Associations of multiple metals with bone mineral density: A population-based study in US adults
Graphical abstract
Introduction
Bone mineral density (BMD) is a commonly used parameter for bone health evaluation. It increases markedly during childhood and adolescence, and most people achieve the peak value at approximately 20 years (Xue et al., 2020). Total body and lumbar spine are two preferred sites suitable for BMD measurement from adolescents to old age (Medina-Gomez et al., 2018). Reduced BMD may result in osteoporosis (OP), which usually progresses silently without symptoms until fractures occur and seriously affects individuals’ health and life quality (Cauley, 2013; Kim et al., 2016). Almost half of women and one in five men suffer a fracture resulting from OP in their lifetime (Greenblatt et al., 2017). Numerous factors, including genetic, nutritional, and metabolic factors, have been identified to associate with BMD reductions (Compston et al., 2019; Ströhle and Hahn, 2016; Trajanoska and Rivadeneira, 2019).
Existing evidence also suggests that exposure to metals, such as cadmium (Cd), lead (Pb), mercury (Hg), manganese (Mn), copper (Cu), selenium (Se), and zinc (Zn), may affect bone health (Galvez-Fernandez et al., 2021; Kim et al., 2016; La-Up et al., 2021; Qu et al., 2018; Sadeghi et al., 2014; Tsai et al., 2016; Wu et al., 2021). Several population-based studies showed that elevated blood Pb, Cd, and Hg levels were positively associated with low BMD (Chen et al., 2014; Kim et al., 2016; H. S. Lim et al., 2016). However, significant correlations between the dietary intake of those heavy metals and bone parameters were not observed (Lavado-García et al., 2017). In addition, a study conducted among African Americans found that children with higher Pb exposure showed higher BMD than those with lower Pb exposure (Campbell et al., 2004). For Mn, one study from Iran showed a positive association between dietary Mn intake level and lumbar BMD in postmenopausal women; Li et al. reported that retired workers with long-term Mn exposure had higher OP risk than controls (Karamati et al., 2014; D. Li et al., 2020). Lower copper levels were associated with low BMD, whereas higher exposure concentrations were observed with increased fracture risk (Qu et al., 2018). Though beneficial effects of Se on BMD were widely reported, the adverse effect of higher Se exposures was also observed (Beukhof et al., 2016; Galvez-Fernandez et al., 2021; Wu et al., 2021). Animal studies indicated that zinc deficiency was associated with reduced BMD, while evidence from epidemiological studies is scarce (Ryz et al., 2009).
Most of existing studies focused on the associations of single-metal exposure with BMD. Minimal is known about the overall health effect of joint exposure to multiple metals, which is a limitation because simultaneous exposure to various metals is more common than exposure to single one. Though several epidemiological studies have investigated the associations of multiple-metal exposure and bone health by adjusting all metals in traditional regression models or introducing interaction analysis, they are still inadequate to deal with the potential correlations among different mixture components or nonlinear associations between exposure and health outcomes (Chen et al., 2014; Li et al., 2020). Multipollutant methods are needed to capture the nature health effects of multiple metals exposure on BMD. The weighted quantile sum (WQS) regression and Bayesian kernel machine regression (BKMR) models are two widely used multipollutant effect assessment methods that have been applied to estimate the health effects of multiple metals exposure on various health outcomes, such as glucose metabolism, obesity, diabetes mellitus, kidney health, and prostate cancer (Ge et al., 2021; Z. Li et al., 2019; J. T. Lim et al., 2019; Sanders et al., 2019; Y. Wang et al., 2019; Zhang et al., 2019).
Therefore, this study was performed to examine the individual and joint effects of seven heavy metals (measured in whole blood or serum), namely, Cd, Pb, Hg, Mn, Cu, Se, and Zn on BMD comprehensively based on data of US adults from the National Health and Nutrition Examination Survey (NHANES) using the WQS regression and BKMR models.
Section snippets
Study population
All data in this study were collected from the NHANES, a national survey, which was conducted to assess the health and nutritional status of adults and children in the US using complex, multistage probability sampling design. The survey data were released to the public in biennial cycles, and data from three cycles (2011–2012, 2013–2014, and 2015–2016) of NHANES were combined in the current study. Participants who had incomplete data of metal concentrations and/or other covariates were
Characteristics of participants
The participants selection process is presented in Figure S1. A total of 2545 participants (n = 764 in 2011–2012; n = 940 in 2013–2014; n = 841 in 2015–2016) with complete data were included in this study. The survey-weighted descriptive statistics are presented in Table 1. The weighted mean age of participants was 39.40 years, and 47.9% (n = 1220) were women. Significant differences were observed in education, smoking status, alcohol consumption, hypertension, osteoarthritis, thyroid problem,
Discussion
In the present study, the joint effect of seven metals (Cd, Pb, Hg, and Mn in whole blood, and Cu, Se, and Zn in serum) exposure on BMD was evaluated using multiple statistical methods. Pb was found significantly and negatively associated with lumbar BMD in either single- or multiple-metal linear regressions and had a marginal effect on total BMD after adjusting for the six other metals and potential confounders. The findings of WQS regression suggested evident associations between co-exposure
Conclusion
In summary, the WQS regression and BKMR models were applied to find the joint effects of multiple metals on lumbar and total BMDs among US adults. Co-exposure to the seven studied metals was associated with reduced BMDs, and Mn, Pb, and Se were the main contributors. Moreover, the synergistic action of Pb and Mn exposures on BMDs were discovered. Given the cross-sectional design of the current study, further prospective and experimental studies are worth conducting to verify our findings and
Author contributions
Mu-hong Wei: Investigation, Methodology, Writing - Original draft preparation, Writing - Review & Editing. Yuan Cui: Investigation, Methodology, Writing - Review & Editing. Hao-long Zhou: Investigation, Writing - Review & Editing. Wen-jing Song: Investigation, Writing - Review & Editing. Dong-sheng Di: Investigation, Writing - Review & Editing. Ru-yi Zhang: Investigation, Writing - Review & Editing. Qin Huang: Investigation, Writing - Review & Editing. Jun-an Liu: Conceptualization, Writing -
Funding
The work was funded by the National Natural Science Foundation of China [Grant no. 72061137006, 81573235], the Natural Science Foundation of Hubei Province [Grant no. 2019CFB647], and the Fundamental Research Funds for the Central Universities [Grant no. 2019kfyXKJC003].
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
References (53)
- et al.
Effects of lead and cadmium co-exposure on bone mineral density in a Chinese population
Bone
(2014) - et al.
Osteoporosis. Lancet.
(2019) - et al.
The effect of Pb(2+) on the structure and hydroxyapatite binding properties of osteocalcin
Biochim. Biophys. Acta
(2001) - et al.
Arsenic, cadmium, and selenium exposures and bone mineral density-related endpoints: the HORTEGA study
Free Radic. Biol. Med.
(2021) - et al.
Sex-specific associations of plasma metals and metal mixtures with glucose metabolism: an occupational population-based study in China
Sci. Total Environ.
(2021) - et al.
Angiotensin II induces mitochondrial oxidative stress and mtDNA damage in osteoblasts by inhibiting SIRT1–FoxO3a–MnSOD pathway
Biochem. Biophys. Res. Commun.
(2014) - et al.
Association between exposure to arsenic, nickel, cadmium, selenium, and zinc and fasting blood glucose levels
Environ. Pollut.
(2019) - et al.
Association between serum heavy metals and prostate cancer risk - a multiple metal analysis
Environ. Int.
(2019) - et al.
Life-course genome-wide association study meta-analysis of total body BMD and assessment of age-specific effects
Am. J. Hum. Genet.
(2018) - et al.
Manganese accumulation in bone following chronic exposure in rats: steady-state concentration and half-life in bone
Toxicol. Lett.
(2014)