Participants

We conducted this randomized, multicenter, double-blind, placebo-controlled trial at 11 academic medical centers and associated medical practices in the United States. Enrollment of patients took place from July 2004 through July 2008. Staff members at each center enrolled patients 45 to 75 years of age who had at least one colorectal adenoma removed within 120 days before enrollment, had no remaining polyps after a complete colonoscopy, and were anticipated to undergo a 3-year or 5-year colonoscopic follow-up examination recommended by the treating endoscopist. Eligible patients were in good general health and did not have familial colorectal cancer syndromes or serious intestinal disease. We did not include patients who had conditions that indicated that the study agents would pose a health risk (e.g., a history of kidney stones or hyperparathyroidism) or who had conditions that would indicate a need for either agent (e.g., osteoporosis). We also did not include patients who had a serum calcium level that was outside the normal range, a creatinine level that was more than 20% above the upper limit of the normal range, or a 25-hydroxyvitamin D level that was lower than 12 ng per milliliter or higher than 90 ng per milliliter.

Study Design and Oversight

In a partial factorial design, we evaluated four regimens, all of which involved two identical tablets taken daily: 1000 IU of vitamin D 3 , 1200 mg of calcium as carbonate, both agents, or placebo. Women could elect to be randomly assigned to receive either calcium or calcium plus vitamin D (two-group randomization); all other patients were randomly assigned to receive one of the four regimens (full factorial randomization). The doses of study agents were chosen to increase the total intake substantially, with a margin of safety below the highest mean daily intake level believed unlikely to cause adverse effects in most people at the time that the trial began (2000 IU of vitamin D and 2.5 g of calcium).22 In accordance with the protocol, study treatment was to continue until the anticipated 3-year or 5-year colonoscopic examination.

At enrollment, participants provided information regarding demographic data, medical history, medications, nutritional supplements, behavioral factors, and diet (using the Block Brief 2000 food frequency questionnaire [Nutritionquest]). Enrollment was followed by a placebo run-in period of 56 to 84 days to identify and exclude participants who were considered unlikely to follow study procedures. Subsequent randomization by the coordinating center was performed with the use of computer-generated random numbers with permuted blocks and stratification according to clinical center, sex, anticipated colonoscopic examination at 3 years or 5 years, and full factorial or two-group randomization. All study staff were unaware of the treatment assignments, with the exception of the data analyst and statistician, some of the programmers, and pharmacy personnel.

Participants agreed to avoid taking study agents outside the trial. However, because of increasing publicity regarding the possible benefits of these supplements (especially vitamin D), daily personal use of up to 1000 IU of vitamin D, 400 mg of elemental calcium, or both were permitted, although discouraged, from April 2008 onward.

Participants were contacted by telephone every 6 months and queried regarding adherence to study agents, illnesses, medication and supplement use, dietary calcium intake (see the Supplementary Appendix, available with the full text of this article at NEJM.org), and colorectal procedures. Records were collected that included data on major medical events, colorectal surgical procedures, and endoscopic examinations. Two physicians who were unaware of the study group assignments adjudicated the diagnosis of adverse events. Bottles of study tablets were mailed to participants every 4 months. Patients who wanted to take a multivitamin were offered a special preparation that did not include calcium and vitamin D. The study intervention ended on August 31, 2013; the treatment-phase follow-up continued until November 30, 2013, to accommodate the final 5-year participants.

Blood levels of 25-hydroxyvitamin D, calcium, and creatinine were measured at baseline and at year 1, as well as at year 3 for participants with 5-year surveillance cycles. The level of 25-hydroxyvitamin D was also measured shortly before the end-of-treatment examination. The laboratory methods are described in the Supplementary Appendix. Levels of 25-hydroxyvitamin D were seasonally adjusted according to the month in which the blood was drawn (see the Supplementary Appendix). The net change in 25-hydroxyvitamin D levels was defined as the posttreatment level minus the pretreatment level in participants who received vitamin D, minus that difference in participants who were given no vitamin D.

The study end points included all adenomas that were diagnosed in any colorectal endoscopic or surgical procedure at least 1 year after randomization and up to 6 months after the anticipated 3-year or 5-year colonoscopic examination. A single study pathologist who was unaware of the treatment assignments reviewed the slides for all excised colorectal lesions. We distinguished between lesions that were proximal to the splenic flexure and lesions that were more distal. Advanced adenomas were defined as those with cancer, high-grade dysplasia, more than 25% villous features, or an estimated diameter of at least 1 cm. Study diagnoses were compared with the diagnoses made by the pathologists at the clinical centers. Discrepancies were resolved by means of a detailed adjudication procedure (see the Supplementary Appendix).

The study was conducted and reported in accordance with the study protocol, which is available at NEJM.org. The authors designed the study, analyzed the data, wrote the manuscript, and vouch for the completeness and accuracy of the data and analysis. Pfizer Consumer Healthcare provided the study agents. No institution or company affected the analysis or the decision to submit the manuscript for publication.

All participants provided written informed consent; the research was approved by the institutional review board at each center. An independent data and safety monitoring committee oversaw the study.

Statistical Analysis

In our primary analysis, we compared the risk of one or more adenomas after randomization to vitamin D versus no vitamin D, calcium versus no calcium, and calcium plus vitamin D versus calcium alone. Participants who did not undergo the anticipated colonoscopic examination at 3 years or 5 years were included in the analysis if they had had a colonoscopic examination performed at least 1 year after randomization. The sample size and statistical power considerations are described in the Supplementary Appendix.

Figure 1. Figure 1. Subgroup Analysis of the Effects of Supplementation with Calcium or Vitamin D on the Development of One or More Adenomas. The body-mass index (BMI) is the weight in kilograms divided by the square of the height in meters. NSAID denotes nonsteroidal antiinflammatory drug.

In the prespecified primary analysis, contingency tables and standard chi-square tests were used for the comparison of adenoma occurrence among randomized groups. The calcium analyses included only the participants who underwent full-factorial randomization. Subsequent multivariable generalized linear models for binary data were used to estimate adjusted risk ratios and confidence intervals. The covariates were age, sex, clinical center, number of baseline adenomas (one, two, or three or more), anticipated 3-year versus 5-year surveillance interval, and two-group versus full-factorial randomization. Clinical centers were grouped geographically when necessary because of sparse data. One subgroup analysis was prespecified: the effects of vitamin D in participants with baseline 25-hydroxyvitamin D levels below the overall median level were compared with the effects in those with levels above the median level. Eight additional post hoc subgroup analyses were conducted, as described in Figure 1. Interactions were assessed with the use of Wald tests. For interactions with variables that had more than two levels, we used a one-degree-of-freedom test for trend over medians within strata. In all analyses of randomly assigned treatments, participants were evaluated according to their assigned treatment group, regardless of their adherence to the study treatment and procedures. Sensitivity analyses were conducted with imputation of missing end points as either adenomas or no adenomas.

In a post hoc observational analysis, we similarly assessed associations between adenoma risk and baseline serum 25-hydroxyvitamin D levels among participants who were not randomly assigned to take vitamin D, as well as the association between adenoma risk and baseline calcium intake among participants who were not randomly assigned to receive calcium. The analyses were adjusted for a number of covariates, including (but not limited to) age, clinical center, surveillance interval (3 or 5 years), and number of baseline adenomas (one, two, or three or more).

Two-sided P values of less than 0.05 were considered to indicate statistical significance. Statistical analyses were conducted with the use of SAS software, version 9.4 (SAS Institute), and STATA software, version 12 (StataCorp).