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Context The role of serum calcium in bone metabolism is unknown, even though calcium/vitamin D supplementations have been widely used and are expected to improve bone health. We aim to determine the independent role of serum calcium in bone mineral density (BMD). Design and setting Two epidemiological analyses with 5478 and 5556 participants from the National Health and Nutrition Examination Survey (NHANES) 2003 to 2006 and the Hong Kong Osteoporosis Study (HKOS) to evaluate the cross-sectional association of serum calcium with BMD. Two-sample Mendelian randomization (MR) studies using genetic variations as instrumental variables to infer causality. Summary statistics of genome-wide association study of serum calcium (N = 39 400) and lifelong whole-body BMD (N = 66 628) were used. Main outcome measure BMD measured by dual-energy X-ray absorptiometry Results In NHANES 2003–6 and HKOS, each standard deviation (SD) increase in serum calcium was significantly associated with 0.036–0.092 SD decrease in BMD at various sites (all P &amp;lt; .05). In multivariable inverse-variance weighted MR analysis, genetic predisposition to higher serum calcium level was inversely associated with whole-body BMD after adjustment for serum parathyroid hormone, vitamin D, and phosphate (–0.431 SD per SD increase in serum calcium; 95% CI: –0.773 to –0.089, P = .014). Similar estimates were obtained in sensitivity analyses. Conclusions Our study reveals that genetic predisposition to higher serum calcium level per se may have a negative impact on bone metabolism. Whether increased serum calcium caused by calcium/vitamin D supplementations would have the same negative effect on bone remains unknown, which warrants further investigation. In addition to other adverse clinical outcomes, careful use of high-dose supplementations is required.

Association of Genetic Variants Related to Serum Calcium Levels with Reduced Bone Mineral Density