E. Tanck

Pathological fracture prediction in patients with metastatic lesions can be improved with quantitative computed tomography based computer models.

PURPOSE In clinical practice, there is an urgent need to improve the prediction of fracture risk for cancer patients with bone metastases. The methods that are currently used to estimate fracture risk are dissatisfying, hence affecting the quality of life of patients with a limited life expectancy. The purpose of this study was to assess if non-linear finite element (FE) computer models, which are based on Quantitative Computer Tomography (QCT), are better than clinical experts in predicting bone strength. MATERIALS AND METHODS Ten human cadaver femurs were scanned using QCT. In one femur of each pair a hole (size 22, 40, or 45 mm diameter) was drilled at the anterior or medial side to simulate a metastatic lesion. All femurs were mechanically tested to failure under single-limb stance-type loading. The failure force was calculated using non-linear FE-models, and six clinical experts were asked to rank the femurs from weak to strong based on X-rays, gender, age, and the loading protocol. Kendall Tau correlation coefficients were calculated to compare the predictions of the FE-model with the predictions of the clinicians. RESULTS The FE-failure predictions correlated strongly with the experimental failure force (r(2)=0.92, p<0.001). For the clinical experts, the Kendall Tau coefficient between the experimental ranking and predicted ranking ranged between tau=0.39 and tau=0.72, whereas this coefficient was considerably higher (tau=0.78) for the FE-model. CONCLUSION This study showed that the use of a non-linear FE-model can improve the prediction of bone strength compared to the prediction by clinical experts.

Predictive value of femoral head heterogeneity for fracture risk.

Osteoporosis (OP) is characterized by low bone mass and weak bone structure, which results in increased fracture risk. It has been suggested that osteoporotic bone is strongly adapted to the main loading direction and less adapted to the other directions. In this study, we hypothesized that osteoporotic femoral heads have 1) an increased anisotropy; 2) a more heterogenic distribution of bone volume fraction (BV/TV) throughout the femoral head; and, 3) a more heterogenic distribution of the trabecular thickness (Tb.Th.) throughout the femoral head, as compared to non-osteoporotic bone. To test these hypotheses, we used 7 osteoporotic femoral heads from patients who fractured their femoral neck and 7 non-fractured femoral heads from patients with osteoarthrosis (OA). Bone structural parameters from the entire trabecular region were analyzed using microCT. We found that the degree of anisotropy was higher in the fractured femoral heads, i.e. 1.72, compared to a value of 1.61 in the non-fractured femoral heads. The BV/TV and Tb.Th. and their variations throughout the femoral head, however, were all significantly lower in the fractured group. Hence, the first hypothesis was confirmed, whereas the other two were rejected. Interestingly, the variation of Tb.Th. throughout the femoral head provided a 100% discrimination between the OP and OA groups, i.e. for the same BV/TV, all fractured cases had a less heterogenic distribution. In conclusion, our results suggest that bone loss in OP takes place uniformly throughout the femoral head, leading to an overall decrease in bone mass and trabecular thickness. Furthermore, the variation of Tb.Th. in the femoral head could be an interesting parameter to improve the prediction of fracture risk in the proximal femur.

The assessment of the risk of fracture in femora with metastatic lesions: Comparing case-specific finite element analyses with predictions by clinical experts

Previously, we showed that case-specific non-linear finite element (FE) models are better at predicting the load to failure of metastatic femora than experienced clinicians. In this study we improved our FE modelling and increased the number of femora and characteristics of the lesions. We retested the robustness of the FE predictions and assessed why clinicians have difficulty in estimating the load to failure of metastatic femora. A total of 20 femora with and without artificial metastases were mechanically loaded until failure. These experiments were simulated using case-specific FE models. Six clinicians ranked the femora on load to failure and reported their ranking strategies. The experimental load to failure for intact and metastatic femora was well predicted by the FE models (R(2) = 0.90 and R(2) = 0.93, respectively). Ranking metastatic femora on load to failure was well performed by the FE models (τ = 0.87), but not by the clinicians (0.11 < τ < 0.42). Both the FE models and the clinicians allowed for the characteristics of the lesions, but only the FE models incorporated the initial bone strength, which is essential for accurately predicting the risk of fracture. Accurate prediction of the risk of fracture should be made possible for clinicians by further developing FE models.

Implementation of asymmetric yielding in case-specific finite element models improves the prediction of femoral fractures

Although asymmetric yielding in bone is widely shown in experimental studies, previous case-specific non-linear finite element (FE) studies have mainly adopted material behaviour using the Von Mises yield criterion (VMYC), assuming equal bone strength in tension and compression. In this study, it was verified that asymmetric yielding in FE models can be captured using the Drucker–Prager yield criterion (DPYC), and can provide better results than simulations using the VMYC. A sensitivity analysis on parameters defining the DPYC (i.e. the degree of yield asymmetry and the yield stress settings) was performed, focusing on the effect on bone failure. In this study, the implementation of a larger degree of yield asymmetry improved the prediction of the fracture location; variations in the yield stress mainly affected the predicted failure force. We conclude that the implementation of asymmetric yielding in case-specific FE models improves the prediction of femoral bone strength.

The fracture risk of adjacent vertebrae is increased by the changed loading direction after a wedge fracture

Study Design. In vitro biomechanical study. Objective. To measure the effect that off-axis vertebral loading has on the stiffness and failure load of vertebrae. Summary of Background Data. Adjacent level vertebral fractures not only are common in patients who received a vertebroplasty treatment but also occur in patients with conservatively treated wedge fractures. The wedge-like deformity, which is present in both groups, changes the spinal alignment. The load of vertebrae adjacent to the fractured vertebra will change from perpendicular to the endplate to a more shearing, off-axis, load. This change may induce a higher fracture risk for vertebrae adjacent to wedge-like deformed vertebrae. Methods. Twenty vertebrae, harvested from one osteopenic cadaver spine and three osteoporotic cadaver spines, were loaded until failure. The vertebrae were loaded either perpendicular to the upper endplate, representing vertebrae in a spine without wedge fractures (0° group, n = 10), or at an angle of 20°, representing vertebrae adjacent to a wedge fracture (20° groups, n = 10). Vertebral failure load and stiffness were the most important outcome measures. Results. The failure load was significantly higher (P = 0.028) when tested at 0° (2854 N, SD = 622 N), compared with vertebrae tested at 20° (2162 N, SD = 670 N). Vertebrae were also significantly stiffer (P < 0.001) when tested at 0° (4017 N/mm, SD = 970 N/mm) than those tested at 20° (2478 N/mm, SD = 453 N/mm). Conclusion. The failure load of osteopenic/osteoporotic vertebrae was 24% lower under off-axis loads (20°) than under axial loads (0°). This study may lead to a better understanding of the etiology of adjacent vertebral fractures after wedge-like deformities and demonstrates the importance of height reconstruction of wedge fractures in order to normalize the loading conditions on adjacent vertebrae.

Finite element analysis and CT-based structural rigidity analysis to assess failure load in bones with simulated lytic defects

There is an urgent need to improve the prediction of fracture risk for cancer patients with bone metastases. Pathological fractures that result from these tumors frequently occur in the femur. It is extremely difficult to determine the fracture risk even for experienced physicians. Although evolving, fracture risk assessment is still based on inaccurate predictors estimated from previous retrospective studies. As a result, many patients are surgically over-treated, whereas other patients may fracture their bones against expectations. We mechanically tested ten pairs of human cadaveric femurs to failure, where one of each pair had an artificial defect simulating typical metastatic lesions. Prior to testing, finite element (FE) models were generated and computed tomography rigidity analysis (CTRA) was performed to obtain axial and bending rigidity measurements. We compared the two techniques on their capacity to assess femoral failure load by using linear regression techniques, Students t-tests, the Bland-Altman methodology and Kendall rank correlation coefficients. The simulated FE failure loads and CTRA predictions showed good correlation with values obtained from the experimental mechanical testing. Kendall rank correlation coefficients between the FE rankings and the CTRA rankings showed moderate to good correlations. No significant differences in prediction accuracy were found between the two methods. Non-invasive fracture risk assessment techniques currently developed both correlated well with actual failure loads in mechanical testing suggesting that both methods could be further developed into a tool that can be used in clinical practice. The results in this study showed slight differences between the methods, yet validation in prospective patient studies should confirm these preliminary findings.

Prophylactic vertebroplasty can decrease the fracture risk of adjacent vertebrae: An in vitro cadaveric study

Adjacent level vertebral fractures are common in patients with osteoporotic wedge fractures, but can theoretically be prevented with prophylactic vertebroplasty. Previous tests on prophylactic vertebroplasties have been performed under axial loading, while in vivo changes in spinal alignment likely cause off-axis loads. In this study we determined whether prophylactic vertebroplasty can also reduce the fracture risk under off-axis loads. In a previous study, we tested vertebral bodies that were loaded axially or 20° off-axis representing vertebrae in an unfractured spine or vertebrae adjacent to a wedge fracture, respectively. In the current study, vertebral failure load and stiffness of our previously tested vertebral bodies were compared to those of a new group of vertebral bodies that were filled with bone cement and then loaded 20° off-axis. These vertebral bodies represented adjacent-level vertebrae with prophylactic bone cement filling. Prophylactic augmentation resulted in failure loads that were comparable to those of the 0° group, and 32% greater than the failure loads of the 20° group. The stiffness of the prophylacticly augmented vertebrae was 21% lower than that of the 0° group, but 27% higher than that of the 20° group. We conclude that prophylactic augmentation can decrease the fracture risk in a malaligned, osteoporotic vertebra. Whether this is enough to actually prevent additional vertebral fractures in vivo remains subject of further study.

Does bone cement in percutaneous vertebroplasty act as a stress riser

Study Design. An in vitro cadaveric study. Objective. To determine whether percutaneous vertebroplasty (PVP) with a clinically relevant amount of bone cement is capable of causing stress peaks in adjacent-level vertebrae. Summary of Background Data. It is often suggested that PVP of a primary spinal fracture causes stress peaks in adjacent vertebrae, thereby leading to additional fractures. The in vitro studies that demonstrated this relationship, however, use bigger volumes of bone cement used clinically. Methods. Ten fresh-frozen vertebrae were loaded until failure, while registering force and displacement as well as the pressure under the lower endplate. After failure, the vertebrae were augmented with clinically relevant amounts of bone cement and then again loaded until failure. The force, displacement, and pressure under the lower endplate were again registered. Results. Stress peaks were not related to the location of the injected bone cement. Both failure load and stiffness were significantly lower after augmentation. Conclusion. On the basis of our findings, we conclude that vertebral augmentation with clinically relevant amounts of bone cement does not lead to stress peaks under the endplate. It is therefore unlikely that PVP, in itself, causes detrimental stresses in the adjacent vertebrae, leading to new vertebral fractures. Level of Evidence: N/A

The effect of radiotherapy, and radiotherapy combined with bisphosphonates or RANK ligand inhibitors on bone quality in bone metastases. A systematic review

PURPOSE The role of radiotherapy in stabilizing metastatic bones is unclear. This systematic review assessed the effects of (1) radiotherapy, (2) radiotherapy combined with bisphosphonates, and (3) radiotherapy combined with RANK ligand (RANKL) inhibitors on bone quality and bone strength in bone metastases originating from solid tumors. METHODS Pubmed, EMBASE and the Cochrane Library were searched. Any type of study design and type and dose of radiotherapy, bisphosphonates and RANKL inhibitors were allowed. RESULTS 39 articles were identified. Animal studies showed that radiotherapy had similar effects on bone quality and strength as receiving no treatment, whereas adding bisphosphonates to radiotherapy restored bone quality and strength. In patient studies, bone density increased after radiotherapy and radiotherapy combined with bisphosphonates. However, due to the often non-optimal study design and study quality, it was unclear whether this increase could be attributed to these treatments. There was insufficient evidence to assess the additional effect of bisphosphonates or RANKL inhibitors. CONCLUSION Despite the clinical experience that radiotherapy is an effective treatment for bone metastases, there was no sufficient evidence for a positive effect on bone quality and fracture risk. Animal studies showed that adding bisphosphonates to radiotherapy restored bone quality and strength, whereas this was not proven in patients. There were no studies addressing the adjunct effect of RANKL inhibitors to radiotherapy. Although associated with several methodological, practical and ethical challenges, randomized controlled trials are needed.

Densitometry test of bone tissue: Validation of computer simulation studies

Bone densitometry measurements are performed to predict the fracture risk in bones. However, the sensitivity of these predictions are not satisfactory. One of the explanations is that densitometry ignores the (architectural) structural aspects of the bone. The effects of varying architectural parameters on the densitometry parameters can be effectively assessed by considering a 3-D image of a bone and vary the bone structure parameters in a controlled manner and determine the consequence of these changes on a simulated (virtual) densitometry analysis. In this paper we present such a computer simulation of densitometry analysis of bone. The simulation allows quantification of densitometry parameters, such as BMD and BMC, on the basis of computed tomography bone scans. The aim of the presented study is the evaluation of our method by comparing its results to the results from real densitometry (DEXA) tests. For the evaluation we selected three femoral bones. These items were CT scanned and individual computer models were created. In addition, the densitometry parameters of these items were assessed by a clinical DEXA scanner. The densitometry parameters obtained from the simulations were very close to the results from the DEXA densitometry measurements. We therefore conclude that our method can be employed in the research on the influence of changes in bone structure on densitometry test results.