Calcium and vitamin D: Promising or proven?

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA SY33-01 Several lines of evidence suggest that higher calcium intake and higher vitamin D status have anti-neoplastic effects. This is most apparent for colorectal carcinogenesis. Animal studies have consistently shown that higher calcium intake reduces the risk of experimental large bowel tumors, and there are similar findings for vitamin D and its analogues. Epidemiological studies regarding calcium intake have generally been consistent with such an effect, although some studies do not show the association. Investigations using serum levels of 25-OH vitamin D consistently suggest a decreased risk from high vitamin D status. For several reasons, epidemiological study of dietary vitamin D has not been as informative: vitamin D status is partly determined by sunlight exposure, and dietary intake entails considerable measurement error. Thus it is not surprising that studies of the association of vitamin D intake with risk of colorectal cancer or adenomas have been conflicting. Perhaps the most compelling evidence supporting an anti-neoplastic effect of calcium intake in the large bowel is derived from intervention trials: these clearly point to an anti-neoplastic effect of calcium. Both calcium intake and vitamin D status may also have cancer-protective effects on breast cancer risk. Animal studies, though not as numerous as for colorectal carcinogenesis, suggest that both calcium and vitamin D may inhibit carcinogenesis in the mammary gland. Epidemiological studies are inconsistent, but in several cohort analyses, there has been an inverse association between calcium intake and risk of (largely premenopausal) breast cancer. Observational data regarding vitamin D similarly show some suggestions of an inverse association of intake (or blood levels of 25-OH vitamin D) with risk, but the data are quite conflicting. Although it has been hypothesized that vitamin D status is protective for prostate cancer, the human epidemiological data are not particularly supportive of this hypothesis. Some studies have reported that high calcium intake has been associated with an increase in risk of prostate cancer (particularly advanced disease). However, many other studies have not found this. One small clinical trial found evidence that calcium supplementation reduced risk of prostate cancer, but the numbers of advanced tumors were too limited for meaningful analysis. Animal studies do not suggest an effect of calcium intake on prostate carcinogenesis. Calcium and vitamin D are closely linked metabolically: vitamin D is an important component of the metabolic system that maintains calcium homeostasis. There is also evidence that there may also be an interaction of calcium and vitamin D in their anti-neoplastic effects, at least in the large bowel. Thus calcium and vitamin D may work synergistically through the same biological pathways in inhibiting the development of colorectal neoplasia. Vitamin D signaling has been shown to have anticarcinogenic effects on many of the molecular and cellular events associated with carcinogenesis. There are two leading hypotheses regarding the mechanisms of the calcium effect in the colorectum: a direct effect through the calcium sensing receptor, and an indirect one, through binding of bile acids (and other fats) in the lumen of the bowel, rendering them relatively inactive. It is not clear how a high calcium intake would affect the risk of cancer at sites outside the luminal digestive tract. The challenge ahead for epidemiologists is to clarify the association of calcium intake and vitamin D status on cancer for the common cancers; for basic scientists, it will be important to clarify the mechanisms of action of these two candidate chemopreventive agents.