healing process. The longer term effect of ibandronate on cortical bone especially in relation to the accumulation of mico-damage requires further study. Bisphosphonate effect on the uninjured limb needs to be considered when reporting proportional strength of fracture repair compared to the uninjured limb

Recently finite element studies have incorporated bone remodelling algorithms in an attempt to simulate bone's mechano-adaptation to loading conditions. In order to simplify these analyses, bone is usually considered to be isotropic, which does not explain the directionality of its internal structures; neither the orthotropic properties measured at the continuum level. Furthermore, simplified loading is usually applied to the bone models, which can result in an unrealistic remodelling stimulus. However, free boundary condition modelling of the femoral and pelvic constructs has been shown to produce more physiological stress and strain distributions. This paper describes the application of a 3D remodelling algorithm (with bone modelled as a strain-adaptive continuum with local orthotropic material properties) to a free boundary model of the femoral construct, where the hip and knee joints, as well as muscles and ligaments crossing the joints were included explicitly. Two load cases were analysed: single leg stance and standing up. Material properties and directionality distributions were produced for the whole femur, showing good agreement with observed structures from clinical studies. This indicates that the loading conditions modelled correspond to those experienced in vivo. In addition, the impact of the different load cases in bone structure modelling could be compared. Observations of the material properties distribution and orientation for standing up indicate that it promotes changes in bone stiffness in the anterior regions of the femoral neck and cortical shaft and the posterior side of the condyles. Development of this approach to modelling and bone structure prediction can lead to a better understanding of bone's mechanical behaviour and to the development and public release of orthotropic heterogeneous models for different constructs. These can be applied in many areas of interest in orthopaedic biomechanics, such as the study of bone-implant interfaces, improvement of the currently used surgical tools and techniques and the influence of certain activities in affecting local bone strength and mineralisation