The emerging role of subchondral bone homeostasis in osteoarthritis

The treatment of progressive articular cartilage degeneration and consequent joint deterioration, also known as osteoarthritis (OA), remains a major challenge in musculoskeletal medicine. The subchondral bone has become a key area of research, as early alterations in bone remodelling and structure may precede cartilage degeneration and contribute to disease initiation and progression. Therefore, this review aims to summarise our current understanding of the role of subchondral bone in the initiation and progression of OA. Scientific databases were analysed, focusing on studies published within the last 15 years. Both preclinical in vitro and in vivo studies, as well as clinical trials, were included. Morphological changes of the subchondral bone in OA – primarily driven by abnormal bone remodelling – have been thoroughly characterised within the last years. However, the underlying cellular and molecular mechanisms remain only partially elucidated. As increasing evidence suggests that metabolically and mechanically driven changes in subchondral bone homeostasis, including signalling pathways such as RANK/RANKL/OPG, PIEZO1, and MMP13/TGF-β, may actively contribute to OA progression, this review discusses how this new understanding may influence current and future therapeutic strategies. Furthermore, we critically assess whether anti-osteoporotic agents may represent disease-modifying strategies in OA by targeting subchondral bone remodelling. The Translational Potential of this Article : This review provides an update on subchondral bone as a potential contributor to OA progression and discusses how mechanistic insights from preclinical studies can lead to clinical therapeutic opportunities, emphasising bone remodelling, mechanosensing, angiogenesis and neural invasion. Furthermore, selective molecular targets for the development of disease-modifying treatments and the rationale for repurposing anti-osteoporotic drugs to translate bone-targeted strategies into clinical OA management are evaluated.