The Effect of Vitamin D Supplementation on Risk of Keratinocyte Cancer

An Exploratory Analysis of the D-health Randomized Controlled Trial

Sitwat Ali; Hai Pham; Mary Waterhouse; Catherine Baxter; Briony Duarte Romero; Donald S.A. McLeod; Bruce K. Armstrong; Peter R. Ebeling; Dallas R. English; Gunter Hartel; Jolieke C. van der Pols; Alison J. Venn; Penelope M. Webb; David C. Whiteman; Rachel E. Neale

Disclosures

The British Journal of Dermatology. 2022;187(5):667-675. 

In This Article

Abstract and Introduction

Abstract

Background: Vitamin D may play a role in prevention of keratinocyte cancer (KC), but observational studies examining the association between serum 25-hydroxy vitamin D concentration and KC are largely uninformative because sun exposure causes both KC and vitamin D production. There is scant evidence from clinical trials of supplementary vitamin D.

Objectives: To examine the effect of vitamin D supplementation on the risk of developing KC.

Methods: We used data from the D-Health Trial, a randomized placebo-controlled trial of vitamin D supplementation (60 000 international units monthly for 5 years) among Australians aged ≥60 years. KC outcomes were captured through linkage to a national administrative dataset for those who consented (N = 20 334; 95%). We used negative binomial regression to analyse the incidence of KC excisions and the incidence of actinic lesions treated using cryotherapy or serial curettage, and flexible parametric survival models for analysis of time to first KC excision.

Results: Randomization to vitamin D supplementation did not reduce the incidence of KC lesions treated by excision [incidence rate ratio (IRR) 1·04; 95% confidence interval (CI) 0·98–1·11], the incidence of actinic lesions treated using other methods (IRR 1·01; 95% CI 0·95–1·08) or time to first histologically confirmed KC excision (hazard ratio 1·02; 95% CI 0·97–1·08). However, in subgroup analysis vitamin D increased the incidence of KC excisions in adults aged ≥ 70 years (IRR 1·13, 95% CI 1·04–1·23; P-value for interaction = 0·01).

Conclusions: Vitamin D supplementation did not reduce the incidence of KC or other actinic lesions.

Introduction

Keratinocyte cancer (KC), comprising basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), is the most common cancer of white-skinned people.[1,2] Australia has the highest incidence of skin cancer globally; every year approximately 2% of Australians develop KC,[3,4] and diagnosing and treating KC accounts for the second-highest financial cost of all cancers to the Australian healthcare system.[5] The main risk factor for KC is exposure to ultraviolet (UV) radiation.[6] However, given the challenges of minimizing sun exposure while maintaining a healthy lifestyle in areas with high ambient UV radiation, there is interest in identifying other actions that can reduce the risk of KC, one of which may be vitamin D supplementation.

Vitamin D is produced in the body when the skin is exposed to UV radiation,[7] and can also be acquired from a small number of dietary sources. Vitamin D is hydroxylated to 25-hydroxy vitamin D [25(OH)D] in the liver,[8] and the serum concentration of this molecule is considered the best biological marker for the assessment of vitamin D status.[9] Hydroxylation of 25(OH)D results in the formation of the active molecule, 1,25-dihydroxy vitamin D [1,25(OH)D],[8,10] which exerts its action by binding to the vitamin D receptor, including in keratinocytes, where it regulates growth, multiplication and differentiation, suggesting a possible role in skin cancer.[11]

Several observational studies have investigated the association between 25(OH)D concentration and KC. Two meta-analyses reported a significantly increased risk of KC with higher serum 25(OH)D concentration,[12,13] and a third meta-analysis observed a nonsignificant positive association.[14] These results are most likely due to confounding by sun exposure, as similar UV wavelengths are responsible for both vitamin D production and cutaneous carcinogenesis. A Mendelian randomization analysis found a positive association between genetically predicted 25(OH)D concentration and BCC, although after adjustment for episodes of childhood sunburn and skin colour the confidence interval (CI) included the null; no association with SCC was observed.[15]

The effect of vitamin D supplementation on KC risk has not been extensively studied. We identified two randomized controlled trials (RCTs). One found no effect of vitamin D and calcium supplementation on the incidence of KC (36182 participants, 3358 KC cases reported over 7 years follow-up) but the dose of supplemental vitamin D used was low [400 international units (IU) per day], compliance with the vitamin D supplements suboptimal, and skin cancer was self-reported.[16] The other trial, carried out among 2259 people with a recent diagnosis of colorectal adenoma, found no significant effect of 1000 IU vitamin D per day (irrespective of calcium supplementation) on risk of BCC (n cases = 200) or SCC (n cases = 68); vitamin D together with calcium reduced the risk of SCC, but not BCC.[17]

Given the likely biases in the observational studies and the paucity of data from clinical trials, we investigated the effect of vitamin D supplementation on the incidence of KC using data from the large Australian population-based D-Health Trial.

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