Femoral Strength Research Articles

In Silico Clinical Trial for Osteoporosis Treatments to Prevent Hip Fractures: Simulation of the Placebo Arm.

Osteoporosis represents a major healthcare concern. The development of novel treatments presents challenges due to the limited cost-effectiveness of clinical trials and ethical concerns associated with placebo-controlled trials. Computational models for the design and assessment of biomedical products (In Silico Trials) are emerging as a promising alternative. In this study, a novel In Silico Trial technology (BoneStrength) was applied to replicate the placebo arms of two concluded clinical trials and its accuracy in predicting hip fracture incidence was evaluated. Two virtual cohorts (N = 1238 and 1226, respectively) were generated by sampling a statistical anatomy atlas based on CT scans of proximal femurs. Baseline characteristics were equivalent to those reported for the clinical cohorts. Fall events were sampled from a Poisson distribution. A multiscale stochastic model was implemented to estimate the impact force associated to each fall. Finite Element models were used to predict femur strength. Fracture incidence in 3years follow-up was computed with a Markov chain approach; a patient was considered fractured if the impact force associated with a fall exceeded femur strength. Ten realizations of the stochastic process were run to reach convergence. Each realization required approximately 2500 FE simulations, solved using High-Performance Computing infrastructures. Predicted number of fractures was 12 ± 2 and 18 ± 4 for the two cohorts, respectively. The predicted incidence range consistently included the reported clinical data, although on average fracture incidence was overestimated. These findings highlight the potential of BoneStrength for future applications in drug development and assessment.

A failure envelope approach to characterizing strength of an amputated femur with a bone-anchored percutaneous implant

Bone-anchored percutaneous implants, commonly referred to as osseointegrated implants, are gaining popularity as an alternative to sockets for attaching a prosthetic limb to an amputated femur. While these implants have several advantages, femoral fractures are relatively common in these patients, occurring in 6.3% of femurs within 4 years. This study aimed to develop a novel method to quantify femoral strength under all possible external loads acting on the distal implant. Finite element analysis was used to explore combinations of forces and moments that, when applied on the bone-anchored implant, were just sufficient to fracture the femur. The 6-dimensional envelope generated in the current study provided a quantitative description of the strength of the femur-implant construct. All the femoral fractures were predicted in the trochanteric region, corresponding to where most in vivo fractures have been reported. The 6-dimensional envelopes developed in the current study may be useful in the design of fail-safe devices that could reduce femoral fractures in patients with bone-anchored percutaneous femoral implants. The framework presented may also be used for determining patient suitability for bone-anchored percutaneous implants, and for evaluating the functional performance of implant designs.

Prediction of Femoral Bone Strength in the Presence of Tumors and Tumor-like Lesions Using Finite Element Analysis.

Patients with bone tumors in their femurs are at risk of developing pathological fractures. Tumors with high fracture risk, especially fragile malignant lesions, are treated surgically. However, it is difficult to estimate bone strength based on clinical and radiographic findings. This study aimed to determine whether finite element analysis (FEA) provides useful information on the bone strength of femurs with tumors and tumor-like lesions. Total femoral computed tomography (CT) data (slice thickness, 0.5 mm) were retrospectively obtained from 18 patients with femoral bone tumors. Three-dimensional FEA of femurs were developed using CT data. The virtual femoral head compression test and direct three-point bending test were performed on the femurs using FEA to predict bone strength and fracture location. The compression direction was parallel to the mechanical axis, whereas that of the three-point bending test was applied to the tumor itself. In the femoral head compression test using FEA, 13 out of 18 femurs with bone tumors fractured at the femoral head, while 14 out of 18 femurs fractured at the tumor site during the virtual direct three-point bending test. The median loads predicted using the femoral head compression test were significantly higher than those predicted by the direct three-point bending test. The FEA results indicated that pathological fractures are unlikely to occur during normal walking. Direct external forces applied to the tumor body may lead to fractures.

Caloric Restriction Diet Attenuates Systemic Bone Fragility after Radiotherapy.

Bone fragility is a well-documented long-term side effect of radiotherapy, which currently has no preventative treatments. In this study, we applied a caloric restriction (CR) diet to attenuate both local and systemic bone loss after irradiation (RTx) in an established female Balb/c mouse model (4 consecutive daily doses of 5 Gy to the right hindlimb only). CR mice were tapered down to a 30% reduced calorie diet (RTx/CR) one week before irradiation, while regular diet (RD) mice received food ad libitum (RTx/RD). Unirradiated (sham) mice received either a 30% CR diet (SH/CR) or received food ad libitum (SH/RD). Irradiated, contralateral, and unirradiated hindlimbs were evaluated at 2, 4, and 8 weeks postirradiation using micro-computed tomography (μCT) to assess bone morphology and 3-point bending to quantify femur strength. Histological analysis of irradiated and unirradiated tibiae was performed to examine general bone tissue cytology and serum biomarker analysis was performed using terminal blood draw samples. After treatment, femur strength and metaphyseal bone quantity was decreased in irradiated and contralateral femora of RTx/RD mice compared to SH/RD femurs; this finding is consistent with previous studies. RTx/CR mice had positive effects when compared to RTx/RD mice, including increased strength relative to body mass in both the irradiated and contralateral limb, increased trabecular bone mass, and decreased marrow adiposity. However, a number of adverse effects were also observed, including a significant decrease in body mass and decreased cortical bone. Overall, CR shows promise as a preventative treatment for postirradiated bone fragility, yet questions remain to be addressed in future studies. Ideal diet duration, impact to normal tissue, and mechanism of action must be explored to better understand the clinical implication of a CR diet.

Leptin signalling altered in infantile nephropathic cystinosis-related bone disorder.

The CTNS gene mutation causes infantile nephropathic cystinosis (INC). Patients with INC develop Fanconi syndrome and chronic kidney disease (CKD) with significant bone deformations. C57BL/6 Ctns-/- mice are an animal model for studying INC. Hyperleptinaemia results from the kidney's inability to eliminate the hormone leptin in CKD. Ctns-/- mice have elevated serum leptin concentrations. Leptin regulates bone metabolism through its receptor that signals further via the hypothalamic melanocortin 4 receptor (MC4R). Leptin signalling may affect bone health in Ctns-/- mice. We first defined the time course of bone abnormalities in Ctns-/- mice between 1 and 12months of age. We used both genetic and pharmacological approaches to investigate leptin signalling in Ctns-/- mice. We generated Ctns-/-Mc4r-/- double knockout mice. Bone phenotype of Ctns-/-Mc4r-/- mice, Ctns-/- mice and wild type (WT) mice at 1, 4, and 9months of age were compared. We then treated 12-month-old Ctns-/- mice and WT mice with a pegylated leptin receptor antagonist (PLA) (7mg/kg/day, IP), a MC4R antagonist agouti-related peptide (AgRP) (2nmol, intracranial infusion on days 0, 3, 6, 9, 12, 15, 18, 21, 24, and 27), or vehicle (normal saline), respectively, for 28days. Whole-body (BMC/BMD, bone area) and femoral bone phenotype (BMC/BMD, bone area, length and failure load) of mice were measured by DXA and femoral shaft biochemical test. We also measured lean mass content by EchoMRI and muscle function (grip strength and rotarod activity) in mice. Femur protein content of JAK2 and STAT3 was measured by ELISA kits, respectively. Bone defects are present in Ctns-/- mice throughout its first year of life. The deletion of the Mc4r gene attenuated bone disorder in Ctns-/- mice. Femoral BMD, bone area, length, and strength (failure load) were significantly increased in 9-month-old Ctns-/-Mc4r-/- mice than in age-matched Ctns-/- mice. PLA and AgRP treatment significantly increased femoral bone density (BMC/BMD) and mechanical strength in 12-month-old Ctns-/- mice. We adopted the pair-feeding approach for this study to show that the protective effects of PLA or AgRP on bone phenotype are independent of their potent orexigenic effect. Furthermore, an increase in lean mass and in vivo muscle function (grip strength and rotarod activity) are associated with improvements in bone phenotype (femoral BMC/BMD and mechanical strength) in Ctns-/- mice, suggesting a muscle-bone interplay. Decreased femur protein content of JAK2 and STAT3 was evident in Ctns-/- mice. PLA or AgRP treatment attenuated femur STAT3 content in Ctns-/- mice. Our findings suggest a significant role for dysregulated leptin signalling in INC-related bone disorder, either directly or potentially involving a muscle-bone interplay. Leptin signalling blockade may represent a novel approach to treating bone disease as well as muscle wasting in INC.

Explainable machine-learning-based prediction of QCT/FEA-calculated femoral strength under stance loading configuration using radiomics features.

Finite element analysis can provide precise femoral strength assessment. However, its modeling procedures were complex and time-consuming. This study aimed to develop a model to evaluate femoral strength calculated by quantitative computed tomography-based finite element analysis (QCT/FEA) under stance loading configuration, offering an effective, simple, and explainable method. One hundred participants with hip QCT images were selected from the Hong Kong part of the Osteoporotic fractures in men cohort. Radiomics features were extracted from QCT images. Filter method, Pearson correlation analysis, and least absolute shrinkage and selection operatormethod were employed for feature selection and dimension reduction. The remainingfeatures were utilized as inputs, and femoral strengths were calculated as the ground truth through QCT/FEA. Support vector regressionwas applied to develop a femoral strength prediction model. The influence of various numbers of input features on prediction performance was compared, and the femoral strength prediction model was established. Finally, Shapley additive explanation, accumulated local effects, and partial dependency plotmethods were used to explain the model. The results indicated that the model performed best when six radiomics features were selected. The coefficient of determination (R2), the root mean square error, the normalized root mean square error, and the mean squared erroron the testing set were 0.820, 1016.299 N, 10.645%, and 750.827 N, respectively. Additionally, these features all positively contributed to femoral strength prediction. In conclusion, this study provided a noninvasive, effective, and explainable method of femoral strength assessment, and it may have clinical application potential.

Effects of Two Types of Resistance Training Modalities (Hypertrophy vs. Contrast Training) on Bone Parameters in a Group of Healthy Elderly Women

The aim of the present study was to explore the effects of two types of resistance training modalities (hypertrophy training vs. contrast training) on bone health parameters in a group of healthy elderly women. Forty-nine healthy elderly women whose ages range between 60 and 70 years were included in this study. The study population was randomly divided into three groups: hypertrophy training group (HTG; n=16), contrast training group (CTG; n=16) and control group (CG; n=17). Bone mineral density (BMD) values at the whole body (WB), lumbar spine (L1-L4), total hip (TH) and femoral neck (FN) were measured by DXA before and after 12 months of resistance training. Composite indices of femoral neck strength were calculated. WB BMD, L1-L4 BMD, TH BMD and FN BMD increased in the contrast training group. WB BMD and L1-L4 BMD increased in the hypertrophy training group, while TH BMD and FN BMD remained unchanged. Significant decreases in WB BMD, L1-L4 BMD, TH BMD and FN BMD were observed in the control group. The contrast training group showed the highest improvements in BMD values compared to the two other groups. Both experimental groups (HTG and CTG) showed similar significant improvements in composite indices of femoral neck strength and muscular strength. In conclusion, contrast training and hypertrophy training can stimulate bone gain at clinically important sites of osteoporotic fractures in elderly women.

Association between composite indices of femoral neck strength and odds of hip fracture.

With the increased incidence of hip fractures worldwide, numerous studies have reported that composite indices of femoral neck strength can improve hip fracture risk assessment. This study aimed to assess the association between composite indices of femoral neck strength and the odds of hip fracture in Chinese adults. This retrospective cross-sectional study conducted at Changzhou Second People's Hospital included 937 Chinese adults (248 with hip fractures). After overnight fasting for ≥ 8h, blood samples were collected from all participants within 24h of admission. Composite indices of femoral neck strength were derived by combining bone mineral density, weight, and height with femoral axis length and width, which were measured by dual-energy X-ray absorptiometry. In total, 937 participants (293 men and 644 women) were enrolled. The mean age was 68.3years (SD 10.5). After adjusting for confounders, higher values of CSI and ISI were associated with a lower odd of hip fracture. Increase in CSI (per 1g/m·kg) was associated with a 46% decrease in the odd of hip fracture (OR = 0.54; 95% CI, 0.39-0.74), and increase in ISI (per 0.1g/m·kg) was associated with an 82% decrease (OR, 0.18; 95% CI, 0.11-0.30). Effect sizes of CSI and ISI on the odds of hip fracture remained robust and reliable in subgroup analyses. Increased CSI and ISI were associated with a lower odd of hip fracture, especially in women, suggesting that composite indices of femoral neck strength may provide useful information for improving hip fracture risk assessment.

The Morphology of the Femur Influences the Fracture Risk during Stumbling and Falls on the Hip-A Computational Biomechanical Study.

Proximal femur fracture risk depends on subject-specific factors such as bone mineral density and morphological parameters. Here, we aim to analyze the dependency of the femoral strength on sixteen morphological parameters. Therefore, finite-element analyses of 20 human femurs during stumbling and lateral falls on the hip were conducted. Pearson correlation coefficients were calculated and morphological parameters with significant correlations were examined in principal component analysis and linear regression analysis. The dependency of the fracture strength on morphological parameters was more pronounced during lateral falls on the hip compared to stumbling. Significant correlations were observed between the neck shaft angle (r = -0.474), neck diameter (r = 0.507), the true distance between the femoral head center and femoral shaft axis (r = 0.459), and its projected distance on the frontal plane (r = 0.511), greater trochanter height (r = 0.497), and distance between the femoral head center and a plane parallel to the frontal plane containing the projection of the femoral head center to the femoral neck axis (r = 0.669). Principal component analysis was strongly weighted by parameters defining the lever arm during a lateral fall as well as the loaded cross-section in the femoral neck.

Influence of test paradigm on loading dynamics during proximal femur fracture tests simulating sideways falls

Fall-related hip fractures are a serious public health issue in older adults. As most mechanistic hip fracture risk prediction models incorporate tissue tolerance, test methods that can accurately characterize the fracture force of the femur (and factors that influence it) are imperative. While bone possesses viscoelastic properties, experimental characterization of rate-dependencies has been inconsistent in the whole-femur literature. The goal of this study was to investigate the influence of experimental paradigm on loading rate and fracture force (both means and variability) during mechanical tests simulating lateral fall loadings on the proximal femur. Six pairs of matched femurs were split randomly between two test paradigms: a ‘lower rate’ materials testing system (MTS) with a constant displacement rate of 60 mm/s, and a hip impact test system (HIT) comprised of a custom-built vertical drop tower utilizing an impact velocity of 4 m/s. The loading rate was 88-fold higher for the HIT (mean (SD) = 2465.49 (807.38) kN/s) compared to the MTS (27.78 (10.03) kN/s) paradigm. However, no difference in fracture force was observed between test paradigms (mean (SD) = 4096.4 (1272.6) N for HIT, and 3641.3 (1285.8) N for MTS). Within-paradigm variability was not significantly different across paradigms for either loading rate or fracture force (coefficients of variation ranging from 0.311 to 0.361). Within each test paradigm, significant positive relationships were observed between loading rate and fracture force (HIT adjusted R2 = 0.833, p = 0.007; MTS adjusted R2 = 0.983, p < 0.0001). Overall, this study provides evidence that energy-based impact simulators can be a valid method to measure femoral bone strength in the context of fall-related hip fractures. This study motivates future research to characterize potential non-linear relationships between loading rate and fracture threshold at both macro and microscales.

Biomechanical evaluation of a central collinear entry reconstruction nail for femoral neck fracture prophylaxis

IntroductionReconstruction nails are commonly used to treat proximal femur fractures, with cephalic screw placement for femoral neck “prophylaxis” becoming standard practice. These implants are traditionally introduced through piriformis fossa (PF) or greater trochanter (GT) entry portals. A third “central collinear” (CC) portal has been proposed that allows entry along the femoral anatomic axis and central placement of cephalic screws. The present study aimed to quantify and compare the CC portal femoral neck strength with the two traditional (PF and GT) entry portals. Materials and MethodsEighteen cadaveric femur specimens (nine matched pairs) were divided into three groups using a balanced incomplete block design to control for variations in age and sex: (1) GT, (2) CC, and (3) PF entry points. Specimens and implants were cut to a standard length and instrumented with straight or valgus bend nails of appropriate laterality and two cephalic screws. Specimens were mounted on a custom jig replicating load distribution along the mechanical axis. A 100 N compressive preload was applied to the femoral head, followed by loading to failure at a rate of 10 mm/s until fracture, indicated by 30 % drop in axial force. Results: The three entry points did not differ in load-to-failureGT (6378.7 ± 1494.9 N), P (6912.4 ± 4924.1 N) and CC (7044.2 ± 2911.4 N) (P = 0.948) or maximum displacement, stiffness, and toughness. Most PF specimens failed at the basicervical neck, whereas most GT specimens failed at the subcapital neck; these differences were not significant. CC specimens failed evenly split between subcapital and basicervical. ConclusionThere were no significant difference in femoral neck load-to-failure after placement of a reconstruction nail through a CC entry portal when compared to both GT and PF entry. Clinically, this suggests the CC entry portal is a viable option when clinical considerations warrant its use.

Tibiofemoral bone configuration is not associated with hamstring muscle strength in male and female patients with ACL reconstruction.

Previous evidence indicated that the tibiofemoral bone configuration might elevate the risk of an anterior cruciate ligament (ACL) injury. Furthermore, a low hamstring-to-quadriceps muscle ratio predisposes especially females to unfavourable knee kinematics. The primary objective of the present study was to investigate sex-specific associations between tibiofemoral bone geometry and isokinetic knee flexion torque in patients with primary ACL injury followed by ACL reconstruction. N = 100 patients (72 = male, 28 = female, age = 31.3 ± 10.2, body mass index = 25.3 ± 3.6) with primary ACL rupture with isokinetic knee flexion torque assessments before and 6 months after ACL reconstruction surgery were analysed. Magnetic resonance imaging scans were analysed for medial posterior tibial slope (MPTS) and lateral posterior tibial slope, notch width index (NWI) and lateral femoral condyle index (LFCI). Additionally, isokinetic knee flexion torque (60°/s) and hamstring-quadriceps ratios were evaluated. Subsequently, functional parameters were correlated with imaging data for gender subgroups. The findings showed that presurgical isokinetic knee flexion torque was not associated with any marker of femoral or tibial bone geometry. Further, while significant differences were observed between female (0.883 ± 0.31 Nm/kg) and male (1.18 ± 0.35 Nm/kg) patients regarding preoperative normalized knee flexion torque (p < 0.001), no significant sex differences were found for percentage increases in normalized knee flexion torque from presurgery to postsurgery. Generally, female patients demonstrated significantly higher MPTS magnitudes (p < 0.05) and lower LFCI values (p < 0.05) compared to men. The present results demonstrated no association between tibial or femoral bone geometry and muscle strength of the hamstrings in patients with ACL reconstruction, indicating an important mismatch of muscular compensation to deviations in bone geometry. There were no sex-specific differences in tibiofemoral bone parameters. Level III.

Calcium-fortified fresh milk ameliorates postmenopausal osteoporosis via regulation of bone metabolism and gut microbiota in ovariectomized rats

The aging of the global population has made postmenopausal osteoporosis prevention essential; however, pharmacological treatments are limited. Herein, we evaluate the effect of calcium-fortified fresh milk (FM) in ameliorating postmenopausal osteoporosis in a rat model established using bilateral ovariectomy. After 3 months of FM (containing vitamin D, and casein phosphopeptides, 1000 mg Ca/100 g) or control milk (110 mg Ca/100 g milk) supplementation, bone changes were assessed using dual-energy X-ray absorptiometry, microcomputed tomography, and bone biomechanical testing. The results revealed that FM can regulate bone metabolism and gut microbiota composition, which act on bone metabolism through pathways associated with steroid hormone biosynthesis, relaxin signaling, serotonergic synapse, and unsaturated fatty acid biosynthesis. Furthermore, FM administration significantly increased bone mineral content and density in the lumbar spine and femur, as well as femoral compressive strength, while improving femoral trabecular bone parameters and microarchitecture. Mechanistically, we found that the effects may be due to increased levels of estrogen, bone formation marker osteocalcin, and procollagen type I N-propeptide, and decreased expression of the bone resorption marker C-telopeptide and tartrate-resistant acid phosphatase 5b. Overall, the findings suggest that FM is a potential alternative therapeutic option for ameliorating postmenopausal osteoporosis.

Cognitive Decline, Depression, and Sarcopenia: A risk for home care

Abstract Background: The aging process involves a decline in mental and physical abilities. Objective: The aim of this study is to assess the relationship between cognitive decline, depression, and sarcopenia in the community-dwelling elderly population. Methods: This is a quantitative, cross-sectional study. The evaluations were started with a form that contained information of body characteristics (age, sex, height, weight, Body Mass Index, Total Muscle Mass, Total Muscle Mass Index, Abdominal Circumference), sarcopenia characteristics (Calf Circumference, Timed Up and Go Test, Walking Speed Test, Sit and Stand Test, Handgrip Strength Test, and Quadriceps Femoral Strength Test), for the assessment of cognitive decline (Clock Drawing Test), and for depression (Geriatric Depression Scale). Results: A total of 266 community-dwelling elderly people participated in this study, of whom 1/3 had pre-sarcopenia. It was possible to verify that in the Clock Drawing Test (p=0.037) and in the Geriatric Depression Scale (p=0.001), as well as in their question repartition, the group of elderly with pre-sarcopenia presented the worst results. Conclusion: At the end of the study, it was possible to conclude that cognitive decline, depression, and sarcopenia, in fact, are associated. Keywords: Aged, Cognitive Decline, Depression, Sarcopenia.

Relationship between Femur Mineral Content and Local Muscle Strength and Mass.

Among the stimuli able to prevent early decreases in bone mineralization, exercise has a noticeable role per se as the source of mechanical stimulus or through lean tissue enlargement by its increasing of tensional stimulus. However, prevention strategies, including exercise, generally do not establish the moment in life when attention should begin to be paid to bone integrity, according to age group- and sex-related differences. Thus, this study analyzed the relationship between variables from the diagnosis of total and regional body composition, muscle strength, and bone mineral content (BMC) of femurs in young adult males. Thirty-four young Caucasian men (24.9 ± 8.6 years) had their body composition and bone density assessed by dual X-ray absorptiometry. The subjects performed a one-repetition maximum test (1-RM) in a bench press, front pulley, seated-row, push press, arm curl, triceps pulley, leg flexion, leg extension, and 45° leg press for the assessment of muscle strength in upper and lower limbs in single- and multi-joint exercises. Lean tissue mass in the trunk and upper and lower limbs were related to femoral BMC (Pearson coefficient ranging from 0.55 to 0.72, p < 0.01), and 1-RM values for different exercises involving both upper and lower limbs also correlated with femoral BMC (Pearson coefficients ranging from 0.34 to 0.46, p < 0.05). Taken together, these correlations suggest that muscle mass and strength are positively linked with the magnitude of femoral mass in men, even in early adulthood. Hence, the importance of an enhanced muscle mass and strength to the health of femoral bones in young adults was highlighted.

Mitofusin 2 plays a critical role in maintaining the functional integrity of the neuromuscular-skeletal axis

PurposeMitofusin 2 (Mfn2) is one of two mitofusins involved in regulating mitochondrial size, shape and function, including mitophagy, an important cellular mechanism to limit oxidative stress. Reduced expression of Mfn2 has been associated with impaired osteoblast differentiation and function and a reduction in the number of viable osteocytes in bone. We hypothesized that the genetic absence of Mfn2 in these cells would increase their susceptibility to aging-associated metabolic stress, leading to a progressive impairment in skeletal homeostasis over time. MethodsMfn2 was selectively deleted in vivo at three different stages of osteoblast lineage commitment by crossing mice in which the Mfn2 gene was floxed with transgenic mice expressing Cre under the control of the promoter for Osterix (OSX), collagen1a1, or DMP1 (Dentin Matrix Acidic Phosphoprotein 1). ResultsMice in which Mfn2 was deleted using DMP1-cre demonstrated a progressive and dramatic decline in bone mineral density (BMD) beginning at 10 weeks of age (n = 5 for each sex and each genotype from age 10 to 20 weeks). By 15 weeks, there was evidence for a functional decline in muscle performance as assessed using a rotarod apparatus (n = 3; 2 males/ 1 female for each genotype), accompanied by a decline in lean body mass. A marked reduction in trabecular bone mass was evident on bone histomorphometry, and biomechanical testing at 25 weeks (k/o: 2 male/1 female, control 2 male/2 female) revealed severely impaired femur strength. Extensive regional myofiber atrophy and degeneration was observed on skeletal muscle histology. Electron microscopy showed progressive disruption of cellular architecture, with disorganized sarcomeres and a bloated mitochondrial reticulum. There was also evidence of neurodegeneration within the ventral horn and roots of the lumbar spinal cord, which was accompanied by myelin loss and myofiber atrophy. Deletion of Mfn2 using OSX-cre or Col1a1-cre did not result in a musculoskeletal phenotype. Where possible, male and female animals were analyzed separately, but small numbers of animals in each group limited statistical power. For other outcomes, where sex was not considered, small sample sizes might still limit the strength of the observation. ConclusionDespite known functional overlap of Mfn1 and Mfn2 in some tissues, and their co-expression in bone, muscle and spinal cord, deletion of Mfn2 using the 8 kB DMP1 promoter uncovered an important non-redundant role for Mfn2 in maintaining the neuromuscular/bone axis.

Magnetic resonance imaging based finite element modelling of the proximal femur: a short-term in vivo precision study

Proximal femoral fractures are a serious life-threatening injury with high morbidity and mortality. Magnetic resonance (MR) imaging has potential to non-invasively assess proximal femoral bone strength in vivo through usage of finite element (FE) modelling (a technique referred to as MR-FE). To precisely assess bone strength, knowledge of measurement error associated with different MR-FE outcomes is needed. The objective of this study was to characterize the short-term in vivo precision errors of MR-FE outcomes (e.g., stress, strain, failure loads) of the proximal femur for fall and stance loading configurations using 13 participants (5 males and 8 females; median age: 27 years, range: 21–68), each scanned 3 times. MR-FE models were generated, and mean von Mises stress and strain as well as principal stress and strain were calculated for 3 regions of interest. Similarly, we calculated the failure loads to cause 5% of contiguous elements to fail according to the von Mises yield, Brittle Coulomb-Mohr, normal principal, and Hoffman stress and strain criteria. Precision (root-mean squared coefficient of variation) of the MR-FE outcomes ranged from 3.3% to 11.8% for stress and strain-based mechanical outcomes, and 5.8% to 9.0% for failure loads. These results provide evidence that MR-FE outcomes are a promising non-invasive technique for monitoring femoral strength in vivo.

A Controlled Variable Study of the Biomechanical Properties of the Proximal Femur before and after Cancellous Bone Removal.

The biomechanical characteristics of proximal femoral trabeculae are closely related to the occurrence and treatment of proximal femoral fractures. Therefore, it is of great significance to study its biomechanical effects of cancellous bone in the proximal femur. This study examines the biomechanical effects of the cancellous bone in the proximal femur using a controlled variable method, which provide a foundation for further research into the mechanical properties of the proximal femur. Seventeen proximal femoral specimens were selected to scan by quantitative computed tomography (QCT), and the gray values of nine regions were measure to evaluated bone mineral density (BMD) using Mimics software. Then, an intact femur was fixed simulating unilateral standing position. Vertical compression experiments were then performed again after removing cancellous bone in the femoral head, femoral neck, and intertrochanteric region, and data were recorded. According to the controlled variable method, the femoral head, femoral neck, and intertrochanteric trabeculae were sequentially removed based on the axial loading of the intact femur, and the displacement and strain changes of the femur samples under axial loading were recorded. Gom software was used to measure and record displacement and strain maps of the femoral surface. There was a statistically significant difference in anteroposterior displacement of cancellous bone destruction in the proximal femur (p < 0.001). Proximal femoral bone mass explained 77.5% of the strength variation, in addition proximal femoral strength was mainly affected by bone mass at the level of the upper outer, lower inner, lower greater trochanter, and lesser trochanter of the femoral head. The normal stress conduction of the proximal femur was destroyed after removing cancellous bone, the stress was concentrated in the femoral head and lateral femoral neck, and the femoral head showed a tendency to subside after destroying cancellous bone. The trabecular removal significantly altered the strain distribution and biomechanical strength of the proximal femur, demonstrating an important role in supporting and transforming bending moment under the vertical load. In addition, the strength of the proximal femur mainly depends on the bone density of the femoral head and intertrochanteric region.

3D-DXA Based Finite Element Modelling for Femur Strength Prediction: Evaluation Against QCT.

Osteoporosis is characterised by the loss of bone density resulting in an increased risk of fragility fractures. The clinical gold standard for diagnosing osteoporosis is based on the areal bone mineral density (aBMD) used as a surrogate for bone strength, in combination with clinical risk factors. Finite element (FE) analyses based on quantitative computed tomography (QCT) have been shown to estimate bone strength better than aBMD. However, their application in the osteoporosis clinics is limited due to exposure of patients to increased X-rays radiation dose. Statistical modelling methods (3D-DXA) enabling the estimation of 3D femur shape and volumetric bone density from dual energy X-ray absorptiometry (DXA) scan have been shown to improve osteoporosis management. The current study used 3D-DXA based FE analyses to estimate femur strength from the routine clinical DXA scans and compared its results against 151 QCT based FE analyses, in a clinical cohort of 157 subjects. The linear regression between the femur strength predicted by QCT-FE and 3D-DXA-FE models correlated highly (coefficient of determination R2 = 0.86) with a root mean square error (RMSE) of 397 N. In conclusion, the current study presented a 3D-DXA-FE modelling tool providing accurate femur strength estimates noninvasively, compared to QCT-FE models.

Deletion of the auxiliary α2δ1 voltage sensitive calcium channel subunit in osteocytes and late-stage osteoblasts impairs femur strength and load-induced bone formation in male mice.

Osteocytes sense and respond to mechanical force by controlling the activity of other bone cells. However, the mechanisms by which osteocytes sense mechanical input and transmit biological signals remain unclear. Voltage-sensitive calcium channels (VSCCs) regulate calcium (Ca2+) influx in response to external stimuli. Inhibition or deletion of VSCCs impairs osteogenesis and skeletal responses to mechanical loading. VSCC activity is influenced by its auxiliary subunits, which bind the channel's α1 pore-forming subunit to alter intracellular Ca2+ concentrations. The α2δ1 auxiliary subunit associates with the pore-forming subunit via a glycosylphosphatidylinositol anchor and regulates the channel's calcium-gating kinetics. Knockdown of α2δ1 in osteocytes impairs responses to membrane stretch, and global deletion of α2δ1 in mice results in osteopenia and impaired skeletal responses to loading in vivo. Therefore, we hypothesized that the α2δ1 subunit functions as a mechanotransducer, and its deletion in osteocytes would impair skeletal development and load-induced bone formation. Mice (C57BL/6) with LoxP sequences flanking Cacna2d1, the gene encoding α2δ1, were crossed with mice expressing Cre under the control of the Dmp1 promoter (10kb). Deletion of α2δ1 in osteocytes and late-stage osteoblasts decreased femoral bone quantity (P < .05) by DXA, reduced relative osteoid surface (P < .05), and altered osteoblast and osteocyte regulatory gene expression (P < .01). Cacna2d1f/f, Cre + male mice displayed decreased femoral strength and lower 10-wk cancellous bone in vivo micro-computed tomography measurements at the proximal tibia (P < .01) compared to controls, whereas Cacna2d1f/f, Cre + female mice showed impaired 20-wk cancellous and cortical bone ex vivo micro-computed tomography measurements (P < .05) vs controls. Deletion of α2δ1 in osteocytes and late-stage osteoblasts suppressed load-induced calcium signaling in vivo and decreased anabolic responses to mechanical loading in male mice, demonstrating decreased mechanosensitivity. Collectively, the α2δ1 auxiliary subunit is essential for the regulation of osteoid-formation, femur strength, and load-induced bone formation in male mice.