Individual and mixed effects of PFAS on osteoporosis: Insights from epidemiological and bioinformatic approaches

This cross-sectional study investigated the associations between individual and mixed exposure to per- and polyfluoroalkyl substances (PFAS) and osteoporosis, and explored potential biological mechanisms in 2764 U.S. adults. Multivariable logistic regression and weighted quantile sum (WQS) regression were applied to examine associations between individual and mixed PFAS exposure and osteoporosis. Restricted cubic spline (RCS) was used to assess dose-response relationships. Mediation analysis was used to evaluate the mediated effects of neutrophil-to-lymphocyte ratio (NLR). Five PFAS compounds (PFOA, perfluorooctanoic acid; PFOS, perfluorooctane sulfonic acid; PFHxS, perfluorohexane sulfonic acid; PFDeA, perfluorodecanoic acid; PFNA, perfluorononanoic acid) with > 80 % detection rates were selected for investigation in this study. Individual exposure to PFOA, PFOS, PFHxS and PFNA were associated with increased lumbar osteoporosis risk (OR _Ln-PFOA = 1.963, 95 %CI: 1.433, 2.687, OR _Ln-PFOS = 1.422, 95 %CI: 1.061, 1.907, OR _Ln-PFHxS = 1.530, 95 %CI: 1.141, 2.052, OR _Ln-PFNA = 1.597, 95 %CI: 1.218, 2.094). Dose-response relationships were observed for PFOA and PFHxS, particularly in women and young adults. WQS regression demonstrated that mixed PFAS exposure increased osteoporosis risk (OR = 1.198, 1.077-1.318) and decreased bone mineral density (BMD, β = -0.017, -0.026 to -0.008), with PFOA contributing most significantly (41-48 % weight). NLR partially mediated these associations. Bioinformatic analyses further identified osteoporosis-related targets and pathways, with inflammation emerging as a key mechanistic link in these associations. Our findings demonstrated a significant association between PFAS exposure and osteoporosis risk, underscoring the importance of reducing PFAS exposure in mitigating bone disease burden.