Simulation of bone remodeling during the development and treatment of osteoporosis

Osteoporosis is a disease characterized by low bone mass that increases an individual's risk of experiencing a fracture. Osteoporosis develops as a result of changes in the bone remodeling process that cause a net reduction in bone mass over time. Modulation of the bone remodeling process is therefore a common strategy for preventing or treating osteoporosis. Our understanding of the short and long-term benefits of osteoporosis treatments is often limited because quantitative relationships between changes in bone remodeling and changes in bone mass have not yet been developed. In this thesis I address this limitation by using clinical data to develop a computational model to quantify the relationship between bone remodeling and bone mass. I then use the model to predict the long-term (decade long) results of different dosing methods and to compare the influence of different risk factors on the development of osteoporosis.

A non-linear, time-dependent computer model of bone remodeling is created using quantitative data from the literature. Model predictions are based on changes in bone volume, mineralization and mechanical properties. I develop methods of simulating the changes in bone remodeling caused by both alendronate treatment and modification of circulating estrogen concentrations (occurring at menopause or during hormone replacement therapy). The model is then used to compare daily alendronate dosing to less frequent dosing and to simulate the development of osteoporosis. Simulations suggest that weekly or more frequent alendronate dosing may be therapeutically equivalent to daily dosing over the first ten years of treatment. Simulations of bone loss during middle age predict that peak bone mass may be much more influential in determining whether or not a woman develops osteoporosis than bone loss caused by menopause or aging. Since the peak bone mass is determined in early adulthood, it may be a strong, early indicator of a woman's risk of developing osteoporosis. The model developed in this thesis is a novel tool for understanding how factors that change bone remodeling influence the development and treatment of osteoporosis and could be useful for the development or comparison of new osteoporosis treatments.