Daily supplementation with 1,000 mg of calcium and 400 IU of vitamin D had no effect on NMSC or melanoma skin cancer incidence in this large randomized double-blinded placebo-controlled trial. One possible reason for the overall null results is that a daily 400-IU dose of vitamin D is inadequate for reducing cancer risk. Since the report of no reduction in colorectal cancer—the key secondary outcome of the CaD trial—at the dose tested,25
have recommended higher intakes of vitamin D for reducing colorectal and other cancers. The daily 400-IU dose of vitamin D3 is estimated to have raised mean serum 25(OH)D levels by approximately 4 ng/mL, which may be inadequate to observe a clinical difference in skin cancers. Indeed, 400 IU per day is 33% lower than the daily adequate intake level of 600 IU recommended in a recent Institute of Medicine consensus statement (November 2010).33
However, this dose was considered adequate to aid calcium absorption at the inception of the trial in the early 1990s and thus appropriate for testing the primary CaD trial hypothesis that CaD supplementation would reduce hip fracture. Although hip fracture incidence was not, in fact, reduced in the WHI cohort of women age 50 to 79 years at baseline, significant reduction was seen in women age 60 years and older.24
Another possible explanation for the null results regarding skin cancer is that the study design allowed off-protocol calcium and/or vitamin D supplementation; women were allowed to take up to 600 IU of vitamin D daily initially and up to 1,000 IU daily from 1999 onward. Therefore, some in the placebo group were taking more vitamin D than some women in the intervention group. However, there is some evidence that active CaD-arm participants had higher overall vitamin D intake than those assigned to receive placebo; in a subset of 227 women assigned to receive active pills versus 221 assigned to receive placebo, serum 25(OH)D levels in women taking active pills were 28% higher than those in women taking placebo pills 2 years after randomization.24
These 448 women with baseline and year-2 serum 25(OH)D levels were randomly selected and were at least 50% adherent to study medication. The 28% difference in 25(OH)D levels between the two groups is likely to be generalizable to the entire trial, because 84% of all participants were more than 50% adherent to study medications. Although the difference in 25(OH)D levels is modest, this substudy confirmed that 400 IU of vitamin D did raise 25(OH)D levels in this trial.
Whether the trial dose was too low or the difference in intake between treatment groups was too small to see an effect of CaD on NMSC, it is of interest that in subgroup analysis, CaD supplementation reduced risk of melanoma by 57% in women with history of NMSC. Additionally, CaD supplementation tended to reduce risk of melanoma in women with higher BMIs (> 25 kg/m2
), with lower baseline vitamin D intake (< 400 IU), and from areas with less sun exposure (< 375 Langleys), although there were no statistically significant interactions of CaD treatment with any of these variables. In the subgroup of women with history of NMSC, the absolute number of melanoma cases in both arms was small: 10 in the CaD arm and 24 in the placebo arm. Thus, this finding may have resulted by chance, particularly because we examined 16 subgroups in these analyses. However, there is some evidence that vitamin D may affect development of melanoma. Vitamin D reduces UV-induced DNA damage in mice and has antiproliferative and prodifferentiative effects on melanoma cell lines in vitro.19,34
In humans, previous studies have reported an association between higher 25(OH)D levels and lower Breslow thickness at melanoma diagnosis as well as decreased risk of relapse and death23
Others have noted a positive relationship between signs of sun damage (and presumably higher vitamin D levels) and decreased death from melanoma.36
but not all38
studies have shown that higher dietary or supplemental intake of vitamin D is associated with reduced risk of melanoma. Previous WHI and other cohort studies have reported that women with history of NMSC are 2.4 times more likely to develop melanoma than those without history of NMSC.39–43
Therefore, NMSC may be a marker for participants with more UV-induced DNA damage6,44–47
and thus higher risk for melanoma.
The possibility that CaD supplementation, or either vitamin D or calcium alone, might prevent melanoma in this high-risk group has important public health implications. Although we cannot rule out a role for calcium in preventing melanoma, we have some evidence that vitamin D may be an important factor in our findings. In exploratory patient case–control analyses of serum 25(OH)D levels measured in 4,868 women for previously reported fracture and breast and colorectal cancer patient case–control studies,25,26
higher 25(OH)D levels were associated with 50% reduction in melanoma (manuscript in preparation). We hypothesize that raising vitamin D levels may prevent development of melanoma in women at high risk. A possible role for vitamin D supplementation in preventing melanoma in women with a history of NMSC warrants further investigation.
This study has several limitations. First, the WHI CaD trial was designed to examine the effect of a specific dose of CaD supplementation on hip fracture and colorectal cancer. Post hoc analyses of other malignancies may lack statistical power to detect differences between active and placebo groups, and it may be that any potential benefit of CaD supplementation on cancer incidence takes more than 7 years to appear. Second, NMSC outcome was based on particpant self-report, and cases were not adjudicated; however, several studies have found self-reported skin cancer to be highly accurate.48,49
We lacked information on specific types of NMSC in this study; thus, we cannot determine if there was a differential effect of CaD supplementation on basal cell versus squamous cell carcinoma risk. Additionally, we lacked systematic measurements of 25(OH)D achieved after intervention and cannot determine the relationship between 25(OH)D levels after CaD supplementation and skin cancer risk. Even though women were randomly assigned to receive 400 IU of vitamin D, serum 25(OH)D levels could have varied as a result of genetic or environmental factors affecting vitamin D metabolism.50,51
Finally, the finding that CaD supplementation reduced risk of incident melanomas in women with a history of NMSC must be interpreted with caution, because the P
value is modest (Pinteraction
= .038) and may reflect a chance finding given the multiple subgroups tested.
Strengths of this study include its randomized double-blinded design, large well-characterized study population, and long follow-up duration. This study controlled for many potential confounding factors, including diverse geographic regions with differing solar radiation, physical activity, smoking and alcohol status, education, socioeconomic status, and nutrient intake.
Despite the large study population, the number of incident melanomas was small (n = 176), illustrating the size of the cohort needed to detect a chemopreventive effect of any agent in a 7-year period. At this time, it seems unlikely that a randomized trial of the scope needed to examine the effect of calcium or vitamin D (or combined) supplementation on skin cancer risk will be performed, and this trial may provide the best data with which to assess this issue in the near future.
In conclusion, daily supplementation of calcium (1,000 mg) and vitamin D (400 IU) did not reduce incidence of NMSC or melanoma in a large cohort of postmenopausal women age 50 to 79 years. Therefore, our results do not support use of these supplements, at these doses, for preventing skin cancer in older women. However, CaD supplementation seems to have reduced the incidence of melanoma in women with history of NMSC, suggesting a possible role for either vitamin D or calcium, or their combination, in reducing melanoma in this high-risk group. Additional investigations of CaD supplementation to prevent melanoma in women with history of NMSC are warranted.