Osteonecrosis of the femoral head is associated with cytomegalovirus reactivation

Abstract Osteonecrosis of the femoral head (ONFH) is a debilitating condition often leading to joint collapse. While corticosteroids use and alcohol consumption are known risk factors, the pathophysiology, especially in idiopathic cases, which account for one-third population, remains unclear. This study aimed to investigate the potential role of human cytomegalovirus (HCMV) reactivation in the pathogenesis of ONFH, focusing on its presence, distribution, and reactivation status. Blood and femoral head samples were obtained from ONFH patients and fracture controls. HCMV exposure was assessed through serology and viral DNA quantification, and reactivation was confirmed by gB immunohistochemistry and IE-1 mRNA RT-qPCR. Tissue samples from different regions of the femoral head (necrotic, transitional, and healthy zones) were analyzed for viral content, reactivation and localization. Results revealed showed significantly higher HCMV DNA levels in necrotic and transitional zones of ONFH, strongly correlated with lesion volume. Furthermore, gB localization was predominantly found in the microvascular structures, such as small vessels and capillaries, suggesting that HCMV reactivation may contribute to microvascular damage and ischemia. IE-1 transcripts, markers of viral reactivation, further confirmed reactivation. Notably, HCMV reactivation was observed across all ONFH etiologies—corticosteroid-related, alcohol-related, and idiopathic—indicating its broad involvement in ONFH progression. This study provides the first clinical evidence linking HCMV reactivation to ONFH, offering potential therapeutic avenues, including antiviral treatments, to address this condition.