A personalized micro-multiphysics agent-based model of human bone remodelling in health, disease, and treatment
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Date
2025
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Doctoral Thesis
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Abstract
This thesis presents the development and application of a micro-multiphysics agent-based model (micro-MPA) to simulate bone remodelling in the context of postmenopausal osteoporosis and its pharmacological treatment. The increase in life expectancy has been accompanied by a significant rise in age-related diseases, particularly osteoporosis, which leads to a heightened risk of fragility fractures. Despite the availability of effective treatments, prescription rates remain low, partly due to the high cost of clinical trials required for drug approval.
To address these challenges, this work relies on in silico approaches based on mechanistically realistic simulations of cellular-scale bone remodelling. The micro-MPA developed here is built on autonomous cellular agents interacting within a three-dimensional lattice derived from micro-CT imaging of human biopsies. It incorporates key biological pathways involved in bone turnover, the mechanisms of action of various drugs, and local mechanical cues via micro-finite element analyses.
The model was used to simulate untreated osteoporosis, ten years of denosumab treatment, and discontinuation after varying treatment durations, enabling a deeper understanding of the cellular and molecular mechanisms driving the rapid bone loss observed after treatment cessation. It was then extended to predict morphometric outcomes of combined and sequential therapies.
Finally, the model was applied to longitudinal clinical datasets including HR-pQCT imaging and biochemical markers of bone turnover, paving the way for personalized predictions of fracture risk and the individualized optimization of therapeutic strategies. This work thus establishes a robust computational framework for investigating metabolic bone diseases
and designing precision treatment plans.
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ETH Zurich
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Subject
OSTEOPOROSIS (PATHOLOGY); Agent-based model; Multiphysics modeling; microCT; denosumab discontinuation; romosozumab; Parathyroid hormone; Bisphosphonates
Organisational unit
03565 - Müller, Ralph / Müller, Ralph