Colorectal cancer may be related to intake of calcium, and will be a secondary endpoint for the CaD branch. The association between calcium, vitamin D, and colon cancer has also been studied in several correlation, case-cohort, and control studies. The evidence is mixed, with some studies suggesting inverse associations between calcium intake and colon cancer, and others showing no association. Fewer studies have focused on the role that vitamin D plays in colorectal cancer risk, but a strong association has not been identified. It is of course not possible to separate the effects of calcium and vitamin D when they are issued together.

Many women of all ages are currently taking calcium supplements. A clinical trial in which definitive results are provided is necessary for women and their physicians to make informed choices, particularly if responsive subgroups can be identified, such as women who are and are not on HRT.

Women who are already randomized to the HRT and DM branches will be asked at their one-year anniversary if they are interested in joining the CaD supplementation branch. It is anticipated that 45,000 of the 63,000 women in the CT will be randomized in a 1:1 ratio to either (a) calcium carbonate containing 1,000 mg elemental calcium per day plus vitamin D₃ 400 International Units per day, with meals (dispensed as two tablets, each with 500 mg elemental calcium plus 200 IU vitamin D₃), or (b) placebo dispensed as two tablets. Participants and clinic staff will not be told who is in which group.

Outcome information on hip fractures will be collected by annual mailed questionnaires and at all follow-up visits, and documented primarily by X-ray report and discharge summary. Outcome information for other fractures will be collected by annual mailed questionnaires and at all follow-up visits with self-report, and documented by a physician's diagnosis or hospital discharge summary. Outcome information on colorectal cancer will be collected by annual mailed questionnaires and at all follow-up visits, and will be documented by medical report.

The committee is concerned about the inability of this branch to separate the effects of calcium and the effects of vitamin D. Several documents sent to the committee by the NIH provide a fragmented picture of the process through which the decision was made to do only a two-way randomization (CaD versus placebo). The minutes of the Concept Review group for the CT/OS Component of the WHI reflect mixed views in the 10-person panel, and recommend that the NIH planning group “reconsider the question of a 3-group versus 2-group design and assess power for combined fractures and hip fractures.” At an advisory meeting on August 15, 1991, the participants strongly encouraged a three-way randomization (calcium, calcium and vitamin D, or placebo). This would permit assessment of whether vitamin D made an independent contribution, although the magnitude of the effect of vitamin D given alone would not be known in this trial.

Front Matter (R1-R16)

Executive Summary (1-18)

Introduction (19-24)

Clinical Trial (25-76)

Observational Study (77-80)

Community Prevention Study (81-84)

Concluding Remarks (85-90)

References (91-94)

Appendix A: Clinical Trial Exclusion Criteria (95-100)

Appendix B: U.S. House of Representatives Appropriations COmmittee (101-102)

Appendix C: Statement of Task (103-104)

Appendix D: Documents Received by the Institute of Medicine from the National Institutes of Health (105-108)

Appendix E: Meeting Participants June, July, and August 1993 (109-112)

Appendix F: Primary and Subsidiary Hypotheses of the Women's Health Initiative Clinical Trial (113-114)

Appendix G: Women's Health Initiative Committees (115-116)

Appendix H: NIH-Sponsored Women's Health Studies (117-122)

Appendix I: NIH Cost and FTE Summary for Vanguard Clinical Centers (123-126)

Appendix J: NIH Power Calculations (127-132)

Appendix K: Women's Health Initiative Clinical Coordinating Center and Vanguard Clinical Centers Principal Investigators (133-134)

Appendix L: Abbreviations and Acronyms (135-136)

Appendix M: Committee and Staff Biographies (137-142)