Treatment of bone loss in proximal femurs of postmenopausal osteoporotic women with AGN1 local osteo-enhancement procedure (LOEP) increases hip bone mineral density and hip strength: a long-term prospective cohort study.

This first-in-human study of AGN1 LOEP demonstrated that this minimally-invasive treatment durably increased aBMD in femurs of osteoporotic postmenopausal women. AGN1 resorption was coupled with new bone formation by 12 weeks and that new bone was maintained for at least 5-7 years resulting in substantially increased FEA-estimated femoral strength. INTRODUCTION: This first-in-human study evaluated feasibility, safety, and in vivo response to treating proximal femurs of postmenopausal osteoporotic women with a minimally-invasive local osteo-enhancement procedure (LOEP) to inject a resorbable triphasic osteoconductive implant material (AGN1). METHODS: This prospective cohort study enrolled 12 postmenopausal osteoporotic (femoral neck T-score ≤ - 2.5) women aged 56 to 89 years. AGN1 LOEP was performed on left femurs; right femurs were untreated controls. Subjects were followed-up for 5-7 years. Outcomes included adverse events, proximal femur areal bone mineral density (aBMD), AGN1 resorption, and replacement with bone by X-ray and CT, and finite element analysis (FEA) estimated hip strength. RESULTS: Baseline treated and control femoral neck aBMD was equivalent. Treated femoral neck aBMD increased by 68 ± 22%, 59 ± 24%, and 58 ± 27% over control at 12 and 24 weeks and 5-7 years, respectively (p < 0.001, all time points). Using conservative assumptions, FEA-estimated femoral strength increased by 41%, 37%, and 22% at 12 and 24 weeks and 5-7 years, respectively (p < 0.01, all time points). Qualitative analysis of X-ray and CT scans demonstrated that AGN1 resorption and replacement with bone was nearly complete by 24 weeks. By 5-7 years, AGN1 appeared to be fully resorbed and replaced with bone integrated with surrounding trabecular and cortical bone. No procedure- or device-related serious adverse events (SAEs) occurred. CONCLUSIONS: Treating femurs of postmenopausal osteoporotic women with AGN1 LOEP results in a rapid, durable increase in aBMD and femoral strength. These results support the use and further clinical study of this approach in osteoporotic patients at high risk of hip fracture.

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 operator method were employed for feature selection and dimension reduction. The remaining features were utilized as inputs, and femoral strengths were calculated as the ground truth through QCT/FEA. Support vector regression was 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 plot methods 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 error on 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.

Prediction of Femoral Strength Based on Bone Density and Biochemical Markers in Elderly Men With Type 2 Diabetes Mellitus.

Purpose: Effects of bone density, bone turnover and advanced glycation end products (AGEs) on femoral strength (FS) are still unclear in patients with type 2 diabetes mellitus (T2DM). This study aims to assess and predict femoral strength and its influencing factors in elderly men with T2DM. Methods: T2DM patients (n = 10, mean age, 66.98 years) and age-matched controls (n = 8, mean age, 60.38 years) were recruited. Femoral bone mineral density (BMD) and serum biochemical indices of all subjects were measured. FS was evaluated through finite element analysis based on quantitative computed tomography. Multiple linear regression was performed to obtain the best predictive models of FS and to analyze the ability of predictors of FS in both groups. Results: FS (p = 0.034), HbA1c (p = 0.000) and fasting blood glucose (p = 0.000) levels of T2DM group were significantly higher than those of control group; however, the P1NP level (p = 0.034) was significantly lower. FS was positively correlated with femoral neck T score (FNTS) (r = 0.794, p < 0.01; r = 0.881, p < 0.01) in both groups. FS was correlated with age (r = -0.750, p < 0.05) and pentosidine (r = -0.673, p < 0.05) in T2DM group. According to multiple linear regression, FNTS and P1NP both contributed to FS in two groups. P1NP significantly improved the prediction of FS in both groups, but significant effect of FNTS on predicting FS was only presented in control group. Furthermore, pentosidine, age and HbA1c all played significant roles in predicting FS of T2DM. Conclusion: Femoral strength was higher in elderly men with T2DM, which might be caused by higher BMD and lower bone turnover rate. Moreover, besides BMD and bone formation level, AGEs, blood glucose and age might significantly impact the prediction of femoral strength in T2DM.

Investigation on distal femoral strength and reconstruction failure following curettage and cementation: In-vitro tests with finite element analyses.

Cement augmentation following benign bone tumor surgery, i.e. curettage and cementation, is recommended in patients at high risk of fracture. Nonetheless, identifying appropriate cases and devices for augmentation remains debatable. Our goal was to develop a validated biomechanical tool to: predict the post-surgery strength of a femoral bone, assess the precision and accuracy of the predicted strength, and discover the mechanisms of reconstruction failure, with the aim of finding a safe biomechanical fixation. Tumor surgery was mimicked in quantitative-CT (QCT) scanned cadaveric human distal femora, and subsequently tested in compression to measure bone strength (FExp). Finite element (FE) models considering bone material non-homogeneity and non-linearity were constructed to predict bone strength (FFE). Analyses of contact, damage, and crack initiation at the bone-cement interface (BCI) were completed to investigate critical failure locations. Results of paired t-tests did not show a significant difference between FExp and FFE (P > 0.05); linear regression analysis resulted in good correlation between FExp and FFE (R2 = 0.94). Evaluation of the models precision using linear regression analysis yielded R2 = 0.89, with the slope = 1.08 and intercept = -324.16 N. FE analyses showed the initiation of damage and crack and a larger cement debonding area at the proximal end and most interior part of BCI, respectively. Therefore, we speculated that devices that reinforce critical failure locations offer the most biomechanical advantage. The QCT-based FE method proved to be a reliable tool to predict distal femoral strength, identify some causes of reconstruction failure, and assist in a safer selection of fixation devices to reduce post-operative fracture risk.

Comparison of femoral strength and fracture risk index derived from DXA-based finite element analysis for stratifying hip fracture risk: A cross-sectional study.

BACKGROUND: Dual-energy X-ray absorptiometry (DXA)-based finite element analysis (FEA) has been studied for assessment of hip fracture risk. Femoral strength (FS) is the maximum force that the femur can sustain before its weakest region reaches the yielding limit. Fracture risk index (FRI), which also considers subject-specific impact force, is defined as the ratio of von Mises stress induced by a sideways fall to the bone yield stress over the proximal femur. We compared risk stratification for prior hip fracture using FS and FRI derived from DXA-based FEA. METHODS: The study cohort included women aged ≥65years undergoing baseline hip DXA, with femoral neck T-scores <-1 and no osteoporosis treatment; 324 cases had prior hip fracture and 655 controls had no prior fracture. Using anonymized DXA hip scans, we measured FS and FRI. Separate multivariable logistic regression models were used to estimate odds ratios (ORs), c-statistics and their 95% confidence intervals (95% CIs) for the association of hip fracture with FS and FRI. RESULTS: Increased hip fracture risk was associated with lower FS (OR per SD 1.36, 95% CI: 1.15, 1.62) and higher FRI (OR per SD 1.99, 95% CI: 1.63, 2.43) after adjusting for Fracture Risk Assessment Tool (FRAX) hip fracture probability computed with bone mineral density (BMD). The c-statistic for the model containing FS (0.69; 95% CI: 0.65, 0.72) was lower than the c-statistic for the model with FRI (0.77; 95% CI: 0.74, 0.80) or femoral neck BMD (0.74; 95% CI: 0.71, 0.77; all P<0.05). CONCLUSIONS: FS and FRI were independently associated with hip fracture, but there were differences in performance characteristics.

Comparison of non-invasive assessments of strength of the proximal femur.

It is not clear which non-invasive method is most effective for predicting strength of the proximal femur in those at highest risk of fracture. The primary aim of this study was to compare the abilities of dual energy X-ray absorptiometry (DXA)-derived aBMD, quantitative computed tomography (QCT)-derived density and volume measures, and finite element analysis (FEA)-estimated strength to predict femoral failure load. We also evaluated the contribution of cortical and trabecular bone measurements to proximal femur strength. We obtained 76 human cadaveric proximal femurs (50 women and 26 men; age 74±8.8years), performed imaging with DXA and QCT, and mechanically tested the femurs to failure in a sideways fall configuration at a high loading rate. Linear regression analysis was used to construct the predictive model between imaging outcomes and experimentally-measured femoral strength for each method. To compare the performance of each method we used 3-fold cross validation repeated 10 times. The bone strength estimated by QCT-based FEA predicted femoral failure load (R2adj=0.78, 95%CI 0.76-0.80; RMSE=896N, 95%CI 830-961) significantly better than femoral neck aBMD by DXA (R2adj=0.69, 95%CI 0.66-0.72; RMSE=1011N, 95%CI 952-1069) and the QCT-based model (R2adj=0.73, 95%CI 0.71-0.75; RMSE=932N, 95%CI 879-985). Both cortical and trabecular bone contribute to femoral strength, the contribution of cortical bone being higher in femurs with lower trabecular bone density. These findings have implications for optimizing clinical approaches to assess hip fracture risk. In addition, our findings provide new insights that will assist in interpretation of the effects of osteoporosis treatments that preferentially impact cortical versus trabecular bone.

Femoral volumetric bone density, geometry, and strength in relation to 25-hydroxy vitamin D in older men.

Low serum 25-hydroxy vitamin D (25(OH)D) concentrations are associated with increased hip fracture risk and decreased femoral areal bone mineral density (BMD) among elderly men. Structural dimensions of the proximal femur and volumetric BMD in cortical and trabecular compartments are also associated with hip fracture risk. However, associations of volumetric BMD or structural dimensions with serum 25(OH)D concentrations among older men remain unclear. In a random sample of 1608 men aged ≥65 years from the Osteoporotic Fractures in Men Study (MrOS), baseline serum 25(OH)D concentrations were measured by liquid chromatography/mass spectrometry assays. Femoral neck geometry and volumetric BMD derived from quantitative computed tomography included integral, cortical, and trabecular volumetric BMD; cross-sectional area; integral and cortical volume; and cortical volume as a percent of integral volume. We studied 888 men with vitamin D, parathyroid hormone (PTH), femoral neck geometry, and BMD measures. Whole-bone femoral strength and load-strength ratio from finite element (FE) analysis were also available for 356 men from this sample. Multivariable linear regression was used to estimate least square means of each femoral measure within quartiles of 25(OH)D adjusted for age, race, body mass index, height, latitude, and season of blood draw. Tests of linear trend in the means were performed across increasing quartile of serum 25(OH)D levels. Mean cortical volume (p trend = 0.006) and cortical volume as a percent of integral volume (p trend < 0.001) increased across increasing quartile of 25(OH)D level. However, overall femoral neck size (area and integral volume) did not vary by 25(OH)D level. Femoral neck volumetric BMD measures increased in a graded manner with higher 25(OH)D levels (p trend < 0.001). Femoral strength, but not load-strength ratio, increased with increasing 25(OH)D. Adjustment for PTH did not materially change these associations. We conclude that in older men, higher levels of endogenous 25(OH)D may increase whole-bone strength by increasing femoral volumetric BMD and cortical volume.

Orthotropic HR-pQCT-based FE models improve strength predictions for stance but not for side-way fall loading compared to isotropic QCT-based FE models of human femurs.

Quantitative computed tomography (QCT) based nonlinear homogenized finite element (hFE) models of the human femur do not take bone׳s microstructure into account due to the low resolution of the QCT images. Models based on high-resolution peripheral quantitative computed tomography (HR-pQCT) are able to include trabecular orientation and allow the modeling of a cortical shell. Such a model showed improvements compared to QCT-based models when studying human vertebral bodies. The goal of this study was to compare the femoral strength prediction ability of subject specific nonlinear homogenized FE (hFE) models based on HR-pQCT and QCT images. Thirty-six pairs of femurs were scanned with QCT as well as HR-pQCT, and tested in one-legged stance (STANCE) and side-ways fall (SIDE) configurations up to failure. Non-linear hFE models were generated from HR-pQCT images (smooth meshes) and compared to recently published QCT based models (voxel meshes) as well as experiments with respect to ultimate force. HR-pQCT-based hFE models improved ultimate force (R(2)=0.87 vs 0.80, p=0.02) predictions only in STANCE configuration but not in SIDE (R(2)=0.86 vs 0.84, p=0.6). Damage locations were similar for both types of models. In conclusion, it was shown for the first time on a large femur dataset that a more accurate representation of trabecular orientation and cortex only improve FE predictions in STANCE configuration, where the main trabecular orientation is aligned with the load direction. In the clinically more relevant SIDE configuration, the improvements were not significant.

Does cam osteochondroplasty compromise proximal femur strength?

Little is known about the effect on load bearing ability of cam-type femurs following osteochondroplasty. The aim of this study was to compare the change in deformation undergone by cam-type femoral acetabular impingement femur models after resection of different volumes. Dry-bone replicas (N = 10) of two cam-type femurs (cam A and B) underwent resections of increasing volume (Surgery I, II and III) representing conservative, adequate and radical resections. Deformation under cyclic loading of 700 N for five cycles after each surgery was compared. The 360° alpha angle and the change in head to neck ratio at four equidistant points along the femoral neck were used as measures of surgical efficacy and volume resected. Intact cam A and B replicas had a maximum alpha angle of 88° and 90°, respectively, which were reduced to 55° and 54° post Surgery I. Cam A replicas showed a significant reduction (p < 0.01) in mean axial displacement after Surgery I (up to 10% reduction in neck volume) and an increase after Surgery III (~20%-40% reduction in neck volume) compared to unresected controls (p < 0.01). Surgery II (~10%-15% reduction in neck volume) produced no significant change in mean displacement (p > 0.05). Cam B models exhibited lower mean displacement after Surgery I, II and III (p < 0.01) compared to unresected controls. Conservative surgery appears to improve the axial load bearing ability of dry-bone models. Radical resections may significantly decrease the fracture-resistant properties of bone following osteochondroplasty which should be noted when planning such a procedure.

Effect of finite element model loading condition on fracture risk assessment in men and women: the AGES-Reykjavik study.

Proximal femoral (hip) strength computed by subject-specific CT scan-based finite element (FE) models has been explored as an improved measure for identifying subjects at risk of hip fracture. However, to our knowledge, no published study has reported the effect of loading condition on the association between incident hip fracture and hip strength. In the present study, we performed a nested age- and sex-matched case-control study in the Age Gene/Environment Susceptibility (AGES) Reykjavik cohort. Baseline (pre-fracture) quantitative CT (QCT) scans of 5500 older male and female subjects were obtained. During 4-7years follow-up, 51 men and 77 women sustained hip fractures. Ninety-seven men and 152 women were randomly selected as controls from a pool of age- and sex-matched subjects. From the QCT data, FE models employing nonlinear material properties computed FE-strength of the left hip of each subject in loading from a fall onto the posterolateral (FPL), posterior (FP) and lateral (FL) aspects of the greater trochanter (patent pending). For comparison, FE strength in stance loading (FStance) and total femur areal bone mineral density (aBMD) were also computed. For all loading conditions, the reductions in strength associated with fracture in men were more than twice those in women (p≤0.01). For fall loading specifically, posterolateral loading in men and posterior loading in women were most strongly associated with incident hip fracture. After adjusting for aBMD, the association between FP and fracture in women fell short of statistical significance (p=0.08), indicating that FE strength provides little advantage over aBMD for identifying female hip fracture subjects. However, in men, after controlling for aBMD, FPL was 424N (11%) less in subjects with fractures than in controls (p=0.003). Thus, in men, FE models of posterolateral loading include information about incident hip fracture beyond that in aBMD.