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This study developed a well-standardized and reproducible approach for micro-finite element (mFE) and homogenized-FE (hFE) analyses that can accurately predict the distal radius failure load using either mFE or hFE models when using the approaches and parameters developed in this study., Introduction: Micro-FE analyses based on high-resolution peripheral quantitative CT (HR-pQCT) images are frequently used to predict distal radius failure load. With the introduction of a second-generation HR-pQCT device, however, the default modelling approach no longer provides accurate results. The aim of this study was to develop a well-standardized and reproducible approach for mFE and hFE analyses that can provide precise and accurate results for distal radius failure load predictions based on second-generation HR-pQCT images., Methods: Second-generation HR-pQCT was used to scan the distal 20-mm section of 22 cadaver radii. The sections were excised and mechanically tested afterwards. For these sections, mFE and hFE models were made that were used to identify required material parameters by comparing predicted and measured results. Using these parameters, the models were cropped to represent the 10-mm region recommended for clinical studies to test their performance for failure load prediction., Results: After identification of material parameters, the measured failure load of the 20-mm segments was in good agreement with the results of mFE models (R 2  = 0.969, slope = 1.035) and hFE models (R 2  = 0.966, slope = 0.890). When the models were restricted to the clinical region, mFE still accurately predicted the measured failure load (R 2  = 0.955, slope = 1.021), while hFE predictions were precise but tended to overpredict the failure load (R 2  = 0.952, slope = 0.780)., Conclusions: It was concluded that it is possible to accurately predict the distal radius failure load using either mFE or hFE models when using the approaches and parameters developed in this study.

A longitudinal analysis of bone microstructure in postmenopausal women of the Geneva Retirees Cohort indicates that age-related cortical bone loss is attenuated at non-bearing bone sites in fermented dairy products consumers, not in milk or ripened cheese consumers, independently of total energy, calcium, or protein intakes., Introduction: Fermented dairy products (FDP), including yogurts, provide calcium, phosphorus, and proteins together with prebiotics and probiotics, all being potentially beneficial for bone. In this prospective cohort study, we investigated whether FDP, milk, or ripened cheese consumptions influence age-related changes of bone mineral density (BMD) and microstructure., Methods: Dietary intakes were assessed at baseline and after 3.0 ± 0.5 years with a food frequency questionnaire in 482 postmenopausal women enrolled in the Geneva Retirees Cohort. Cortical (Ct) and trabecular (Tb) volumetric (v) BMD and microstructure at the distal radius and tibia were assessed by high-resolution peripheral quantitative computerized tomography, in addition to areal (a) BMD and body composition by dual-energy X-ray absorptiometry, at the same time points., Results: At baseline, FDP consumers had lower abdominal fat mass and larger bone size at the radius and tibia. Parathyroid hormone and β-carboxyterminal cross-linked telopeptide of type I collagen levels were inversely correlated with FDP consumption. In the longitudinal analysis, FDP consumption (mean of the two assessments) was associated with attenuated loss of radius total vBMD and of Ct vBMD, area, and thickness. There was no difference in aBMD and at the tibia. These associations were independent of total energy, calcium, or protein intakes. For other dairy products categories, only milk consumption was associated with lower decrease of aBMD and of failure load at the radius., Conclusion: In this prospective cohort of healthy postmenopausal women, age-related Ct bone loss was attenuated at non-bearing bone sites in FDP consumers, not in milk or ripened cheese consumers, independently of total energy, calcium, or protein intakes., Study Registration: ISRCTN11865958 ( http://www.isrctn.com ).

Continuum finite element (FE) models of bones are commonly generated based on CT scans. Element material properties in such models are usually derived from bone density values using some empirical relationships. However, many different empirical relationships have been proposed. Most of these will provide isotropic material properties but relationships that can provide a full orthotropic elastic stiffness tensor have been proposed as well. Presently it is not clear which of these relationships best describes the material behavior of bone in continuum models, nor is it clear to what extent anisotropic models can improve upon isotropic models. The best way to determine the accuracy of such relationships for continuum analyses would be by quantifying the accuracy of the calculated stress/strain distribution, but this requires an accurate reference distribution that does not depend on such empirical relationships. In the present study, we propose a novel approach to generate such a reference stress distribution. With this approach, stress results obtained from a micro-FE model of a whole bone, that can represent the bone trabecular architecture in detail, are homogenized and the homogenized stresses are then used as a reference for stress results obtained from continuum models. The goal of the present study was to demonstrate this new approach and to provide examples of comparing continuum models with anisotropic versus isotropic material properties. Continuum models that implemented isotropic and orthotropic material definitions were generated for two proximal femurs for which micro-FE results were available as well, one representing a healthy and the other an osteoporotic femur. It was found that the continuum FE stress distributions calculated for the healthy femur compared well to the homogenized results of the micro-FE although slightly better for the orthotropic model (r=0.83) than for the isotropic model (r=0.79). For the osteoporotic bone also, the orthotropic model did better (r=0.83) than the isotropic model (r=0.77). We propose that this approach will enable a more relevant and accurate validation of different material models than experimental methods used so far., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

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.

Bisphosphonates are antiresorptive drugs commonly used to treat osteoporosis. It is not clear, however, what the influence of the time point of treatment is. Recently developed in vivo micro-computed tomographic (CT) scanners offer the possibility to study such effects on bone microstructure in rats. The aim of this study was to determine the influence of early and late zoledronic acid treatment on bone in ovariectomized rats, using in vivo micro-CT. Twenty-nine female Wistar rats were divided into the following groups: ovariectomy (OVX, n = 5), OVX and zoledronic acid (ZOL) at week 0 (n = 8), OVX and ZOL at week 8 (n = 7), and sham (n = 9). CT scans were made of the proximal tibia at weeks 0, 2, 4, 8, 12, and 16; and bone structural parameters were determined in the metaphysis. Two fluorescent labels were administered to calculate dynamic histomorphometric parameters. At week 16, all groups were significantly different from each other in bone volume fraction (BV/TV), connectivity density, and trabecular number (Tb.N), except for the early ZOL and control groups which were not significantly different for any structural parameter. After ZOL treatment at week 8, BV/TV, structure model index, Tb.N, and trabecular thickness significantly improved in the late ZOL group. The OVX and ZOL groups showed, respectively, higher and lower bone formation rates than the control group. Early ZOL treatment inhibited all bone microstructural changes seen after OVX. Late ZOL treatment significantly improved bone microstructure, although the structure did not recover to original levels. Early ZOL treatment resulted in a significantly better microstructure than late treatment. However, late treatment was still significantly better than no treatment.

Due to remodeling of bone architecture, an optimal structure is created that minimizes bone mass and maximizes strength. In the case of osteoporotic vertebral bodies, however, this process can create over-adaptation, making them vulnerable for non-habitual loads. In a recent study, micro-finite element models of a healthy and an osteoporotic human proximal femur were analyzed for the stance phase of gait. In the present study, tissue stresses and strains were calculated with the same proximal femur micro-finite element models for a simulated fall to the side onto the greater trochanter. Our specific objectives were to determine the contribution of trabecular bone to the strength of the proximal femurs for this non-habitual load. Further, we tested the hypothesis that the trabecular structure of osteoporotic bone is over-adapted to habitual loads. For that purpose, we calculated the load distributions and estimated the apparent yield and ultimate loads from linear analyses. Two different methods were used for this purpose, which resulted in very similar values, all in a realistic range. Distributions of maximal principal strain and effective strain in the entire model suggest that the contributions to bone strength of the trabecular and cortical structures are similar. However, a thick cortical shell is preferred over a dense trabecular core in the femoral neck. When the load applied to the osteoporotic femur was reduced to approximately 61% of the original value, strain distributions were created similar in value to those obtained for the healthy femur. Since a comparable reduction factor was found for habitual load cases, it was concluded that the osteoporotic femur was not 'over-adapted'.

Osteoporotic vertebral fractures typically have a gradual onset, frequently remain clinically undetected, and do not seem to be related to traumatic events. The osteoporotic vertebrae may therefore be expected to display a less "optimal" bone architecture, leading to an uneven load distribution over the bone material. We evaluated the trabecular load distribution in an osteoporotic and a healthy vertebra under normal daily loading by combining three recent innovations: high resolution computed tomography (microCT) of entire bones, microfinite element analyses (microFEA), and parallel supercomputers. Much to our surprise, the number of highly loaded trabeculae was not higher in the osteoporotic vertebra than in the healthy one under normal daily loads (8% and 9%, respectively). The osteoporotic trabeculae were more oriented in the longitudinal direction, compensating for effects of bone loss and ensuring adequate stiffness for normal daily loading. The increased orientation did, however, make the osteoporotic structure less resistant against collateral "error" loads. In this case, the number of overloaded trabeculae in the osteoporotic vertebra was higher than in the healthy one (13% and 4%, respectively). These results strengthen the paradigm of a strong relationship between bone morphology and external loads applied during normal daily life. They also indicate that vertebral fractures result from actions like forward flexion or lifting, loads that may not be "daily" but are normally not traumatic either. If future clinical imaging techniques would enable such high-resolution images to be obtained in vivo, the combination of microCT and microFEA would produce a powerful tool to diagnose osteoporosis.

Unlabelled: Quantitative information about bone tissue-level loading is essential for understanding bone mechanical behavior. We made microfinite element models of a healthy and osteoporotic human femur and found that tissue-level strains in the osteoporotic femoral head were 70% higher on average and less uniformly distributed than those in the healthy one., Introduction: Bone tissue stresses and strains in healthy load-adapted trabecular architectures should be distributed rather evenly, because no bone tissue is expected to be overloaded or unused. In this study, we evaluate this paradigm with the use of microfinite element (microFE) analyses to calculate tissue-level stresses and strains for the human femur. Our objectives were to quantify the strain distribution in the healthy femur, to investigate to what extent this distribution is affected by osteoporosis, to determine if osteoporotic bone is simply bone adapted to lower load levels, and to determine the "safety factor" for trabecular bone., Materials and Methods: microFE models of a healthy and osteoporotic proximal femur were made from microcomputed tomography images. The models consisted of over 96 and 71 million elements for the healthy and osteoporotic femur, respectively, and represented their internal and external morphology in detail. Stresses and strains were calculated for each element and their distributions were calculated for a volume of interest (VOI) of trabecular bone in the femoral head., Results: The average tissue-level principal strain magnitude in the healthy VOI was 304 +/- 185 microstrains and that in the osteoporotic VOI was 520 +/- 355 microstrains. Calculated safety factors were 8.6 for the healthy and 4.9 for the osteoporotic femurs. After reducing the force applied to the osteoporotic model to 59%, the average strain compared with that of the healthy femur, but the SD was larger (208 microstrains)., Conclusions: Strain magnitudes in the osteoporotic bone were much higher and less uniformly distributed than those in the healthy one. After simulated joint-load reduction, strain magnitudes in the osteoporotic femur were very similar to those in the healthy one, but their distribution is still wider and thus less favorable.

The authors have developed a system for the characterization of trabecular bone structure from high-resolution MR images. It features largely automated coil inhomogeneity correction, trabecular bone region segmentation, serial image registration, bone/marrow binarization, and structural calculation steps. The system addresses problems of efficiency and inter- and intraoperator variability inherent in previous analyses. The system is evaluated on repetitive scans of 8 volunteers for both two-dimensional (2D) apparent structure calculations and three-dimensional (3D) mechanical calculations using micro-finite element analysis. Coil correction methods based on a priori knowledge of the coil sensitivity and on low-pass filtering of the high-resolution mages are compared and found to perform similarly. Image alignment is found to cause small but significant changes in some structural parameters. Overall the automated system provides on the order of a 3-fold decrease in trained operator time over previous manual methods. Reproducibility is found to be dependent on image quality for most parameters. For 7 subjects with good image quality, reproducibility of 2-4% is found for 2D structural parameters, while 3D mechanical parameters vary by 4-9%, with percent standardized coefficients of variation in the ranges of 15-34% and 20-38% respectively.

The architecture of trabecular bone is thought to be controlled by mechanosensitive bone cells, where hormones provide a background for their responses to mechanical signals. It has been suggested that, in osteoporosis, this response is hampered by changed hormonal levels, thereby increasing the mechanical set point of the cells, which would lead to bone loss. We have investigated if a temporary increase of the mechanical set point causes deterioration of trabecular bone architecture, such as seen in osteoporosis. Furthermore, the effects of a changed loading pattern were investigated for the same reason. For this purpose, we used a computer simulation model, which was based on the regulation of bone architecture by mechanosensitive osteocytes. It was found that a temporary shift of the mechanical set point causes no lasting changes in architecture. Although an increase of the mechanical set point induces bone loss, the mechanism of bone loss (trabecular thinning) differs from what is observed in osteoporosis (loss of whole trabeculae). Hence, a change of the mechanical set point alone cannot explain bone loss as seen in osteoporosis. On the other hand, the removal of load components in a particular direction resulted in irreversible loss of whole trabeculae. These results indicate that such temporary changes in loading patterns could be important risk factors for osteoporosis.

Most standard methods to predict bone quality are merely based on apparent density measurements. However, apparent density alone does neither explain all variation of the mechanical properties nor does it account for the structural anisotropy of trabecular bone. Thus, apparent density alone might not be sufficient to accurately predict the quality of bone. This study investigates if a new approach based on microstructural computer models can provide additional and relevant information on bone quality. 58 human trabecular bone samples from the femoral head were measured with a 3-D micro-Computed Tomography (micro-CT) system providing a voxel representation of the bone microarchitecture with a resolution of 28 microns. Based on such representations, the orthotropic stiffness matrices and the principal directions were computed for 5 mm cubes with microstructural Finite Element Analysis (FEA). For a subset of six samples the moduli were then validated with tri-axial mechanical compression tests. The results show that on average 15% of the variation of the elastic properties are not explained by bone volume fraction. Differences of elastic properties between samples with the same bone volume fraction range up to 53%. The variation of the degree of anisotropy is unrelated to that of the bone volume fraction. Finally, the direction-dependent stiffness of the trabecular bone differs by a factor of four, indicating that one single (isotropic) modulus as predicted from apparent density measurements might not be adequat. It is concluded that micro-CT-based FEA provides new and additional information about anisotropy and mechanical properties in a direct and non-destructive way, and thus will be important in the future for advanced failure risk prediction. An extension to patient examinations using high-resolution CT or MRI techniques is envisaged.

Summary: We evaluated the association between prevalent vertebral fractures and bone micro-architecture and strength measured using HR-pQCT in postmenopausal women with a recent non-vertebral fracture visiting the Fracture Liaison Service. The presence and severity of prevalent vertebral fracture reflect generalized bone deterioration. Introduction: We evaluated the association between prevalent vertebral fractures (VFs) and bone micro-architecture and strength measured using HR-pQCT in postmenopausal women visiting the Fracture Liaison Service. Methods: In this cross-sectional study in women aged 50–90 with a recent non-vertebral fracture (NVF), VFs were identified on lateral spine images by dual-energy X-ray absorptiometry. Bone micro-architecture and strength were measured at the non-dominant distal radius and distal tibia using HR-pQCT. Linear regression analyses were used to estimate the association between prevalent VFs and HR-pQCT parameters. Results: We included 338 women of whom 74 (21.9%) women had at least one prevalent VF. After adjustment for femoral neck aBMD (FN aBMD) and other parameters, women with at least one prevalent vertebral fracture had significantly lower total and trabecular vBMD and trabecular number (β − 16.7, − 11.8, and − 7.8 in the radius and − 21.4, − 16.6, and − 7.2 in the tibia, respectively), higher trabecular separation at the radius and tibia (β 9.0 and 9.3, respectively), and lower cortical thickness and calculated ultimate failure load and compressive bone strength at the tibia (β − 5.9, − 0.6, and − 10.9, respectively) as compared with those without prevalent VFs. Furthermore, more severe prevalent VFs were associated with even lower total and trabecular vBMD and lower ultimate failure load and compressive stiffness at the radius and tibia, and lower trabecular number and higher trabecular separation at the radius. Conclusion: This study indicates that the presence and severity of prevalent VFs reflect generalized bone deterioration in women with a recent NVF, independently of FN aBMD. [ABSTRACT FROM AUTHOR]

Micro-Finite Element (micro-FE) analysis is now widely used in biomedical research as a tool to derive bone mechanical properties as they relate to its microstructure. With the development of in vivo high-resolution peripheral quantitative CT (HR-pQCT) scanners, it can now be applied to analyze bone in-vivo in the peripheral skeleton. In this survey, the results of several experimental and clinical studies are summarized that addressed the feasibility of this approach to predict bone strength in-vivo. Specific questions that will be addressed are: how accurate are strength predictions based on micro-FE; how reproducible are the results; and, is it a better predictor of bone fracture risk than DXA based measures? Based on results of experimental studies, it is first concluded that micro-FE based on HR-pQCT images can accurately predict the strength of the distal radius during a fall on the outstretched hand using either linear elastic analysis, implementing a 'Pistoia criterion' or similar criterion in combination with an 'effective' Young's modulus or using non-linear analyses. When evaluating results of clinical reproducibility studies, it is concluded that for single-center studies, errors at the radius are less than 4.4% and 3.7% and at the tibia less than 3.6% and 2.3% for stiffness and strength, respectively. In multicenter trials, however, these errors can be increased by some 1.8% and 1.4% for stiffness and strength, respectively. Finally, based on the results of large cohort studies, it is concluded that micro-FE calculated stiffness better separates cases from controls than bone density parameters for subjects with fragility fractures at any site, but not for subjects with only radius fractures. In this latter case, however, combinations of micro-FE derived parameters can significantly improve the separation. [ABSTRACT FROM AUTHOR]

Metabolic bone diseases such as osteoporosis usually cause a decrease in bone mass and a deterioration of bone microarchitecture leading to a decline in bone strength. Methods to predict bone strength in patients are currently based on bone mass only. It has been suggested that an improved prediction of bone strength might be possible if structural changes are taken into account as well. In this study we evaluated which structural parameters (other than bone mass) are the best predictors for changes in bone mechanical properties of the human radius after different bone atrophy scenarios and whether the original strength of the affected bone can be recovered if bone loss is restored by thickening of the remaining structures. To answer these questions, a human radius was measured with a microcomputer tomography scanner to extract the full three-dimensional architecture of the distal radius at an isotropic resolution of 80 μm. Eight models with modified bone architecture were created and the mechanical variations due to these modifications were studied using microfinite element (micro-FE) simulations. In four models mass was lowered by 20%, either by reducing cortical thickness, trabecular thickness, or number of trabeculae or by overall thinning of structures. In the other four models bone mass was restored to the original value using a trabecular bone thickening procedure. The micro-FE analyses revealed that most load was carried by the cortical bone. For this reason, bone strength was affected most in the reduced cortical thickness model. For the same reason, the trabecular bone atrophy scenarios, all of which affected bone strength in a very similar way, resulted in less dramatic bone strength reduction. The restoration of bone mass did not recover the original bone strength. These findings demonstrate that the importance of different parameters for the prediction of bone strength also depends on the mechanical loading. This could explain why results of earlier studies on the importance of structural parameters can be inconsistent and site-dependent. [Copyright &y& Elsevier]

Objective. To investigate whether recently developed in vivo high-resolution magnetic resonance-imaging and micro-finite element techniques can monitor changes in bone mechanical properties during long-term clinical trials aiming at evaluating the efficacy of new drugs for the treatment of osteoporosis.Design. Comparison of baseline and follow-up mechanical parameters calculated using micro-finite element analysis of the calcaneus for subjects participating in a study investigating the effect of idoxifene.Background. Contemporary measurements for the evaluation of bone mechanical properties, based on dual-energy X-ray absorptiometry measurements, are not very accurate and require large trial populations.Methods. A total of 56 postmenopausal subjects received either a placebo, 5 mg or 10 mg per day of idoxifene. Magnetic resonance-images of the calcaneus were made at baseline and after one year. Mechanical parameters of a trabecular volume of interest in the calcaneus were calculated using micro-finite element analysis.Results. Although there were no significant differences between the mean changes in the treated groups and the placebo group, there were significant changes from baseline within groups after one year of treatment. Significant changes, however, were found only for mechanical parameters and only in the treated groups.Conclusions. The present study is the first demonstration that longitudinal changes in bone mechanical properties due to trabecular micro-architectural changes may be quantified in long-term clinical studies. Since significant changes in mechanical parameters were obtained for the treated groups whereas no significant change in bone mass was found we conclude that the application of these techniques may increase the clinical significance of these trials.Relevance A precise diagnosis of in vivo bone mechanical properties that accounts for (changes in) trabecular bone architecture is of particular importance for longitudinal clinical trials aiming at evaluating the efficacy of new drugs since it can lead to clinically relevant results from shorter follow-up intervals and may enable a reduction of the number of patients involved in the trial. [Copyright &y& Elsevier]