ORIGINAL RESEARCH article
Front. Bioeng. Biotechnol.
Sec. Biomechanics
Digital twin simulations with a micro-multiphysics agent-based model reveal key drivers of bone loss after denosumab discontinuation
Provisionally accepted
- 1Eidgenossische Technische Hochschule Zurich Institut fur Biomechanik, Zürich, Switzerland
- 2Virginia Tech Department of Biomedical Engineering and Mechanics, Blacksburg, United States
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Denosumab is a widely used pharmacological treatment for osteoporosis-related bone fragility; however, its discontinuation is followed by a rapid drop in bone density. 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. 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. 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.
Keywords: digital twin simulations, micro-multiphysics agent-based model, bone loss, Denosumab discontinuation, Post-menopausal osteoporosis
Received: 23 Jun 2025; Accepted: 11 Nov 2025.
Copyright: © 2025 Ledoux, Kendall, Boaretti, Müller and Collins. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Charles Ledoux, charles.ledoux@hest.ethz.ch
Caitlyn J. Collins, cjcollins@vt.edu
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