John Muller

Age- and sex-specific differences in the factor of risk for vertebral fracture: a population-based study using QCT.

We used QCT scans obtained in 687 men and women, 21–97 years of age, to estimate the factor of risk for vertebral fracture, Φvert, defined as the ratio of spinal loading to vertebral strength. With age, vertebral strength declined and Φvert increased significantly more in women than men. Age‐ and sex‐specific differences in Φvert closely resembled previously reported vertebral fracture incidence.

Comparison of hip fracture risk prediction by femoral aBMD to experimentally measured factor of risk

Areal BMD (aBMD) derived from DXA is currently the gold standard for diagnosis of osteoporosis. A biomechanical approach to fracture risk assessment comparing the ratio of applied load to bone strength, termed the factor of risk (Phi), may be useful to better identify patients at risk for fracture. We obtained 73 human cadaveric femurs (48 women and 25 men, aged 74.2+/-8.7 years, range 55-98 years), measured femoral neck (FN) aBMD by DXA, and mechanically tested the femurs to failure in a sideways fall configuration. The force applied to the hip during a sideways fall was estimated from height and weight, and accounted for trochanteric soft tissue thickness. Compared to men, women had significantly lower FN aBMD and femoral strength, and tended to have higher factor of risk for hip fracture Phi. Fifty-three of 54 (98%) specimens that had a FN aBMD T-score below -2.5 also had a Phi>1. However, 10/19 (53%) specimens with FN aBMD T-score above -2.5 also had Phi>1. These data indicate that whereas an aBMD-based diagnosis of osteoporosis is highly associated with fracture risk as assessed by the factor of risk, about 50% of individuals not designated as osteoporotic by aBMD testing would be at high risk for hip fracture should they experience a sideways fall. These findings strongly support the investigation of new biomechanically-based methods of fracture risk prediction.

Effects of tissue preservation on murine bone mechanical properties

Murine bone specimens are used extensively in skeletal research to assess the effects of environmental, physiologic and pathologic factors on their mechanical properties. Given the destructive nature of mechanical testing, it is normally performed as a terminal procedure, where specimens must be preserved without affecting their mechanical properties. To this end, we aimed to study the effects of tissue preservation (freezing and formalin fixation) on the elastic and viscoelastic mechanical properties of murine femur and vertebrae. A total of 120 femurs and 180 vertebral bodies (L3-L5) underwent non-destructive cyclic loading to assess their viscoelastic properties followed by mono-cyclic loading to failure to assess their elastic properties. All specimens underwent re-hydration in 0.9% saline for 30min prior to mechanical testing. Analysis indicated that stiffness, modulus of elasticity, yield load, yield strength, ultimate load and ultimate strength of frozen and formalin-fixed femurs and vertebrae were not different from fresh specimens. Cyclic loading of both femurs and vertebrae indicated that loss, storage and dynamic moduli were not affected by freezing. However, formalin fixation altered their viscoelastic properties. Our findings suggest that freezing and formalin fixation over a 2-week period do not alter the elastic mechanical properties of murine femurs and vertebrae, provided that specimens are re-hydrated for at least half an hour prior to testing. However, formalin fixation weakened the viscoelastic properties of murine bone by reducing its ability to dissipate viscous energy. Future studies should address the long-term effects of both formalin fixation and freezing on the mechanical properties of murine bone.

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.