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IoM July 2009 Table of Contents

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

 

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.

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 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)

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

 

Calcium and pregnancy-related outcomes

Preeclampsia

High blood pressure with or without proteinuria during pregnancy

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 body weight

Combined vitamin D and calcium and cancer

Cancer from all causes and total cancer mortality

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

 

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 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 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 F
igure 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.