In silico model of mechano-biochemical bone remodeling characterizes the therapeutic effects of osteoporosis drugs depending on the action mechanism

Abstract

Osteoporosis stems from an imbalance between bone resorption and formation during bone remodeling, a mechano-biochemical coupling event that intercellular signaling regulates among the bone cells in response to the mechanical environment. Osteoporosis treatment necessitates the modulation of impaired bone remodeling by drug administration to restore an appropriate balance in bone resorption–formation. Characterizing the therapeutic effects of osteoporosis drugs based on their molecular mechanisms of action is crucial to prevent adverse effects and improve the therapeutic efficacy. Herein, we characterized the therapeutic effects of osteoporosis drugs using an in silico model of mechano-biochemical bone remodeling, enabling examination of its spatial and temporal behaviors. We conducted computer simulations to assess osteoporosis drug treatments using two drugs with different mechanisms of action: an anti-receptor activator of nuclear factor-κB ligand (RANKL) antibody (denosumab) and a RANKL production inhibitor. Both drugs restored functionally-adapted trabecular bone morphology when dosages were appropriately adjusted. However, denosumab exhibited more stable therapeutic effects despite dosage changes in osteoporosis treatment. Thus, our medication simulation effectively depicted the therapeutic effects of osteoporosis drugs, illustrating their efficacy based on their mechanisms of action. We expect that medication simulations utilizing an in silico model of mechano-biochemical bone remodeling will expedite the drug discovery process by thoroughly analyzing molecular, cellular, tissue, and organ dynamics during drug treatment.