Abstract
BACKGROUND: Denosumab is a widely used pharmacological treatment for osteoporosis-related bone fragility; however, its discontinuation is followed by a rapid drop in bone density. METHODS: We investigate proposed mechanistic hypotheses from literature for this rapid bone loss using a computational micro-multiphysics agent-based model validated against clinical data. Using a representative selection of iliac crest patient biopsies scanned with micro-computed tomography, this model generates digital twin simulations of denosumab discontinuation after various treatment periods, with ceteris paribus implementations of each mechanistic hypothesis. RESULTS: Our mixed effects linear regression analysis suggests that only the gate-blocking effect (p=0.014) and osteomorphs recycling (p=0.007) explain the rapid bone loss post denosumab discontinuation. In silico cell and cytokine dynamics emphasize that fusion of osteomorphs is more rapid than osteoclast precursor differentiation in the short-term. CONCLUSION: These findings highlight potential targets for managing fracture risk when discontinuing denosumab and emphasize the importance of personalized treatment strategies based on high-resolution imaging in addition to bone turnover marker measurements.