Abstract: BACKGROUND:  Epidemiologic investigations and some experiments have shown that there is a close relationship between peripheral blood cells and osteoporosis, but the causal relationship between the two at the genetic level is still unclear.
OBJECTIVE: To explore the causal relationship between peripheral blood cells and osteoporosis using Mendelian randomization methods. 
METHODS: Genome-wide association study data sets on peripheral blood cells, overall bone density at different ages, and calcaneal bone density were obtained from databases such as Blood Cell Consortium and MRC Integrative Epidemiology Unit. Blood cells were used as exposure data, with bone density at different ages and calcaneal bone density serving as outcome data. Mendelian randomization analyses were performed using methods such as inverse variance weighting, MR-Egger, weighted median method, and simple median. The results were assessed for heterogeneity, pleiotropy, and sensitivity using Cochran’s Q, MR-Egger regression, and Leave-one-out method. The causal relationship between exposure and outcomes was evaluated using β values.
RESULTS AND CONCLUSION: Due to the heterogeneity revealed by Cochran’s Q test in the Mendelian randomization results, the results of the study were based on the inverse variance weighting method. The inverse variance weighting results showed that when age-specific bone density was used as an outcome, there was a negative causal relationship between white blood cell count and whole-body bone mineral density at the age of 45-60 years [β=-0.07, 95% confidence interval (CI): -0.13, -0.01, P=0.02], a positive causal relationship between monocyte count and whole-body bone mineral density at the age of 45-60 years (β=0.05, 95% CI: 0.00, 0.10, P=0.037), a negative causal relationship between white blood cell and basophil counts and whole-body bone mineral density over 60 years old (β=-0.04, 95% CI: -0.07, -0.01, P=0.005; β=-0.04, 95% CI: -0.07, -0.00, P=0.038), a positive causal relationship between hemoglobin concentration and hematocrit and whole-body bone mineral density over 60 years old (β=0.04, 95% CI: 0.01, 0.08, P=0.012; β=0.04, 95% CI: 0.00, 0.07, P=0.039), and a negative causal relationship between white cell count and whole-body bone mineral density at an undistinguished age (β=-0.10, 95% CI: -0.16, -0.03, P=0.002). When heel bone mineral density was used as an outcome, there was a negative causal relationship between white cell count and heel bone mineral density (β=-0.04, 95% CI: -0.07, -0.01, P=0.016), and a positive causal relationship between hemoglobin concentration and hematocrit and heel bone mineral density (β=0.05, 95% CI: 0.01, 0.08, P=0.007; β=0.05, 95% CI: 0.01, 0.08, P=0.004). To ensure the robustness of the results, meta-analyses of Mendelian randomization results of peripheral blood cells and whole-body bone mineral density as well as heel bone mineral density in different age groups were conducted. The results suggested that for every standard deviation decrease in log-transformed white blood cell count, there was a 5% reduction in the risk of decreased bone mineral density (OR=0.95, 95% CI: 0.94, 0.97, P < 0.001); whereas for every standard deviation increase in hemoglobin concentration and hematocrit, there was a 4% reduction in the risk of decreased bone density (OR=1.04, 95% CI: 1.03, 1.06, P < 0.001). In conclusion, increased white blood cell count in peripheral blood is a risk factor for bone mineral density; whereas increased hematocrit and hemoglobin concentration are protective factors for bone mineral density.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

Key words: Mendelian randomization, osteoporosis, bone mineral density, peripheral blood cell, causal relationship