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Cover of Vitamin D and Calcium: A Systematic Review of Health Outcomes (Update)

Vitamin D and Calcium: A Systematic Review of Health Outcomes (Update)

Evidence Reports/Technology Assessments, No. 217

Investigators: , PhD, , PhD, MPH, , MD, PhD, , MS, , MS, , MD, , BA, , MPH, , BHM, , MLS, and , MD, MPH.

Author Information and Affiliations
Rockville (MD): Agency for Healthcare Research and Quality (US); .
Report No.: 14-E004-EF

Structured Abstract


In 2009, the Institute of Medicine/Food and Nutrition Board constituted a Dietary Reference Intakes (DRI) committee to undertake a review of the evidence that had emerged (since the 1997 DRI report) on the relationship of vitamin D and calcium, both individually and combined, to a wide range of health outcomes, and potential revision of the DRI values for these nutrients. To support that review, several United States and Canadian Federal Government agencies commissioned a systematic review of the scientific literature for use during the deliberations by the committee. The intent was to support a transparent literature review process and provide a foundation for subsequent reviews of the nutrients. The committee used the resulting literature review in their revision of the DRIs.

In 2013, in preparation for a project the National Institutes of Health Office of Dietary Supplements (NIH/ODS) was undertaking related to evidence-based decisionmaking for vitamin D in primary care, based on the updated DRI report, the ODS and AHRQ requested an update to the 2009 systematic review to incorporate the findings of studies conducted since the 2009 evidence review on the relationship between vitamin D alone or vitamin D plus calcium to selected health outcomes and to report on the methods used to assay vitamin D in the included trials.


To systematically summarize the evidence on the relationship between vitamin D alone or in combination with calcium on selected health outcomes included in the earlier review: primarily those related to bone health, cardiovascular health, cancer, immune function, pregnancy, all-cause mortality, and vitamin D status; and to identify the vitamin D assay methods and procedures used for the interventional studies that aimed to assess the effect of vitamin D administration on serum 25(OH)D concentrations, and to stratify key outcomes by methods used to assay serum 25(OH)D concentrations.

Data sources:

MEDLINE®; Cochrane Central; Cochrane Database of Systematic Reviews; and the Health Technology Assessments; search limited to English-language articles on humans.

Study selection:

Primary interventional or prospective observational studies that reported outcomes of interest in human subjects in relation to vitamin D alone or in combination with calcium, as well as systematic reviews that met the inclusion and exclusion criteria.

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 154 newly identified primary articles and two new systematic reviews that incorporated more than 93 additional primary articles. Available evidence focused mainly on bone health, cardiovascular diseases, or cancer outcomes. Findings were inconsistent across studies for bone health; breast, colorectal, and prostate cancer; cardiovascular disease and mortality; immune function; and pregnancy-related outcomes. Few studies assessed pancreatic cancer and birth outcomes. One new systematic review of observational studies found that circulating 25(OH)D was generally inversely associated with risk for cardiovascular disease. Methods used to assay serum 25(OH)D in studies reporting on key outcomes diverged widely. The current report also identified one new systematic review published since the original report that addressed whether a dose response relationship exists between dietary and supplemental vitamin D intake and serum 25(OH)D concentrations. The systematic review, based on 76 RCTs, reported widely varying increases in serum concentrations of 25(OH)D for similar doses of vitamin D, with a general increase in serum concentration with dietary intake. The RCTs identified for the current report found increases in serum 25(OH)D with supplementation; however, the findings varied by age group and health status of participants, baseline vitamin D status, dose, duration, and assay used to assess serum 25(OH)D.


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 and were often underpowered for their intended outcomes. Studies vary widely in methodological quality and in the assays used to measure vitamin D status.


In solid agreement with the findings of the original report, the majority of the findings concerning vitamin D, alone or in combination with calcium, on the health outcomes of interest were inconsistent. Associations observed in prospective cohort and nested case-control studies were inconsistent, or when consistent, were rarely supported by the results of randomized controlled trials. Clear dose-response relationships between intakes of vitamin D and health outcomes were rarely observed. Although a large number of new studies (and longer followups to older studies) were identified, particularly for cardiovascular outcomes, all-cause mortality, several types of cancer, and intermediate outcomes for bone health, no firm conclusions can be drawn. Studies identified for the current report suggest a possible U-shaped association between serum 25(OH)D concentrations and both all-cause mortality and hypertension and also suggest that the level of supplemental vitamin D and calcium administered in the Women's Health Initiative Calcium-Vitamin D Trial are not associated with an increased risk for cardiovascular disease or cancer among postmenopausal women who are not taking additional supplemental vitamin D and calcium. Studies suggest the method used to assay 25(OH)D may influence the outcomes of dose-response assessments. Beyond these observations, it is difficult to make any substantive statements on the basis of the available evidence concerning the association of either serum 25(OH)D concentration, vitamin D supplementation, calcium intake, or the combination of both nutrients, with the various health outcomes because most of the findings were inconsistent.


Prepared for: Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services1, Contract No. 290-2012-00006-I. Prepared by: Southern California Evidence-based Practice Center, Santa Monica, CA

Suggested citation:

Newberry SJ, Chung M, Shekelle PG, Booth MS, Liu JL, Maher AR, Motala A, Cui M, Perry T, Shanman R, Balk EM. Vitamin D and Calcium: A Systematic Review of Health Outcomes (Update). Evidence Report/Technology Assessment No. 217. (Prepared by the Southern California Evidence-based Practice Center under Contract No. 290-2012-00006-I.) AHRQ Publication No. 14-E004-EF. Rockville, MD: Agency for Healthcare Research and Quality. September 2014. www.effectivehealthcare.ahrq.gov/reports/final.cfm. DOI: https://doi.org/10.23970/AHRQEPCERTA217.

This report is based on research conducted by the Southern California Evidence-based Practice Center under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. 290-2012-00006-I). The findings and conclusions in this document are those of the author(s), who are responsible for its contents; the findings and conclusions do not necessarily represent the views of AHRQ. Therefore, no statement in this report should be construed as an official position of AHRQ or of the U.S. Department of Health and Human Services.

The information in this report is intended to help health care decisionmakers—patients and clinicians, health system leaders, and policymakers, among others—make well-informed decisions and thereby improve the quality of health care services. This report is not intended to be a substitute for the application of clinical judgment. Anyone who makes decisions concerning the provision of clinical care should consider this report in the same way as any medical reference and in conjunction with all other pertinent information, i.e., in the context of available resources and circumstances presented by individual patients.

This report may be used, in whole or in part, as the basis for development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied.

This report may periodically be assessed for the urgency to update. If an assessment is done, the resulting surveillance report describing the methodology and findings will be found on the Effective Health Care Program Web site at: www.effectivehealthcare.ahrq.gov. Search on the title of the report.

None of the investigators have any affiliations or financial involvement that conflicts with the material presented in this report.


540 Gaither Road, Rockville, MD 20850; www‚Äč.ahrq.gov

Bookshelf ID: NBK253540


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