Multilevel computational modeling and quantitative analysis of bone remodeling.

Our work focuses on bone remodeling with a multiscale breadth that ranges from modeling intracellular and intercellular RANK/RANKL signaling to tissue dynamics, by developing a multilevel modeling framework. Several important findings provide clear evidences of the multiscale properties of bone formation and of the links between RANK/RANKL and bone density in healthy and disease conditions. Recent studies indicate that the circulating levels of OPG and RANKL are inversely related to bone turnover and Bone Mineral Density (BMD) and contribute to the development of osteoporosis in postmenopausal women, and thalassemic patients. We make use of a spatial process algebra, the Shape Calculus, to control stochastic cell agents that are continuously remodeling the bone. We found that our description is effective for such a multiscale, multilevel process and that RANKL signaling small dynamic concentration defects are greatly amplified by the continuous alternation of absorption and formation resulting in large structural bone defects. This work contributes to the computational modeling of complex systems with a multilevel approach connecting formal languages and agent-based simulation tools.