Causal Effect of Blood Pressure on Bone Mineral Density and Fracture: A Mendelian Randomization Study.

Hypertension may have some association with osteoporosis. This Mendelian randomization (MR) study aimed to explore the causal effect of blood pressure (BP) on bone mineral density (BMD), fall, and fracture. We used the genome-wide association study (GWAS) summary data among 330,956 European-descent individuals to identify 107 single-nucleotide polymorphisms (SNPs) as the instrumental variables of BP. MR analyses of these instruments were performed on 53,236 European individuals for the association with forearm BMD (FA-BMD), femoral neck BMD (FN-BMD), and lumbar spine BMD (LS-BMD); 451,179 European individuals for fall susceptibility; and up to 1.2 million individuals from European descent for fracture. Conventional inverse variance weighted (IVW) method was adopted to obtain the causal estimates of BP on different outcomes, while weighted median, MR-egger, and MR pleiotropy residual sum and outlier (MR-PRESSO) test were used for sensitivity analyses. Genetically high pulse pressure (PP) could significantly improve FA-BMD (beta-estimate: 0.038, 95% confidence interval [CI]: 0.013 to 0.063, SE:0.013, P-value=0.003<Bonferroni correction P) in the IVW analysis, indicating that 1-SD increase in PP was associated with the improvement in FA-BMD levels by 0.038 g/cm2 (95% CI: 0.013 to 0.063). This positive finding was also confirmed by weighted-median analysis (beta-estimate: 0.034, 95% CI: 0.000 to 0.067, SE:0.017, P-value=0.046) and MR-Egger analysis (beta-estimate: 0.117, 95% CI: 0.026 to 0.208, SE:0.046, P-value=0.011). However, there was no remarkable MR association between BP and other outcomes (i.e., FN-BMD, LS-BMD, fall, and fracture). Our findings reveal a potentially causal relationship between high PP and improved FA-BMD, which may provide new sights for the treatment of osteoporosis.

He B ，Yin L ，Zhang M ，Lyu Q ，Quan Z ，Ou Y ... -  《Frontiers in Endocrinology》

Metformin treatment reduces the incidence of osteoporosis: a two-sample Mendelian randomized study.

It remains unclear whether the association between metformin and osteoporosis (OP) risk is causal. This two-sample Mendelian randomization (MR) study suggests a causal relationship between metformin treatment and a decrease in OP and fracture incidence, as well as an increase in bone mineral density (BMD) in the lumbar spine, femoral neck, and heel. Nonetheless, no significant causal effect is observed on forearm BMD. We utilize a MR approach to investigate the association between metformin treatment and the risk of OP. Metformin treatment was selected as exposures. Outcomes included OP; BMD at the forearm (FA), femoral neck (FN), and lumbar spine (LS); estimated heel bone mineral density (eBMD); and fracture. Summary statistics for exposures and outcomes were obtained from corresponding genome-wide association studies. Inverse variance-weighted (IVW) analysis was mainly applied; the weighted median (WM), penalized weighted median (PWM), maximum likelihood (ML), and MR-Egger regression (MR-Egger) method were also used to obtain robust estimates. A series of sensitivity analyses including Cochran's Q test, MR-Egger regression, leave-one-out analysis, and Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) were used to detect pleiotropy or heterogeneity. In the main analysis, IVW estimates demonstrated that metformin treatment had a definite causal effect on the risk of OP (odds ratio (OR): 0.859, 95% CI: 0.774-0.953, P = 0.004), LS-BMD (OR: 1.063, 95% CI: 1.023-1.105, P = 0.002), FN-BMD (OR: 1.034, 95% CI: 1.000-1.069, P = 0.049), eBMD (OR: 1.035, 95% CI: 1.023-1.047, P ≤ 0.001), and fracture(OR: 0.958, 95% CI: 0.928-0.989, P = 0.008). However, it did not have an effect on FA-BMD(OR: 1.050, 95% CI: 0.969-1.138, P = 0.237). This study indicated that metformin treatment is significantly associated with a reduction in the risk of OP, fracture and higher LS-BMD, FN-BMD, and eBMD. However, there was no significant association with FA-BMD.

Cai Y ，Jun G ，Zhuang X 《-》

Causal relationship between circulating levels of cytokines and bone mineral density: A mendelian randomization study.

Xu T ，Li C ，Liao Y ，Zhang X ... -  《-》

Assessment of causal association between the socio-economic status and osteoporosis and fractures: a bidirectional Mendelian randomization study in European population.

The correlation between socio-economic status (SES) and bone-related diseases garners increasing attention, prompting a bidirectional Mendelian randomization (MR) analysis in this study. Genetic data on SES indicators (average total household income before tax, years of schooling completed, and Townsend Deprivation Index at recruitment), femoral neck bone mineral density (FN-BMD), heel bone mineral density (eBMD), osteoporosis, and five different sites of fractures (spine, femur, lower leg-ankle, foot, and wrist-hand fractures) were derived from genome-wide association summary statistics of European ancestry. The inverse variance weighted method was employed to obtain the causal estimates, complemented by alternative MR techniques, including MR-Egger, weighted median, and MR-pleiotropy residual sum and outlier (MR-PRESSO). Furthermore, sensitivity analyses and multivariable MR were performed to enhance the robustness of our findings. Higher educational attainment exhibited associations with increased eBMD (β: .06, 95% confidence interval [CI]: 0.01-0.10, P = 7.24 × 10-3), and reduced risks of osteoporosis (OR: 0.78, 95% CI: 0.65-0.94, P = 8.49 × 10-3), spine fracture (OR: 0.76, 95% CI: 0.66-0.88, P = 2.94 × 10-4), femur fracture (OR: 0.78, 95% CI: 0.67-0.91, P = 1.33 × 10-3), lower leg-ankle fracture (OR: 0.79, 95% CI: 0.70-0.88, P = 2.05 × 10-5), foot fracture (OR: 0.78, 95% CI: 0.66-0.93, P = 5.92 × 10-3), and wrist-hand fracture (OR: 0.83, 95% CI: 0.73-0.95, P = 7.15 × 10-3). Material deprivation appeared to increase the risk of spine fracture (OR: 2.63, 95% CI: 1.43-4.85, P = 1.91 × 10-3). A higher FN-BMD level positively affected increased household income (β: .03, 95% CI: 0.01-0.04, P = 6.78 × 10-3). All these estimates were adjusted for body mass index, type 2 diabetes, smoking initiation, and frequency of alcohol intake. The MR analyses show that higher educational levels is associated with higher eBMD, reduced risk of osteoporosis and fractures, while material deprivation is positively related to spine fracture. Enhanced FN-BMD correlates with increased household income. These findings provide valuable insights for health guideline formulation and policy development.

Duan JY ，You RX ，Zhou Y ，Xu F ，Lin X ，Shan SK ，Zheng MH ，Lei LM ，Li FX ，Guo B ，Wu YY ，Chen X ，Tang KX ，Cao YC ，Wu YL ，He SY ，Xiao R ，Yuan LQ ... -  《-》

Causal relationship between bone mineral density and intervertebral disc degeneration: a univariate and multivariable mendelian randomization study.

Although previous studies have suggested a possible association between bone mineral density (BMD) and intervertebral disc degeneration (IDD), the causal relationship between them remains unclear. Evidence from accumulating studies indicates that they might mutually influence one another. However, observational studies may be affected by potential confounders. Meanwhile, Mendelian randomization (MR) study can overcome these confounders to assess causality. This Mendelian randomization (MR) study aimed to explore the causal effect of bone mineral density (BMD) on intervertebral disc degeneration (IDD). Summary data from genome-wide association studies of bone mineral density (BMD) and IDD (the FinnGen biobank) have been acquired. The inverse variance weighted (IVW) method was utilized as the primary MR analysis approach. Weighted median, MR-Egger regression, weighted mode, and simple mode were used as supplements. The Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) and MR-Egger regression were performed to assess horizontal pleiotropy. Cochran's Q test evaluated heterogeneity. Leave-one-out sensitivity analysis was further conducted to determine the reliability of the causal relationship. Multivariate MR (MVMR) analyses used multivariable inverse variance-weighted methods to individually and jointly adjust for four potential confounders, body mass index (BMI), Type2 diabetes, hyperthyroidism and smoking. A reverse MR analysis was conducted to assess potential reverse causation. In the univariate MR analysis, femoral neck bone mineral density (FNBMD), heel bone mineral density (eBMD), lumbar spine bone mineral density (LSBMD), and total body bone mineral density (TB BMD) had a direct causal effect on intervertebral disc degeneration (IDD) [FNBMD-related analysis: OR(95%CI) = 1.17 (1.04 to 1.31), p = 0.008, eBMD-related analysis: OR(95%CI) = 1.06 (1.01 to 1.12), p = 0.028, LSBMD-related analysis: OR(95%CI) = 1.20 (1.10 to 1.31), p = 3.38E-7,TB BMD-related analysis: OR(95%CI) = 1.20 (1.12 to 1.29), p = 1.0E-8]. In the MVMR analysis, it was revealed that, even after controlling for confounding factors, heel bone mineral density (eBMD), lumbar spine bone mineral density (LSBMD), and total body bone mineral density (TB BMD) still maintained an independent and significant causal association with IDD(Adjusting for heel bone mineral density: beta = 0.073, OR95% CI = 1.08(1.02 to 1.14), P = 0.013; Adjusting for lumbar spine bone mineral density: beta = 0.11, OR(95%CI) = 1.12(1.02 to 1.23), P = 0.03; Adjusting for total body bone mineral density: beta = 0.139, OR95% CI = 1.15(1.06 to 1.24), P = 5.53E - 5). In the reverse analysis, no evidence was found to suggest that IDD has an impact on BMD. The findings from our univariate and multivariable Mendelian randomization analysis establish a substantial positive causal association between BMD and IDD, indicating that higher bone mineral density may be a significant risk factor for intervertebral disc degeneration. Notably, no causal effect of IDD on these four measures of bone mineral density was observed. Further research is required to elucidate the underlying mechanisms governing this causal relationship.

Li L ，Li D ，Geng Z ，Huo Z ，Kang Y ，Guo X ，Yuan B ，Xu B ，Wang T ... -  《BMC MUSCULOSKELETAL DISORDERS》