In the early 1990s, studies reported an association between cancer-mortality and geographic region, with the greatest mortality in northern regions where there is less UV light exposure [28
]. This observation led to the hypothesis that vitamin D may play a role in cancer development and progression. The geographic distribution of mortality was consistent with an inverse relationship between prostate cancer risk and UV exposure, and presumably, serum vitamin D levels [29
]. This relationship between low UV exposure and increased risk of prostate cancer has been confirmed by several other investigators [30
This association of low UV exposure and increased cancer risk has also been demonstrated in seasonal studies, where patients who were diagnosed with cancer in the summer and fall had increased survival compared to patients diagnosed in the winter [34
]. For example, Robsahm et al. found that being diagnosed with prostate cancer in the summer conferred a 20–30% reduction in the risk of death. This was supported by Lagunova et al. who showed that patients diagnosed with prostate cancer in the summer and autumn had a better prognosis than those patients diagnosed in winter or spring with a relative risk of death of 0.80.
Prior to this study, there have been 12 studies that have examined the association between vitamin D levels and prostate cancer risk (Table ). Four of these studies have suggested an association between increased prostate cancer risk and low serum levels of vitamin D [9
]. Two demonstrated an inverse association between 1,25-OH2
vitamin D levels and prostate cancer risk [10
]. The two other studies demonstrated a link between low 25-OH vitamin D levels and increased risk of prostate cancer [9
]. Tuohimaa et al. showed an increased risk of prostate cancer with extreme 25-OH vitamin D deficiency (<7.6 ng/mL), and they also showed an increased risk of prostate cancer in those with the highest 25-OH vitamin D levels suggesting a U-shaped relationship between vitamin D status and prostate cancer risk [12
]. In a 2007 study by Li et al., there was an increased risk of aggressive prostate cancer when both 1,25-OH2
vitamin D and 25-OH vitamin D levels were low, but no increased risk was found in patients with low 25-OH vitamin D levels, but normal 1,25-OH2
vitamin D levels. This additive risk of low levels of both forms of vitamin D was also shown by Corder et al. suggesting that perhaps low 25-OH vitamin D levels may only be associated with increased prostate cancer risk when they are low enough to effect 1,25-OH2
vitamin D levels. However, eight other epidemiologic studies have shown no significant relationship between measured serum vitamin D levels and prostate cancer risk [13
Studies correlating serum vitamin D and prostate cancer risk
Additionally, a recent study examined the role of vitamin D on mortality in patients with known prostate cancer [20
]. Tretli et al. found that higher levels of 25-OH vitamin D were associated with a better prognosis with a relative risk of mortality of 0.33 compared with patients who had lower levels of 25-OH vitamin D.
In the laboratory, prostate carcinoma cell lines and human specimens have been shown to express vitamin D receptors [3
]. Normal prostate cells express alpha-1-hydroxylase [40
] and this activity can be lost when cancer develops [40
], although the incidence of this loss in patients has not been fully characterized. Extrarenal alpha-1-hydroxylase, that is responsible for autocrine and paracrine, but not endocrine vitamin D activation, is thought to be constitutively active [43
] and not down-regulated by its downstream product, 1,25-OH2
vitamin D [45
]. If this model for the role of vitamin D in prostate carcinogenesis is correct, one would expect little effect of 25-OH deficiency unless it is severe enough to reduce autocrine 1,25-OH2
vitamin D production. We did not detect a relationship between severe vitamin D deficiency and prostate cancer risk, but our ability to do so was limited by the modest number of subjects (both cases and non-cases) with severe deficiency (n
= 148). Unfortunately, we were unable to measure prostatic tissue vitamin D status, which would clearly be of interest.
While this study had many strengths including relatively large numbers of cases, a representation of multiple populations across the US where vitamin D deficiency is common (Portland, OR, and Minneapolis, MN, for example), a population of older men who are usually at the greatest risk of prostate cancer, and a relatively large number of high-grade prostate cancers, the results were not consistent with the hypothesis that low serum levels of 25-OH vitamin D increase the risk for prostate cancer. 1,25-OH2
vitamin D, while of interest, was outside the scope of this study and only 25-OH vitamin D was measured. When compared to other similar studies (Table ), our study had a large, geographically diverse population, common to less than half the prior studies [11
]. Also, our study had an acceptable number of highly aggressive prostate cancers (Gleason ≥7) compared to other studies.
In general, the studies that were done in locations with a high prevalence of vitamin D deficiency have more frequently shown a relationship between low vitamin D levels and prostate cancer risk. Even though our population came from at least two sites with a high prevalence of vitamin D deficiency (Portland, OR, and Minneapolis, MN), there was still no association with 25-OH vitamin D levels and prostate cancer risk. Despite this, only 24% of participants in this analysis had vitamin D deficiency (<20 ng/mL), and only 9% had 25-OH vitamin D levels <15 ng/mL. Similarly, as illustrated by only the top quartile having normal vitamin D levels (>30 ng/mL), our subjects were largely clustered in around and just below the normal range of vitamin D. Thus, it is possible that our cohort did not include enough patients with severe vitamin D deficiency to demonstrate an effect. It is also possible that the study did not have a sufficient number of high-grade cancers. Some recent data and hypotheses suggest a link between vitamin D status and prostate cancer aggressiveness rather than incidence [13
]. It is also possible that measurement of vitamin D status in men age 65 or older, as reported here, occurs too late in life to detect an effect on an oncogenic process that is thought to be initiated earlier in life [47
The compelling biologic links between vitamin D and prostate cancer cell growth has motivated the search for such a link in patients. For this reason, it is worthwhile to contemplate possible explanation of how our analysis may have missed an effect. Nevertheless, the most obvious explanation for our findings is that an association between prostate cancer risk and vitamin D status does not exist. While we cannot rule out the existence of such an association in this study, our findings indicate that the vitamin D status, measured by 25-OH vitamin D, in men age 65 or older, does not predict for the subsequent development of prostate cancer.