Correspondence
Calcium plus Vitamin D and the Risk of Colorectal Cancer
N Engl J Med 2006; 354:2287-2288May 25, 2006
- Article
To the Editor:
The findings of the Women's Health Initiative (WHI) trial of calcium and vitamin D supplementation and the risk of colorectal cancer reported by Wactawski-Wende et al. (Feb. 16 issue)1 are not surprising. The chief problem with the study, in retrospect, is that, as the authors acknowledge, the dose of 400 IU of vitamin D3 was inadequate to raise blood levels of 25-hydroxyvitamin D to what is now considered a healthful range above 78 nmol per liter (30 ng per milliliter). It is now generally recommended that 1000 IU of vitamin D3 per day is necessary to attain this level2 and to maximize intestinal absorption of calcium3 for optimal bone health and the prevention of cancer.4 Virtually all the subjects in the study had vitamin D insufficiency according to the criterion given above, both at the beginning and at the end of the trial. The most important finding of this study is that women in the lowest quartile of serum 25-hydroxyvitamin D levels (less than 31 nmol per liter) had an incidence of colorectal cancer that was 253 percent of the incidence in the highest quartile (serum 25-hydroxyvitamin D level, ≥58.4 nmol per liter). These data are consistent with the observation that there was an inverse relationship between serum 25-hydroxyvitamin D levels and the risk of colon cancer.5,6 These women needed more vitamin D.
6 ReferencesMichael F. Holick, M.D., Ph.D.
Boston University Medical Center, Boston, MA 02118
mfholick@bu.edu 1
Wactawski-Wende J ,Kotchen JM ,Anderson GL , et al. Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med 2006;354:684-696[Erratum, N Engl J Med 2006;354:1102.]
Full Text | Web of Science | Medline2
Tangpricha V ,Koutkia P ,Rieke SM ,Chen TC ,Perez AA ,Holick MF . Fortification of orange juice with vitamin D: a novel approach to enhance vitamin D nutritional health. Am J Clin Nutr 2003;77:1478-1483
Web of Science | Medline3
Heaney RP ,Dowell MS ,Hale CA ,Bendich A . Calcium absorption varies within the reference range for serum 25-hydroxyvitamin D. J Am Coll Nutr 2003;22:142-146
Web of Science | Medline4
Holick MF . Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr 2004;80:Suppl:1678S-1688S
Web of Science | Medline5
Gorham ED ,Garland CF ,Garland FC , et al. Vitamin D and prevention of colorectal cancer. J Steroid Biochem Mol Biol 2005;97:179-194
CrossRef | Web of Science | Medline6
Grant WB . An estimate of premature cancer mortality in the U.S. due to inadequate doses of solar ultraviolet-B radiation. Cancer 2002;94:1867-1875
CrossRef | Web of Science | Medline
To the Editor:
The findings from the WHI trial with regard to colorectal cancer appear to be in contrast to epidemiologic data. Two critical issues are the dose and the duration of treatment. On the basis of the association between plasma 25-hydroxyvitamin D and colorectal cancer in the Nurses' Health Study (NHS),1 the calculated risk reduction for the intervention in the WHI trial would be only about 13 percent. Moreover, in the NHS, a statistically significant reduction in colorectal cancer in association with a higher intake of vitamin D emerged only among women who used supplements for more than 10 years.2 In randomized trials, calcium reduces the recurrence of adenoma, including that of large adenomas, consistent with a role of calcium in early stages of carcinogenesis.3 Epidemiologic data suggest that the benefits of calcium may level off at a dose of approximately 700 mg per day.4 In the WHI trial, the calcium intake was 1151 mg per day at baseline and was reported to increase during the trial. It is unclear how many women were consuming calcium at a dose low enough to benefit from the intervention, or whether the duration of the intervention was sufficient. Although the WHI trial provides important data, the benefits of calcium and vitamin D may exist at doses and durations not assessed in this study.
4 ReferencesEdward Giovannucci, M.D., Sc.D.
Harvard School of Public Health, Boston, MA 02115
edward.giovannucci@channing. harvard. edu 1
Feskanich D ,Ma J ,Fuchs CS , et al. Plasma vitamin D metabolites and risk of colorectal cancer in women. Cancer Epidemiol Biomarkers Prev 2004;13:1502-1508
Web of Science | Medline2
Martinez ME ,Giovannucci EL ,Colditz GA , et al. Calcium, vitamin D, and the occurrence of colorectal cancer among women. J Natl Cancer Inst 1996;88:1375-1382
CrossRef | Web of Science | Medline3
Baron JA ,Beach M ,Mandel JS , et al. Calcium supplements for the prevention of colorectal adenomas. N Engl J Med 1999;340:101-107
Full Text | Web of Science | Medline4
Wu K ,Willett WC ,Fuchs CS ,Colditz GA ,Giovannucci E . Calcium intake and risk of colon cancer in women and men. J Natl Cancer Inst 2002;94:437-446
CrossRef | Web of Science | Medline
Author/Editor Response
Drs. Holick and Giovannucci raise points regarding the vitamin D3 dose, the participants' personal calcium intake, and the duration of the trial. The calcium-plus-vitamin-D intervention used in the WHI trial was chosen in the early 1990s, and the trial was designed to evaluate the primary effect of supplementation on hip fracture. Vitamin D3 was provided to aid in calcium absorption. At that time, supplementation with 400 IU of vitamin D3 was considered substantial. Subsequently, the Institute of Medicine recommended intakes of 400 to 600 IU for women over 50 years of age to maintain bone density and prevent disorders associated with vitamin D deficiency.1 Some have recommended larger intakes, although there is no current consensus on optimal intake, especially for the prevention of colorectal cancer.
Dr. Holick asserts that the 400-IU dose used in the WHI trial was too small to be efficacious. Recent dose–response data2 suggest that the supplements used in the trial would probably have raised mean serum 25-hydroxyvitamin D levels by about 4 ng per milliliter, which may be insufficient to have an effect in colorectal cancer. The main effect in the subgroup analyses in our trial was the finding that lower serum vitamin D levels were associated with a higher risk of colorectal cancer, lending some support to Dr. Holick's hypothesis. However, these results should be interpreted cautiously, because our analyses did not control for all potential confounders.
Dr. Giovannucci contends that the personal intake of calcium by participants in the WHI trial (mean intake, 1151 mg) was near the recommended levels1 and too high for a preventive effect to be demonstrated. Nevertheless, more than 12,000 participants reported personal calcium intakes of less than 800 mg at baseline. Among these women, there was no evidence of a benefit (hazard ratio for colorectal cancer, 1.10; 95 percent confidence interval, 0.75 to 1.60).
Dr. Giovannucci also points out that the average trial duration of seven years may have been too short to demonstrate protection against colorectal cancer. We appreciate this point and note that additional follow-up through 2010 is under way. Our optimism regarding a longer-term effect is dampened somewhat by the lack of a protective trend in incidence rates through eight years of follow-up and the similarity in the rate of self-reports of polyps in the two study groups.
We believe a better understanding of the discrepancies in the preceding observational studies and in this randomized trial is needed before the role of calcium and vitamin D in the prevention of colorectal cancer can be established.
2 ReferencesJean Wactawski-Wende, Ph.D.
University at Buffalo, S.U.N.Y., Buffalo, NY 14214
jww@buffalo.edu Garnet L. Anderson, Ph.D.
Fred Hutchinson Cancer Research Center, Seattle, WA 98109MaryJo O'Sullivan, M.D.
University of Miami, Miami, Florida 331011
Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board, Institute of Medicine. Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D, and fluoride. Washington, D.C.: National Academy Press, 1999.
2
Heaney RP ,Davies KM ,Chen TC ,Holick MF ,Barger-Lux MJ . Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr 2003;77:204-210[Erratum, Am J Clin Nutr 2003;78:1047.]
Web of Science | Medline
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