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Department of Pathology and Laboratory Medicine Mount Sinai Hospital 600 University Avenue Toronto, Ontario M5G 1X5 Canada E-mail: rvieth{at}mtsinai.on.ca
Dear Sir:
The recent paper in the Journal by Chan et al (1) may affect decisions a person may make to optimize nutrient intakes and to determine which clinical strategies to use to treat prostate cancer. They report that high intakes of dairy products or calcium increase the risk of prostate cancer and propose that anything that lowers circulating 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] concentrations—particularly the consumption of calcium or dairy products—could increase the risk of prostate cancer.
They state in the discussion section, "epidemiologic studies suggest that 1,25(OH)2D3 may protect against prostate cancer" (1). However, most of the epidemiologic studies they cite (2–5) do not support this statement. No study, except that by Corder et al (6), shows a relation between circulating 1,25(OH)2D3 concentrations and prostate cancer. Corder et al reported that the mean prediagnostic 1,25(OH)2D3 concentration was significantly lower in patients with prostate cancer than in a control cohort by 4.6 pmol/L (1.83 pg/mL). This difference in 1,25(OH)2D3 concentrations is poor evidence of a role for 1,25(OH)2D3 in prostate cancer given that normal concentrations typically range from 40 to 140 pmol/L.
The epidemiologic evidence relating prostate cancer to vitamin D or 25-hydroxyvitamin D3 concentrations [25(OH)D3] is based on ecologic studies that show an inverse correlation between ultraviolet light exposure and mortality rates from prostate cancer in the United States (5). Ultraviolet light has profound effects on circulating concentrations of 25(OH)D3 but practically no effect on circulating 1,25(OH)2D3, the concentration of which is stimulated by low calcium intakes.
Chan et al report that the mean 1,25(OH)2D3 concentration was significantly different only between the lowest and highest quartiles of calcium intake. However, the full increase in the relative risk of prostate cancer was already present, both in the third quartile of dairy calcium intake and in the third quintile of dairy product intake (Table 2 in reference 1). In other words, anything beyond just one glass of milk daily seems to increase the risk of prostate cancer, yet the risk is not correlated with 1,25(OH)2D3 concentrations. We are left to wonder whether the beneficial effect of calcium in lowering blood pressure, preventing osteoporosis, and even preventing the progression of existing prostate cancer (7) needs to be balanced against the risk of developing prostate cancer.
The mechanism explaining why ultraviolet light might prevent prostate cancer was elucidated by Schwartz et al (8) and others (9, 10), who showed that prostate cells synthesize their own 1,25(OH)2D3 from 25(OH)D3. More importantly, the desirable in vitro effects of 1,25(OH)2D3 on prostate cells are achievable with 25(OH)D3 supplementation alone (9).
In groups of men likely to have higher circulating 25(OH)D3 concentrations than the subjects in the study by Chen et al, dietary calcium and circulating 1,25(OH)2D3 concentrations do not correlate with the prevalence of prostate cancer. Nomura et al (11) and Giovannucci (12) attributed the lack of a relation between 1,25(OH)2D3 concentrations and prostate cancer in men in Hawaii to their higher 25(OH)D3 concentrations. Likewise, high 25(OH)D3 concentrations might also explain the lack of an effect of calcium on prostate cancer risk in men in Milan, Italy (13).
When circulating 25(OH)D3 is high enough, the prostate can generate the amount of 1,25(OH)2D3 needed to regulate proliferation and differentiation of its cells. In contrast, when circulating 25(OH)D3 is so low that the prostate cannot produce enough of its own 1,25(OH)2D3, a higher circulating 1,25(OH)2D3 concentration resulting from a severe calcium intake restriction, as shown by Chan et al (1), appears relevant to the biology of the prostate gland.
The health implication becomes clear when the epidemiologic studies comparable with those of Chan et al are considered as a group (1, 11, 13). If 1,25(OH)2D3 is a locally manufactured paracrine hormone that regulates prostate cells (8–10), then we need to ensure that the 25(OH)D3 concentration is optimal for this purpose. Unfortunately, the seasonal cycle of 25(OH)D3 concentrations makes it difficult to test this implication in the Physicians’ Health Study cohort, unless the concentrations are adjusted according to season.
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