In this renewal request, the applicants continue to seek to investigate the structural consequences of post-yield behavior of bone, which has important biomechanical implications for understanding the etiology of age-related osteoporotic spine fractures and perhaps developing new diagnostics and treatments. Their previous work has shown that there are substantial reductions in stiffness and strength of trabecular bone when overloaded, i.e., substantial mechanical damage occurs. The mechanisms of this damage are unclear, but involve microdamage and fracture of individual trabeculae. At the whole vertebral level, significant permanent deformations result from overloads. Together, these findings provide a plausible mechanism for development of clinical spine fractures based on accumulative effects of isolated overloads. New preliminary data point towards collagen cross-linking as being a significant source of age-related brittleness in bone that would affect such a mechanism. They now propose to investigate age-related changes in brittleness and damage behavior, in a hierarchical manner, from the collagen to the whole vertebral body. Further, they intend to demonstrate how aging can change parameters such as collagen cross-linking and other structural assays of the collagen molecule, percent mineralization, trabecular architecture, and trabecular bone volume fraction. Biomechanical test experiments on human cadaveric material to determine mechanical damage and ductility will be performed on cortical bone, demineralized cortical bone, trabecular hard tissue, trabecular bone, and whole vertebral bodies, spanning an age range of 20-100 years. This will be accompanied by a comprehensive set of biochemical and microstructural assays. Finite element computer simulations on the effects of bone brittleness, trabecular architecture, and bone volume fraction will also be performed to help interpret and generalize the experimental results and so separate out the effects of the different explanatory variables. Specifically, their hypotheses are that: 1) significant age changes occur in collagen in both cortical and trabecular bone; 2) these cause both types of bone to become more brittle; 3) aging causes more damage and permanent deformations to develop when the bone is subjected to an isolated overload beyond its elastic regime. This is true for trabecular bone and the whole vertebral body; and 4) these changes in post-yield mechanical properties of the bone are associated with changes in the collagen biochemistry, independently of factors such as mineralization and trabecular architecture. This work is intended to provide a mechanistic description of how older bones are damaged more after an isolated overload than younger bones, and identify mechanisms which dominate such behavior. It is suggested that results should lead, therefore, to improved understanding of vertebral fracture etiology, and may motivate development of new drug treatments.
NIH ExPorter
NIH ExPorter