Vitamin D: should public health recommendations also consider cancer outcomes?
Authors: A. Naska, P. Lagiou
Journal: Annals of Oncology (2019)

Keum et al. [1.Keum N. Lee D.H. Greenwood D. et al.Vitamin D supplements and total cancer incidence and mortality: a meta-analysis of randomized controlled trials.Ann Oncol. 2019; 30: 733-743Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar] present a meta-analysis of randomized controlled trials (RCTs) to assess whether vitamin D supplementation (in the form of cholecalciferol or ergocalciferol, with or without other nutrients) can have an impact on total cancer incidence or mortality. Having included RCTs of long duration and with larger doses of vitamin D, the authors conclude that vitamin D supplementation is not associated with cancer incidence (relative risk 0.98; 95% confidence interval 0.93–1.03), but may reduce cancer mortality (relative risk 0.87; 95% confidence interval 0.79–0.96). Early evidence that vitamin D status may be associated with cancer risk stemmed from ecological observations of an inverse relation between exposure to UV-B radiation and cancer mortality [2.Apperly F.L. The relation of solar radiation to cancer mortality in North America.Cancer Res. 1941; 1: 191-195Google Scholar, 3.Grant W.B. An estimate of premature cancer mortality in the US due to inadequate doses of solar ultraviolet-B radiation.Cancer. 2002; 94: 1867-1875Crossref PubMed Scopus (617) Google Scholar]. A number of observational studies have since evaluated the association of cancer incidence or mortality with vitamin D assessed mainly through serum levels of the 25(OH)D metabolite but also to a lesser extent on the basis of dietary intakes recorded through questionnaires. Overall, they have yielded inconsistent results, providing evidence for either inverse or null associations. Observational studies, however, may be hindered by reverse causation, since people in poor health are more likely to have limited sun exposure and consequently lower cutaneous synthesis of vitamin D. Issues related to various assays used to measure vitamin D status in survey settings, together with confounding by outdoor physical activity, adiposity [related to 25(OH)D bioavailability] and overall dietary intake may also impair the interpretability of their findings. The vitamin D and cancer hypothesis have also been tested in RCTs, but cancer risk has mainly been assessed as a secondary outcome or through post hoc analyses, since most trials were primarily designed to examine the effects of vitamin D supplementation on bone health or cardiovascular disease risk. In general, RCTs have been of short duration (median follow-up period of 4.5 years) and have utilized vitamin doses in the range of 400 to 1100 IU/day. In 2014, two meta-analyses of RCTs were published: one by Bjelakovic et al. [4.Bjelakovic G. Gluud L.L. Nikolova D. et al.Vitamin D supplementation for prevention of cancer in adults.Cochrane Database Syst Rev. 2014; : CD007469PubMed Google Scholar] and a second by Keum and Giovannucci [5.Keum N. Giovannucci E. Vitamin D supplements and cancer incidence and mortality: a meta-analysis.Br J Cancer. 2014; 111: 976-980Crossref PubMed Scopus (109) Google Scholar]. In the latter, small size (≤10 participants with outcomes) and short-term (≤1 year of follow-up) studies were excluded. Both analyses suggested a benefit of higher vitamin D status in relation to cancer mortality (12% reduction with doses not exceeding 1000 IU/day). A more recent meta-analysis of RCTs was published in 2018 [6.Goulao B. Stewart F. Ford J.A. et al.Cancer and vitamin D supplementation: a systematic review and meta-analysis.Am J Clin Nutr. 2018; 107: 652-663Crossref PubMed Scopus (45) Google Scholar] including studies that had tested supplementation with vitamin D only or in any form. In this analysis, Goulao et al. reported an inverse, albeit not significant, association between vitamin D status and cancer mortality. An effect of vitamin D on cancer risk is biologically plausible, since (i) several cell types, including cancer cells, express 1-a-hydroxylase, an enzyme needed to produce the 1, 25(OH)2D, the most active vitamin D metabolite and (ii) cells contain vitamin D receptors which, when activated by 1, 25(OH)2D, induce cell differentiation and inhibit proliferation [7.Miller G.J. Stapleton G.E. Ferrara J.A. et al.The human prostatic carcinoma cell line LNCaP expresses biologically active, specific receptors for 1 alpha, 25-dihydroxyvitamin D3.Cancer Res. 1992; 52: 515-520PubMed Google Scholar, 8.Vandewalle B. Adenis A. Hornez L. et al.1, 25-dihydroxyvitamin D3 receptors in normal and malignant human colorectal tissues.Cancer Lett. 1994; 86: 67-73Crossref PubMed Scopus (71) Google Scholar]. Vitamin D has also been reported to exhibit anti-inflammatory, anti-oxidative and immunomodulatory effects. Furthermore, vitamin D has been associated with slower tumor progression as well as reduction of tumor invasiveness, thus weakening metastatic potential [9.Hewison M. Burke F. Evans K.N. et al.Extra-renal 25-hydroxyvitamin D3-1alpha-hydroxylase in human health and disease.J Steroid Biochem Mol Biol. 2007; 103: 316-321Crossref PubMed Scopus (333) Google Scholar, 10.Feldman D. Krishnan A.V. Swami S. et al.The role of vitamin D in reducing cancer risk and progression.Nat Rev Cancer. 2014; 14: 342-357Crossref PubMed Scopus (887) Google Scholar]. Keum et al. [1.Keum N. Lee D.H. Greenwood D. et al.Vitamin D supplements and total cancer incidence and mortality: a meta-analysis of randomized controlled trials.Ann Oncol. 2019; 30: 733-743Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar] now report an update of their 2014 meta-analysis, in which they have included six RCTs testing higher doses (up to 2000 IU) of vitamin D per day, as well as infrequent bolus dosing of up to 100 000 IU per month with or without an initial bolus dose of 200 000 IU. Among the RCTs included in this meta-analysis, the VITamins and Lifestyle (VITAL) trial is notable on account of its size (25 871 individuals, 1617 cancer outcomes and a median follow-up period of 5.3 years). Keum et al. confirm their previous findings that vitamin D supplementation does not seem to have an effect on total cancer incidence but could reduce total cancer mortality, mostly through interventions with daily dosing up to 2000 IU rather than infrequent intakes of large doses. On the basis of their analyses, they suggest that circulating levels of 25(OH)D around 54–135 nmol/l may contribute to reducing cancer mortality. To achieve these levels, however, the current recommended dietary allowance for adults should be raised to 1500–2000 IU/day, which is more than twice the relevant recommendations of the Institute of Medicine [11.Institute of Medicine. Dietary reference intakes for calcium and vitamin D. Washington, DC: National Academies Press 2011; 1115.Google Scholar] the UK Scientific Advisory Committee on Nutrition [12.SACN (Scientific Advisory Committee on Nutrition). Vitamin D and Health report 2016; 304. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/537616/SACN_Vitamin_D_and_Health_report.pdf.Google Scholar] and the reference values set by the European Food Safety Authority [13.EFSA NDA Panel (EFSA Panel on Dietetic Products, Nutrition and AllergiesScientific opinion on dietary reference values for vitamin D.EFSA Journal 2016. 2016; 14: 4547Google Scholar]. Until now, in setting dietary reference values for vitamin D for the general population, national and international scientific bodies have relied on evidence concerning the relation of vitamin D status with musculoskeletal health alone [11.Institute of Medicine. Dietary reference intakes for calcium and vitamin D. Washington, DC: National Academies Press 2011; 1115.Google Scholar, 12.SACN (Scientific Advisory Committee on Nutrition). Vitamin D and Health report 2016; 304. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/537616/SACN_Vitamin_D_and_Health_report.pdf.Google Scholar] or in combination with evidence regarding maternal serum 25(OH)D in relation to pregnancy health outcomes [13.EFSA NDA Panel (EFSA Panel on Dietetic Products, Nutrition and AllergiesScientific opinion on dietary reference values for vitamin D.EFSA Journal 2016. 2016; 14: 4547Google Scholar]. In all instances, the scientific bodies have concluded that the available evidence on non-musculoskeletal health outcomes (including cancer) is not sufficient to serve as a criterion for setting reference values for vitamin D. Furthermore, the latest WCRF/AICR report on Diet, Nutrition, Physical Activity and Cancer [14.World Cancer Research Fund/American Institute for Cancer Research. Diet, Nutrition, Physical Activity and Cancer: A Global Perspective. Continuous Update Project Expert Report 2018.Google Scholar] recommends against high-dose dietary supplements for cancer prevention and emphasizes that the aim should be for nutritional needs to be met through diet alone. The results of the meta-analysis by Keum et al. [1.Keum N. Lee D.H. Greenwood D. et al.Vitamin D supplements and total cancer incidence and mortality: a meta-analysis of randomized controlled trials.Ann Oncol. 2019; 30: 733-743Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar] are indeed intriguing, albeit far from conclusive. Although toxicity does not appear to be a concern [15.Holick M.F. Vitamin D is not as toxic as was once thought: a historical and an up-to-date perspective.Mayo Clin Proc. 2015; 90: 561-564Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar], even at the higher doses for adults suggested by the authors, before public health recommendations on vitamin D intake are formed taking into account potential benefits toward cancer mortality, further experimental studies are needed to fully ascertain potential effects and appropriate doses, as the authors themselves also acknowledge. Cancer is a multifactorial disease, diet a complex exposure and nutrients have been reported to exert different effects in the context of a diet or when provided as supplements [16.Gibson T.M. Ferrucci L.M. Tangrea J.A. et al.Epidemiological and clinical studies of nutrition.Semin Oncol. 2010; 37: 282-296Crossref PubMed Scopus (48) Google Scholar]. In the case of vitamin D, the central role of sun exposure on the vitamin synthesis is also a factor in the equation. In this complex interplay, public health bodies and policy makers need to balance benefits and risks also taking into account their populations’ cultural norms and behaviors, when reference values for vitamin D are formulated. None declared.