The effects of SARS-CoV-2 on bone homeostasis

Accumulating evidence suggests that SARS-CoV-2 is associated with disruptions in skeletal homeostasis through both direct viral effects on bone-remodeling cells and indirect inflammatory mechanisms, contributing to bone loss and increased skeletal fragility. The maintenance of healthy bone structure depends on the coordinated activities of bone-resorbing osteoclasts and bone-forming osteoblasts. Recent studies demonstrate that differentiated human osteoblasts support productive SARS-CoV-2 infection, whereas MSC and osteoclast precursors undergo abortive infection. These interactions impair osteoblast differentiation, increase IL-6 and receptor activator of nuclear factor κB Ligand (RANKL) expression, and promote osteoclastogenesis, shifting bone remodeling toward pathological resorption. Additional virus-associated mediators, including Spike protein, ORF8, and miR-4485-3p, further amplify inflammatory and pro-osteoclastogenic signaling. Clinical studies report associations between acute and persistent reductions in bone mineral density, increased vertebral fracture prevalence, and alterations in musculoskeletal (MSK) imaging biomarkers associated with worse COVID-19 outcomes, while animal models confirm osteoclast-driven trabecular bone loss. This review integrates emerging evidence of productive and abortive SARS-CoV-2 infection of human bone cells with recent clinical and experimental findings, providing an updated osteoimmunological perspective on COVID-19-associated bone remodeling. Prospective longitudinal studies and clinical trials are needed to determine the long-term skeletal consequences of COVID-19 and evaluate targeted strategies to prevent infection-associated bone loss.