In this large prospective cohort of middle-aged US male physicians, almost one-third of the men had vitamin D deficiency (25[OH]D <20 ng/ml), and more than two-thirds had insufficient vitamin D status (25[OH]D <32 ng/ml) in the winter/spring. Even in the summer/fall, more than 10% were vitamin D deficient, and more than half had insufficient vitamin D status (). These findings, consistent with most observations from other studies [16
] as well as the recent NHANES [1
], suggest an alarming problem of low vitamin D status in the US and in Northern European countries.
D levels tended to be inversely associated with risk of aggressive prostate cancer, especially among men aged 65+ y at diagnosis () or among men with low levels of 25(OH)D (). Our findings were consistent with Corder et al., who first reported an inverse association for circulating 1,25(OH)2
D and aggressive prostate cancer, particularly in older men, although the lowest risk was observed among men with high 1,25(OH)2
D but low 25(OH)D levels [15
]. Normura et al. found that men with low levels of both metabolites had the greatest risks (not statistically significant); however, they did not distinguish aggressive from nonaggressive cancer [18
]. Ahonen et al. found an inverse association of 25(OH)D with prostate cancer in Finland [19
], and Tuohimaa et al. found a U-shaped relationship between 25(OH)D and prostate cancer [20
], but none of these two studies measured 1,25(OH)2
D levels. Other prospective studies generally found no associations [16
]. One major factor that may contribute to these inconsistent findings is that most studies did not specifically examine aggressive prostate cancer, the etiology of which appears to differ from that of indolent disease [16
]. Another related factor may be the apparent differences in vitamin D status in various populations () [15
]. The overall vitamin D status of the participants was fairly low in the three studies showing significant inverse association with 1,25(OH)2
] or 25(OH)D levels [19
]. The median levels of 25(OH)D for men of these studies were around or below 20 ng/ml so that at least half of the study participants were vitamin D deficient. In contrast, among the studies that did not find a direct association between circulating vitamin D metabolites and prostate cancer risk (including ours), the median levels of 25(OH)D (all seasons combined) were 29 ng/ml or higher, and the prevalence of vitamin D deficiency was approximately 20% [16
]. Thus, men in Hawaii [18
] and Baltimore [16
] may have more sun exposure compared to those in Nordic countries [19
], and the physicians [17
] and health professionals [22
] may be more conscious about nutrition and consume more supplements than the general population.
Prospective Studies of Circulating Level of Vitamin D Metabolites and Prostate Cancer Risk
We defined low 25(OH)D status as below the median (i.e., <24.4 ng/ml), close to deficient for blood samples collected in winter/spring, and <32.0 ng/ml, close to insufficient levels for blood samples collected in summer/fall. In our study, men with low levels of both 25(OH)D and 1,25(OH)2D, which may be a true indication of vitamin D deficiency, were at significantly increased risk for aggressive prostate cancer. Although with few men of non-European descent in this cohort, the data suggested stronger inverse associations between plasma vitamin D levels and risk of prostate cancer among them (versus men of European descent), probably because these men had poorer 25(OH)D status related to their darker skin color.
A significant association of plasma 1,25(OH)2
D levels and risk of aggressive prostate cancer was apparent only among older men or men with insufficient 25(OH)D status, suggesting a role of 1α-hydroxylase activity in prostate cancer development and progression. Levels of the active hormone 1,25(OH)2
D could be influenced by 25(OH)D status as well as 1α-hydroxylase activity. With low 25(OH)D status, 1,25(OH)2
D levels could be maintained by increased 1α-hydroxylase activity, possibly explaining why we observed no correlation between the two metabolites in blood samples collected in winter/spring. Reduced enzyme activity of 1α-hydroxylase due to aging [48
] or other factors, especially under low 25(OH)D status, could predispose a man to a higher risk of prostate cancer as observed in our study. This notion is indirectly supported by two studies that recently showed profoundly reduced 1α-hydroxylase activity in prostate cancer cell lines compared with cells from normal tissues [49
], suggesting that these cells may have reduced or lost the ability to convert 25(OH)D to 1,25(OH)2
D locally [51
]. Because circulating 1,25(OH)2
D level is relatively stable, an alternative explanation is that low 1,25(OH)2
D, in concert with low 25D, may act as a better marker of low vitamin D status.
Neither the FokI nor the BsmI polymorphism was directly associated with prostate cancer in our study, which is consistent with previous observations [35
]. However, we found an increased risk of prostate cancer associated with the less functional FokI ff
genotype only in the presence of low 25(OH)D status. Most previous studies, summarized by Berndt et al. [35
], were small and studied primarily localized disease. However, two studies reported an increased risk of prostate cancer associated with the FokI ff
genotype was found in the presence of high sun exposure (thus, presumably higher 25[OH]D status) [37
]. More studies are needed to resolve these apparently contradictory findings.
The strengths of this study include a prospective design with up to 18 y of follow-up and careful collection and storage of blood specimens and thorough ascertainment of events. Our large sample size, especially for patients with clinical aggressive prostate cancer, allowed us to assess the associations of 25(OH)D and 1,25(OH)2D, individually and jointly, with total and aggressive disease, as well as their potential interactions with the VDR polymorphisms. One limitation is that vitamin D levels were assessed in plasma collected at one time point and measured in two batches. However, the reproducibility of these assays was good as indicated by the low mean intra-pair coefficients of variation (both were <10%). Furthermore, the mean levels and their distribution were similar to those reported using fresh samples, and the overall- and batch specific-correlations between 25(OH)D with age and seasons of the year were as expected, supporting the internal validity of these assays. To ensure the comparability between patients and control participants and to reduce the nondifferential measurement errors due to batch-to-batch variation, patients and control participants were assayed together and analyzed in matched pairs, and we used batch-specific cutoff points to define the categories and utilized conditional logistic regression models for all the analyses. Nevertheless, if any such nondifferential measurement error exists, we expect that the strength of the association could be diluted toward the null. Other limitations included the lack of information on family history of prostate cancer and PSA screening practice, as well as PSA levels at diagnosis for these men. Findings in this cohort of physicians of predominantly European descent may not be easily generalized to other ethnic groups. Studies of other ethnic groups are necessary to better understand the role of vitamin D on prostate cancer.
In summary, the inverse association of 1,25(OH)2D alone or together with 25(OH)D with aggressive prostate cancer provide further evidence that both 25(OH)D and 1,25(OH)2D may play an important role in preventing prostate cancer progression, especially among older men. The FokI polymorphism may interact with 25(OH)D and modify prostate cancer risk. Men with the FokI ff genotype (14% in the European-descent population of this cohort) are more susceptible to this disease in the presence of low 25(OH)D status. Vitamin D insufficiency is a common problem, and improving vitamin D status through moderate sun exposure and vitamin D supplements, in particular, is essential for optimal health.