In silico models of bone remodeling from macro to nano--from organ to cell

Computational modeling is a tool through which researchers can achieve a greater understanding of the mechanisms governing biological systems. In the field of bone biology, a plethora of models exist which attempt to replicate and investigate bone's dynamic behavior at different scales. At organ level, models are continuum based and describe the variation of bone's apparent density as a function of both biological and external mechanical stimuli. At tissue level, models include bone microarchitecture and more descriptive parameters such as trabecular thickness, osteoclast resorption depth, and activation frequency. Finally, at cell level, models employ partial differential equations to describe complex cellular interactions in the temporal domain. Although informative, these models exist in isolation. Consequently, their interpretation is limited. In this review, we present an overview of the organ-, tissue-, and cell-level models and assess their ability to reflect bone's metabolic processes reliably. Existing interscale synergies are then presented along with a computational framework which could be exploited to achieve a fully integrated, multiscale modeling approach.