Vitamin D Supplementation: Timing and Dosage Still Uncertain

By Dónal P. O'Mathúna, PhD. Dr. O'Mathúna is Senior Lecturer in Ethics, Decision- Making & Evidence, School of Nursing, Dublin City University, Ireland; he reports no financial relationship to this field of study.

Source: Chlebowski RT, et al; for the Women's Health Initiative Investigators. Calcium plus vitamin D supplementation and the risk of breast cancer. J Natl Cancer Inst 2008;100:1581-1591.

Although some observational studies have associated higher calcium intake and especially higher vitamin D intake and 25-hydroxyvitamin D levels with lower breast cancer risk, no randomized trial has evaluated these relationships.

Postmenopausal women (n = 36,282) who were enrolled in a Women's Health Initiative clinical trial were randomly assigned to 1,000 mg of elemental calcium with 400 IU of vitamin D3 daily or placebo for a mean of 7.0 years to determine the effects of supplement use on incidence of hip fracture. Mammograms and breast exams were serially conducted. Invasive breast cancer was a secondary outcome. Baseline serum 25-hydroxyvitamin D levels were assessed in a nested case-control study of 1,067 case patients and 1,067 control subjects. A Cox proportional hazards model was used to estimate the risk of breast cancer associated with random assignment to calcium with vitamin D3. Associations between 25-hydroxyvitamin D serum levels and total vitamin D intake, body mass index (BMI), recreational physical activity, and breast cancer risks were evaluated using logistic regression models. Statistical tests were two-sided.

Invasive breast cancer incidence was similar in the two groups (528 supplement vs 546 placebo; hazard ratio = 0.96; 95% confidence interval = 0.85-1.09). In the nested case-control study, no effect of supplement group assignment on breast cancer risk was seen. Baseline 25-hydroxyvitamin D levels were modestly correlated with total vitamin D intake (diet and supplements) (r = 0.19, P < 0.001) and were higher among women with lower BMI and higher recreational physical activity (both P < 0.001). Baseline 25-hydroxyvitamin D levels were not associated with breast cancer risk in analyses that were adjusted for BMI and physical activity (Ptrend = 0.20).

Calcium and vitamin D supplementation did not reduce invasive breast cancer incidence in postmenopausal women. In addition, 25-hydroxyvitamin D levels were not associated with subsequent breast cancer risk. These findings do not support a relationship between total vitamin D intake and 25-hydroxyvitamin D levels with breast cancer risk.

Commentary

Breast cancer is the most common cancer in women in the United States. In spite of important developments in screening for and treating breast cancer, it remains the second leading cause of cancer-related deaths among U.S. women.1 Therefore, much attention has been given to methods of preventing breast cancer, including the use of various dietary supplements.

In the 1980s, it was proposed that higher levels of vitamin D would reduce the risk of colon cancer, breast cancer, ovarian cancer, and other cancers.2 The hypothesis was based on observations that sun exposure increases vitamin D levels and people living in areas with less sun exposure had higher incidences of these cancers. Biochemical studies confirmed that vitamin D metabolites induced several anticancer systems in the body. A number of epidemiological studies, including the Nurses' Health Study, investigated potential connections between vitamin D levels and risk of cancer. The strongest association was with risk of colon cancer, with breast cancer having the second largest reduction in risk. In the Nurses' Health Study, plasma levels of 25-hydro-xyvitamin D were significantly lower in women with breast cancer compared to controls, with the strongest association in postmenopausal women. However, vitamin D intake was associated with risk of cancer only in premenopausal women, and not in postmenopausal women. Thus, the age at which supplementation begins may be significant, and may have impacted the results of the Women's Health Initiative (WHI) trial reviewed here because only postmenopausal women were enrolled.

Some observational studies have supported a connection between vitamin D intake and risk of breast cancer, but others have not. Similarly, the results of observational studies examining calcium intake or calcium levels and risk of breast cancer have been variable, with not all studies finding an association. Hence the motivation for this randomized controlled trial of calcium with vitamin D supplementation and the incidence of breast cancer.

The results presented here from the WHI were planned secondary endpoints from a highly complex and rigorously designed trial. The primary endpoint was reduction in risk of hip fracture, with risk of colon cancer being another secondary endpoint. The risk of colon cancer was not reduced by calcium and vitamin D supplementation.3 The results reported here also found no benefit from supplementation in reducing the risk of breast cancer. However, there were some limitations to the study, which has led other commentators to suggest that further study of these supplements is still warranted.1

The dose of vitamin D used in the WHI trial was 400 IU/d, which is that recommended by the Institute of Medicine. However, more recent investigations have suggested that 1,000-2,000 IU/d may be necessary for cancer prevention.4 The researchers acknowledged this limitation and noted that approximately half of the women in the WHI trial took an additional 400 IU vitamin D themselves. The participants were permitted to use dietary supplements in additional to whatever they were assigned in the trial. This non-protocol use of calcium and vitamin D is another limitation with the WHI study. The authors monitored total supplement intake and found in was comparable between groups. However, about 15% of the placebo group took vitamin D themselves at the dose used in the trial. The analysis was conducted on an intention-to-treat basis, with the authors claiming this non-protocol use did not overly influence the results.

An interesting finding in the WHI trial was the correlation between 25-hydroxyvitamin D levels and lower BMI and higher recreational physical activity. When analyses were adjusted for these two factors, 25-hydro-xyvitamin D levels were no longer associated with risk of breast cancer. This suggests that observational studies which did find an association may have been confounded by BMI and exercise levels. Since exercise and leanness are associated with breast cancer risk, these factors will need to be taken into account in future studies.

The main findings do not support a causal relationship between calcium with vitamin D supplementation and breast cancer risk. However, further studies are warranted, especially to examine whether higher doses may be beneficial, or whether supplements are beneficial when begun at an earlier age. This study provides an excellent model for further examination of these questions.

References

1. Speers C, Brown P. Breast cancer prevention using calcium and vitamin D: A bright future? J Natl Cancer Inst 2008;100:1562-1564.

2. Giovannucci E. Vitamin D and cancer incidence in the Harvard cohorts. Ann Epidemiol 2008 Feb 19; Epub ahead of print.

3. Wactawski-Wende J, et al. Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med 2006;354:684-696.

4. Gorham ED, et al. Optimal vitamin D status for colorectal cancer prevention: A quantitative meta analysis. Am J Prev Med 2007;32:210-216.