Abstract
OBJECTIVES: Osteoporosis is a systemic metabolic disease characterized by decreased bone mass, deterioration of bone microstructure, and increased fracture risk. Its occurrence is closely related to sex, age, and lifestyle factors. Environmental exposure to heavy metals and metalloids may also influence its development, although existing findings remain inconsistent. The sex differences in the association between mixed metal exposure and osteoporosis are still unclear. This study aims to investigate whether sex differences exist in the associations between cadmium (Cd), lead (Pb), mercury (Hg), selenium (Se), manganese (Mn), and their mixtures and osteoporosis among men aged ≥50 years and postmenopausal women, and to analyze the potential moderating effect of dairy product consumption on these associations. METHODS: Data from the National Health and Nutrition Examination Survey (NHANES) 2013-2014 and 2017-2018 cycles were used. In men and women separately, generalized linear regression models (univariate regression analysis and multivariate logistic regression) were applied to examine the relationships between single-metal exposure and osteoporosis at the femoral neck and vertebrae. A weighted quantile sum (WQS) model was used to construct a weighted index of mixed metal exposure to quantify the joint effects of multiple metals. Bayesian kernel machine regression (BKMR) was used to systematically evaluate the associations between blood Cd, Pb, Hg, Se, Mn, and their mixtures and osteoporosis at different skeletal sites, capturing potential nonlinear relationships and interactions among metals. Participants were further stratified into high dairy consumption (≥7 times/week) and low dairy consumption (<7 times/week) groups to explore the potential moderating effect of dairy consumption on the association between Cd exposure and osteoporosis. RESULTS: Multivariate logistic regression analysis showed that, in the fully adjusted model, Cd was positively associated with femoral neck osteoporosis in men aged ≥50 years [odds ratio (OR)=8.563, 95% confidence interval (CI) 1.888 to 38.845, P<0.05], whereas Se was negatively associated with femoral neck osteoporosis (OR<0.001, 95% CI 0 to 0.150, P<0.05). In postmenopausal women, Cd was positively associated with femoral neck osteoporosis risk (OR=2.148, 95% CI 1.038 to 4.443, P<0.05), while Se was negatively associated with femoral neck osteoporosis risk (OR=0.027, 95% CI 0.001 to 0.986, P<0.05). No significant association was observed between any metal and vertebral osteoporosis (all P>0.05). The WQS model indicated that mixed metal exposure was positively associated with vertebral osteoporosis in men (OR=1.452, 95% CI 0.277 to 2.626, P<0.05), whereas no significant association was observed in women. BKMR analysis showed that mixed metal exposure was positively associated with osteoporosis risk at the femoral neck and vertebrae in men, with Cd contributing most to osteoporosis risk, while no association was observed between mixed metal exposure and osteoporosis risk in women. The positive association between mixed blood metal exposure and osteoporosis risk might be partially offset by Se. In stratified analysis, the association between Cd exposure and osteoporosis was stronger in the high dairy consumption group (OR=1.19, 95% CI 0.51 to 2.78, P>0.05) than in the low dairy consumption group (OR=3.12, 95% CI 1.84 to 5.30, P<0.05), suggesting that frequent dairy consumption may attenuate the positive association between Cd exposure and femoral neck osteoporosis in women. CONCLUSIONS: In men aged ≥50 years, mixed metal exposure was positively associated with osteoporosis risk at different skeletal sites (femoral neck and vertebra), with Cd contributing most to the risk. In postmenopausal women, no association between mixed metal exposure and osteoporosis risk was observed, indicating clear sex differences. Selenium and dairy consumption may be potential protective factors for osteoporosis in women, whereas such protective effects were not observed in men.