compared with the placebo group. Notably, the investigators could not exclude that cancers had been present at baseline or that cancers remained unnoticed at the end of the study. Moreover, the analysis of the multitude of outcomes in safety data raises the possibility of chance results that seem to be statistically significant but are the result of multiple comparisons being made within one data set.

Observational evidence in AHRQ-Tufts included a large 12-year prospective study of a cohort from the Third National Health and Nutrition Examination Survey (NHANES III) that examined associations between serum 25OHD levels and total cancer mortality as well as specific cancer mortalities. Serum 25OHD levels were found to be associated with gender, educational level, and race/ethnicity, but not with season/latitude. No interaction was detected, however, between serum 25OHD level and total cancer mortality (Freedman et al., 2007). In one frequently cited study included in the AHRQ-Tufts review, Giovannucci et al. (2006) prospectively examined a large cohort from the Health Professionals Follow-up Study (HPFS) for 14 years for multiple determinants of vitamin D, including diet, supplements, skin pigmentation, adiposity, and geography, and their associations with cancer mortality. This study found that each incremental increase in serum 25OHD level of 25 nmol/L was associated with a 17 percent reduction in total cancer incidence and a 29 percent reduction in total cancer mortality. Each of the determinants considered was found to influence plasma 25OHD levels among older men. These results should be viewed with caution, however, because of heterogeneity in serum 25OHD levels that is not accounted for by the variables used in the study, which included intakes based on self-administered semiquantitative food frequency questionnaires and self-reported weight and physical activity levels.

Taken together, the studies reviewed by AHRQ-Tufts, IARC (2008), and WCRF/AICR (2007) as a whole are not supportive of a role for vitamin D, with or without calcium in reducing risk for cancer.

Additional evidence from randomized controlled trials In addition to the trials identified in AHRQ-Tufts, a secondary analysis of data from the Women’s Health Initiative (WHI) trial examined the effect of combined supplementation of vitamin D and calcium (400 International Units [IU] of vitamin D and 1,000 mg of elemental calcium) on various health outcomes including cancer mortality (Lacroix et al., 2009). The results, with an average of 7 years of follow-up, indicated a non-significant trend toward reduction in risk for cancer mortality among postmenopausal women.

Observational studies One additional large cohort study, not included in the AHRQ reviews, was identified that examined serum 25OHD levels and risk for cancer mortality. This study examined cancer mortality among patients referred for coronary disease after a median of 7.75 years and