Null Association between Vitamin D and PSA Levels among Black Men in a Vitamin D Supplementation Trial

A number of studies have suggested that low levels of vitamin D may account for higher prostate cancer mortality in Blacks (1). The major risk factors for prostate cancer—older age, black race, and residence at northern latitudes—are all associated with lower synthesis of vitamin D (1). Prostate cancer cells have vitamin D receptors that convert 25(OH)D to 1,25(OH)₂D via 1-α-hydroxylase (1). Some studies have found that administration of 1,25(OH)₂D can slow or moderate the rate of prostate-specific antigen (PSA) increase in patients with advanced prostate cancer (2–4). Other studies have observed no effect of vitamin D supplementation on PSA (5, 6). To summarize, findings about the effects of vitamin D on PSA are mixed (7–10). Most studies, however, have assessed this association among small (11), nonminority patient populations, and when supplementation has been studied, the administration period has been relatively short (i.e., days or weeks; ref. 12). To our knowledge, this is the first study to examine the preventive benefits of vitamin D intake on PSA levels among men without a cancer diagnosis.

This study was conducted as part of a prospective, randomized, double blind, placebo-controlled clinical trial of vitamin D3 in a healthy Black population. The main aim of the study was to examine the effect of daily supplementation (placebo, 1,000 U, 2,000 U, and 4,000 U) of vitamin D3 on plasma 25(OH)D levels. All capsules also contained 200 mg of calcium. Details of study procedures are presented elsewhere. Participants received supplementation during early winter (November or December) and were taken orally once daily for 3 months (completed in February or March).

The primary endpoints of the study were changes in total and free PSA from baseline to 3-month follow-up (after supplementation). Total and free PSA was measured separately by a sandwich electrochemiluminescence immunoassay on the 2010 Elecsys autoanalyzer (Roche Diagnostics). The lowest detection limit of the total PSA assay is 0.002 ng/mL and the day-to-day imprecision values at concentrations of 0.30, 4.76, and 51.1 ng/mL are 2.4%, 2.9%, and 3.8%, respectively. The lowest detection limit of the free PSA assay is 0.01 ng/mL and the day-to-day imprecision at concentrations of 0.17, 1.36, and 24.30 ng/mL are 4.5%, 4.9%, and 4.2%, respectively.

Statistical power for this trial was based on the intent-to-treat population of 80 subjects per arm. Using a two-sided t test at the 0.05 significance level, the minimum detectable difference in 25(OH)D between treatment arms was 5.3 with 80% power. All statistical analyses were performed using SAS 9.2 (SAS Institute). Differences in the baseline characteristics of participants across the four treatment groups were compared using the Kruskal–Wallis test for continuous variables and χ² test for categorical comparisons. The primary endpoints were 3-month change in total and free PSA at the end of treatment. For our primary analysis, we used linear regression with the dose of vitamin D3 (per 1,000 U/d) as the independent variable and the 3-month change in total PSA (or 3-month change in free PSA) as the dependent variables. This targeted population of healthy vitamin D–deficient Black males allows for small sample size with adequate power to test the hypothesis that vitamin D supplementation lowers PSA.

All participants provided written informed consent. The project was approved by the Institutional Review Boards of Harvard School of Public Health and Dana-Farber Cancer Institute. All procedures were followed in accordance with institutional guidelines.

Among the 105 eligible participants, no significant differences in baseline characteristics between dose groups was observed with an overall median age [interquartile (IQR)] of 48.9 (42.0–57.8) years and a median body mass index (BMI; IQR) of 29.2 (25.7–35.3) kg/m² (Table 1).

Oral vitamin D supplementation produced no change in the plasma levels of PSA (Table 2). We examined the influence of 25(OH)D level at 3 months on the free and total PSA levels. No significant effect of 25(OH)D level at 3 months on free and total PSA (P > 0.05) was observed. Narrow confidence intervals for the differences in the means (month 3 − month 0 for free and total PSA) suggest adequate precision to reject the null hypothesis. An interaction between baseline 25(OH)D and vitamin D supplementation was assessed with free and total PSA as the outcomes and no significant association (P > 0.05) was found.

To our knowledge, this is among the first randomized placebo-controlled trials to examine the impact of oral vitamin D3 supplementation on PSA in a healthy Black male cohort. Vitamin D3 supplementation did not alter PSA levels in this relatively young cohort despite a clear trend in the change of follow-up serum 25(OH)D concentrations with increasing doses of supplemental vitamin D3. Vitamin D promotes the differentiation of prostate cancer cells, highlighting the possibility that vitamin D deficiency over time may contribute to the progression from subclinical prostate cancer to clinical disease (13). Prior research has shown that vitamin D deficiency is an indicator of aggressive prostate cancer and spread of the disease in men who underwent their first prostate biopsy because of an abnormal PSA test (14). Furthermore, a dose–response relationship between tumor grade and vitamin D levels was observed (14). In a study of patients with prostate cancer (Gleason 6 or 7), oral vitamin D3 (400, 10,000, or 40,000 U/d) administered before prostatectomy, raised prostate calcitriol levels and lowered PSA (12). In a study of early-stage low-risk prostate cancer patients given vitamin D3 4,000 U/d for 1 year, a decrease in the number of positive cores at repeat biopsy was observed in more than half of the participants without a change in PSA (15).

Strengths of this study include the use of healthy Black men without prior prostate cancer. Our multiple doses of vitamin D3 allowed us to examine whether vitamin D supplementation is associated with plasma levels of PSA, and whether a threshold effect exists within this association. The narrow confidence intervals for the outcome values highlight the adequate sample size for testing the hypothesis that vitamin D supplementation reduces PSA in Blacks in a dose-dependent manner. The time frame during which vitamin D protects against prostate cancer is unknown. Limitations of our study include the fact that PSA is not an ideal endpoint for assessment of prostate cancer risk, as it may also be indicative of a number of other noncancerous outcomes. Given the high prostate cancer incidence and mortality in Black men combined with vitamin D deficiency, future trials of vitamin D3 supplementation for longer duration are needed to evaluate the possible clinical benefit of vitamin D3 supplementation for prostate cancer prevention.

No potential conflicts of interest were disclosed.

The funding sources had no role in the conception or conduct of the study, took no part in the data collection or analysis, and had no role in the drafting, review, or approval of the article.

Conception and design: E.L. Giovannucci, G.G. Bennett, B.W. Hollis, K.M. Emmons, C.S. Fuchs, B.F. Drake

Development of methodology: E.L. Giovannucci, G.G. Bennett, B.W. Hollis, K.M. Emmons, C.S. Fuchs, B.F. Drake

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): P.D. Chandler, J.B. Scott, K. Ng, A.T. Chan, B.W. Hollis, C.S. Fuchs, B.F. Drake

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): P.D. Chandler, E.L. Giovannucci, J.B. Scott, K. Ng, A.T. Chan, B.W. Hollis, K.M. Emmons, C.S. Fuchs, B.F. Drake

Writing, review, and/or revision of the manuscript: P.D. Chandler, E.L. Giovannucci, J.B. Scott, G.G. Bennett, K. Ng, A.T. Chan, B.W. Hollis, K.M. Emmons, C.S. Fuchs, B.F. Drake

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): P.D. Chandler, J.B. Scott, K. Ng, C.S. Fuchs

Study supervision: J.B. Scott, K.M. Emmons, C.S. Fuchs

The authors thank Cara Marcus, MSLIS, AHIP, Director of Library Services, Brigham and Women's Faulkner Hospital, for facilitating access to reference articles and Harvard Catalyst for statistical support.

This trial was funded by the National Cancer Institute (U01CA138962 to P.D. Chandler; K24DK098311 to A.T. Chan; P50CA127003 and K07CA148894 to K. Ng; K22CA126992 and 5K05CA124415 to K.M. Emmons); CA127003 (DF/HCC SPORE to E.L. Giovannucci), the Department of Defense Prostate Cancer Research Program (PC081669 to B.F. Drake), the American Society of Clinical Oncology Career Development Award (K. Ng), and Pharmavite LLC (Mission Hill, CA). This trial has been registered at www.clinicaltrials.gov (identifier NCT00585637).