UC Berkeley

While bones are highly adaptable and regulated by external and internal stimuli, their structural integrity can be compromised by aging, diseases such as osteoporosis, and treatments such as radiation therapy. Thus, understanding of the fundamental connection between the effect of treatment on bone strength and fracture risk is critical to understanding the etiology of bone fractures as well as the mechanisms by which aging, disease, and treatments can alter the mechanical performance of bone. However, the connection between treatment effects on changes in bone strength, and bone strength changes on fracture risk, is not completely understood. First, it is unclear how much treatment-induced changes in bone strength are due to changes in bone mass versus in microstructure versus in tissue material. Second, it is unknown why small treatment-induced changes in bone strength are associated with large changes in fracture risk. To address this, we conducted two studies exploring the connection between treatment effects on bone strength and fracture risk. The overall goal of this dissertation was to develop a better understanding of the relative treatment effects on bone strength and to elucidate how small changes in bone strength can be associated with large changes in fracture risk. Together, the work in this dissertation will lead to improved understanding of radiation and osteoporosis treatments and provide new insight into how small changes in bone strength influence fracture risk.

First, using the latest advances in microcomputed tomography and high-resolution finite element modeling combined with biomechanical characterization, we investigated the effect of radiation treatment on bone strength in a rat model of localized irradiation. Changes in material accounted for 24% of the overall observed biomechanical effect, while changes in mass and microstructure together accounted for about 76% of the observed reduction in vertebral strength (~60% and 16%, respectively). For the first time we have directly quantified the contribution of tissue material changes to whole bone strength following irradiation treatment. If the observed material effect is present clinically, it may help to explain the increased fracture risk for patients undergoing radiation therapy despite the inconclusive correlation between irradiation and decreased bone mass. Importantly, we have presented a useful evaluation tool in any application where the effects of mass, microstructure, and material on bone strength are at play, including aging, disease, or pre-clinical evaluation of therapies. This work expands our understanding of the radiosensitivity of bone tissue and emphasizes the complex nature of bone strength loss following exposure to radiation.

Next, we developed a theoretical framework to mechanistically evaluate how changes in bone strength are linked to changes in fracture risk. As there are no clinical bone strength data available to develop a relevant model for radiation therapy-induced fracture risk, we utilized a better characterized treatment—osteoporosis antiresorptive drugs. Through a Monte Carlo approach with conditional probability and data from placebo-controlled osteoporosis trials, we replicated a clinically observed treatment efficacy of 41% using simulated treatment-induced changes in bone strength. Our results demonstrated the sensitivity of fracture risk reduction to the net difference in treatment-induced bone strength changes, the baseline bone strength, and the eligibility criteria bounding the population. Importantly, by incorporating bone strength changes into the model, we were able to duplicate the risk reduction in a clinical trial and provide a mechanistic explanation for the observed large changes in fracture risk—a relatively low number of fractures with an inordinately large weight on efficacy calculations. While the results are specific to hip fracture risk reduction due to osteoporotic treatments in post-menopausal women, this model can be easily adapted to explore the influence of other treatments on fracture risk. For example, the current model has provided important understanding and may help to explain the increased fracture risk for patients undergoing radiation therapy despite the inconclusive correlation between irradiation and decreased bone mass.

Together, the resulting insight from these studies can aid in understanding the underlying mechanisms influencing changes in bone strength and their connection to fracture risk, which may help to improve pre-clinical evaluation of therapies and their potential for fracture risk. Specifically, this dissertation provided insight into the effect of treatment on bone strength and fracture risk, especially the role of radiation and osteoporosis drug therapies. Collectively, this dissertation answered fundamental open questions regarding treatment effects on bone strength and fracture risk and highlighted areas in need of further research.