Evidence Report/Technology Assessment
Number 183
Vitamin D and Calcium: A Systematic Review of
Health Outcomes
Prepared for:
Agency for Healthcare Research and Quality U.S. Department of Health and Human Services 540 Gaither Road
Rockville, MD 20850
www.ahrq.gov 
Contract No. HHSA 290-2007-10055-I Task Order No. 4
Prepared by:
Tufts Evidence-based Practice Center, Boston, MA
Investigators:
Mei Chung, M.P.H.
Ethan M Balk, M.D., M.P.H. Michael Brendel, B.A.
Stanley Ip, M.D.
Joseph Lau, M.D.
Jounghee Lee, Ph.D.
Alice Lichtenstein, D.Sc. Kamal Patel, M.B.A., M.P.H. Gowri Raman, M.D.
Athina Tatsioni, M.D., Ph.D. Teruhiko Terasawa, M.D.
Thomas A Trikalinos, M.D., Ph.D.
AHRQ Publication No. 09-E015 August 2009

This document is in the public domain and may be used and reprinted without permission except those copyrighted materials noted for which further reproduction is prohibited without the specific permission of copyright holders.

Outcomes. Evidence Report No. 183. (Prepared by the Tufts Evidence-based Practice Center under Contract No. HHSA 290-2007-10055-I.) AHRQ Publication No. 09-E015. Rockville, MD: Agency for Healthcare Research and Quality. August, 2009.

Preface
The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-based Practice Centers (EPCs), sponsors the development of evidence reports and technology assessments to assist public- and private-sector organizations in their efforts to improve the quality of health care in the United States. The Office of Dietary Supplements/National Institutes of Health, the Public Health Agency of Canada, Health Canada, and Food and Drug Administration requested and provided funding for this report. The reports and assessments provide organizations with comprehensive, science-based information on common, costly medical conditions and new health care technologies. The EPCs systematically review the relevant scientific literature on topics assigned to them by AHRQ and conduct additional analyses when appropriate prior to developing their reports and assessments.
To bring the broadest range of experts into the development of evidence reports and health technology assessments, AHRQ encourages the EPCs to form partnerships and enter into collaborations with other medical and research organizations. The EPCs work with these partner organizations to ensure that the evidence reports and technology assessments they produce will become building blocks for health care quality improvement projects throughout the Nation. The reports undergo peer review prior to their release.
AHRQ expects that the EPC evidence reports and technology assessments will inform individual health plans, providers, and purchasers as well as the health care system as a whole by providing important information to help improve health care quality.
We welcome comments on this evidence report. They may be sent by mail to the Task Order Officer named below at: Agency for Healthcare Research and Quality, 540 Gaither Road, Rockville, MD 20850, or by email to epc@ahrq.gov.
Carolyn M. Clancy, M.D.	Jean Slutsky, P.A., M.S.P.H.
Director	Director, Center for Outcomes and Evidence
Agency for Healthcare Research and Quality	Agency for Healthcare Research and Quality
Beth A. Collins Sharp, R.N., Ph.D.	Stephanie Chang, M.D., M.P.H.
Director, EPC Program	EPC Program Task Order Officer
Agency for Healthcare Research and Quality	Agency for Healthcare Research and Quality
Paul M. Coates, Ph.D.	Elizabeth A. Yetley, Ph.D.
Director, Office of Dietary Supplements	Senior Nutrition Research Scientist, Retired
National Institutes of Health	Office of Dietary Supplements
National Institutes of Health

Mary Frances Picciano, Ph.D.	Kimberly D. Elmslie, M.Sc.
Senior Nutrition Research Scientist	Director General
Office of Dietary Supplements	Centre for Chronic Disease Prevention and
National Institutes of Health	Control
Public Health Agency of Canada
Margaret de Groh, Ph.D.	Hasan Hutchinson, Ph.D., N.D.
Manager, Risk Factors Unit	Director General
Centre for Chronic Disease Prevention and Control Office of Nutrition Policy and Promotion Health Canada	Public Health Agency of Canada
Linda Greene-Finestone, Ph.D., R.D.	Paula R. Trumbo, Ph.D.
Nutrition Advisor	Supervisor, Nutrition Science Evaluation
Centre for Chronic Disease Prevention and Control Office of Nutrition, Labeling and Dietary Public Health Agency of Canada	Supplements
Center for Food Safety and Applied Nutrition
Food and Drug Administration

Acknowledgments
We would like to acknowledge with appreciation the following members of the Technical Expert Panel for their advice and consultation to the Tufts Evidence-based Practice Center during the preparation for this report:

Steven Abrams, M.D.
Professor of Pediatrics
Baylor College of Medicine Section of Neonatology Texas Children's Hospital Houston, Texas
Stephanie Atkinson, Ph.D.
Professor and Associate Chair Department of Pediatrics
Biochemistry and Biomedical Sciences Health Sciences
McMaster University
Hamilton, Canada
Patsy M. Brannon, Ph.D.
Professor
Division of Nutritional Sciences Cornell University
Ithaca, New York
Rebecca D. Jackson, M.D. Associate Professor
Department of Internal Medicine
Division of Endocrinology, Diabetes, and Metabolism
The Ohio State University Columbus, Ohio

Glenville Jones, Ph.D.
Professor and Head
Department of Biochemistry Queen's University
Ontario, Canada
Susan Taylor Mayne, Ph.D., F.A.C.E. Professor
Division of Chronic Disease Epidemiology Yale School of Public Health
New Haven, Connecticut
Clifford J. Rosen, M.D.
Senior Scientist
Maine Medical Center Research Institute Scarborough, Maine

Structured Abstract
Background: Since the 1997 Dietary Reference Intake (DRI) values for vitamin D and calcium were established new data have become available on their relationship, both individually and combined, to a wide range of health outcomes. The Institute of Medicine/Food and Nutrition Board has constituted a DRI committee to undertake a review of the evidence and potential revision of the current DRI values for these nutrients. To support this review, several US and Canadian federal government agencies commissioned a systematic review of the scientific literature for use during the deliberations by the committee. The intent of providing a systematic review to the committee is to support transparency of the literature review process and provide a foundation for subsequent reviews of the nutrients.
Purpose: To systematically summarize the evidence on the relationship between vitamin D, calcium, and a combination of both nutrients on a wide range of health outcomes as identified by the IOM, AHRQ and technical expert panel convened to support the project.
Data sources: MEDLINE; Cochrane Central; Cochrane Database of Systematic Reviews; and the Health Technology Assessments; search limited to English-language articles in humans.
Study selection: Primary interventional or observational studies that reported outcomes of interest in human subjects in relation to vitamin D and/or calcium, as well as systematic reviews that met the inclusion and exclusion criteria. Cross sectional and retrospective case-control studies were excluded.
Data extraction: A standardized protocol with predefined criteria was used to extract details on study design, interventions, outcomes, and study quality.
Data synthesis: We summarized 165 primary articles and 11 systematic reviews that incorporated over 200 additional primary articles. Available evidence focused mainly on bone health, cardiovascular diseases or cancer outcomes. For many outcomes, it was difficult to draw firm conclusions on the basis of the available literature concerning the association of either serum 25(OH)D concentration or calcium intake, or the combination of both nutrients. Findings were inconsistent across studies for colorectal and prostate cancer, and pregnancy-related outcomes including preeclampsia. There were few studies for pancreatic cancer and immune function. Among trials of hypertensive adults, calcium supplementation lowered systolic, but not diastolic, blood pressure by 2-4 mm Hg. For body weight, the trials were consistent in finding no significant effect of increased calcium intake on weight. For growth rates, a meta-analysis did not find a significant effect on weight or height gain attributable to calcium supplement in children. For bone health, one systematic review found that vitamin D plus calcium supplementation resulted in small increases in BMD of the spine and other areas in postmenopausal women. For breast cancer, calcium intakes in premenopausal women were associated with a decreased risk. For prostate cancer, some studies reported that high calcium intakes were associated with an increased risk.
Limitations: Studies on vitamin D and calcium were not specifically targeted at life stages (except for pregnant and postmenopausal women) specified for the determination of DRI. There

is large variation on the methodological quality of studies examined. Use of existing systematic reviews limits analyses that could be performed on this source of information.
Conclusions: The majority of the findings concerning vitamin D, calcium, or a combination of both nutrients on the different health outcomes were inconsistent. Synthesizing a dose-response relation between intake of either vitamin D, calcium, or both nutrients and health outcomes in this heterogeneous body of literature prove challenging.

Contents
Executive Summary
Evidence Report	15
Chapter 1. Introduction
Background
Sources, metabolism and functions of vitamin D Sources, metabolism and functions of calcium Challenges for the DRI committees
Key Questions addressed in this report
Chapter 2. Methods
Overview
Sponsoring Federal agencies
AHRQ Task Order Officer (TOO)
Technical Expert Panel (TEP)
EPC methodologists
Development of the analytic framework and refinement of key questions
Definitions
Vitamin D and calcium exposures
Clinical outcomes
Indicators of exposure (nutrient intake)
Surrogate outcomes Intermediate outcomes Life stages
Key questions
Literature search strategy Study selection
Abstract screening
Full text article eligibility criteria
Primary studies
Systematic reviews
Other specific eligibility criteria
Data extraction
Data analysis
Meta-analysis
Grading of studies analyzed in this evidence report
Critical appraisal and grading of primary studies
Additional considerations of methodological quality of primary studies for the
purpose of DRI decision making
Critical appraisal of systematic reviews
Reporting of the evidence
Evidence tables
Summary tables

Graphical presentation of dose-response relationship Grand summary tables (evidence map)
Units of measurement
Assay method
Sunlight exposure
Primary and secondary outcomes
Study quality
Organization of the Results Section
Chapter 3. Results
Literature search results Vitamin D and health outcomes
Vitamin D and growth
Vitamin D and cardiovascular disease
Vitamin D and body weight
Vitamin D and cancer
Cancer from all causes and total cancer mortality
Prostate cancer Colorectal cancer Colorectal adenoma Breast cancer
Pancreatic cancer
Vitamin D and immunologic outcomes
Vitamin D and pregnancy-related outcomes
Preeclampsia
Other outcomes
Vitamin D and clinical outcomes of bone health
Rickets
Fractures, falls, or performance measures
Vitamin D and all-cause mortality
Vitamin D and hypertension and blood pressure Hypertension
Vitamin D and blood pressure
Vitamin D and bone mineral density or bone mineral content Calcium and health outcomes
Calcium and growth
Calcium and cardiovascular disease
Calcium and body weight
Calcium and cancer
Cancer from all cause and total cancer mortality
Prostate cancer Colorectal cancer Colorectal adenoma Breast cancer incidence
Breast Mammographic Density
Pancreatic cancer

Calcium and pregnancy-related outcomes
Preeclampsia
High blood pressure with or without proteinuria during pregnancy
Preterm birth
Small for gestational age infant
Calcium and all-cause mortality
Calcium and hypertension and blood pressure
Calcium and hypertension
Calcium and blood pressure
Combined vitamin D and calcium and health outcomes
Combined vitamin D calcium and growth
Combined vitamin D and calcium and cardiovascular disease
Combined vitamin D and calcium and body weight
Combined vitamin D and calcium and cancer
Cancer from all causes and total cancer mortality
Colorectal cancer
Colorectal adenoma
Breast cancer
Combined vitamin D and calcium and pregnancy-related outcomes
Preeclampsia
Other pregnancy-related outcomes
Combined vitamin D and calcium and clinical outcomes of bone health
Rickets, fractures, falls, or performance measures
Combined vitamin D and calcium and all-cause mortality
Combined vitamin D and calcium and hypertension and blood pressure
Combined vitamin D and calcium and hypertension
Combined vitamin D and calcium and blood pressure
Combined vitamin D and calcium and bone mineral density or bone mineral content How does dietary intake of vitamin D from fortified foods and vitamin D supplementation affect serum 25(OH)D concentrations (arrow 4)?
RCTs on dietary intakes of vitamin D from fortified foods and serum 25(OH)D concentrations
RCTs on vitamin D supplementation and serum 25(OH)D concentrations
Outcomes for Tolerable Upper Intake Levels
Renal outcomes
Adverse events reported in RCTs
Chapter 4. Discussion
Strengths of this report
DRI and the literature on vitamin D and calcium
Limitations of our methodological approach
Comments on the observational studies
Sources of heterogeneity and potential biases
Vitamin D intake and response in serum 25(OH)D concentration Considerations for future DRI committees

Abbreviations
Latitudes of selected cities

Tables
Table 1. Number of primary studies on vitamin D intake or concentration and specific
health outcomes that could be applicable to certain life stages
Table 2. Number of primary studies on calcium intake and specific health outcomes that
could be applicable to certain life stages
Table 3. Number of primary studies on combined vitamin D and calcium intake and
specific health outcomes that are relevant to certain life stages
Table 4. Vitamin D on growth outcome: Characteristics of interventional studies 
Table 5. Vitamin D and growth outcomes: Characteristics of cohort studies 
Table 6. Vitamin D and growth outcomes: Results of RCTs
Table 7. Vitamin D and growth outcomes: Results of cohort studies
Table 8. Vitamin D and cardiovascular outcomes: Characteristics of RCTs 
Table 9. Vitamin D and cardiovascular outcomes: Results of RCTs
Table 10. Vitamin D and cardiovascular outcomes: Characteristics of cohort studies 
Table 11. Vitamin D and cardiovascular outcomes: Results of cohort studies
Table 12. Vitamin D and weight: Characteristics of RCTs 
Table 13. Vitamin D and weight: Results of RCTs
Table 14. Vitamin D and total cancer: Characteristics of RCTs
Table 15. Vitamin D and total cancer: Characteristics of cohort studies 
Table 16. Vitamin D and total cancer: Results of RCTs
Table 17. Vitamin D and total cancer: Results of cohort studies
Table 18. Vitamin D and prostate cancer: Characteristics of nested case-control studies 
Table 19. Vitamin D and prostate cancer: Results of nested case-control studies
Table 20. Vitamin D and colorectal cancer: Characteristics of RCTs 
Table 21. Vitamin D and colorectal cancer: Results of RCTs
Table 22. Vitamin D and colorectal cancer: Characteristics of observational studiesA 
Table 23. Vitamin D and colorectal cancer: Results of observational studies
Table 24. Vitamin D and colorectal adenoma: Characteristics of observational studies 
Table 25. Vitamin D and colorectal adenoma: Results of observational studies
Table 26. Vitamin D and breast cancer: Characteristics of observational studies 
Table 27. Vitamin D and breast cancer: Results of observational studies
Table 28. Vitamin D and pancreatic cancer: Characteristics of observational studies 
Table 29. Vitamin D and pancreatic cancer: Results of observational studies
Table 30. Vitamin D (mother) and immunologic outcomes (offspring): Characteristics of cohort studies
Table 31. Vitamin D (mother) and immunologic outcomes (offspring): Results of cohort studies
Table 32. Vitamin D and preeclampsia: Characteristics of nested case-control studies 
Table 33. Vitamin D and preeclampsia: Results of nested case-control studies
Table 34. Summary of systematic review of the effect of vitamin D on bone health
Table 35. Vitamin D and bone health: Characteristics of RCTs published after the Ottawa EPC report
Table 36. Vitamin D and bone health: Results of RCTs published after the Ottawa EPC report

Table 37. Summary of systematic review on vitamin D supplementation and all-cause mortality
Table 38. Vitamin D and all-cause mortality: Characteristics of cohort studies 
Table 39. Vitamin D and all-cause mortality: Results of cohort studies
Table 40. Vitamin D and hypertension: Characteristics of cohort studies
Table 41. Vitamin D and hypertension: Results of cohort and nested case control studies 
Table 42. Vitamin D and blood pressure: Characteristics of RCTs
Table 43. Vitamin D and blood pressure: Results of RCTs
Table 44. Vitamin D and bone mineral density: Characteristics of RCTs published after the Ottawa EPC report
Table 45. Vitamin D and bone mineral density or bone mineral contents: Results of RCTs published after the Ottawa EPC report
Table 46. Summary of systematic review of calcium on growth in children 
Table 47. Calcium and growth: Characteristics of primary studies
Table 48. Calcium and growth: Results of primary studies
Table 49. Calcium and cardiovascular outcomes: Characteristics of cohort studiesB 
Table 50. Calcium and cardiovascular outcomes: Results of cohort studies
Table 51. Systematic reviews of calcium supplementation and weight 
Table 52. Calcium and weight: Characteristics of RCTs
Table 53. Calcium and weight: Results of RCTs
Table 54. Calcium and total cancer mortality: Characteristics of RCTs
Table 55. Calcium and total cancer incidence or mortality: Characteristics of cohort studies
Table 56. Calcium and total cancer mortality: Results of RCTs
Table 57. Calcium and total cancer incidence or mortality: Results of cohort studies 50-71, males
Table 58. Calcium and prostate cancer: Characteristics of observational studies 
Table 59. Calcium and prostate cancer: Results of observational studies
Table 60. Systematic review of calcium supplementation and colorectal cancer incidence or adenoma recurrence
Table 61. Calcium and colorectal cancer: Characteristics of observational studies 
Table 62. Calcium and colorectal cancer: Results of cohort studies
Table 63. Calcium and colorectal cancer: Results of nested case-control studies 
Table 64. Calcium and colorectal adenoma: Characteristics of interventional studies 
Table 65. Calcium and colorectal adenoma: Characteristics of cohort studies
Table 66. Calcium and colorectal adenoma recurrence: Results of RCTs
Table 67. Calcium and colorectal adenoma recurrence: Results of nonrandomized comparative study
Table 68. Calcium and colorectal adenoma: Results of cohort studies
Table 69. Calcium and breast cancer: Characteristics of cohort studies 
Table 70. Calcium and breast cancer: Results of cohort studies
Table 71. Calcium and breast mammography density: Characteristics of cohort studies 
Table 72. Calcium and breast cancer: Results of cohort studies
Table 73. Calcium and pancreatic cancer: Characteristics of cohort studies 
Table 74. Calcium and pancreatic cancer: Results of cohort studies

Table 75. Summary table of systematic review on calcium supplementation and preeclampsia, small for gestational age, preterm birth
Table 76. Calcium and preeclampsia and other pregnancy outcomes: Characteristics of cohort studies
Table 77. Calcium and preeclampsia and other pregnancy outcomes: Results of cohort studies
Table 78. Calcium intake and all-cause mortality: Characteristics of cohort studies
Table 79. Calcium intake and all-cause mortality: Results of cohort studies
Table 80. Calcium and hypertension incidence: Characteristics of cohort studies
Table 81. Calcium and hypertension incidence: Results of cohort studies
Table 82. Summary of systematic reviews of calcium and blood pressure
Table 83. Calcium and blood pressure: Characteristics of RCTs
Table 84. Calcium and blood pressure: Results of RCTs
Table 85. Combined vitamin D and calcium and cardiovascular outcomes: Characteristics of RCTs
Table 86. Combined vitamin D and calcium and cardiovascular outcomes: Results of RCTs
Table 87. Combined vitamin D and calcium and weight: Characteristics of RCTs
Table 88. Combined vitamin D and calcium and weight: Results of RCTs
Table 89. Combined vitamin D and calcium and total cancer incidence: Characteristics of RCTs
Table 90. Combined vitamin D and calcium and total cancer incidence: Results of RCTs Table 91. Combined vitamin D with calcium and colorectal cancer: Characteristics of RCTs
Table 92. Combined vitamin D with calcium and colorectal cancer: Results of RCTs Table 93. Combined vitamin D and calcium and breast cancer outcomes: Characteristics of RCTs
Table 94. Combined vitamin D and calcium and breast cancer outcomes: Results of RCTs
Table 95. Combined vitamin D and calcium and preeclampsia: Characteristics of RCTs Table 96. Combined vitamin D and calcium and preeclampsia: Results of RCTs
Table 97. Combined vitamin D and calcium and bone health: Characteristics of RCTs published after the Ottawa EPC report
Table 98. Combined vitamin D and calcium and bone health: Results of RCTs published after the Ottawa EPC report (stress fracture)
Table 99. Combined vitamin D and calcium and bone health: Results of RCTs published after the Ottawa EPC report (performance measures)
Table 100. Combined vitamin D and calcium and incident hypertension: Characteristics of RCTs
Table 101. Combined vitamin D and calcium and incident hypertension: Results of RCTs
Table 102. Combined vitamin D and calcium and blood pressure: Characteristics of RCTs
Table 103. Combined vitamin D and calcium and blood pressure: Results of RCTs
Table 104. Combined vitamin D and calcium and bone mineral density/content: Characteristics of RCTs published after the Ottawa EPC report

Table 105. Combined vitamin D and calcium and bone mineral density/content: Results of RCTs published after the Ottawa EPC report
Table 106. The relationship between vitamin D3 daily doses and changes in 25(OH)D concentrations in RCTs
Table 107. Adverse events reported in RCTs
Figures
Figure 1. Summary of the vitamin D endocrine system
Figure 2. Generic analytic framework to assist formulation of key questions for the development of DRIs
Figure 3. Analytic framework for vitamin D and/or calcium EARs Figure 4. Analytic framework for vitamin D and/or calcium ULs Figure 5. Literature flow in this report
Figure 6. Cardiovascular outcomes risk stratified by vitamin D concentration
Figure 7. Prostate cancer risk stratified by vitamin D concentration Figure 8. Colorectal cancer risk stratified by vitamin D concentration Figure 9. Colon cancer risk stratified by vitamin D concentration Figure 10. Rectal cancer risk stratified by vitamin D concentration Figure 11. Cardiovascular outcomes risk stratified by calcium intake Figure 12. Stroke risk stratified by calcium intake
Figure 13. Prostate cancer risk stratified by calcium intake
Figure 14 Colorectal cancer risk in both sexes stratified by calcium intake
Figure 15 Colorectal cancer risk in men stratified by calcium intake Figure 16 Colorectal cancer risk in women stratified by calcium intake Figure 17 Colon cancer risk stratified by calcium intake
Figure 18. Rectal cancer risk stratified by calcium intake
Figure 19. Colorectal adenomatous polyp risk stratified by calcium intake
Figure 20. Breast cancer risk stratified by calcium intake 
Figure 21. Hypertension risk stratified by calcium intake 
Figure 22. Forest plot of trials of combined vitamin D and calcium supplementation and
effects on all-cause mortality
Figure 23. Relationship between doses of Vitamin D3 supplementation and net changes in serum 25(OH)D concentrations in RCTs
Figure 24. Relationship between doses of Vitamin D3 supplementation and net changes in serum 25(OH)D concentrations in RCTs by baseline vitamin D status among adults
Figure 25. Relationship between doses of Vitamin D3 supplementation and net changes in serum 25(OH)D concentrations in RCTs by duration of supplementation among adults
Appendixes
Appendix A. Search Strategy for Primary Studies Appendix B. Search Strategy for Systematic Reviews Appendix C. Evidence Tables
Appendix D. Existing Systematic Reviews

Appendix E. Blank Data Extraction Form and Quality Assessment Checklists Appendix F. Excluded Studies With Reasons
Appendixes and Evidence Tables for this report are provided electronically at http://www.ahrq.gov/downloads/pub/evidence/pdf/vitadcal/vitadcal.pdf.