IL-4 Correlates With Bone Mineral Density in Men, and IL-4 Depletion May Drive Bone Loss in Men With HIV.

BACKGROUND: Fractures are common in people with HIV (PWH). Interleukin 4 (IL-4), an antiosteoclastogenic product of CD4 Th2 T cells, becomes depleted in PWH; however, its role in skeletal deterioration in PWH is unknown. We therefore examined associations between IL-4 and bone mineral density (BMD), bone resorption and formation markers (β-C-terminal telopeptide of type I collagen and osteocalcin), and the osteoclastogenic regulators receptor activator of NF-κB ligand (RANKL) and osteoprotegerin in PWH who were antiretroviral therapy (ART) naive and people without HIV (PWoH). METHODS: Commercial enzyme-linked immunosorbent assays were used to measure factors in a cohort of 37 ART-naive PWH and 28 PWoH and in an independent cohort of 29 ART-experienced PWH. BMD was quantified by bone densitometry, and IL-4 associations were analyzed by sex and HIV status via Spearman correlation and multivariable linear regression. RESULTS: IL-4 was significantly lower in ART-naive PWH as compared with PWoH and higher in ART-experienced PWH vs ART-naive PWH. With ART-naive PWH and PWoH combined, IL-4 correlated inversely with β-C-terminal telopeptide of type I collagen, RANKL, and RANKL/osteoprotegerin ratio in males and females, individually and when aggregated, but not in ART-naive PWH or PWoH individually. In PWoH and ART-naive PWH combined, IL-4 was significantly associated with higher lumbar spine Z score and most femoral BMD T and Z scores in males but not females. CONCLUSIONS: IL-4 levels are reduced in treatment-naive PWH and higher in ART-experienced PWH. IL-4 positively correlates with BMD in men but not women, suggesting that IL-4 protects the male skeleton and that IL-4 decline may contribute to bone loss in men with HIV.