Bone maintains its structure by repairing microdamage and functionally adapts to the mechanical environment by remodeling, where bone-resorbing osteoclasts and bone-forming osteoblasts play important roles through their interactions as well as mechano-biochemical couplings. An imbalance in the activities of osteoclasts and osteoblasts causes bone diseases such as osteoporosis, thereby increasing the risk of fracture. In these remodeling activities, osteocytes, which differentiate from osteoblasts and are embedded in the mineralized bone matrix, have been suggested to sense the mechanical environment and regulate the remodeling activities by communicating through cellular networks. Several signaling molecules and their transduction pathways in bone cells have been identified to understand the mechanism of bone metabolism and diseases. However, it is challenging to predict bone remodeling as a system because of the complexities of their interactions, mechano-biochemical couplings, changes in the mechanical environment, and the effects of drugs.

In this study, we focused on the role of osteocyte mechanosensing and communication and developed a computational simulation platform that predicts complex bone adaptation and microdamage repair by remodeling in silico based on the mathematical models of molecular and cellular behaviors. We believe that such in silico experiments of bone remodeling, combined with in vivo and in vitro experiments will be a beneficial tool to improve bone remodeling research.

First, the basics of these mathematical models and computer simulations will be summarized, and the in silico experiments will be discussed. Next, a mouse femur model will be used to demonstrate the adaptation of the trabecular bone by remodeling in response to applied forces, and the usefulness of the developed platform will be confirmed by reproducing the osteoporosis associated with reduced mechanical force and abnormal signaling conditions. Furthermore, the administration of several osteoporosis drugs that inhibit bone resorption and promote bone formation will be presented, showing the spatiotemporal behaviors of molecules and cells that are difficult to observe in vivo.

In addition to these mechano-biochemical couplings, microdamage accumulation and repair by remodeling are also involved to simulate the target remodeling. We have developed a mathematical model of bone microdamage according to continuum damage mechanics, which assumed that the mechanical properties of bone tissue and cell behavior depend on this variable. The validity of the proposed model will be discussed by simulating the mechanical adaptation for a single trabecula and the cancellous bone. These in silico experiments on bone remodeling will clarify the relationships between bone remodeling and bone microdamage accumulation. This simulation has the potential to improve the prevention and treatment strategies of bone diseases from biological and biomechanical viewpoints.