Effects of Osteoporosis Therapies on Bone Biomechanics

Anti-fracture therapies for the treatment of osteoporosis have been shown clinically to reduce the incidence of fracture; however, standard clinical measurements of bone density cannot sufficiently explain these large reductions. Therefore, the overall goal of this research is to develop a better understanding of the mechanisms through which anti-fracture therapies improve bone strength -- a critical determinant of fracture risk -- which should lead to improved assessment of treatment efficacy.Combining the latest advances in micro-computed tomography and high-resolution micro-CT-based finite element modeling, we used repeated measures and parameter variations to isolate specific biomechanical effects of various bone characteristics that can be altered by disease and treatment. Specifically, we found that simulated microcavities in trabecular bone from a wide range of bone volume fraction and microarchitecture reduced the strength and altered the relationship between strength and bone volume fraction. While this effect was greater in low-density bone and when the microcavities were targeted to regions of high tissue strain, an appreciable biomechanical effect persisted for all types of bone. Since previous work with antiresorptive-treated canine bone did not find such an effect, questions remain regarding accurate representation of the morphology and micromechanics of actual resorption-induced cavities. Despite these uncertainties, our results provide new insight into the clinical relevance of stress risers caused by resorption cavities, suggesting that antiresorptive therapies may be most effective via mitigation of stress risers in a subset of patients with low bone volume fraction and high bone turnover.Studying vertebrae from treated rats revealed that any treatment-induced changes in intra-specimen variations in tissue mineralization, as detected by quantitative micro-CT, had a negligible biomechanical effect at the whole bone level and in isolated trabecular bone. Intra-specimen variations in tissue mineralization did have a role in general biomechanical behavior, but this role was remarkably uniform across the four different treatment groups: sham control, ovariectomized (OVX), OVX+PTH, and OVX+raloxifene. Finite element results showed that biomechanical treatment effects were dominated by treatment-induced changes in geometry and microarchitecture.This research also produced an efficient pre-clinical framework for characterizing bone quality which should provide considerable insight into the mechanisms of biomechanical effects in a broad range of bone research applications, including aging, diseases, and pharmaceutical and genetic therapy. The approach takes advantage of the hierarchical structure of bone by evaluating the most biomechanically relevant characteristics at each physical scale to isolate the source of bone quality effects and prescribing subsequent analysis only when such effects are found. Using this framework, we found that neither ovariectomy nor PTH treatment had a net effect on bone quality of rat vertebrae during compressive loading suggesting that the observed changes in vertebral strength were primarily due to changes in bone quantity.In closure, this dissertation research has increased knowledge regarding the mechanisms through which osteoporosis therapies improve bone strength without appreciably increasing bone mass. Further, it provides new methods for pre-clinical assessment of treatment efficacy. This dissertation also outlines areas of research to further advance our understanding of the effects of disease and drug therapies on bone biomechanics in human bone.