Calcium plus vitamin D supplementation and the risk of nonmelanoma and melanoma skin cancer: post hoc analyses of the women's health initiative randomized controlled trial

Abstract

Purpose: In light of inverse relationships reported in observational studies of vitamin D intake and serum 25-hydroxyvitamin D levels with risk of nonmelanoma skin cancer (NMSC) and melanoma, we evaluated the effects of vitamin D combined with calcium supplementation on skin cancer in a randomized placebo-controlled trial.

Methods: Postmenopausal women age 50 to 79 years (N = 36,282) enrolled onto the Women's Health Initiative (WHI) calcium/vitamin D clinical trial were randomly assigned to receive 1,000 mg of elemental calcium plus 400 IU of vitamin D3 (CaD) daily or placebo for a mean follow-up period of 7.0 years. NMSC and melanoma skin cancers were ascertained by annual self-report; melanoma skin cancers underwent physician adjudication.

Results: Neither incident NMSC nor melanoma rates differed between treatment (hazard ratio [HR], 1.02; 95% CI, 0.95 to 1.07) and placebo groups (HR, 0.86; 95% CI, 0.64 to 1.16). In subgroup analyses, women with history of NMSC assigned to CaD had a reduced risk of melanoma versus those receiving placebo (HR, 0.43; 95% CI, 0.21 to 0.90; P(interaction) = .038), which was not observed in women without history of NMSC.

Conclusion: Vitamin D supplementation at a relatively low dose plus calcium did not reduce the overall incidence of NMSC or melanoma. However, in women with history of NMSC, CaD supplementation reduced melanoma risk, suggesting a potential role for calcium and vitamin D supplements in this high-risk group. Results from this post hoc subgroup analysis should be interpreted with caution but warrant additional investigation.

Fig 1.

CONSORT diagram of the Women's Health Initiative (WHI) randomized trial of calcium and vitamin D (CaD). HT, hormone therapy. Data adapted.

Fig 2.

Kaplan-Meier estimates of the cumulative hazard ratio (HR) for nonmelanoma skin cancer with supplemental calcium plus vitamin D (CaD) as compared with placebo.

Fig 3.

Kaplan-Meier estimates of the cumulative hazard ratio (HR) for melanoma with supplemental calcium plus vitamin D (CaD) as compared with placebo.

Fig 4.

Estimated effects of supplemental calcium with vitamin D (CaD) on risk of nonmelanoma skin cancer (NMSC), according to selected baseline characteristics. All models were adjusted for age, assignment in Women's Health Initiative (WHI) hormone therapy trial (active, placebo, not randomly assigned), assignment in WHI dietary modification trial (intervention, comparison, not randomly assigned), and outcome prevalent condition (NMSC). BMI, body mass index; Langley exposure, average regional solar radiation.

Fig 5.

Estimated effects of supplemental calcium with vitamin D (CaD) on risk of melanoma, according to selected baseline characteristics. All models were adjusted for age, assignment in Women's Health Initiative (WHI) hormone therapy trial (active, placebo, not randomly assigned), assignment in WHI dietary modification trial (intervention, comparison, not randomly assigned), and outcome prevalent condition (melanoma). BMI, body mass index; Langley exposure, regional solar radiation; NMSC, nonmelanoma skin cancer.