Low Plasma Ionized Calcium Is Associated With Increased Mortality: A Population-based Study of 106 768 Individuals

Context: Low circulating total calcium or albumin-adjusted calcium has been associated with higher mortality, especially in hospital settings; however, these measures tend to misclassify patients with derangements in calcium homeostasis. Objective: As the association of the biologically active ionized calcium with mortality is poorly elucidated, we tested the hypothesis that low plasma ionized calcium is associated with higher risk of all-cause and cause-specific mortality in the general population. Methods: We included 106768 individuals from the Copenhagen General Population Study. Information on all-cause and cause-specific mortality was from registries and risks were calculated using Cox regression and competing-risks regression by the STATA command stcompet. Results: During a median follow-up period of 9.2 years, 11269 individuals died. Each 0.1 mmol/L lower plasma ionized calcium below the median of 1.21 mmol/L was associated with a multivariable adjusted hazard ratio of 1.23 (95% CI, 1.10-1.38) for all-cause mortality. Corresponding hazard ratios for cancer and other mortality were 1.29 (1.06-1.57) and 1.24 (1.01-1.53), respectively. In contrast, for cardiovascular mortality, only high plasma ionized calcium was associated with mortality with a hazard ratio of 1.17 (1.02-1.35) per 0.1 mmol/L higher plasma ionized calcium above the median. We found no interactions between plasma ionized calcium and preexisting cardiovascular or renal disease on all-cause mortality. Conclusion: In the general population, low plasma ionized calcium was associated with increased all-cause, cancer, and other mortality, while high levels were associated with increased cardiovascular mortality.