Vitamin D, calcium and colorectal cancer

The Women's Health Initiative (WHI) trial followed 18,176 post-menopausal women taking calcium and vitamin D supplements. After about seven years of follow-up the researchers reported neither a reduced or an increased risk of colorectal cancer.

Volunteers with an average age of 62 at the start of the trial were randomly assigned to receive 1000 mg of elemental calcium in the carbonate form and 400 IU of vitamin D3 per day. A similar population (N=18,106) were given a placebo.

"Supplementation with calcium plus vitamin D was not associated with any significant risk or benefit with respect to any major disease outcomes,"​ wrote lead researcher Jean Wactawski-Wende from the University at Buffalo.

The study, published in the New England Journal of Medicine​ (Vol 354, pp. 684-696), reported that the total risk of cancer and death between the supplementation and placebo groups were not significant, as was the self-reported occurrence of polyps.

A nested case-control study showed that people with low levels of serum 25-hydroxyvitamin D, the non-active 'storage' form of vitamin D in the body, were at a higher risk of colorectal cancer.

This agreed with the findings of the Nurses' Health Study (Cancer Epidemiology Biomarkers Prev.​ 2004 Vol. 13, pp. 1502-1508)).

Previous randomised clinical trials have reported an inverse link between calcium supplements and the risk of colorectal cancer, a disagreement that raises questions about calcium plus vitamin D and the cancer.

In an accompanying editorial, Michele Forman and Bernard Levin from the MD Anderson Cancer Center at the University of Texas, noted that the WHI trial had three overlapping components, with 69 per cent of the women enrolled on the Dietary Modification trial, 54 per cent enrolled on the Hormone Therapy trial, and 14 per cent enrolled on both.

"The enrolment in three overlapping trials maximised the participation and size of the WHI trial but created a complex approach with potential confounders for biological interpretation,"​ said Forman and Levin.

Other limitations with the design, admitted by the researchers, included the free-living population being allowed to take supplements on their own. This resulted in the placebo group having similar vitamin D and calcium intake as the intervention group.

"These high intakes may have limited our ability to affect the rates of colorectal cancer further,"​ wrote the researchers.

Another limitation, highlighted by the researchers and Forman and Levin, is the long latency period of 10 to 20 years for colorectal cancer. None of the participants had the cancer at baseline.

"Since the mean age of the women was 62 years at entry into the calcium with vitamin D trial, the women were just reaching the high-risk age for colorectal cancer when the trial ended,"​ said Forman and Levin.

The strength of this study lies in the large-scale, randomised, double-blind, placebo-based design. The study population was also racially and ethnically diverse, enabling wider generalisations to be observed.

However, the limitations of the study appear to outweigh the strengths.

"The role of calcium plus vitamin D supplementation in the prevention of colorectal cancer needs to be interpreted in the light of the complexities of the WHI study and the probability that the doses of these substances may have been too low to achieve the desired effect,"​ concluded Forman and Levin.

An exclusive feeding trial is needed to fully monitor dietary and supplemental intake of both nutrients, say Forman and Levin, and could provide a fuller investigation of the effects of different doses and sex-specific risks of colorectal cancer.

Colorectal cancer accounts for nine per cent of new cancer cases every year worldwide. The highest incidence rates are in the developed world, while Asia and Africa have the lowest incidence rates.

It remains one of the most curable cancers if diagnosis is made early.