Immune-Mediated Bone Loss: A Mendelian Randomization and NHANES-Based Study of Viral Infections and Osteoporosis

Osteoporosis is a major risk factor for fractures, yet the contribution of immune responses to its pathogenesis remains poorly understood. This study investigates whether common viral infections, including Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), and varicella-zoster virus (VZV), contribute to osteoporosis through immune-mediated pathways. We performed two-sample Mendelian randomization (MR) using genome-wide association study (GWAS) summary data and complemented this with observational analyses from the NHANES 2003-2004 cycle. Antibody responses to EBV, HHV-6, and VZV were examined for potential causal effects on bone mineral density (BMD) at key skeletal sites. MR analyses indicated that stronger antibody responses to EBV, HHV-6, and VZV were associated with reduced BMD, particularly at the lumbar spine and femoral neck (OR = 1.18, 95% CI: 1.02-1.36, p = 0.040). Subgroup analyses suggested more pronounced reductions among young men with EBV and elderly women with VZV. Sensitivity tests supported the robustness of these findings. Our findings suggest that common herpesvirus infections may contribute to bone loss via immune-mediated mechanisms, especially in vulnerable subgroups. These results provide epidemiological support for a viral-immune link in osteoporosis and underscore the need for mechanistic and longitudinal studies to clarify underlying pathways and guide future preventive strategies.