Dynamic modelling of liver-bone axis: A microphysiological approach to hepatic osteodystrophy

Hepatic osteodystrophy (HOD) is a metabolic bone disorder associated with chronic liver disease (CLD), marked by disrupted bone remodelling, reduced mineralization, and altered osteoblast-osteoclast dynamics. Despite its clinical relevance, mechanistic understanding of the liver-bone axis remains limited due to the shortcomings of conventional in-vitro and in-vivo models in capturing inter-organ crosstalk. To address this, we developed dual-organ perfusion-based micro-physiological devices (MPDs) that integrates human-derived liver and bone tissues-like scaffolds enabling unidirectional perfusion, permitting dynamic exchange of metabolites, cytokines, and signalling factors between hepatocyte spheroids and osteogenic co-cultures under physiologically relevant and controlled dynamic flow. Hepatic fibrosis was induced using carbon tetrachloride (CCl₄), effectively mimicking fibrotic liver pathology. The fibrotic liver environment increased inflammatory cytokines which significantly impacted bone homeostasis, promoting osteoclast activation and reducing osteoblast function and mineral deposition-hallmarks of HOD. Compared to static cultures, the MPDs more accurately replicated pathological liver-bone interactions. The MPDs were also analysed as a potential tool for drug screening and toxicity, where diclofenac was used as a model drug. A clear response of diclofenac and its metabolites on bone homeostasis could be observed in dual-organ MPDs conditions, closely mirroring physiological healthy outcomes. This platform offers a physiologically relevant, perfusable, mechanically tunable and translational approach for investigating HOD pathogenesis and assessing therapeutic interventions. By bridging the gap between static cultures and animal models, it enables real-time monitoring of inter-organ interactions and serves as a powerful tool for advancing research in CLD-related bone disorders.