Background: Higher levels of total and ionized serum calcium have been shown to predict fatal prostate cancer in prospective studies. Because the follow-up time in these studies was relatively short, these associations could reflect the effect of clinically significant but occult prostate tumors on serum calcium levels. If this were true, prostate cancer mortality rates among men with higher levels of serum calcium should be higher during the early follow-up period and should decline thereafter. Methods: We tested this hypothesis by estimating the relative risk of death from prostate cancer in the National Health and Nutrition Examination Survey III for incremental increases in total and ionized serum calcium using Cox proportional hazards regression with time-dependent effects. Results: Forty-nine (49) fatal prostate cancers occurred over 204 months of follow-up and 1,069,327 person-months of observation. Men with higher total serum calcium and higher serum ionized calcium had increased risks of fatal prostate cancer during the first 96months of follow-up [Relative Hazard (RH) = 1.50 per 0.1 mmol/L total serum calcium, 95% confidence interval (CI) = 1.04-2.17; RH = 1.72 per 0.05 mmol/L ionized calcium, 95% CI = 1.11-2.66]. Evidence of an association between total and ionized serum calcium and prostate cancer deaths was not significant after 96 months. Conclusions: Our analyses support the hypothesis that the elevated risk for fatal prostate cancer observed in men with high serum calcium is because of the presence of extant, but occult prostate cancer. Impact: These findings have implications for the potential use of serum calcium in the detection of clinically significant prostate cancer.
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