In silico exploration of osteoclast precursor inhibition for preventing rapid bone loss after denosumab discontinuation

Denosumab is a potent anti-resorptive drug for osteoporosis treatment that increases bone mass and reduces fracture risk. However, its discontinuation causes a rebound phenomenon where bone is rapidly lost by activated resorption, possibly because of the accumulation of osteoclast precursors. Here, we propose a therapeutic strategy wherein osteoclast precursor apoptosis is induced to prevent the rebound. To investigate the efficacy of this undeveloped osteoclast precursor inhibitor (OCPI), we performed in silico experiments with denosumab treatment followed by OCPI or alendronate. The accumulated osteoclast precursors caused excessive osteoclast activity after denosumab discontinuation. Switching to OCPI inhibited bone cell activity in an osteoclast-dominant manner without direct effects on osteoblasts, as opposed to alendronate. The combination of OCPI and denosumab prevented the rebound and preserved modelling-based formation induced by denosumab. Our in silico approach provides proof of a proposed drug concept before development, thereby accelerating the development of new treatment for human diseases.