The incidence of distal forearm fractures peaks during the adolescent growth spurt, but the structural basis for this is unclear. Thus, we studied healthy 6-to 21-yr-old girls (n = 66) and boys (n = 61) using high-resolution pQCT (voxel size, 82 mm) at the distal radius. Subjects were classified into five groups by bone-age: group I (prepuberty, 6-8 yr), group II (early puberty, 9-11 yr), group III (midpuberty, 12-14 yr), group IV (late puberty, 15-17 yr), and group V (postpuberty, 18-21 yr). Compared with group I, trabecular parameters (bone volume fraction, trabecular number, and thickness) did not change in girls but increased in boys from late puberty onward. Cortical thickness and density decreased from pre-to midpuberty in girls but were unchanged in boys, before rising to higher levels at the end of puberty in both sexes. Total bone strength, assessed using microfinite element models, increased linearly across bone age groups in both sexes, with boys showing greater bone strength than girls after midpuberty. The proportion of load borne by cortical bone, and the ratio of cortical to trabecular bone volume, decreased transiently during mid-to late puberty in both sexes, with apparent cortical porosity peaking during this time. This mirrors the incidence of distal forearm fractures in prior studies. We conclude that regional deficits in cortical bone may underlie the adolescent peak in forearm fractures. Whether these deficits are more severe in children who sustain forearm fractures or persist into later life warrants further study.

Bone is able to react to changing mechanical demands by adapting its internal microstructure through bone forming and resorbing cells. This process is called bone modeling and remodeling. It is evident that changes in mechanical demands at the organ level must be interpreted at the tissue level where bone (re)modeling takes place. Although assumed for a long time, the relationship between the locations of bone formation and resorption and the local mechanical environment is still under debate. The lack of suitable imaging modalities for measuring bone formation and resorption in vivo has made it difficult to assess the mechanoregulation of bone three-dimensionally by experiment. Using in vivo micro-computed tomography and high resolution finite element analysis in living mice, we show that bone formation most likely occurs at sites of high local mechanical strain (p<0.0001) and resorption at sites of low local mechanical strain (p<0.0001). Furthermore, the probability of bone resorption decreases exponentially with increasing mechanical stimulus (R2 = 0.99) whereas the probability of bone formation follows an exponential growth function to a maximum value (R2 = 0.99). Moreover, resorption is more strictly controlled than formation in loaded animals, and ovariectomy increases the amount of non-targeted resorption. Our experimental assessment of mechanoregulation at the tissue level does not show any evidence of a lazy zone and suggests that around 80% of all (re)modeling can be linked to the mechanical micro-environment. These findings disclose how mechanical stimuli at the tissue level contribute to the regulation of bone adaptation at the organ level.

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Purpose-To test the clinical utility of approaches for assessing forearm fracture risk.Methods-Among 100 postmenopausal women with a distal forearm fracture (cases) and 105 with no osteoporotic fracture (controls), we measured areal bone mineral density (aBMD) and assessed radius volumetric BMD, geometry and microstructure using high-resolution peripheral QCT; ultradistal radius failure load was evaluated in micro-finite element (μFE) models.Results-Fracture cases had inferior bone density, geometry, microstructure and strength. The most significant determinant of fracture in five categories were: bone density (femoral neck aBMD: odds ratio [OR] per SD, 2.0; 95% CI, 1.4-2.8), geometry (cortical thickness: OR, 1.5; 95% CI, 1.1-2.1), microstructure (structure model index [SMI]: OR, 0.5; 95% CI, 0.4-0.7), and strength (μFE failure load: OR, 1.8; 95% CI, 1.3-2.5); the factor-of-risk (applied load in a forward fall ÷ μFE failure load) was 15% worse in cases (OR, 1.9; 95% CI, 1.4-2.6). Areas under ROC curves (AUC) ranged from 0.62 to 0.68. The predictors of forearm fracture risk that entered a multivariable model were femoral neck aBMD and SMI (combined AUC, 0.71).Conclusions-Detailed bone structure and strength measurements provide insight into forearm fracture pathogenesis, but femoral neck aBMD performs adequately for routine clinical risk assessment.

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The risk of osteoporotic fractures is currently estimated based on an assessment of bone mass as measured by dual-energy X-ray absorptiometry. However, patient-specific finite element (FE) simulations that include information from multiple scales have the potential to allow more accurate prognosis. In the past, FE models of bone were limited either in resolution or to the linearization of the mechanical behaviour. Now, nonlinear, high-resolution simulations including the bone microstructure have been made possible by recent advances in simulation methods, computer infrastructure and imaging, allowing the implementation of multiscale modelling schemes. For example, the mechanical loads generated in the musculoskeletal system define the boundary conditions for organ-level, continuum-based FE models, whose nonlinear material properties are derived from microstructural information. Similarly microstructure models include tissuelevel information such as the dynamic behaviour of collagen by modifying the model's constitutive law. This multiscale approach to modelling the mechanics of bone allows a more accurate characterization of bone fracture behaviour. Furthermore, such models could also include the effects of ageing, osteoporosis and drug treatment. Here we present the current state of the art for multiscale modelling and assess its potential to better predict an individual's risk of fracture in a clinical setting.

More accurate techniques to estimate fracture risk could help reduce the burden of fractures in postmenopausal women. Although micro-finite element (µFE) simulations allow a direct assessment of bone mechanical performance, in this first clinical study, we investigated whether the additional information obtained using geometrically and materially nonlinear µFE simulations allows a better discrimination between fracture cases and controls. We used patient data and high-resolution peripheral quantitative computed tomography (HRpQCT) measurements from our previous clinical study on fracture risk which compared 100 postmenopausal women with a distal forearm fracture to 105 controls. Analyzing these data with the nonlinear µFE simulations, the odds ratio (OR) for the factor-of-risk (yield load divided by the expected fall load) was marginally higher (1.99; 95% CI, 1.41–2.77) than for the factor-of-risk computed from linear µFE (1.89; 95% CI, 1.37–2.69). The yield load and the energy absorbed up to the yield point as computed from nonlinear µFE were highly correlated with the initial stiffness (R2, 0.97 and 0.94, respectively) and could therefore be derived from linear simulations with little loss in precision. However, yield deformation was not related to any other measurement performed and was itself a good predictor of fracture risk (OR, 1.89; 95% CI, 1.39–2.63). Moreover, a combined risk score integrating information on relative bone strength (yield load-based factor-of-risk), bone ductility (yield deformation) and the structural integrity of the bone under critical loads (cortical plastic volume) improved the separation of cases and controls by one third (OR, 2.66; 95% CI, 1.84–4.02). We therefore conclude that nonlinear µFE simulations provide important additional information on the risk of distal forearm fractures not accessible from linear µFE nor from other techniques assessing bone microstructure, density or mass.

The local interpretation of microfinite element (μFE) simulations plays a pivotal role for studying bone structure–function relationships such as failure processes and bone remodeling.In the past μFE simulations have been successfully validated on the apparent level,however, at the tissue level validations are sparse and less promising. Furthermore,intra trabecular heterogeneity of the material properties has been shown by experimental studies. We proposed an inverse μFE algorithm that iteratively changes the tissue level Young's moduli such that the μFE simulation matches the experimental strain measurements.The algorithm is setup as a feedback loop where the modulus is iteratively adapted until the simulated strain matches the experimental strain. The experimental strain of human trabecular bone specimens was calculated from time-lapsed images that were gained by combining mechanical testing and synchrotron radiation microcomputed tomography(SRlCT). The inverse μFE algorithm was able to iterate the heterogeneous distribution of moduli such that the resulting μFE simulations matched artificially generated and experimentally measured strains.