Abstract

Methods

Results

In our research, 32 SNPs robustly linked to PM_2.5, 18 SNPs strongly related to PM_2.5-10, 156 SNPs robustly associated with PM₁₀, 70 SNPs robustly correlated with nitrogen dioxide, and 53 SNPs strongly related to nitrogen oxides. F-statistics of all IVs surpassed a threshold of 10. Detailed information about these IVs is provided in Supplementary Table SI.

The IVW method showed that the Beta and corresponding 95% confidence intervals (CI) for various exposures are as follows: PM_2.5: Beta = –0.135, 95% CI = [–0.201, –0.070], p = 8.23 × 10^–5; PM_2.5-10: Beta = –0.006, 95% CI = [–0.006, 0.085], p = 9.03 × 10^–1; PM₁₀: Beta = –0.091, 95% CI = [–0.124, –0.058], p = 3.3 × 10^–7; nitrogen dioxide: Beta = –0.056, 95% CI = [–0.113, 0.001], p = 6.59 × 10^–2; nitrogen oxides: Beta = –0.137, 95% CI = [–0.191, –0.083], p = 1.52 × 10^–6 (Figure 1). All significance levels are FDR-adjusted. As indicated by the finding, we identified a causality linking air pollution (PM_2.5, PM₁₀, nitrogen oxides) with BMD. Other methods demonstrated that these relationships persisted (Figure 1). Furthermore, this study did not observe any evidence of causality between PM_2.5-10, nitrogen dioxide, and BMD (Figure 1).

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Figure 1

The causal relationship between exposure to air pollution and outcomes in BMD

This study showed no evidence of pleiotropy (Table II), indicating IVs do not affect the outcome via the confounding factors. No heterogeneity was observed in our study for PM_2.5, PM_2.5-10, PM₁₀, and nitrogen oxides, except for nitrogen dioxide (p = 0.034, Q = 91.968) (Table II). The “leave-one-out” analysis indicated that findings remained consistent even with the exclusion of any individual SNP.

Discussion

The connection between air pollutants and bone mineral metabolism is not fully comprehended due to the complexity of the biological processes involved. However, an increasing amount of proof suggests that increased inflammatory reactions caused by air pollution exposure can be considered a contributing element [10]. Exposure to air pollutants can increase overall inflammation by triggering certain proinflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and IL-17. These cytokines, in turn, influence the differentiation and function of osteoblasts and osteoclasts [11]. Additionally, air pollution is likely to induce cellular oxidative stress, which is one of the pathogenic mechanisms. Studies suggest that bone loss in estrogen-deficient mice is caused by oxidative stress, which activates T cells through increased activation of bone marrow dendritic cells [12]. Besides, vitamin D (Vit D) deficiency serves as an additional factor connecting air pollution to OP. Low levels of Vit D can lead to decreased serum calcium levels, which can then increase osteoclast activity and the transfer of calcium from the bones to the outside of cells [13]. Air pollution might be associated with a decrease in outdoor activities, leading to reduced exposure to solar ultraviolet B (UVB) radiation. Insufficient absorption of UVB by the skin is a significant contributor to Vit D deficiency [14]. Additional studies are needed to elucidate the biological mechanisms linking air pollutant exposure and reduced BMD.

This study presents several advantages. Firstly, our study harnessed Mendel’s principle of independent assortment, opting for IVs as the exposure in MR analysis. This choice greatly boosts the reliability of our results as we investigate the cause-and-effect connection between air pollution and BMD. Secondly, reverse causality is precluded as genes precede the onset of the disease. Thirdly, our study leveraged data from publicly available GWAS pooled investigations, benefiting from a substantial sample size that enhances the robustness of our analysis. Additionally, our study offers a novel theoretical and practical groundwork to address the hazards posed by air pollution to bone health.

Nevertheless, our study comes with inherent limitations. Firstly, it is noteworthy that the population under investigation for air pollution and BMD predominantly comprises individuals of European descent. This potential ethnic homogeneity may limit the broader applicability of our findings to the entire population. Secondly, due to our reliance solely on summary statistics from the MR study, our conclusions are limited to finding that air pollution (PM_2.5 and nitrogen oxides) is negatively correlated with BMD. Further research is imperative to elucidate the specific mechanisms.

In conclusion, this MR study has robust evidence affirming a causal relationship between air pollution-related indicators (PM_2.5, PM₁₀ and nitrogen oxides) and decreased BMD. The outcomes of this study offer the potential to guide clinical decision-making and shape public health strategies. Ultimately, these findings can contribute to the formulation of targeted interventions and alleviate the impact of air pollution on bone health, thereby enhancing the quality of life for individuals affected by this condition.

Supplementary Material

Acknowledgments

Funding Statement

Funding No external funding.

References