Defining Viro-Osteopathology: Unresolved Mechanistic Questions in the Pathogenesis of RNA Virus-Associated Bone Disorders.

The recent review by Zhang et al. provides a valuable consolidation of clinical evidence linking Dengue virus (DENV), Chikungunya virus (CHIKV), and SARS-CoV-2 to bone-related diseases. While their work aptly highlights this emerging clinical paradigm, our letter offers a critical analysis to propel the field from descriptive association to mechanistic causation. We identify and dissect several substantive gaps in the current narrative. Firstly, we challenge the prevailing yet often circumstantial evidence for direct viral infection of bone cells, arguing for the need to distinguish between productive infection and passive viral presence. Secondly, we call for a more nuanced deconstruction of the "cytokine storm" hypothesis, urging the identification of master regulators and a clearer delineation between viral persistence and virally-induced autoimmunity in driving chronic pathology, such as post-CHIKV arthritis. Furthermore, we emphasise the critical need for longitudinal studies to define the long-term trajectory of bone health post-SARS-CoV-2 infection, distinguishing transient from permanent metabolic defects. Finally, we propose a unified, comparative research framework utilising advanced models to uncover fundamental principles of virus-bone interactions. This critical perspective underscores the necessity of a deeper, mechanism-driven investigative agenda to inform future therapeutic strategies.