Vitamin D Supplementation and Total Cancer Incidence and Mortality

A Meta-Analysis of Randomized Controlled Trials

N. Keum; D. H. Lee; D. C. Greenwood; J. E. Manson; E. Giovannucci


Ann Oncol. 2019;30(5):733-743. 

In This Article

Abstract and Introduction


Background: Previous meta-analyses of randomized controlled trials (RCTs) of vitamin D supplementation and total cancer incidence and mortality found inconsistent results, and most included trials administered generally low doses of vitamin D (≤1100 IU/day). We updated the meta-analysis by incorporating recent RCTs that have tested higher doses of vitamin D supplements.

Materials and methods: PubMed and Embase were searched from the inception to November 2018. Summary relative risks (RRs) and 95% confidence intervals (CIs) were estimated using a random-effects model.

Results: For total cancer incidence, 10 trials were included [6537 cases; 3–10 years of follow-up; 54–135 nmol/l of attained levels of circulating 25(OH) vitamin D [25(OH)D] in the intervention group]. The summary RR was 0.98 (95% CI, 0.93–1.03; P = 0.42; I 2 = 0%). The results remained null across subgroups tested, including even when attained 25(OH)D levels exceeded 100 nmol/l (RR, 0.95; 95% CI, 0.83–1.09; P = 0.48; I 2 = 26%). For total cancer mortality, five trials were included [1591 deaths; 3–10 years of follow-up; 54–135 nmol/l of attained levels of circulating 25(OH)D in the intervention group]. The summary RR was 0.87 (95% CI, 0.79–0.96; P = 0.005; I 2 = 0%), which was largely attributable to interventions with daily dosing (as opposed to infrequent bolus dosing). No statistically significant heterogeneity was observed by attained levels of circulating 25(OH)D (P heterogeneity = 0.83), with RR being 0.88 (95% CI, 0.78–0.98; P = 0.02; I 2 = 0%) for ≤100 nmol/l and 0.85 (95% CI, 0.70–1.03; P = 0.11; I 2 = 0%) for >100 nmol/l.

Conclusions: In an updated meta-analysis of RCTs, vitamin D supplementation significantly reduced total cancer mortality but did not reduce total cancer incidence.


In 1980, vitamin D was hypothesized to lower risk of cancer incidence and mortality.[1] Subsequently in various animal models, vitamin D has demonstrated promotion of cell differentiation and apoptosis, and inhibition of cancer cell proliferation and angiogenesis, as well as anti-inflammatory and immunomodulatory properties.[2] As a whole, these data support an effect of vitamin D on cancer development and progression.

Observational epidemiologic studies, however, suggest divergent patterns, with evidence for a broad benefit of vitamin D weakening for cancer incidence but strengthening for cancer mortality. Studies based on circulating levels of 25(OH) vitamin D [25(OH)D] (approximate range: ≤13–≥150 nmol/l) have generally not confirmed associations with the risk of most cancers,[3–11] except for colorectal cancer.[12] In addition, Mendelian randomization studies have not found that genetic variation in 25(OH)D levels is associated with cancer incidence,[13–15] with the possible exception of ovarian cancer.[16] In contrast, studies of circulating 25(OH)D (approximate range: 5.7–188 nmol/l), measured either during the prediagnostic period or shortly after diagnosis of cancer, have demonstrated superior survival in cancer patients with higher circulating 25(OH)D levels.[17–20] An inverse association between 25(OH)D status and cancer mortality has also been supported by at least some Mendelian randomization data.[14] Moreover, the geographical association between solar UV-B exposure and cancer was stronger for mortality than for incidence for many cancers in the United States and China.[21,22]

In testing the hypothesis that enhancing vitamin D status may lower cancer incidence or mortality, randomized controlled trials (RCTs) provide high-level evidence. Two meta-analyses of RCTs published in 2014 did not support an effect of vitamin D3 on cancer incidence, but did find an approximately 12% reduced cancer mortality,[23,24] which were limited by number (n ≤ 4) and administration of generally low dose of vitamin D (≤1100 IU/day). In 2014, the U.S. Preventive Services Task Force concluded that data were insufficient to evaluate the effectiveness of vitamin D supplementation for cancer or cardiovascular disease prevention.[25] The most recent meta-analysis including RCTs published up to 2016 did not find evidence to suggest that vitamin D supplementation reduce cancer incidence or mortality.[26] Subsequently, a number of large RCTs have been published, generally utilizing a higher dose of vitamin D (2000 IU/day or 100 000/month).[27–29] We thus updated the meta-analysis of RCTs on cancer incidence and mortality to resolve inconsistency in previous findings, and to derive insights on the potential effects of dose or attained 25(OH)D levels on the efficacy of vitamin D.