| Summary: | Meta-analyses of randomized controlled trials (RCTs) have demonstrated a protective effect of vitamin D<sub>3</sub> (cholecalciferol) supplementation against cancer mortality. In the VITAL study, a RCT including 25,871 men ≥ 50 years and women ≥ 55 years, protective effects of vitamin D<sub>3</sub> supplementation (2000 IU/day over a median of 5.3 years) with respect to incidence of any cancer and of advanced cancer (metastatic cancer or cancer death) were seen for normal-weight participants but not for overweight or obese participants. We aimed to explore potential reasons for this apparent variation of vitamin D effects by body mass index. We conducted complementary analyses of published data from the VITAL study on the association of body weight with cancer outcomes, stratified by vitamin D<sub>3</sub> supplementation. Significantly increased risks of any cancer and of advanced cancer were seen among normal-weight participants compared to obese participants in the control group (relative risk (RR), 1.27; 95% confidence interval (CI), 1.07–1.52, and RR, 1.44; 95% CI, 1.04–1.97, respectively). No such patterns were seen in the intervention group. Among those with incident cancer, vitamin D<sub>3</sub> supplementation was associated with a significantly reduced risk of advanced cancer (RR, 0.86; 95% CI, 0.74–0.99). The observed patterns point to pre-diagnostic weight loss of cancer patients and preventive effects of vitamin D<sub>3</sub> supplementation from cancer progression as plausible explanations for the body mass index (BMI)—intervention interactions. Further research, including RCTs more comprehensively exploring the potential of adjuvant vitamin D therapy for cancer patients, should be pursued with priority.
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