Bone biomechanics and skeletal fragility

For several decades we have been investigating the biomechanical mechanisms underlying skeletal fragility in osteoporosis and other bone disorders, and how various interventions improve bone strength and reduce fracture risk. Our work has included studies in animal models, human cadaveric specimens and clinical studies. Our overall goals are to better understand the origins and causes of skeletal fragility, to better identify those at risk for fracture and to enhance the monitoring of treatment efficacy.

Predicting Femoral Strength:

Measurement of BMD by DXA is the current gold standard for diagnosis of osteoporosis. However, several studies have identified limitations in BMD measurements with regard to assessing fracture risk and monitoring efficacy of osteoporosis therapies. New imaging methods, combined with state-of-the art biomechanical analyses, may improve prediction of hip fracture risk. This main goal of this study is to evaluate the ability of different imaging modalities to predict the strength of human proximal femur in a sideways fall configuration. Secondary goals are to determine the relative contribution of BMD, femoral geometry, and cortical and trabecular bone microarchitecture to femoral strength.

Human cadaveric femora will be selected to represent the target population of individuals likely to suffer a hip fracture (ie, age > 65, BMD T-score < -1.5). Non-invasive imaging modalities will include image analysis of radiographs, DXA, multi-angle DXA, hip structural analysis, QCT, and QCT-based finite element analysis. Femurs will be divided into two groups, providing a “training set” for establishment of statistical models for prediction of bone strength (n=60 femurs) and a “test set” used to validate the model predictions (n=20 femurs). Several aspects of this study will be novel, as it will be the first to evaluate a wide variety of imaging modalities in the same experiment, to enroll specimens from individuals with low BMD only, and to use the training/test set approach to evaluate the fidelity of strength predictions for femurs tested in a sideways fall configuration. Results will provide strong evidence for qualification of surrogate markers for hip fracture risk.

We are also collaborating with Professor Tony Keaveny at UC Berkeley to examine micro-finite element models of the proximal femur to better understand how the femur fails in a sideways fall configuration, and what are the contributions of trabecular and cortical morphology to this failure.

Determinants of vertebral strength:

This work was done in collaboration with Julien Wergyzn and Jean-Paul from Professor Pierre Delmas’ and Roland Chapurlat’s group in Lyon, France. We used human lumbar vertebrae to determine the contribution of trabecular bone heterogeneity and cortical shell thickness to whole vertebral strength. In addition, we investigated the factors the influence the mechanical behavior of lumbar vertebra after simulating a mild vertebral fracture (ie, 25% deformation). We are also interested in the relative contribution of bone volume, collagen cross-links, mineralization and microdamage to mechanical behavior of human vertebral trabecular bone.

Assessment of bone material properties by reference point indentation:

Structural mechanics dictates that whole-bone mechanical behavior depends on bone size (or mass), geometry, and the intrinsic material properties of bone tissue. The effect of geometry on whole-bone strength is well documented, but the role of tissue material properties is less well understood. Indentation measurements offer an opportunity to study the material properties of bone tissue independent of geometrical and bone mass contributions. A novel microindentation instrument, termed reference probe indentation (RPI), uses cyclic loading to assess the ability of bone to resist crack generation and propagation. The insights gained from RPI may be useful for identifying mechanisms underlying different forms of skeletal fragility. We are examining a number of mouse models — either exposing the excised bones to conditions that alter the bone matrix or using genetically modified mice with alterations to the bone matrix. Images of bone indentation in mouse bone are shown in SEM images.

Recent publications:

Roberts BJ, Thrall E, Muller J, Bouxsein ML. Comparison of hip fracture risk by femoral aBMD to Comparison of hip fracture risk prediction by femoral BMD and by the factor-of-risk for hip fracture derived from direct measurements of femoral strength. Bone. 2010; 46(3):742-6. PDF

Roux J, Wegrzyn J, Arlot M, Guyen O, Delmas P, Chapurlat R, Bouxsein M. Contribution of trabecular and cortical components to biomechanical behavior of human vertebrae: an ex-vivo study. J Bone Miner Res. 2010; 25(2): 356-61. PDF

Wegrzyn J, Roux JP, Arlot ME, Boutroy S, Vilayphiou N, Guyen O, Delmas PD, Chapurlat R, Bouxsein ML. Role of trabecular microarchitecture and its heterogeneity parameters in the mechanical behavior of ex-vivo human L3 vertebrae. J Bone Miner Res. 2010; 25(11): 2324-31. PDF

Wegrzyn J, Roux JP, Arlot ME, Boutroy S, Vilayphiou N, Guyen O, Delmas PD, Chapurlat R, Bouxsein ML. Determinants of the mechanical behavior of human lumbar vertebrae after simulated mild fracture. J Bone Miner Res. 2011; 26(4):739-46. PDF

Follet H, Viguet-Carrin S, Burt-Pichat B, Depalle B, Bala Y, Gineyts E, Munoz F, Arlot M, Boivin G, Chapurlat R, Delmas PD, Bouxsein ML. Effects of preexisting microdamage, collagen cross-links, degree of mineralization, age and architecture on compressive mechanical properties of elderly human vertebral trabecular bone. J Orthop Res. 2011; 29(4):481-8. PDF