Impact of serum calcium levels on total body bone mineral density: A mendelian randomization study in five age strata

Summary Background & aims Mendelian randomization (MR) studies have reported the causal association between serum calcium levels and bone mineral density (BMD). The results showed that genetically increased serum calcium levels in individuals with normal calcium levels did not increase BMD and could even reduce BMD. However, whether there are differences in the association between serum calcium and BMD in different age strata remains unclear. Methods We selected eight serum calcium genetic variants with genome-wide significance (P  Results Univariable MR analysis using the inverse-variance weighted method indicated that per 0.5-mg/dL increase (about 1 standard deviation) in serum calcium levels was statistically significantly associated with reduced total body BMD only in the ≥60 years stratum (effect estimate (beta) = −0.545, 95% confidence interval (CI): −0.892 to −0.198, P = 0.002). The weighted median regression (beta = −0.446, 95% CI: −0.821 to −0.094, P = 1.40E−02) and MR-PRESSO (beta = −0.545, 95% CI: −0.892 to −0.198, P = 0.022) MR methods further supported this suggestive association. The multivariable MR analysis also found a significant association between increased serum calcium levels and reduced total body BMD in the ≥60 years stratum (beta = −0.547, 95% CI: −0.934 to −0.16, P = 0.006). Conclusions Our results provide genetic evidence that increased serum calcium levels did not improve BMD in the general population and that the elevated serum calcium levels in generally healthy populations, especially in adults older than 60 years, may even reduce the BMD. Our results are comparable with those of recent MR findings.