Risk of Prostate Cancer in a Randomized Clinical Trial of Calcium Supplementation John A. Baron, 1,3,4 Michael Beach, 2 Kristin Wallace, 3 Maria V. Grau, 3 Robert S. Sandler, 5 Jack S. Mandel, 6 David Heber, 7 and E. Robert Greenberg 3,4 Departments of 1 Medicine, 2 Anesthesia, 3 Community and Family Medicine and 4 Norris Cotton Cancer Center, Dartmouth Medical School, Hanover, New Hampshire; 5 Department of Medicine, University of North Carolina, Chapel Hill, North Carolina; 6 Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia; and 7 Center for Human Nutrition, University of California at Los Angeles Medical Center, Los Angeles, California Abstract Background: In some studies, high calcium intake has been associated with an increased risk of prostate cancer, but no randomized studies have investigated this issue. Methods: We randomly assigned 672 men to receive either 3 g of calcium carbonate (1,200 mg of calcium), or placebo, daily for 4 years in a colorectal adenoma chemoprevention trial. Participants were followed for up to 12 years and asked periodically to report new cancer diagnoses. Subject reports were verified by medical record review. Serum samples, collected at randomization and after 4 years, were analyzed for 1,25-(OH) 2 vitamin D, 25-(OH) vitamin D, and prostate-specific antigen (PSA). We used life table and Cox proportional hazard models to compute rate ratios for prostate cancer incidence and generalized linear models to assess the relative risk of increases in PSA levels. Results: After a mean follow-up of 10.3 years, there were 33 prostate cancer cases in the calcium-treated group and 37 in the placebo-treated group [unadjusted rate ratio, 0.83; 95% confidence interval (95% CI), 0.52-1.32]. Most cases were not advanced; the mean Gleason’s score was 6.2. During the first 6 years (until 2 years post-treatment), there were significantly fewer cases in the calcium group (unadjusted rate ratio, 0.52; 95% CI, 0.28-0.98). The calcium risk ratio for conversion to PSA >4.0 ng/mL was 0.63 (95% CI, 0.33-1.21). Baseline dietary calcium intake, plasma 1,25- (OH) 2 vitamin D and 25-(OH) vitamin D levels were not materially associated with risk. Conclusion: In this randomized controlled clinical trial, there was no increase in prostate cancer risk associated with calcium supplementation and some suggestion of a protective effect. (Cancer Epidemiol Biomarkers Prev 2005;14(3):586 – 9) Introduction In contrast to likely protective effects on colorectal neoplasia (1), high intake of dietary and supplemental calcium has been associated with an increased risk of prostate cancer in some epidemiologic studies (2-5). Other investigations have reported contrary data (6-12), but no randomized clinical trial of calcium supplementation has considered prostate cancer as an end point. To clarify this association, we tested the hypothesis that calcium intake increases prostate cancer risk, by analyzing data from a multicentered, randomized double-blind clinical trial of calcium supplementation for prevention of colorectal adenomas. Materials and Methods In 1988, with Institutional Review Board approval, our research group began a clinical trial of calcium supplemen- tation to prevent colorectal adenomas (1). We randomly assigned 930 participants to receive either placebo or 3 g of calcium carbonate (equal to 1,200 mg elemental calcium) daily for 4 years. Every 6 months during the scheduled 4 years of active treatment, we sent questionnaires to participants regarding their adherence to study treatment, their use of medications and nutritional supplements, and the occurrence of symptoms, illness, and hospitalizations. We assessed diet using a validated food frequency ques- tionnaire (13) at enrollment and at the end of the study treatment. The treatment phase of the study ended in 1996, and in 1999, we initiated post-treatment follow-up of medical events (such cardiovascular disease, fractures, and cancer) and use of medications and nutritional supplements. Of the 672 men who were randomized, 42 died during his anticipated treatment period and 588 provided post-treatment follow- up data. Losses after the end of the 4-year intervention were due to our inability to contact 13 men, later deaths of 14, and refused follow-up for 15. No patient had a history of prostate cancer at study entry. Incident cases were sought through the periodic follow-up questionnaires described above. All reports of prostate cancer (by questionnaire or death certificate) were verified by review of hospital records. Using the available clinical records, we also retrieved the Gleason’s score and assessed whether the prostate cancer had apparently spread beyond the gland itself. All reported cases had been histologically verified. Specimens of venous blood were collected at enrollment and upon completion of the active phase of treatment at 4 years and were stored at À70jC. Serum samples were assayed for 1,25-(OH) 2 vitamin D and 25-(OH) vitamin D using a competitive protein-binding assay (Quest Diagnostics, San Juan Capistrano, CA), as described previously (14). To monitor the precision of the assays, serum samples from 182 subjects were split, and the paired aliquots distributed among batches shipped for analysis. The interbatch Pearson correlation for the 25-(OH) vitamin D measurements was 0.95; for 1,25-(OH) 2 vitamin D, it was 0.58. Received 4/28/04; revised 9/27/04; accepted 10/8/04. Grant support: National Cancer Institute grants CA 37287, CA23108, and CA42710 and GlaxoSmithKlein. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: Maria V. Grau, Section of Biostatistics and Epidemiology, Dartmouth Medical School, Evergreen Center, Suite 300, 46 Centerra Parkway, Lebanon, NH 03766. Phone: 603-650-3423; Fax: 603-650-3473. E-mail: maria.grau@dartmouth.edu Copyright D 2005 American Association for Cancer Research. Cancer Epidemiology, Biomarkers & Prevention 586 Cancer Epidemiol Biomarkers Prev 2005;14(3). 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