Dietary Calcium and Fructose in the Development of Prostate Cancer
abstract & commentary
Synopsis: In this prospective evaluation of the large cohort of men participating in the Health Professionals Follow-Up Study (n = 47,781), 1414 developed prostate cancer within six years. Dietary information obtained by the questionnaire indicates that in this group, high levels of calcium intake increased the risk of advanced prostate cancer, whereas higher levels of fructose (both from fruit and non-fruit sources) reduced the risk. The results, if confirmed, imply a potential adverse effect of high calcium intakes in middle-aged and older men but also a potential beneficial effect of increased fruit consumption.
Source: Giovannucci E, et al. Cancer Res 1998;58:442-447.
In addition to the pivotal role of 1,25-(oh)2d3 in calcium and phosphorus metabolism, this hormone/vitamin is also an important regulator of normal and malignant cell differentiation and maturation. There is now substantial literature on the antiproliferative effects of vitamin D analogues in vitro and in vivo derived from experimental models. Furthermore, in older men with low circulating vitamin D levels, the risk of clinically advanced prostate cancer is higher than those with normal levels.1
In this report from the Health Professionals Follow-Up Study, which is an ongoing prospective cohort study2 involving 51,529 male professionals who were aged 40-75 in 1986 and who had completed the initial and subsequent questionnaires in 1988, 1990, 1992, and 1994, an examination of dietary calcium, phosphorus, and fructose were determined in relation to the occurrence of clinically advanced prostate cancer. Data were available from 47,781 individuals, and, in this group, there were 1414 incident cases of prostate cancer. Higher consumption of calcium, either from dietary sources or as a supplement, was associated with advanced prostate cancer, whereas high fructose intake, particularly from fruit but also from non-fruit sources, was associated with a lower risk. There was a moderate association of fat intake with advanced prostate cancer, but this was attenuated and no longer statistically significant when controlled for calcium and fructose. Giovannucci and colleagues suggest that the data provide an association of calcium and fructose intake and the development of prostate cancer and interpret this as indirect evidence for the association of higher levels of 1,25-(OH)2D3 and protection from the development of this tumor.
COMMENT BY DAN LONGO, MD
Vitamin D exerts important effects on cellular proliferation and maturation. Whether cells are grown in vitro in the presence 1,25-(OH)2D3 or tumor growth in vivo is analyzed in animals with varying levels of this vitamin D, the evidence strongly suggests a growth inhibitory effect. Furthermore, in human tumor cells grown in culture3 and in murine tumor models,4 vitamin D analogues have been shown to inhibit tumor proliferation and tumor growth, and higher 1,25-(OH)2D3 levels in older men correlate with a lower risk for developing advanced prostate cancer.1
One of the factors regulating levels of circulating 1,25-(OH)2D3 is calcium. To the extent that 1,25-(OH)2D3 inhibits prostate cell proliferation and invasiveness, it was proposed that a diet high in calcium (by inhibiting 1,25-(OH)2D3 might be associated with a greater risk for prostate cancer. Whereas this regulation is important for calcium and phosphorus metabolism, a higher level of circulating 1,25-(OH)2D3 has been shown to induce cellular maturation and reduce normal and neoplastic cell proliferation. Indeed, circulating vitamin D levels inversely correlate with the presence of advanced prostate cancer. Thus, it was hypothesized and subsequently supported by this survey that high levels of dietary calcium were associated with the development of advanced prostate cancer.
Similarly, dietary phosphorus might inhibit circulating 1,25-(OH)2D3 levels and also have an association with advanced prostate cancer. However, this was not observed, perhaps because dietary phosphates tend to bind to calcium reducing its bioavailability. A low phosphate level will stimulate parathyroid hormone, which will inhibit 1,25-(OH)2D3. Thus, the overall effect of dietary phosphorus on serum phosphate or 1,25-(OH)2D3 levels is less predictable. Nonetheless, dietary fructose has been shown to result in a prompt but transient drop in circulating phosphate, primarily because of the substantial hepatic requirement for phosphorus in the metabolism of this sugar. This transient hypophosphatemia may, in turn, briefly raise the circulating level of 1,25-(OH)2D3. Thus, the observed inverse relationship of fructose consumption and prostate cancer could possibly be explained by this same mechanism involving the dietary influence upon circulating 1,25-(OH)2D3 and its inhibitory effects on prostate cancer.
This report needs to be considered for the facts it presents in the context of an epidemiological study. As such, it supports an association of certain dietary factors (calcium and fructose) and the risk for the development of advanced prostate cancer. That the mechanism of this association relates to the influence of these nutrients on circulating 1,25-(OH)2D3 remains an unproven but highly tenable hypothesis. With the projected increase in prevalence of this malignancy, this is a hypothesis worthy of intensive exploration. (Dr. Longo is Scientific Director, National Institute on Aging, Baltimore, MD.)