Osteoporosis is one of the main causes of fractures in the elderly, and since effective prevention and treatment options are limited, it is essential to reduce the incidence of the disease through lifestyle changes. Although some previous studies have also shown a link between sleep behaviour and bone density. For example, a clinical study using a multivariate logistic regression model showed that poor sleep behaviour was significantly associated with an increased risk of low bone mineral density, and most patients with senile osteoporotic fractures also had unhealthy sleep behaviour [36]. Sleep characteristics, including sleep apnea, daytime and nighttime sleep duration, and daytime naps, have also been associated with the onset of osteoporosis [37]. In particular, it should be noted that obstructive sleep apnea-hypopnea syndrome (OSAHS) can also affect bone metabolism through the hypoxia caused by OSAHS, which is mainly manifested by the decrease of volumetric bone density, tibial cortex and bone trabecular thickness, thus increasing the risk of osteoporosis [38–40]. At the same time, a multi-centre study showed that patients with OSAHS were more likely to develop sarcopenia and osteoporosis; A prospective cohort study of snoring in Korean women showed that the frequency of snoring may be related to the incidence of fragility fractures, and observing the frequency of snoring can improve the accuracy of brittle-fracture risk prediction [41–42]. However, to further explore the relationship between sleep behaviour and bone mineral density, we conducted a two-sample Mendelian randomization analysis using the IEU Open GWAS public database. The results showed that there was a positive causal relationship between snoring and lumbar bone density during sleep, that is, the severity of snoring during sleep was positively correlated with the decrease of lumbar bone density.
In addition, based on the results of the two-sample Mendelian randomization study, we conducted a preliminary exploration of the potential mechanism of snoring that may affect lumbar bone density. Using a multivariate approach to intermediate Mendelian randomization, we determined a causal relationship between triglyceride and low-density lipoprotein cholesterol-mediated snoring and lumbar bone density. While the study provides valuable insights into the relationship between sleep behaviour and bone density, further research is needed to understand the underlying mechanisms in more detail.
Previous Mendelian randomized studies have shown that osteoarthritis is causally related to bone mineral density, sleep disorders, and lower LDL cholesterol levels [43]. A study using the NHANES database showed that LDL cholesterol is negatively correlated with lumbar bone density, and measuring LDL cholesterol can be used as a reactive biomarker for early detection of osteoporosis and guidance for treatment [44]. As for the relationship between triglycerides and bone mineral density, it was mentioned in a cross-sectional study on type 2 diabetes in African Americans, which suggested that there was a contradictory relationship between vitamin D and BMD status and TG levels in African Americans [45]. All these kinds of literature provided a theoretical basis for us to explore the potential mediating role of LDL cholesterol and triglycerides in the relationship between sleep behaviour and bone mineral density and confirmed the mediating role of both by mediating Mendelian randomization. However, the mediating rate was 7.7%, so the clinical significance of this mediating factor may be limited.
This study has several important advantages, first, it is the first two-sample bidirectional mediated MR Study to investigate the causal relationship between sleep behaviour and bone mineral density, which is the closest approach to RCT and allows for random assignment based on genotype. This study design can avoid some limitations of traditional observational studies, including reverse causality and potential confounding factors, and significantly expand relevant research [46]. Second, we have taken several steps to meet MR's core assumptions. Specifically, instrumental variables for sleep behaviour were derived from large-scale GWAS data, which provided strong and reliable genome-wide association SNPS and avoided potentially weak instrumental biases. This gives it sufficient statistical validity to estimate causality. These advantages all enhance the credibility of the research results [47].
From the perspective of traditional clinical research, poor sleep behaviour has been proven to be a risk factor for bone mineral density loss. In this study, we selected SNPS with genome-wide associations and independent genetics with the removal of linkage imbalances as instrumental variables to assess the causal relationship between sleep characteristics and bone mineral density, which makes our results more robust. In addition, both the pleomorphy test and the one-by-one elimination test were negative, indicating that our results are robust.
Nevertheless, some limitations of MR Analysis need to be considered. First, the aggregated GWAS data are mostly for individuals of European descent, so it is debatable whether our results are fully representative of the entire population. Therefore, we should be cautious about applying our conclusions to populations of different races and ethnicities. Secondly, we cannot rule out the influence of confounding factors on the results. Even if we use such methods as MR Egger and MR-PROSSO to control confounding factors, it is necessary to recognize that residual confounding factors may still exist. Finally, our study focused only on the mediating role of triglycerides and LDL cholesterol, ignoring other potential factors that have not yet been explored.