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The pathophysiology of osteoporosis (OP) is influenced by exposure to nonessential harmful metals and insufficient or excessive intake of necessary metals. Investigating multiple plasma metals, metabolites, and OP risk among older adults may reveal novel clues of underlying mechanisms for metal toxicity on bone mass. A total of 294 adults ≥ 55 years from Wuhan communities were included. Plasma concentrations of 23 metals and metabolites were measured via inductively coupled plasma-mass spectrometry and global metabolite detection. To investigate the relationships between plasma metals, OP risk, and OP-related metabolites, three different statistical techniques were used: generalized linear regression model, two-way orthogonal partial least-squares analysis (O2PLS), and weighted quantile sum (WQS). The mean ages were 66.82 and 66.21 years in OP (n = 115) and non-OP (n = 179) groups, respectively. Of all 2999 metabolites detected, 111 differential between-group members were observed. The OP risk decreased by 58.5% (OR=0.415, 95% CI: 0.237, 0.727) per quartile increment in the WQS index indicative of metal mixture exposure. Consistency remained for bone mineral density (BMD) measurements. The O2PLS model identified the top five OP-related metabolites, namely, DG(18:2_22:6), 3-phenoxybenzoic acid, TG(16:1_16:1_22:6), TG(16:0_16:0_20:4), and TG(14:1_18:2_18:3), contributing most to the joint covariation between the metal mixture and metabolites. Significant correlations between each of them and the metal mixture were found using WQS regression. Furthermore, the five metabolites mediated the associations of the metal mixtures, BMD, and OP risk. Our findings shed additional light on the mediation functions of plasma metabolites in the connection between multiple metal co-exposure and OP pathogenesis and offer new insights into the probable mechanisms underpinning the bone effects of the metal mixture. [Display omitted] • Mechanisms behind essential and non-essential metals mixture on bone still unclear. • Untargeted metabolomics approach was used to provide clues • Mixtures of essential and non-essential metals affect osteoporosis (OP). • Mixtures of essential and non-essential metals affect OP-related metabolites. • Metabolites cloud mediate the associations of metal mixtures and OP risk. [ABSTRACT FROM AUTHOR]

Strontium is receiving widespread attention due to its remarkable biological qualities in preventing bone resorption and fostering osteogenesis. However, the chemical processes behind strontium's dual activities on bone cells are not yet fully understood. This study used the metabolomic technique to identify and examine potential biomarkers between strontium exposure and osteoporosis (OP) risk. A total of 806 participants were recruited for the detection of plasma strontium content via inductively coupled plasma–mass spectrometry. Plasma metabolites were profiled in 254 participants through an untargeted metabolomics technique. Generalized linear models were primarily used to analyze associations among plasma strontium, metabolites, and OP. The mediating effects of metabolites on the strontium–OP association were further investigated. A total of 31 differential metabolites were observed, 10 of which were upregulated and 21 were downregulated in the OP group compared with the non-OP group. Five metabolites (3-phenoxybenzoic acid, Cer (t18:0/16:1), HexCer(t16:1/12:1(2OH)), HexCer(t14:2/18:1(2OH)), and TG(16:0–18:1–24:4)) were selected as potential mediators based on their significant association with OP risk and with femoral neck and lumbar spine bone mineral density (BMD). Moreover, all except TG(16:0–18:1–24:4) were involved in the OP discrimination model with excellent power combined with several traditional variables. 3-Phenoxybenzoic acid and Cer(t18:0/16:1) had significant indirect effects on the strontium–OP association. The five candidate metabolites mediated 83.79 % of the strontium–OP association. Plasma strontium level was associated with reduced OP risk in the Han population in Wuhan. Thus, plasma metabolite profiling revealed five BMD/OP-associated metabolites that acted as mediators in the strontium–OP association. Our findings provided evidence of the mediating role of host plasma metabolites in strontium's effect on OP pathology. [Display omitted] • Strontium contributes to reduced osteoporosis (OP) risk in Chinese population. • Plasma metabolites are associated with OP risk and bone mineral density. • Candidate metabolites exert improved prediction performance for OP risk. • Candidate metabolites mediate a total of 83.79 % of the strontium–OP association. [ABSTRACT FROM AUTHOR]