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A correction has been published: N Engl J Med 2006;354(10):1102.
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Background Higher intake of calcium and vitamin D has been associated with a reduced risk of colorectal cancer in epidemiologic studies and polyp recurrence in polyp-prevention trials. However, randomized-trial evidence that calcium with vitamin D supplementation is beneficial in the primary prevention of colorectal cancer is lacking.
Methods We conducted a randomized, double-blind, placebo-controlled trial involving 36,282 postmenopausal women from 40 Women's Health Initiative centers: 18,176 women received 500 mg of elemental calcium as calcium carbonate with 200 IU of vitamin D3 twice daily (1000 mg of elemental calcium and 400 IU of vitamin D3) and 18,106 received a matching placebo for an average of 7.0 years. The incidence of pathologically confirmed colorectal cancer was the designated secondary outcome. Baseline levels of serum 25-hydroxyvitamin D were assessed in a nested case–control study.
Results The incidence of invasive colorectal cancer did not differ significantly between women assigned to calcium plus vitamin D supplementation and those assigned to placebo (168 and 154 cases; hazard ratio, 1.08; 95 percent confidence interval, 0.86 to 1.34; P=0.51), and the tumor characteristics were similar in the two groups. The frequency of colorectal-cancer screening and abdominal symptoms was similar in the two groups. There were no significant treatment interactions with baseline characteristics.
Conclusions Daily supplementation of calcium with vitamin D for seven years had no effect on the incidence of colorectal cancer among postmenopausal women. The long latency associated with the development of colorectal cancer, along with the seven-year duration of the trial, may have contributed to this null finding. Ongoing follow-up will assess the longer-term effect of this intervention. (ClinicalTrials.gov number, NCT00000611
[ClinicalTrials.gov]
.)
Methods
Study Population, Eligibility, and Consent
Between 1993 and 1998, postmenopausal women 50 to 79 years of age were enrolled in the WHI randomized trials assessing the risks and benefits of hormone therapy and dietary modification.15,16,17,18 Exclusion criteria were related to competing risks, safety, adherence, and retention. One year later, these participants were invited to enroll in the calcium plus vitamin D trial, designed to determine whether calcium plus vitamin D supplementation would prevent hip fracture (the primary outcome) and colorectal cancer (a designated secondary outcome), as described by Jackson et al.14 Exclusion criteria for the calcium plus vitamin D supplementation trial included a predicted survival of less than three years, a history of renal calculi or hypercalcemia, current use of oral corticosteroids, and current daily use of at least 600 IU of supplemental vitamin D or calcitriol.19 Ninety-one percent joined the calcium with vitamin D portion of the study during their first annual visit, and 9 percent the following year. Fifty-four percent of the participants had been enrolled in the trials assessing hormone therapy, 69 percent had been enrolled in the trial assessing dietary modification, and 14 percent had participated in both trials. The protocol and consent forms were approved by the institutional review board at each participating institution. All women provided written informed consent.
Randomization, Blinding, and Intervention
A permuted-block algorithm was used for randomization, with participants stratified according to clinical center and age. Among the 36,282 participants, 18,176 were randomly assigned to receive one tablet of 500 mg of elemental calcium as calcium carbonate combined with 200 IU of vitamin D3 (GlaxoSmithKline) twice daily (total, 1000 mg of elemental calcium and 400 IU of vitamin D3) and 18,106 to receive an identical-appearing placebo tablet twice daily. Blinding of the study was achieved by bottle labeling.15 Participants were given chewable tablets until 1997, at which time tablets that could be swallowed were also offered. Initially, 61 percent of the women in both groups were given chewable tablets. By the end of the study, 70 percent chose the formulation that could be swallowed. Two years after randomization, a comparison of serum 25-hydroxyvitamin D levels in 227 women in the group given calcium with vitamin D and 221 women in the placebo group revealed that the levels were 28 percent higher in the supplement group.
Before enrollment, participants had blood drawn after a 12-hour fast. Samples were processed, frozen at –70°C, and stored according to standardized protocols. After a review of initial findings, a nested case–control study was proposed to determine whether the serum 25-hydroxyvitamin D level at baseline modified the outcome. As of April 8, 2005, 317 women with confirmed invasive colorectal cancer were matched according to age, center, race or ethnic group, and the date of blood sampling with 317 control women who were randomly selected from the group of participants who were free of colorectal cancer. Of these 317 pairs, 306 had adequate stored serum for analysis. Bruce Hollis, Ph.D. (Stillwater, Minn.), measured serum 25-hydroxyvitamin D levels using the DiaSorin Liaison 25(OH)D chemiluminescent radioimmunoassay system, which has an interassay coefficient of variation of 11.8 percent.
Follow-up Procedures and Ascertainment of Outcomes
Participants were telephoned four weeks after randomization to assess abdominal symptoms and reinforce the importance of adherence; they were contacted semiannually thereafter for self-reported updates on medical history. Any reported colorectal cancers were verified in a blinded fashion by local and central physician adjudicators and coded with the use of the Surveillance, Epidemiology, and End Results system20,21; 99.4 percent of reported cancers were centrally confirmed. Adherence was assessed by weighing returned pill bottles. Regardless of their level of adherence, participants were followed up until they died, were lost to follow-up, or requested no further contact or until the study ended.
The protocol did not include a requirement for colorectal-cancer screening; any such tests were ordered by each participant's personal physician. The frequency of rectal examination, fecal occult-blood testing, sigmoidoscopy or colonoscopy, and barium enema was ascertained during medical-history updates. The frequency of abdominal symptoms (bloating or gas, constipation, diarrhea, nausea, a change in appetite, heartburn, and stomach upset) was assessed by a self-administered questionnaire at the time of enrollment in the calcium with vitamin D study; in a random subsample at years 3, 6, and 9; and among all participants, at the completion of the study. Such symptoms were managed by temporary reduction in the number of pills taken. Study pills were discontinued if kidney stones, hypercalcemia, dialysis, or the use of calcitriol or of daily supplements of more than 1000 IU of vitamin D was reported.
Study Monitoring and Termination
An independent data and safety monitoring board reviewed the trial data semiannually.15 By design, early stopping considerations were based on comparisons between groups of the incidence of hip fracture, colorectal cancer, breast cancer, and death from other causes. Closeout visits occurred as planned between October 1, 2004, and March 31, 2005, with outcomes assessed before the treatment assignment was revealed.
WHI investigators and National Institutes of Health sponsors all contributed to the study design and execution. All authors helped write or revise the manuscript. Statistical analyses and data management were conducted at the WHI Clinical Coordinating Center, whose members vouch for the completeness and veracity of the data and analyses.
Statistical Analysis
Primary analyses used time-to-event methods, according to the intention-to-treat principle. The incidence of colorectal cancer was compared in the two groups with the use of hazard ratios (with 95 percent confidence intervals) and Wald statistic P values from Cox proportional-hazards models,22 stratified according to age, history of colorectal cancer, and treatment assignment in the Hormone Therapy and Dietary Modification trials. The use of a two-sided, weighted log-rank test was specified in the protocol, with weight increasing linearly from zero at randomization to a maximum of one at 10 years, to enhance the statistical power of the study according to the design assumptions. Both Bonferroni's adjusted and unadjusted tests of significance are given for the weighted log-rank test. The adjusted tests take into account the four end points indicated in the study monitoring plan. Kaplan–Meier estimates were used to describe event rates over time. Potential differential effects across subgroups of important risk factors for colorectal cancer were tested individually with the use of a likelihood ratio test for interaction between the risk factor and treatment assignment after including both as main effects. Thirty-seven subgroup comparisons were tested, with 19 reported (those not reported include the number of first-degree relatives with colorectal cancer; geographic location, tested with the use of two additional methods; any personal use of calcium supplements; the duration and recency of use of hormone therapy; the use of hormone therapy among participants in the dietary-modification trial; and 10 interactions evaluated in women with invasive colon, not rectal, cancer). Accordingly, the results of two tests would be expected to be significant at the 0.05 level by chance. Participants with missing values were excluded from analyses requiring that value.
In planning the study, we calculated that for the secondary end point of colorectal cancer, a trial involving 35,000 women who were followed for an average of eight years would have a statistical power of 83 percent to detect an absolute reduction in the incidence of colorectal cancer of 22 percent with calcium with vitamin D supplementation, as compared with placebo (given an 
value of 0.05). The interaction between serum 25-hydroxyvitamin D levels at baseline and randomized assignment to calcium with vitamin D supplementation or placebo was assessed with the use of conditional logistic regression. Tests for trend and interaction used the logarithm of serum 25-hydroxyvitamin D levels. All reported P values are two-sided and, along with the confidence intervals, were not adjusted for multiplicity, unless noted.
Results
Between 1995 and 2000, 36,282 women underwent randomization. Age, self-reported race or ethnic group, level of education, body-mass index, presence or absence of a family history of colorectal cancer, presence or absence of a history of polyps, level of physical activity, caloric intake, saturated fat intake, multivitamin use, personal intake of elemental calcium, personal intake of vitamin D, level of ultraviolet exposure, cigarette-smoking status, history of hormone use, and randomized assignment in the Hormone Therapy and Dietary Modification trials were similar in the two groups (Figure 1).14 The mean (±SD) duration of follow-up was 7.0 ±1.4 years, with a maximum of 9.7 years. During year 1, 60 percent of the participants took at least 80 percent of their study medication, and this percentage remained stable through year 6, with small differences between groups (Figure 2A). At least 70 percent took 50 percent or more of their study medication through year 6.
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Data on events were available for 97 percent of living participants within 18 months before the end of the study. At the time the study ended, 352 women assigned to calcium with vitamin D supplements and 332 women assigned to placebo had withdrawn; 144 and 152, respectively, had been lost to follow-up; and 744 and 807, respectively, had died. A total of 339 colorectal cancers were reported. Of these, nine were in situ and eight were primary cancers of other sites.
Analyses limited to the 322 invasive colorectal cancers revealed that calcium with vitamin D supplementation, as compared with placebo, had no effect on the risk of colorectal cancer (168 vs. 154 cases; hazard ratio, 1.08; nominal 95 percent confidence interval, 0.86 to 1.34; P=0.51) (Figure 3). The protocol-specified, weighted log-rank test yielded an unadjusted P value of 0.26 and a P value of 0.32 after adjustment for multiple outcomes. Sensitivity analyses censoring follow-up on participants six months after their rate of adherence to the study medication dropped below 50 percent did not change the findings (hazard ratio in the supplement group as compared with the placebo group, 1.08; 95 percent confidence interval, 0.83 to 1.39), nor did censoring follow-up six months after adherence dropped below 80 percent (hazard ratio, 0.98; 95 percent confidence interval, 0.73 to 1.32). Analyses excluding the 36 women in the supplement group and the 38 women in the placebo group with prior colorectal cancer yielded similar results (hazard ratio for the comparison of the supplement group with the placebo group, 1.09; 95 percent confidence interval, 0.87 to 1.36; P=0.44). No significant interactions were found with any baseline characteristic examined (Figure 1).
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The location, histologic characteristics, grade, stage, and size of colorectal cancers were similar in the two groups (Table 1). In the supplement group, as compared with the placebo group, hazard ratios for invasive colon cancer (hazard ratio, 1.00; 95 percent confidence interval, 0.78 to 1.28; P=0.99), invasive rectal cancer (hazard ratio, 1.46; 95 percent confidence interval, 0.92 to 2.32; P=0.11), proximal-colon cancer (hazard ratio, 0.95; 95 percent confidence interval, 0.69 to 1.30; P=0.74), and distal-colon cancer (hazard ratio, 1.08; 95 percent confidence interval, 0.69 to 1.69; P=0.73) did not differ from unity. The hazard ratio for death from colorectal cancer was 0.82 in the supplement group as compared with the placebo group (95 percent confidence interval, 0.52 to 1.29; P=0.39); however, too few events had occurred (34 vs. 41) to make the comparison meaningful.
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As of March 31, 2005, 744 women in the supplement group had died, as compared with 807 women in the placebo group (hazard ratio, 0.91; 95 percent confidence interval, 0.83 to 1.01; P=0.07). Supplementation with calcium plus vitamin D was not associated with any significant risk or benefit with respect to any major disease outcomes, including cardiovascular diseases and cancer. The effects of calcium plus vitamin D supplementation, as compared with placebo, on the total risk of cancer (hazard ratio, 0.98; 95 percent confidence interval, 0.91 to 1.05; P=0.53) and the risk of death from cancer (hazard ratio, 0.89; 95 percent confidence interval, 0.77 to 1.03; P=0.12) were not significant.
The self-reported occurrence of polyps (all types combined) was similar in the supplement group and the placebo group (hazard ratio, 0.99; 95 percent confidence, 0.94 to 1.04; P=0.71). Kidney stones were reported by 449 women in the supplement group, as compared with 381 women in the placebo group (hazard ratio, 1.17; 95 percent confidence interval, 1.02 to 1.34; P=0.02).
Overall, the supplements were well tolerated. There was no significant difference between groups in the frequency of reported symptoms at any time. The frequency of any moderate or severe abdominal symptom in the four weeks preceding enrollment was 34 percent in both groups, increasing to 39 percent in the group assigned to calcium with vitamin D supplementation and to 37 percent in the placebo group at annual visit 3 (P=0.29).
Serum Vitamin D Levels
Findings from the nested case–control study revealed no significant interaction between serum 25-hydroxyvitamin D levels at baseline and treatment assignment (P=0.54). However, analyses adjusting only for case–control matching demonstrated a significant inverse trend with lower baseline levels of serum 25-hydroxyvitamin D associated with an increased risk of colorectal cancer (P for trend=0.02) (Table 2).
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In this randomized clinical trial, daily supplementation with 1000 mg of elemental calcium as calcium carbonate combined with 400 IU of vitamin D3 for an average of seven years had no detectable effect on the incidence of colorectal cancer among postmenopausal women. This absence of an effect was consistent across subgroups, including personal calcium and vitamin D intake and serum vitamin D levels at baseline. Thus, our findings fail to validate previous observational studies and polyp-prevention trials associating calcium and vitamin D intake with reduced risk.
Adherence was relatively good throughout the trial among the more than 36,000 women enrolled; thus, we had sufficient power to detect a 20 percent difference in risk. How should our findings be interpreted in the context of the body of published literature and a growing public perception that calcium and vitamin D supplementation can prevent colorectal cancer? Previous observational studies have often interpreted the protection afforded by calcium and vitamin D supplementation only in the context of comparisons of extreme quintiles of intake. Findings from observational studies should be reviewed cautiously, since they are more prone to confounding and bias than are randomized clinical trials,24 especially with respect to the assessment of preventive behaviors that may be difficult to detect, measure, and control for. The randomized trial design we used has greater potential to limit bias.
Previous trials demonstrating beneficial effects of calcium and vitamin D supplementation, such as polyp prevention, have led to the use of these agents in risk-reduction strategies. However, there has been no demonstration that secondary prevention of polyps with calcium and vitamin D supplementation translates into a reduction in colorectal cancer. We found no evidence that calcium with vitamin D supplementation prevented colorectal cancer. Although self-reported, the incidence of polyps was also similar in the supplement and placebo groups. As such, our results raise questions regarding the widely held concept that calcium and vitamin D supplementation will prevent colorectal cancer.
Our randomized clinical trial had the potential to limit biases inherent in observational studies and moved beyond trials of secondary prevention of colon polyps. However, issues regarding the design and study population may have limited our ability to demonstrate a protective effect of calcium with vitamin D supplementation on the risk of colorectal cancer, if one does exist. Participants were healthy postmenopausal women selected to be generally free of disability and clinically dominant chronic illness. By design, participants were not restricted from taking calcium or vitamin D supplements on their own. At enrollment, participants had mean total calcium (1151 mg) and vitamin D (367 IU) intakes that were twice the national average25 and nearly met current recommendations.26 Intakes rose during the trial, while national averages remained relatively stable.27 These high intakes may have limited our ability to affect the rates of colorectal cancer further. One prospective study found no additional protective effect of calcium intakes beyond 700 mg per day, and significant associations were limited to cancers of the distal colon.28 In our study, calcium with vitamin D supplementation was not protective among women with baseline intakes below 800 mg per day, tempering enthusiasm for this explanation. Although our initial analyses of nested case–control studies found lower baseline serum 25-hydroxyvitamin D levels to be associated with an increased risk of colorectal cancer, in contrast to the findings of a previous study,13 we did not find that serum levels modified the effect of the intervention on the outcome.
Our study has several other potential limitations. The calcium doses as well as vitamin D doses we used may have been insufficient to demonstrate a protective effect, particularly given the fraction of participants who were not fully adherent throughout the study. When we began the study, a daily supplement of 400 IU of vitamin D was considered relatively high. Studies published since that time have led some to recommend daily intakes of vitamin D higher than the one we used.29 We evaluated a single regimen and cannot assess whether other formulations or doses would have changed the results.
Since the protocol did not require participants to undergo bowel examinations, some cancers may have been missed. However, the frequency of bowel examinations was very similar in the two groups throughout follow-up. Abdominal pain and a change in bowel habits are common initial manifestations of colorectal cancer that may lead to more aggressive screening30,31; however, the types and frequency of symptoms were similar in the two groups. Annualized rates of invasive colon cancer (0.10 percent) and rectal cancer (0.03 percent) in our study were similar to Surveillance, Epidemiology, and End Results rates for women of corresponding age during the years 1992 through 2002 (0.09 percent and 0.03 percent, respectively).32 Nonetheless, regular or end-of-study colonoscopies may have enabled us to make a more accurate assessment of the effect of calcium with vitamin D supplementation on these tumors.
Two other limitations are the timing of administration of the intervention and the length of follow-up. If the benefit of calcium with vitamin D supplementation is to prevent or slow the progression of colorectal cancer in its early stages and if colorectal cancer has a latency of 10 to 20 years, the average intervention and follow-up of 7 years in our study may have been insufficient to demonstrate an effect. The duration of follow-up was shorter in our trial than in some observational studies that have found a link between calcium and vitamin D intake and the risk of colorectal cancer. Although we did not find a trend toward protection in the later years of follow-up, the ongoing five-year WHI extension study, without intervention, will continue to assess incident colorectal cancers and allow us to identify later effects of this intervention, if they exist.
The strengths of our study include its randomized, double-blind, placebo-controlled design; the large racially and ethnically diverse study population; the comprehensive assessment of risk factors for colorectal cancer at baseline; and the standardized assessment of colorectal-cancer events in a blinded fashion.
In summary, we found that seven years of calcium carbonate plus vitamin D3 supplementation had no effect on the incidence of colorectal cancer in a randomized trial. Although calcium plus vitamin D supplementation may provide some protection against fracture,23 it did not protect against colorectal cancer. The long latency associated with the development of colorectal cancer, in concert with the seven-year duration of the trial, may have contributed to this null finding. However, these results do not provide support for the general use of calcium plus vitamin D supplementation to prevent colorectal cancer.
Supported by the National Heart, Lung, and Blood Institute, Department of Health and Human Services. Many clinical centers received assistance from the General Clinical Research Center program of the National Center for Research Resources. The active study drug and placebo were supplied by GlaxoSmithKline Consumer Healthcare (Pittsburgh).
Dr. Assaf reports being an employee of Pfizer since December 2002 and reports owning stock and having stock options in Pfizer. Dr. Brunner reports being principal investigator of a study funded by the National Cancer Institute of Canada and Pfizer. Dr. O'Sullivan reports receiving grant support from Pfizer-Viracept PK. Dr. Robbins reports having received grants with industry support but without salary support. Dr. Sharma reports having received grant support from Merck and GlaxoSmithKline for an HPV vaccine study. Dr. Hays reports having received lecture fees for a conference sponsored by Procter & Gamble. Dr. Howard reports having received lecture fees from Schering-Plough and serving as a consultant for Merck, the Egg Nutrition Council, and General Mills. Dr. Jackson reports having received consulting fees from Procter & Gamble, lecture fees from Aventis/Procter & Gamble, and grant support from Novartis. Dr. LaCroix reports having received consulting fees from Pfizer, Procter & Gamble, and the Alliance for Better Bone Health and a lecture fee from Schering Plough. Dr. Lewis reports receiving grant support from Pfizer and Novartis. No other potential conflict of interest relevant to this article was reported.
We are indebted to the investigators and staff of the WHI clinical centers, the WHI Clinical Coordinating Center, and the National Heart, Lung, and Blood Institute program office for their dedication and effort; to Rebecca J. Rodabough for her invaluable assistance and expertise in completing the statistical analyses for this article; and to the WHI participants for their extraordinary commitment to the study.
Source Information
Address reprint requests to Dr. Wactawski-Wende at the Department of Social and Preventive Medicine, University at Buffalo, 270 Farber Hall, Buffalo, NY 14214, or at jww{at}buffalo.edu.
References
Appendix 1
The following persons and facilities participated in the WHI study: Program Office: National Heart, Lung, and Blood Institute, Bethesda, Md. — B. Alving, J. Rossouw, L. Pottern, S. Ludlam, J. McGowan, N. Geller, L. Ford; Clinical Coordinating Center: Fred Hutchinson Cancer Research Center, Seattle — R. Prentice, G. Anderson, A. LaCroix, R. Patterson, A. McTiernan, B. Cochrane, J. Hunt, L. Tinker, C. Kooperberg, M. McIntosh, C.Y. Wang, C. Chen, D. Bowen, A. Kristal, J. Stanford, N. Urban, N. Weiss, E. White; Wake Forest University School of Medicine, Winston-Salem, N.C. — S. Shumaker, R. Prineas, M. Naughton; Medical Research Laboratories, Highland Heights, Ky. — E. Stein, P. Laskarzewski; San Francisco Coordinating Center, San Francisco — S.R. Cummings, M. Nevitt, L. Palermo; University of Minnesota, Minneapolis — L. Harnack; Fisher BioServices, Rockville, Md. — F. Cammarata, S. Lindenfelser; University of Washington, Seattle — B. Psaty, S. Heckbert; Clinical Centers: Albert Einstein College of Medicine, Bronx, N.Y. — S. Wassertheil-Smoller, W. Frishman, J. Wylie-Rosett, D. Barad, R. Freeman; Baylor College of Medicine, Houston — J. Hays, R. Young, J. Anderson, S. Lithgow, P. Bray; Brigham and Women's Hospital, Harvard Medical School, Boston — J.E. Manson, J.M. Gaziano, C. Chae, K. Rexrode, C. Solomon; Brown University, Providence, R.I. — A.R. Assaf, C. Wheeler, C. Eaton, M. Cyr; Emory University, Atlanta — L. Phillips, M. Pedersen, O. Strickland, M. Huber, V. Porter; Fred Hutchinson Cancer Research Center, Seattle — S.A.A. Beresford, V.M. Taylor, N.F. Woods, M. Henderson, R. Andersen; George Washington University, Washington, D.C. — J. Hsia, N. Gaba, J. Ascensao; Harbor–UCLA Research and Education Institute, Torrance, Calif. — R. Chlebowski, R. Detrano, A. Nelson, M. Geller; Kaiser Permanente Center for Health Research, Portland, Oreg. — E. Whitlock, P. Elmer, V. Stevens, N. Karanja; Kaiser Permanente Division of Research, Oakland, Calif. — B. Caan, S. Sidney, G. Bailey, J. Hirata; Medical College of Wisconsin, Milwaukee — J. Morley Kotchen, V. Barnabei, T.A. Kotchen, M.C. Gilligan, J. Neuner; MedStar Research Institute/Howard University, Washington, D.C. — B.V. Howard, L. Adams-Campbell, L. Lessin, M. Rainford, G. Uwaifo; Northwestern University, Chicago — L. Van Horn, P. Greenland, J. Khandekar, K. Liu, C. Rosenberg; Rush University Medical Center, Chicago — H. Black, L. Powell, E. Mason; M. Gulati; Stanford Prevention Research Center, Stanford, Calif. — M.L. Stefanick, M.A. Hlatky, B. Chen, R.S. Stafford, S. Mackey; State University of New York at Stony Brook, Stony Brook — D. Lane, I. Granek, W. Lawson, G. San Roman, C. Messina; Ohio State University, Columbus — R. Jackson, R. Harris, E. Paskett, W.J. Mysiw, M. Blumenfeld; University of Alabama at Birmingham, Birmingham — C.E. Lewis, A. Oberman, J.M. Shikany, M. Safford, M. Fouad; University of Arizona, Tucson — T. Bassford, C. Thomson, M. Ko, A. Lopez, C. Ritenbaugh; University at Buffalo, Buffalo, N.Y. — J. Wactawski-Wende, M. Trevisan, E. Smit, S. Graham, J. Chang; University of California at Davis, Sacramento — J. Robbins, S. Yasmeen; University of California at Irvine, Irvine — F.A. Hubbell, G. Frank, N. Wong, N. Greep, B. Monk; University of California at Los Angeles, Los Angeles — H. Judd, D. Heber, R. Elashoff; University of California at San Diego, La Jolla — R.D. Langer, M.H. Criqui, G.T. Talavera, C.F. Garland, M.A. Allison; University of Cincinnati, Cincinnati — M. Gass, S. Wernke; University of Florida, Gainesville — M. Limacher, M. Perri, A. Kaunitz, R.S. Williams, Y. Brinson; University of Hawaii, Honolulu — J.D. Curb, H. Petrovitch, B. Rodriguez, K. Masaki, S. Sharma; University of Iowa, Iowa City — R. Wallace, J. Torner, S. Johnson, L. Snetselaar, J. Robinson; University of Massachusetts, Fallon Clinic, Worcester — J. Ockene, M. Rosal, I. Ockene, R. Yood, P. Aronson; University of Medicine and Dentistry of New Jersey, Newark — N. Lasser, B. Singh, V. Lasser, J. Kostis, P. McGovern; University of Miami, Miami — M.J. O'Sullivan, L. Parker, T. DeSantis, D. Fernandez, P. Caralis; University of Minnesota, Minneapolis — K.L. Margolis, R.H. Grimm, M.F. Perron, C. Bjerk, S. Kempainen; University of Nevada, Reno — R. Brunner, W. Graettinger, V. Oujevolk, M. Bloch; University of North Carolina, Chapel Hill — G. Heiss, P. Haines, D. Ontjes, C. Sueta, E. Wells; University of Pittsburgh, Pittsburgh — L. Kuller, J. Cauley, N.C. Milas; University of Tennessee Health Science Center, Memphis — K.C. Johnson, S. Satterfield, R.W. Ke, S. Connelly, F. Tylavsky; University of Texas Health Science Center, San Antonio — R. Brzyski, R. Schenken, J. Trabal, M. Rodriguez-Sifuentes, C. Mouton; University of Wisconsin, Madison — G.E. Sarto, D. Laube, P. McBride, J. Mares-Perlman, B. Loevinger; Wake Forest University School of Medicine, Winston-Salem, N.C. — D. Bonds, G. Burke, R. Crouse, M. Vitolins, S. Washburn; Wayne State University School of Medicine and Hutzel Hospital, Detroit — S. Hendrix, M. Simon, G. McNeeley; Former Principal Investigators and Project Officers: Baylor College of Medicine, Houston — J. Foreyt; Emory University, Atlanta — D. Hall, S. McNagny, N. Watts; George Washington University, St. Louis — V. Miller; Kaiser Permanent, Oakland, Calif. —R. Hiatt; Kaiser Permanente, Portland, Oreg. — B. Valanis; National Cancer Institute, Bethesda, Md. — C. Clifford (deceased); University of Arizona, Tucson — T. Moon; University of California, Irvine — F. Meyskens, Jr.; University of Cincinnati, Cincinnati — J. Liu; University of Miami, Miami — M. Baum; University of Nevada, Las Vegas — S. Daugherty (deceased); University of North Carolina, Chapel Hill — D. Sheps, Barbara Hulka; University of Tennessee, Memphis — W. Applegate; University of Wisconsin, Milwaukee — C. Allen (deceased); Data and Safety Monitoring Board: J. Wittes (chair), E. Braunwald, M. Chesney, H. Cohen, E. Barrett-Connor, D. DeMets, L. Dunn, J. Dwyer, R.P. Heaney, D. Marson, V. Vogel, L. Walters, S. Yusuf.
Appendix 2
From the University at Buffalo, Buffalo, N.Y. (J.W.-W.); the Medical College of Wisconsin, Milwaukee (J.M.K.); Fred Hutchinson Cancer Research Center, Seattle (G.L.A., R.L.P., C.L.K., A.Z.L.); Memorial Hospital of Rhode Island, Pawtucket (A.R.A.); Pfizer, New London, Conn. (A.R.A.); the University of Nevada School of Medicine, Reno (R.L.B.); the University of Miami, Miami (M.J.O.); the University of Minnesota, Minneapolis (K.L.M.); the University of Massachusetts, Fallon Clinic, Worcester (J.K.O.); Emory University, Atlanta (L. Phillips); the National Heart, Lung, and Blood Institute, Bethesda, Md. (L. Pottern); the University of California at Davis, Sacramento (J.R.); Albert Einstein College of Medicine, Bronx, N.Y. (T.E.R.); the University of Wisconsin, Madison (G.E.S.); the University of Hawaii, Honolulu (S.S.); Stanford Prevention Research Center, Stanford, Calif. (M.L.S.); Northwestern University, Chicago (L.V.H.); the University of Iowa, Iowa City (R.B.W.); Kaiser Permanente Center for Health Research, Portland, Oreg. (E.W.); the University of Arizona, Tucson (T.B.); the University of Washington, Seattle (S.A.A.B.); Rush Medical Center, Chicago (H.R.B.); Wake Forest University School of Medicine, Winston-Salem, N.C. (D.E.B.); the University of Texas Health Science Center, San Antonio (R.G.B.); Kaiser Permanente Division of Research, Oakland, Calif. (B.C.); Los Angeles Biomedical Research Institute at Harbor–UCLA Medical Center, Torrance, Calif. (R.T.C.); the University of Washington School of Nursing, Seattle (B.C.); the University of California at San Diego, La Jolla (C.G., R.D.L.); the University of Cincinnati, Cincinnati (M.G.); Baylor College of Medicine, Houston (J. Hays); the University of North Carolina, Chapel Hill (G.H.); Wayne State University School of Medicine and Hutzel Hospital, Detroit (S.L.H.); MedStar Research Institute, Howard University, Washington, D.C. (B.V.H.); George Washington University Medical Center, Washington, D.C. (J. Hsia); the University of California at Irvine, Irvine (F.A.H.); Ohio State University, Columbus (R.D.J.); the University of Tennessee Health Science Center, Memphis (K.C.J.); the University of California at Los Angeles, Los Angeles (H.J.); the University of Pittsburgh, Pittsburgh (L.H.K.); State University of New York at Stony Brook, Stony Brook (D.S.L.); the University of Medicine and Dentistry of New Jersey, Newark (N.L.L.); the University of Alabama at Birmingham, Birmingham (C.E.L.); the University of Florida, Gainesville (M.C.L.); and Brigham and Women's Hospital and Harvard Medical School, Boston (J.E.M.).
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Related Letters:
Calcium plus Vitamin D and the Risk of Colorectal Cancer
Holick M. F., Giovannucci E., Wactawski-Wende J., Anderson G. L., O'Sullivan M.
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N Engl J Med 2006;
354:2287-2288, May 25, 2006.
Correspondence
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