Metal mixture and osteoporosis risk: Insights from plasma metabolite profiling

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.