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Dietary Reference Intakes for Calcium and Vitamin D (2011)

Chapter: Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium

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Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
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D
Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium

The purpose of this systematic evidence-based review, referred to as AHRQ-Tufts,1 requested by the Office of Dietary Supplements/National Institutes of Health, the Public Health Agency of Canada, Health Canada, and the Food and Drug Administration and conducted by the Tufts Evidence-based Practice Center (EPC), was to answer key scientific questions on how dietary vitamin D and calcium intake effect health outcomes. The key questions addressed in the AHRQ-Tufts reports are as follows:


Key Question 1. What is the effect of vitamin D, calcium, or combined vitamin D and calcium intakes on clinical outcomes, including growth, cardiovascular diseases, body weight outcomes, cancer, immune function, pregnancy or birth outcomes, mortality, fracture, renal outcomes, and soft tissue calcification?


Key Question 2. What is the effect of vitamin D, calcium, or combined vitamin D and calcium intakes on surrogate or intermediate outcomes, such as hypertension, blood pressure, and bone mineral density?

1

Chung, M., E. M. Balk, M. Brendel, S. Ip, J. Lau, J. Lee, A. Lichtenstein, K. Patel, G. Raman, A. Tatsioni, T. Terasawa and T. A. Trikalinos. 2009. Vitamin D and Calcium: A Systematic Review of Health 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.

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
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Key Question 3. What is the association between serum 25(OH)D concentrations or calcium balance and clinical outcomes?


Key Question 4. What is the effect of vitamin D or combined vitamin D and calcium intakes on serum 25(OH)D concentrations?


Key Question 5. What is the association between serum 25(OH)D concentrations and surrogate or intermediate outcomes?


The review focused on electronic searches of the medical literature (1969–April 2009) to identify publications addressing the aforementioned questions. One hundred and sixty-five primary articles and 11 systematic reviews that incorporated more than 200 additional primary articles were systematically reviewed, and each was rated on quality and used to assess the strength of evidence for each outcome.

The methods and results chapters of the AHRQ-Tufts evidence review are reprinted below. The report in its entirety, including appendices and evidence tables, can be accessed and viewed at http://www.ahrq.gov/clinic/tp/vitadcaltp.htm.

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
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Chapter 2.
Methods

Overview

This report is based on a systematic review of key questions on the relationships between vitamin D [either 25(OH)D concentrations or supplements] or dietary calcium intake, and health outcomes. The methodologies employed in this evidence report generally follow the methods outlined in the AHRQ Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews (http://effectivehealthcare.ahrq.gov/repFiles/2007_10DraftMethodsGuide.pdf). The initial questions identified by the federal sponsors of this report were refined with input from a Technical Expert Panel (TEP). This report does not make clinical or policy recommendations. The report is being made available to an IOM committee charged with updating vitamin D and calcium DRIs.

A description of roles and responsibilities of sponsoring federal agencies, AHRQ, the TEP and the EPC is included to clarify the relationships that support the process and ensure transparency and that the approach adhered to the highest standards of scientific integrity.

Because of the large number of abbreviations for unfamiliar terms are used, their explanations have been repeated whenever deemed necessary. A table of Abbreviations can be found after the references in page 316. We also provide a table with the latitudes of several major cities in Central and North America, right after the Abbreviations table, on page 320.

Sponsoring federal agencies

The sponsoring agencies were responsible for specifying the topic-specific task order requirements. They participated in a Kick-Off meeting with the EPC and the Task Order Officer (TOO) to facilitate a common understanding of the topic-specific work requirements, and responded to inquiries from the TOO if modifications to the work order were requested by the EPC. Any communication between the sponsoring agencies and the EPC occurred with oversight from the TOO.

Review by Federal sponsors was limited to comments on factual errors, requests for clarification, and consistency with the original contract task order. Comments on the scientific content of the report were not provided. In all cases, reviewer comments are advisory only and are not binding on the scientific authors of the final report.

AHRQ Task Order Officer (TOO)

The TOO was responsible for overseeing all aspects of this Task Order. The TOO served as the point person for all communication required between the sponsoring agencies, the EPC, and other AHRQ officials. The purpose of this communication was to facilitate a common understanding of the task order requirements among the sponsors, the TOO, and the EPC, resolve ambiguities and to allow the EPC to focus on the scientific issues and activities.

Technical Expert Panel (TEP)

The TEP is comprised of qualified experts including, but not limited to, individuals with knowledge of DRI decision making processes, vitamin D and calcium nutrition and biology across the life cycle, health outcomes of interest, and the methodology of conducting systematic reviews. The EPC worked closely with the TEP in the formative stages of the project on question

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
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refinement and throughout the evidence review process to address questions that occurred. The EPC conducted the actual systematic review of the questions independent of the TEP and other stakeholders. It was specified, a priori, that external peer reviewers of the final report could not also serve as a member of the IOM’s calcium and vitamin D DRI Committee.

Those serving on the TEP provided input on such factors as reviewing search terms to ensure they were adequately inclusive, assessing search strategies to ensure they comprehensively covered the questions of interest, and answering questions about technical details (e.g., nuances of laboratory methods of performing an assay). Members of the TEP did not participate in EPC research meetings or in reviewing and synthesizing evidence. Their function was limited to providing domain-specific knowledge and advising the proper context that is relevant to the process of evaluating DRI. They did not have any decision making role and did not participate in writing any part of the evidence report.

EPC methodologists

This evidence report was carried out under the AHRQ EPC program, which has a 12-year history of producing over 175 evidence reports and numerous technology assessments for various users including many federal agencies. EPCs are staffed by experienced methodologists who continually refine approaches to conducting evidence reviews and develop new methods on the basis of accumulated experience encompassing a wide range of topics. The Tufts EPC has produced many evidence reports on nutrition topics19-24 (http://www.ahrq.gov/clinic/epcix.htm). We have also conducted methodological research to identify the issues and challenges of including evidence-based methods as a component of the process used to develop nutrient reference values, such as the DRI, using vitamin A as an example.3

Development of the analytic framework and refinement of key questions

The focus of this report is on the relationship of vitamin D only, calcium only, and combinations of vitamin D and calcium with specific health outcomes. Key questions and analytic frameworks were developed by defining each box in the generic analytic framework described in Chapter 1 with specific reference to vitamin D and calcium.

A one-day meeting of the federal sponsors, TEP and Tufts EPC staff was held in Boston on September 20, 2008. At this meeting, the analytic framework was discussed, the key questions refined, and study eligibility criteria established. Two analytic frameworks were developed: one for intakes of vitamin D and/or calcium related to their beneficial effects and one for intakes associated with adverse effects (Figures 3 & 4). We used the PI(E)CO method to establish study eligibility criteria. This method defines the Population, Intervention (or Exposure in the case of observational studies), Comparator, and Outcomes of interest. Details are described in the sections that follow.

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
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Figure 3. Analytic framework for vitamin D and/or calcium generic health outcomes

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
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Figure 4. Analytic framework for vitamin D and/or calcium safety-related (adverse) outcomes

Definitions

Vitamin D and calcium exposures

Vitamin D exposure included intake of vitamin D2 or vitamin D3 from foods and supplements, including human milk and commercial infant formulas. Because the primary source of vitamin D in the human body is produced in skin exposed to sunlight, background information on ultraviolet B (UVB) exposure was captured to the extent possible. However, we did not include studies that evaluated the effect of or association between exposure to sunlight (or UVB) and clinical outcomes or serum 25(OH)D concentrations. In other words, we did not investigate sunlight exposure as a proxy for or a source of vitamin D intake. Sunlight exposure was considered only as a potential confounder or effect modifier of associations between vitamin D or calcium and clinical outcomes.

Calcium exposure included intake of calcium from foods and supplements, including calcium-containing antacids, mineral-supplemented water, human milk and commercial infant formulas.

Combined vitamin D and calcium exposure included any relevant combinations of the above.

Clinical outcomes

Clinical outcomes are measures of how a person (e.g., a study participant) feels, functions or survives, or a clinical measurement of the incidence or severity of a disease (e.g., diagnosis of disease or change from one disease state to another). Examples of clinical outcomes used in this report are incidence of cancer, cardiovascular events, and preeclampsia. The clinical outcomes of interest in this report are described in the “Specific Outcomes of Interest” section.

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×
Indicators of exposure (nutrient intake)

Indicators of exposure are measures that correlate with dietary intake of a nutrient, such as nutrient biomarkers, nutritional status, or markers of nutritional status.

Indicators of vitamin D exposure (i.e., vitamin D intake and sun exposure) included serum 25(OH)D and 1,25(OH)2D concentrations.

Indicators of dietarycalcium intakes included calcium balance (i.e., calcium accretion, retention, and loss).

Surrogate outcomes

Surrogate outcomes are biomarkers or physical measures that are generally accepted as substitutes for or predictors of specific clinical outcomes.18 Changes induced by the exposure or intervention on a surrogate outcome marker are expected to reflect changes in a clinical outcome. Examples of surrogate outcomes used in this report are bone mineral density (as a surrogate marker of fracture risk) and breast mammographic density (as a surrogate marker of breast cancer risk). The surrogate outcomes of interest in this report are described in “Specific Outcomes of Interest” section.

Intermediate outcomes

Intermediate outcomes are possible predictors of clinical outcomes that are not generally accepted to fulfill the criteria for a surrogate outcome. However, in the absence of data for surrogate outcomes, intermediate markers are often used. Examples of intermediate markers used in this report are prostate cancer antigen (as a marker of prostate cancer risk) and blood pressure (as a marker of stroke risk). All intermediate markers of interest in this report are described in “Specific Outcomes of Interest” section.

Life stages

In consultation with the TEP, the 22 life stages defined by the FNB/IOM for the development of DRI were consolidated to 9 categories to facilitate the reporting of results. Within each life stages, men and women (or boys and girls) were considered separately when possible. There are also some inevitable overlaps between these categories. For example, most women in 51-70 years life stage are postmenopausal women. The 9 categories created for this report are:

  • 0 – 6 months

  • 7 months – 2 years

  • 3 – 8 years

  • 9 – 18 years

  • 19 – 50 years

  • 51 – 70 years

  • ≥71 years

  • Pregnant and lactating women

  • Postmenopausal women

In summarizing studies for each given outcome, we used our best judgment to describe the study results for each applicable life stage.

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Key questions

In agreement with the TEP, the following key questions were addressed in this evidence report. It was decided that arrow 6 in the analytic framework (What is the relationships between intermediate or surrogate outcomes and clinical outcomes?) is outside the scope of the DRI literature review in this report. All outcomes of interest in this report are described in “Eligibility Criteria” section.


Key Question 1. What is the effect of vitamin D, calcium, or combined vitamin D and calcium intakes on clinical outcomes, including growth, cardiovascular diseases, weight outcomes, cancer, immune function, pregnancy or birth outcomes, mortality, fracture, renal outcomes, and soft tissue calcification? (Arrow 1)


Key Question 2. What is the effect of vitamin D, calcium or combined vitamin D and calcium intakes on surrogate or intermediate outcomes, such as hypertension, blood pressure, and bone mineral density? (Arrow 2)


Key Question 3. What is the association between serum 25(OH)D concentrations or calcium balance and clinical outcomes? (Arrow 3)


Key Question 4. What is the effect of vitamin D or combined vitamin D and calcium intakes on serum 25(OH)D concentrations? (Arrow 4)


Key Question 5. What is the association between serum 25(OH)D concentrations and surrogate or intermediate outcomes? (Arrow 5)

Literature search strategy

We conducted a comprehensive literature search to address the key questions. For primary studies, the EPC used the Ovid search engine to conduct searches in the MEDLINE® and Cochrane Central database. A wide variety of search terms were used to capture the many potential sources of information related to the various outcomes (see Appendix A). Search terms that were used to identify outcomes of interest, for both EARs and ULs, can be categorized into the following groups: 1) bodyweight or body mass index; 2) growth (height and weight); 3) fracture or bone mineral density; 4) falls or muscle strength; 5) cardiovascular diseases; 6) hypertension or blood pressure; 7) cancer or neoplasms, including adenomas, colon polyps, and mammography; 8) autoimmune diseases (e.g., type 1 diabetes, psoriasis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, and Crohn's disease); 9) preeclampsia, eclampsia and pregnancy-related hypertension; 10) preterm or low birth weight; 11) breast milk or lactation; 12) death; 13) infectious diseases; 14) soft tissue calcification (for ULs only); and 15) kidney disease or hypercalcemia (for ULs only). The different outcomes were crossed with terms to identify vitamin D and calcium exposure: “vitamin D”, “plasma vitamin D”, “25-hydroxyvitamin D” and its abbreviations, “25-hydroxycholecalciferol”, “25-hydroxyergocalciferol”, “calcidiol”, “calcifediol”, “ergocalciferol”, “cholecalciferol”, “calciferol”, “calcium”, “calcium carbonate”, “calcium citrate”, “calcium phosphates” and

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

“calcium malate”. Literature searches of the outcomes alone without references to vitamin D or calcium were not conducted.

The searches were limited to human studies, English language publications, and citations from 1969 to September 2008 for all but bone outcomes. For outcomes related to bone health (i.e., bone mineral density, fracture, fall or muscle strength), we relied on a recent comprehensive systematic review performed by the Ottawa EPC.6 The Ottawa EPC report was updated from January 2006 to September 2008. The electronic search was supplemented by bibliographies of relevant review articles. Unpublished data, including abstracts and conference proceedings, were not included. An updated literature search was performed in April 2009 for all the topics to include relevant primary studies published since September 2008 for the final report.

For potentially relevant systematic reviews, we also searched MEDLINE®, the Cochrane Database of Systemic Reviews, and the Health Technology Assessments database up to December 2008. We searched for systematic reviews of the relationships between vitamin D or calcium and the prespecified outcomes. In this search, terms for identifying vitamin D or calcium exposures were crossed with terms for identifying systematic reviews, such as “systematic,” “evidence,” “evidence-based,” “meta-analysis,” or “pooled analysis”; specific terms for the outcomes were not included (Appendix B).

Study selection

Abstract screening

All abstracts identified through the literature search were screened. Eligible studies included all English language primary interventional or observational studies that reported any outcome of interest in human subjects in relation to vitamin D and/or calcium.

Full text article eligibility criteria

Articles that potentially met eligibility criteria at the abstract screening stage were retrieved and the full text articles were reviewed for eligibility. Rejected full text articles were examined only once, unless the articles were equivocal for inclusion or exclusion. In that event, the article in question was examined again by a different reviewer and a consensus was reached after discussion with the first reviewer. We recorded the reason for rejection of all full text articles.

Primary studies

Because the outcomes of interest ranged from very broad topics with common occurrences (e.g., cardiovascular disease) to narrowly focused topics with relatively few occurrences (e.g., preeclampsia), the number and types of studies available for each outcome varied widely in the distribution of study designs and sample sizes. It was neither possible nor desirable to use a uniform, strict set of inclusion and exclusion criteria applicable to all outcomes. Therefore, additional eligibility criteria germane to the specific outcome were applied to all accepted full text articles. Details are described in the “Eligibility criteria” section.

General eligibility criteria for the full text articles were:

Population of interest:

  • Primary population of interest is generally healthy people with no known disorders

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×
  • Studies that include a broad population that might have included some people with diseases. For example, some hypertensive and diabetic patients were included.

  • People with prior cancers (or cancer survivors), prior fractures, and precancer conditions (e.g., colon polyps) were included

  • Studies that enrolled more than 20% subjects with any diseases at baseline were excluded. An exception was made for older adults (mean age ≥65 years old) due to high prevalence of diseases in this population. For studies of older adults, only studies that exclusively enrolled subjects with particular disease (e.g., 100% type 2 diabetes) were excluded. In addition, for studies of blood pressure, studies of people exclusively with hypertension were included.

  • For adverse or safety outcomes, we included any adverse effects of high intake in any population.

Intervention/exposure of interest

  • For observational studies:

    • Serum 25(OH)D or 1,25(OH)2D concentration

    • Dietary intake level of vitamin D were not included due to inadequacy of nutrient composition tables for vitamin D.25

    • Dietary intake level of calcium from food and/or supplements

    • Calcium balance (i.e., calcium accretion, retention, and loss)

  • For interventional studies:

    • Vitamin D supplements (but not analogues) with known doses

    • Calcium supplements with known doses

    • The only combination of dietary supplements of interest was the combination of vitamin D and calcium. Any other combinations of supplements and/or drug treatments were excluded unless the independent effects of vitamin D and/or calcium can be separated. Thus studies of multivitamins were excluded.

    • Trials in which participants in both study groups took the same calcium (or vitamin D) supplement were evaluated as vitamin D (or calcium) versus control trials. In other words, the intervention common to both study groups was ignored (though it was noted).

    • Food based interventions were included if the doses of vitamin D and/or calcium were quantified and there were differences in the doses between the comparison groups. For example, a trial of dairy supplementation (with 500 mg/d calcium) versus no supplementation was qualified to be included. However, a trial of calcium fortified orange juice (with 1200 mg/d calcium) versus milk (with 1200 mg/d calcium) was not qualified to be included because there are no differences in the calcium doses.

    • Nonoral routes of nutrient delivery were excluded

Specific Outcomes of interest

  • Growth outcomes

    • In infants and premenarchal girls and boys of corresponding age: weight and height gain

  • Cardiovascular disease clinical outcomes

    • Cardiac events or symptoms (e.g., myocardial infarction, angina)

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
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  • Cerebrovascular events (stroke, transient ischemic attacks)

  • Peripheral vascular events or symptoms (diagnosis, claudication)

  • Cardiovascular death

  • Study-specific combinations of cardiovascular events

  • CVD intermediate outcomes

    • Diagnosis of hypertension

    • Blood pressure

  • Weight outcomes

    • In adults only: incident overweight or obesity, body mass index, or weight (kg)

  • Cancer (incident or mortality)

    • Cancer from all cause (or total cancer)

    • Prostate

    • Colorectal cancer

    • Breast cancer

    • Pancreatic cancer

    • Cancer-specific mortality

  • Cancer intermediate outcomes

    • Colorectal adenoma

    • Aberrant cryptic

    • Breast mammographic density (quantitative whole breast density)

  • Immune function clinical outcomes

    • Infectious diseases

    • Autoimmune diseases

    • Infectious disease-specific mortality

  • Pregnancy-related outcomes

    • Preeclampsia

    • High blood pressure with or without proteinuria

    • Preterm birth or low birth weight

    • Infant mortality

  • Mortality, all cause

  • Bone health clinical outcomes

    • Rickets

    • Fracture

    • Fall or muscle strength

  • Bone health intermediate outcomes

    • Bone mineral density or bone mineral content

  • Dose-response relationship between intake levels and indicators of exposure (arrow 4 of Figures 2 and 3)

    • Serum 25(OH)D concentration

    • Breast milk or circulating concentrations of 25(OH)D in infants

  • Outcomes of tolerable upper intake levels (ULs)

    • All-cause mortality

    • Cancer and cancer-specific mortality

    • Renal outcomes

    • Soft tissue calcification

    • Adverse events from vitamin D and/or calcium supplements

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Study design

  • Randomized controlled trials (RCTs)

  • Nonrandomized, prospective comparative studies of interventions

  • Prospective, longitudinal, observational studies (where the measure of exposure occurred before the outcome)

  • Prospective nested case-control studies (case-control study nested in a cohort so the measure of exposure occurred before the outcome)

  • We excluded cross-sectional studies and traditional, retrospective case-control studies (where the measure of exposure occurred after or concurrent with the outcome)

Systematic reviews

We included relevant systematic reviews that addressed the key questions. Systematic review is defined as a study that has at a minimum the following three components: a statement of the research questions (aims or objectives); a description of the literature search; and a listing of the study eligibility criteria. We did not attempt to contact authors for clarifications of outstanding questions. In addition, the following types of reviews were excluded: reviews of foods or diets that did not quantify vitamin D or calcium intake; reviews that included nonoral routes of nutrient delivery; reviews that did not evaluate the association between vitamin D or calcium intake to health outcomes; reviews of nonhuman data; and pooled analyses of primary databases (i.e., secondary database analyses of multiple cohorts) that did not include a systematic review (except possibly as a replacement for data from the original cohorts).

To determine the relevance of a systematic review to this report, the following inclusion criteria were applied:

  • Address key question(s) of interest (i.e., similar PI(E)CO criteria used):

    1. Systematic review must include only healthy population at baseline or have separate analyses for population with diseases and without diseases.

    2. Systematic reviews of interventional studies had to include only vitamin D or calcium interventions. Cointerventions with other nutrients had to be disallowed or separate analyses were needed for studies of vitamin D or calcium interventions alone.

    3. Systematic review of observational studies had to report the baseline concentrations of serum 25(OH)D and the assay methods used or the dietary assessment methods used to measure dietarycalcium intake (e.g. food frequency questionnaire, 24 hour recall).

    4. Exposure levels (e.g., level of 25(OH)D or calcium intake) or doses of interventions had to be reported

    5. Outcome definitions had to be reported

    6. Designs of primary studies had to be reported. If cross-sectional or case-control studies were included, the systematic review must provide sufficient information or separate analyses to separate them from RCTs or cohort studies.

  • We include only the most recent update if there were multiple systematic reviews from the same group of investigators using the same review process.

  • Where there were several systematic reviews on the same topic with similar conclusions and the same set of primary studies, we selected the systematic review with either the latest cutoff date for the end of the literature search or the most included primary studies. Where there were several systematic reviews, each of which included only a sample of

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

the total literature included by the several systematic reviews, all systematic reviews were included.

Other specific eligibility criteria
  • Growth outcomes (weight and height gain)

    • Only infants (<1 year old) and children (age <18 years old) were included

    • For infants, we include all eligible study designs. The vitamin D and/or calcium intervention or exposure can be administered to the mothers or to the infants in the study.

    • For infants, premenarchal girls, and boys of similar age, only RCTs that reported weight as a primary or secondary outcome were included. RCTs of weight loss were excluded.

  • Cardiovascular disease clinical outcomes

    • Only adults (aged ≥18 years old) were included.

  • Blood pressure and bodyweight

    • Only adults (aged ≥18 years old) were included.

    • Only RCTs of calcium or vitamin D interventions were included. We did not include observational studies of associations between calcium or vitamin D intake or serum vitamin D concentrations and blood pressure or weight measurements (as continuous outcomes). This decision was made in agreement with the TEP in part because it was agreed that any conclusions based on observational studies (e.g., associations between baseline calcium intake and change in systolic blood pressure) would be weak and difficult to interpret.

  • Bone health clinical outcomes

    • The Ottawa EPC report6 was updated with literature published between January 2006 and September 2008. Only RCTs qualified for inclusion.

    • Studies of calcium and bone health clinical outcomes were excluded.

  • Bone health intermediate outcomes

    • The Ottawa EPC report6 was updated with literature published between January 2006 and September 2008. For adults, we included only BMD indices. For children, we included only BMC indices. Only RCTs with duration of more than 1 year were qualified for inclusion.

    • Studies of calcium and bone health clinical outcomes were excluded.

  • Dose-response relationship between intake levels and indicators of exposure (arrow 4 of Figures 2 and 3)

    • Studies for this question were identified in our literature search that crossed vitamin D terms with various outcomes terms. Some studies that addressed this question but do not report any of the outcomes of interest would not have been identified in this manner. Because the availability of serum 25(OH)D concentration is unlikely to be adequately indexed in the Medline citation, it would be difficult to comprehensively search the literature for this question. To do so would require retrieving all full text articles mentioning vitamin D supplements (in excess of 10,000) to look for data on serum 25(OH)D concentration.

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×
  • Only RCTs were included for this question. However, RCTs of different regimens but the same dose of vitamin D supplementation were excluded (e.g., comparison of daily, weekly versus monthly dose).

Data extraction

For outcomes that had not been subjected to a prior systematic review, we extracted and summarized the relevant data from the primary studies. Where previous systematic reviews were available, we summarized their results into our report. In addition, we updated the previous systematic reviews (with our eligibility criteria) and extracted and summarized the additional primary studies.

Data extraction forms (evidence tables) were developed separately for extraction of systematic reviews and primary studies. For primary studies, the items extracted were: study characteristics, baseline population characteristics, background diet data, dietary assessment methods for calcium intake, 25(OH)D assay methods, interventions (for interventional studies only), confounders and effect modifiers that were adjusted for in statistical analysis, results, and quality assessments. Whenever the type of vitamin D supplement (D2 or D3) was clearly reported, we extracted and reported this information. Otherwise, we used the general term “vitamin D”. Evidence tables for all eligible studies are available in Appendix C. For systematic reviews, items extracted were: design, population, intervention (exposure) and comparator, results, and AMSTAR26 checklist criteria (a measurement tool created to assess the methodological quality of systematic reviews). A table with a list of all systematic reviews with the evaluation of their relevance to this report, and evidence tables of the qualified systematic reviews are available in Appendix D.

Data analysis

We explored the dose-response relationship between the level of intake of vitamin D (with or without calcium) and serum 25(OH)D concentrations graphically, using a scatter (“bubble”) plot. We plotted the observed net changes in 25(OH)D concentration, against the doses of vitamin D supplementation. In these plots studies were represented by empty circles (bubbles) with area proportional to the inverse of the within-study variances. Typically, the larger the bubble, the larger the sample size and the smaller the standard error of the changes in 25(OH)D.

Studies were included only if they reported sufficient data to estimate both mean net change and SE of the net change. We required data on both the mean net change in outcome level and the SE of the change. However, many studies provided only the SEs for the baseline and final outcome levels. In order to include these studies in the analyses we had to make several assumptions to estimate the SE of the change. To do this we used the

where SE1, SE2, and SE12 are the SEs for baseline, final and change, respectively, and ρ is the correlation between the baseline and final measurements.27 We arbitrarily chose the correlation, ρ, to be 0.50, the midpoint value. In our experience, using different values for ρ generally does not greatly affect the meta-analysis results of quantitative analyses or conclusions.

For each RCT, the SE of the net change was then calculated using the standard calculation for determining the SE of 2 independent cohorts. Namely, in the above equation where the correlation factor becomes 0, and thus the final term drops out. Where studies reported either within-cohort SEs or net change SEs, these numbers were used. Some RCTs may have more than

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
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two arms (e.g., two different doses of vitamin D supplement compared to the placebo), and in this case, the same control arm was used to calculate the net change and the SE of the net change as for two independent comparisons.

Meta-analysis

Overall, we did not perform new meta-analyses in this report because of large degree of clinical and methodological heterogeneity across studies. However, we reanalyzed an existing meta-analysis using available data in the all-cause mortality section. We performed random effects model meta-analyses of risk ratios using the DerSimonian and Laird model.28 The random effects model assigns a weight to each study that is based both on the individual study variance and the between-study heterogeneity. Compared with the fixed effect model, the random effects model is more conservative in that it results in broader confidence intervals when hen between-study heterogeneity is present. We tested for heterogeneity using Cochran’s Q (considered significant for P <0.10) and quantified its extent with I2 29,30. I2 ranges between 0 and 100% and quantifies the proportion of between-study variability that is attributed to heterogeneity rather than chance.

Intercooled Stata SE version 9.2 and Meta-Analyst version 3.2 (developed by Tufts EPC) were used for analyses. All P values are two tailed and considered significant when less than 0.05, unless otherwise indicated.

Grading of studies analyzed in this evidence report

Studies included as part of accepted in this report have been designed, conducted, analyzed, and reported with various degrees of methodological rigor and completeness. Deficiencies in any of these items may lead to biased reporting or interpretation of the results. While it is desirable to have a simple evidence grading system using a single quantity, the quality of evidence is multidimensional. A single metric cannot adequately capture information needed to interpret a study. Not withstanding these limitations, providing an indication of study quality adds an important dimension to the summary of published data.

We note that we did not grade the strength of evidence per outcome. Grading the strength of the evidence considers several dimensions beyond the methodological quality of the individual studies. These include but are not limited to consistency of studies, directness, precision, as well as judgments on whether conclusions are affected by systematic errors and biases.

Critical appraisal and grading of primary studies

Critical appraisal of the evidence is an important aspect of conducting a systematic review. For the assessment of interventional studies, the criteria were based on the CONSORT31 statement for reporting RCTs (a checklist with specifications for reporting important aspects of a trial). We primarily considered the methods used for randomization, allocation concealment, and blinding as well as the use of intention-to-treat analysis, the report of well-described valid primary outcomes, and the dropout rate.

For interventional studies with nonrandomized design, we used the report of eligibility criteria and assessed the adequacy of controlling for differences between compared groups in terms of baseline characteristics and prognostic factors. We also considered the reporting of

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

intention-to-treat analyses and crossovers when so designed, as well as important differential loss to followup between the compared groups or overall high loss to followup. The validity and the adequate description of outcomes and results were re also assessed.

For the assessment of prospective cohorts and nested case-control studies (crosssectional and retrospective case-control studies were excluded from this review), we developed a rating checklist specifically designed for nutritional epidemiology study based on some of the reporting items for cohort study in STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) checklist32 and the nutrition-specific items in our previous publication.33 Items assessed include: eligibility criteria and sampling of study population, blinding of exposure and outcome assessors, dietary assessment methodology (when applicable), assay methodology of biomarkers of intake (when applicable), clear reporting of comparisons in the study, statistical analyses, adequacy of controlling for baseline characteristics and prognostic factors (including confounders), clear reporting of outcome definitions, and prospective study design with preplanned hypotheses.

The quality assessment checklists for intervention or observational studies can be found in Appendix E. Additional considerations that were not included in the checklists are described later in this section.

In this report we adapted a three-category grading system of the AHRQ Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews. Note that a single study can receive different grades for different outcomes. This system defines a generic grading system that is applicable to each type of study design including interventional and observational studies:


A

Studies have the least bias and results are considered valid. These studies adhere mostly to the commonly held concepts of high quality including the following: a formal study design; clear description of the population, setting, interventions, and comparison groups; appropriate measurement of outcomes; appropriate statistical and analytic methods and reporting; no reporting errors; less than 20 percent dropout; clear reporting of dropouts; and no obvious bias. Studies must provide valid estimation of nutrient exposure, from dietary assessments and/or biomarkers with reasonable ranges of measurement errors, and justifications for approaches to control for confounding in their design and analyses.

B

Studies are susceptible to some bias, but not sufficient to invalidate the results. They do not meet all the criteria in category “A”, they have some deficiencies but none likely to cause major bias. The study may be missing information, making it difficult to assess limitations and potential problems.

C

Studies have significant bias that may invalidate the results. These studies have serious errors in design, analysis, or reporting; there are large amounts of missing information, or discrepancies in reporting.

If the initial assigned grade was equivocal, then the study received a second round of review by an independent reviewer, and the final grade was reached via consensus. Lastly, it should be noted that the qualitygrading system evaluates and grades the studies within their own design strata (i.e., RCTs, cohorts, nested case-control). It does not attempt to assess the comparative

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

validity of studies across different design strata. Thus, it is important to be cognizant of the study design when interpreting the methodological quality grade of a study.

Additional considerations of methodological quality of primary studies for the purpose of DRI decision making

Randomized controlled trials of all outcomes

The Tufts EPC debated about the quality assessment of RCTs. A consensus was reached to include additional considerations for RCTs to receive grade A. The general quality assessment of interventional studies as described earlier has been widely adopted for the purpose of grading high quality effectiveness trials (in contrast with a more standardized efficacy trial) which are most relevant to the actual use of supplements. Thus the crossover of interventions (i.e., contamination between supplementation and placebo groups) affects the applicability more than the methodological quality. However, it was the consensus among the Tufts EPC methodologists that the RCTs with contamination between supplementation and placebo groups cannot receive grade A because this issue affects the actual differences in the doses given to the subjects. Therefore it is particularly important when the trial results are used to guide decisions about DRI, as opposed to decisions about whether to actively recommend supplementation for an individual.

Observational studies of cancer outcomes

When cancer cases were identified based on cancer registries or questionnaire-based data, we perused whether the investigators verify the diagnoses independently (e.g., by use of medical records or pathological reports). An observational study of cancer outcomes cannot receive grade A if the cancer diagnoses were not verify independently. We also examined if the study adequately control for other risk factors for specific cancer. We used the suggested risk factors by National Cancer Institute (www.cancer.org). An observational study of cancer outcomes cannot receive grade A if important risk factors for the specific cancer were not fully controlled for in their analyses.

Critical appraisal of systematic reviews

We also critically appraised systematic reviews utilized in this report. However, a summary quality grade for systematic review is difficult to interpret. While it may be straight forward to assign a high quality grade to a rigorously carried out systematic review of high quality primary studies, a rigorously conducted systematic review finding only poor quality primary studies to summarize has uncertain value. Similarly, a poorly conducted systematic review of high quality studies may also result in be misleading conclusions. Therefore, to appreciate its validity, the various dimensions and nuances of the systematic review must be understood.

To help readers appreciate the methodological quality of a systematic review, we applied the AMSTAR checklist,26 a tool that was created for this purpose. This tool does not assign a composite grade. Instead, the items evaluated are made explicit for the reader. Another challenge in evaluating systematic reviews is that none of the existing systematic reviews were specifically conducted to be used for DRI development; therefore their “quality”, for the purpose of DRI development, is impossible to reliably define.

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

In addition to using AMSTAR, we made comments on special considerations, issues or limitations concerning design, conduct and analyses of the systematic review, and interpretability of the results for the purpose of DRI development.

Reporting of the evidence

Evidence tables

Evidence tables offer a detailed description of the primarys tudies we identified that address each of the key questions. These tables provide detailed information about the study design, patient characteristics, background diet, inclusion and exclusion criteria, interventions (or exposures), comparators used, and outcomes assessed in the study. A study, regardless of how many interventions (or exposures) or outcomes were reported, appears once in the evidence tables. Evidence tables are ordered alphabetically by the first author’s last name to allow for easy searching within the tables. Evidence tables are available electronically in Appendix C.

Summary tables

Summary tables were created to assist (qualitative) synthesis of primary studies of the same outcomes and life stage. If feasible, data were also grouped by sex. Typically, in each outcome section, we presented one summary table for the study characteristics of all included studies, followed by another summary table for study findings.

We created different summary tables for different exposures (i.e., vitamin D or calcium) and for different study designs (i.e., interventional or observational studies). Key study characteristics, such as population characteristics (i.e., health status, age and sex), vitamin D assay method and season in which blood was drawn, dietary assessment methods and whether the instrument was internally validated, patient or participant adherence, and study comparisons, were presented in the summary table for study characteristics. We reported daily vitamin D doses (IU/d) and/or elemental calcium doses (mg/d) in all summary tables.

For observational studies, we also list the confounders adjusted in either design (e.g., matching factors) or analyses. If any confounders or effect modifiers in each prespecified category (i.e., nutrients, demographics, anthropometry, medical conditions, ultraviolet exposure, and life styles) were controlled for, we marked “X” in the category. Otherwise, the category was left blank.

Graphical presentation of dose-response relationship

We present graphically the results of studies associating outcomes with categorical exposures (e.g., percentiles or other arbitrary categories of 25(OH)D concentration or of total calcium intake). The graphs complement the information mentioned in the tables and allow the reader to appreciate the direction of the estimated effects, even when the choice of the reference category is inconsistent across studies. The graphs do not readily convey the slope (strength) of the dose-response relationship between exposure and outcome, because the exposure categories are simply ranked and their spacing does not necessarily correspond to the actual values that they represent within study or across studies.

Grand summary tables (evidence map)

In the beginning of the Results section, we created a grand overview table. The table details how many studies reported an outcome of interest (either as a primary or nonprimary outcome) and also listed the total number of unique studies (including systematic reviews) as each study

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

may have provided data on more than one outcome. The number of primary studies included in each existing systematic review is also reported.

Units of measurement

In this report, we converted serum 25(OH)D concentrations as reported by various studies as different units (i.e., ng/mL, μg/dL, μg/L and ng/dL) to nmol/L. The conversion formula is 1 ng/mL = 2.5 nmol/L. To limit the variation in the reporting of vitamin D unit (e.g., nmol, IU, μg and mg), IU was chosen as the standard unit and all other units were converted using a standard formula. The conversion formula for micrograms is 1 μg = 40 IU.

Assay method

For 25(OH)D measurements, we present information on the assay used in our evidence tables, and summary tables describing individual studies. When reported, we also recorded details on the methodology or kit used (e.g., RIA–radioimmunoassay, RIA “DiaSorin”) used. Often, additional information was lacking. We did not perform any subgroup analyses based on the type of 25(OH)D assay used.

Sunlight exposure

We report information on country where the study took place and its latitude (when this was meaningful), and when available, the season when serum 25(OH)D concentrations were measured. A substantial amount of vitamin D is formed in the skin in humans. The amount of vitamin D synthesized in the skin depends on a person’s exposure to UV irradiation. Therefore, information on country’s latitude (and season of serum 25(OH)D measurements) informs on whether different populations are likely to have similar or different amount of endogenous vitamin D production. Latitudes were extracted directly from the published reports, or extrapolated from the city or country where the study took place (by searching Google for “<county/city> latitude”). For national or international studies that spanned a wide range of latitudes (e.g., NHANES), the latitude information was summarized simply as "various." To facilitate the reader, we also provide a Table with the latitudes of major cities in Central and North America (this table is found right after the Abbreviations table on page 316.

Primary and secondary outcomes

For intervention studies, we distinguished primary from secondary (or nonspecified) outcomes. Outcomes were considered primary only when they were clearly reported as such or when the outcome was used in an ad hoc sample size calculation. For observational studies we did not separate primary from secondary outcomes. For example, many observational studies are analyses of the same well known cohorts for several different outcomes. Each of these studies may have a different “primary” outcome.

Study quality

We summarize methodological and reporting quality of individual studies and meta-analyses. More details on the reporting characteristics of individual studies and systematic reviews are found in the evidence tables (Appendix C).

Organization of the Results Section

The Results section is organized in the following way:

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×
  • Nutrient (vitamin D | calcium | combined calcium and vitamin D)

    • Outcome (e.g., growth, cardiovascular diseases)

      • Synopsis

      • Detailed presentation (depending on availability of data)

        • Findings per calcium intake level / vitamin D concentration

        • Findings per age and sex

      • Findings by life stage

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Chapter 3.
Results

Literature search results

The original MEDLINE® and Cochrane Central database search for primary studies yielded 15,621 citations of generic health outcomes and 194 citations of adverse or safety outcomes. The update search for primary studies published between September, 2008 and April, 2009 yielded 918 citations. We identified 654 of these as potentially relevant and retrieved the full-text articles for further evaluation. Of these, 478 did not meet eligibility criteria (Appendix E); thus, a total of 165 primary study articles met the inclusion criteria and were included in this report (Figure 5). Of the 165 primary study articles, 60 were randomized controlled trials (RCTs), 3 were nonrandomized comparative studies, and 102 were observational studies (either cohort or nested case-control studies). The publication dates of the 165 primary study articles ranged from 1980 to 2009.

The MEDLINE®, Cochrane Database of Systemic Reviews, and the Health Technology Assessments database search for systematic reviews yielded 1746 citations. We identified 68 of these as potentially relevant and retrieved the full-text articles for further evaluation. Of these, 46 did not meet eligibility criteria. After examining the 22 qualifying systematic reviews, 11 were re excluded for various reasons (Appendix D; Figure 5).

The grand overview tables (Tables 1, 2, and 3) detailed how many studies reported an outcome (either as a primary or secondary outcome) that is of interest and also listed the total number of unique studies (including those from systematic reviews) as each study may have provided data for more than one outcome.

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Figure 5. Literature flow in this report

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Table 1. Number of primary studies on Vitamin D intake or concentration and specific health outcomes that could be applicable to certain life stages

Shaded cells indicate that either the eligibility criteria excluded outcomes in those life stages or the outcomes are not applicable to those life stages. Blank unshaded cells indicate no primary studies were identified in this report in those life stages.

A only RCTs were eligible for this outcome

B Relationship between maternal 25(OH)D concentration and a topic eczema in infants

C 1 study was a combined analysis of Nurses Health Study and Health Professionals Follow-up Study

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Table 2. Number of primary studies on calcium intake and specific health outcomes that could be applicable to certain life stages

Shaded cells indicate that either the eligibility criteria exclued outcomes in those life stages of the outcomes are not applicable to those life stages. Blank unshaded cells indicate no primary studies were identified in this life stages.

A Only RCTs were eligible for this outcome

B Association between total calcium intake in childhood and colorectal cancer after 65 years of followup

C 1 study was a combined analysis of Nurses Health Study and Health Professionals Follow-up Study

D 6 analyses, including 2 separate analyses of NHANES I

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Table 3. Number of primary studies on combined vitamin D and calcium intake and specific health outcomes that are relevant to certain life stages

Shaded cells indicate that either the eligibility criteria excluded outcomes in those life stages or the outcomes are not applicable to those life stages. Blank unshaded cells indicate no primary studies were identified in this report in those life stages.

A Only RCTs were eligible for this outcome

B Including the Women’s Health Initiative (WHI) trial

C A de novo reanalysis of the 10 RCTs in a previous systematic review and one newly added trial

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Vitamin D and health outcomes

Vitamin D and growth

We reviewed primary studies that evaluated relationships between vitamin D and growth parameters in infants and children.

Synopsis

Seven intervention studies and two observational studies evaluated intake or exposure to vitamin D and growth parameters in infants and children. Two intervention studies from the same center found a significant association of maternal vitamin D intakes with infant birth weights. Study methodologies were incompletely reported in these two studies. The rest of the studies did not find a significant association between either maternal or offspring vitamin D intake and offspring’s weight or height. No overall conclusions could be drawn as the studies reviewed had diverse populations and methodological approaches.

Detailed presentation (Tables 4, 5, 6 & 7)

Six RCTs34-40 and one nonrandomized comparative study41 in eight publications reported on the effect of vitamin D supplementation on growth parameters in infants and children. Two cohort studies reported on the association between maternal serum 25(OH)D concentration and her offspring’s growth parameters.42,43 The number of subjects in the RCTs ranged from 19 to 200. The two cohort studies had 374 and 466 subjects, respectively. The latitudes of the studies ranged from 38º to 51º. Four studies administered vitamin D exclusively to expectant mothers during the third trimester of pregnancy. One study administered vitamin D to both the lactating mothers and her offspring. Two studies administered vitamin D only to the infants or children. Followup ranged from delivery until 9 years. Methodological quality of two studies were rated B and seven studies were rated C. T he studies were limited by such factors as incomplete reporting and small sample sizes.

Infant 0 - 6 months; 7 months - 2 years; pregnant or lactating women

One RCT from UK administered vitamin D 1000 IU/d or placebo to 126 expectant mothers (first generation Asian immigrants) during the third trimester and found no significant difference between the infants’ birth weights or birth lengths and those of the control population.34,38 There were twice as many low birth weight infants (<2500 g) in the control group compared to the supplemented group (21.7% vs. 11.9%); however, this difference was not significant. A study from US supplemented 10 lactating mothers with vitamin D 400 IU/d and their infants with 300 IU/d for 6 months. Compared to the group where nine mothers received 6400 IU/d and their infants none, there was no significant difference in the infants’ weight or length at 1 month, 4 months, and 7 months of age.39 A study from China randomly assigned 255 newborn infants to 100, 200, or 400 IU/d of vitamin D for 6 months and reported no significant difference in weight or length among the three groups at 6 months of age.36 One study from India randomly selected 100 expectant mothers to receive a total of 1.2 million IU of vitamin D (600,000 IU of vitamin D2 in 7th and 8th month) during the third trimester. The newborns’ birth weight was significantly increased compared to those from 100 unsupplemented expectant mothers (difference 190 g).37 Important elements of the study methodology like randomization technique and any blinding of outcome assessors were not reported. An earlier nonrandomized comparison from the same study center involving smaller samples reported similar findings.41 The estimated baseline mean

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

dietary vitamin D intake in the expectant mothers from these two studies was less than 30 to 35 IU/d (the validity of these measures is unclear). An RCT from France supplemented 48 expectant mothers with either vitamin D 1000 IU/d in the third trimester or 200,000 IU one time dose at 7 month pregnancy and found no significant difference in the infants’ birth weights between the two methods.40 A cohort study from Australia analyzed the maternal serum 25(OH)D concentration in 374 women at 28-32 week gestation (geometric mean in winter 48 nmol/L; summer 69 nmol/L) and found no association with infant birth weight or length.43 One cohort study from UK analyzed the serum 25(OH)D concentration in 466 white women in late pregnancy (~33 wk) and found the concentrations (from <30 to >75 nmol/L) were not related to their offspring’s weight or height at birth, 9 months, and 9 years.42

9 - 18 years

One RCT of vitamin D3 (placebo, 200, or 2000 IU/d for 1 year) on girls in Lebanon aged 10-17 years found no significant difference at 1 year followup in weight or height among the 34 girls who were premenarchal at time of enrollment.35

Findings by life stage

  • 0 – 6 mo One RCT found that supplementing expectant mothers with vitamin D 1000 IU/d during the 3rd trimester has no effect on infant birth weight or length. Another RCT found that supplementing expectant mothers with a total of 1.2 million IU of vitamin D during the 3rd trimester effected a significant increase in birth weight (+190 g). Background diet is low in vitamin D in this study. A studycompared supplementing lactating mothers with vitamin D 400 IU/d and their infants 300 IU/d for 6 months with mothers supplemented with 6400 IU/d and their infants none, there was no significant difference in the infants’ weight or length at 1 month, 4 months, and 7 months of age. Another study compared supplementing newborn infants with 100, 200, or 400 IU/d of vitamin D for 6 months and reported no significant difference in weight or length at 6 months of age. An RCT supplemented expectant mothers with either vitamin D 1000 IU/d during the third trimester or 200,000 IU one time dose at 7 month pregnancy and found no significant difference in the infants’ birth weights between the two methods. A cohort study analyzed the maternal serum 25(OH)D concentration at 28-32 week gestation (geometric mean in winter 48 nmol/L; summer 69 nmol/L) and found no association with infant birth weight or length. Another cohort study found that serum 25(OH)D concentration (ranged from <30 to >75 nmol/L) in late pregnancy (~33 wk) was not related to the newborn’s weight or height at birth, 9 months, and 9 years.

  • 7 mo – 2 y A cohort study found that serum 25(OH)D concentration (ranged from <30 to >75 nmol/L) in late pregnancy (~33 wk) was not related to the newborn’s weight or height at birth, 9 months, and 9 years.

  • 3 – 8 y No study covered this life stage.

  • 9 – 18 y A cohort study found that serum 25(OH)D concentration (ranged from <30 to >75 nmol/L) in late pregnancy (~33 wk) was not related to the newborn’s weight or height at birth, 9 months, and 9 years. One RCT of vitamin D3 (placebo, 200, or 2000 IU/d for 1 year) on girls 10-17 years old found no significant difference at 1 year followup in weight or height among the girls who were premenarchal at time of enrollment.

  • 19 – 50 y Not reviewed

  • 51 – 70 y Not reviewed

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×
  • 71 y Not reviewed

  • Postmenopause Not reviewed

  • Pregnant & lactating women One RCT found that supplementing expectant mothers with vitamin D 1000 IU/d during the 3rd trimester has no effect on infant birth weight or length. Another RCT found that supplementing expectant mothers with a total of 1.2 million IU of vitamin D during the 3rd trimester effected a significant increase in birth weight (+190 g). Background diet is low in vitamin D in this study. A study compared supplementing lactating mothers with vitamin D 400 IU/d and their infants 300 IU/d for 6 months with mothers supplemented with 6400 IU/d and their infants none, there was no significant difference in the infants’ weight or length at 1 month, 4 months, and 7 months of age. An RCT supplemented expectant mothers with either vitamin D 1000 IU/d during the third trimester or 200,000 IU one time dose at 7 month pregnancy and found no significant difference in the infants’ birth weights between the two methods.

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Table 4. Vitamin D on growth outcome: Characteristics of interventional studies

Author Year

Study Name

Location (Latitude)

[PMID]

Population

Background Calcium Intake & Vitamin D Data

Comparisons

Compliance

Comments

RCTs

Maxwell 198138

Brooke 198034

UK (51ºN)

[6793058] [6989438]

• Health status

pregnancy

25(OH)D at 28-32 wk: 20.1 nmol/L

Vit D 1000 IU/d 3rd trimester only

nd

First generation Asian immigrants only

• Mean age (range/SD), y

nd

 

• Male (%)

0

Feliciano 199436

China (22ºN to 47ºN)

[8078115]

• Health status

healthy term

86% infant breastfed until 5-6 mo

Vit D 100 IU/d vs. 200 IU/d vs. 400 IU/d

nd

 

• Mean age (range/SD), y

newborn

 

 

• Male (%)

nd

 

 

 

El-Hajj 200635

Lebanon (33ºN)

[16278262]

• Health status

healthy

25(OH)D 35 nmol/L; dietary Ca 677 mg/d

Vit D3200 IU/d vs. 2000 IU/d vs. placebo × 1 y

98% in placebo; 98% in low dose; 97% in high dose

7.4 h sun exposure/wk

• Mean age (range/SD), y

13.2 (10-17)

 

 

• Male (%)

0

 

 

Wagner 200639

Charleston, US (32ºN)

[17661565]

• Health status

Fully lactating; <1 mo postpartum

Lactating mother’s dietary vit D 273 IU/d; dietary calcium intake: 1125 mg/d;

Mother Vit D3 400 IU/d + infant 300 IU/d vs. mother 6400 IU/d + infant 0 IU/d

80% in mothers; as low as 61% for infants

78% white; 11% black; 11% Hispanic

• Mean age (range/SD), y

29

 

• Male (%)

0

 

 

Marya 198837

India (28ºN)

[3243609]

• Health status

no pregnancy-related complications

Expectant mother’s dietary Vit D 35 IU/d; calcium 429 mg/d

Mother Vit D 1.2 mil IU (total; 600,000 IU vit D2 in 7th & 8th mo) vs. no supplement

nd

 

• Mean age (range/SD), y

24

 

 

• Male (%)

0

 

 

Mallet 198640

France (48º N)

[3755517]

• Health status

pregnancy

Ca intake 550 to 1000 mg/d in 55% of the subjects

Vit D 1000 IU/d vs. 200,000 IU 1× dose

nd

 

• Mean age (range/SD), y

newborn

 

• Male (%)

nd

 

 

 

Nonrandomized comparative study

Marya 198141

India (28ºN)

[7239350]

• Health status

no pregnancy-related complications

Expectant mother’s daily milk intake <500 mL; dietary Vit D <30 IU/d

Vit D 1200 IU/d + Ca 375 mg/d (3rd trimester) or Vit D 1.2 mil IU (total; 600,000 IU in 7th & 8th mo) or no supplement

nd

 

• Mean age (range/SD), y

nd

 

• Male (%)

0

 

 

 

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Table 5. Vitamin D and growth outcomes: Characteristics of cohort studies

Author Year

Study Name

Location (Latitude)

[PMID]

Population

Vitamin D Concentration

Comparisons

Confounders/Effect Modifiers Adjusted

Comments

Nutrients

Demograph

Anthrop

Medical

UV exposure

Lifestyle

Morley 200643

Australia (38ºS)

[16352684]

• Health status

singleton pregnancy; no disease

• Assay method

RIA

Length and weight in offspring stratified by mother’s 25(OH)D

 

X

X

 

X

X

99% white; excluded dark skin or women with concealing clothing

• Mean age (range/SD), y

29

 

 

 

 

 

 

 

 

 

• Male (%)

0

• Season blood drawn

winter & summer

 

 

 

 

 

 

 

Gale 200842

PAHSG

UK (50ºN)

[17311057]

• Health status

singleton pregnancy <17 wk

• Assay method

RIA

Length and weight in offspring stratified by mother’s 25(OH)D

 

X

 

 

X

 

White only

• Mean age (range/SD), y

26.3

 

• Male (%)

0

• Season blood drawn

nd

 

 

 

 

 

 

 

 

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Table 6. Vitamin D and growth outcomes: Results of RCTs

Author Year

Study Name

[PMID]

Life Stage

Outcome

1°/2°

Mean Followup

Interventions, Daily Dose

No. Analyzed

Unit

Baseline

Change (SD)

Change 95% CI

Net Diff

Net Diff 95% CI

P Btw

Study Quality

Maxwell 198138

Brooke 198034

[6793058]

[6989438]

Pregnant women & infant 0-6 mo (Asians)

Infant birth weight

until delivery

Vit D 1000 IU

59

g

NA

Final 3157

3037, 3277

Diff +123

−50, 296C

NS

B

 

 

Control

67

 

NA

3034

2909, 3159

 

 

 

Infant birth length

until delivery

Vit D 1000 IU

59

cm

NA

Final 49.7

49.6, 49.8

Diff +0.2

0.1, 0.3C

NS

 

 

 

Control

67

 

NA

49.5

49.4, 49.6

 

 

 

Feliciano 199436

[8078115]

0-6 mo

Weight gain born in spring, N. ChinaA

6 mo

Vit D 400 IU

12

g

nd

3745

2613, 4877

−463

926C

NS

C

 

 

 

Vit D 200 IU

13

 

nd

5296

4718, 5874

1088

96, 2080C

NS

 

 

 

Vit D 100 IU

17

 

nd

4208

3402, 5013

 

 

 

 

 

Length gain born in spring, N. China

6 mo

Vit D 400 IU

12

cm

nd

18.8

17.4, 20.2

−0.5

−2.7, 1.7C

NS

 

 

 

 

Vit D 200 IU

13

 

nd

19.0

18.1, 19.9

−0.3

−2.2, 1.6C

NS

 

 

 

 

Vit D 100 IU

15

 

nd

19.3

17.6, 21.0

 

 

 

El-Hajj 200635

[16278262]

9-18 y female, premenarche

Height

1 y

Vit D3 2000 IU

nd, ≤34 total

%

nd

5.6%

 

~1.8%

~0.6, 3.0

0.07

C

 

 

Vit D3 200 IU

 

nd

5.0%

 

~1.2%

−0.01, 2.4C

 

 

 

Placebo

 

nd

3.8%

 

 

 

 

 

 

Weight

1 y

Vit D3 2000 IU

nd, ≤34 total

%

nd

18.4%

 

~3.5%

~-1.3, 8.3C

0.25

 

 

 

 

Vit D3 200 IU

 

nd

15.3%

 

~0.4

−3.7, 4.5C 

 

 

 

 

 

Placebo

 

nd

14.9%

 

 

 

 

Wagner 200639

[17661565]

Lactating mothers & infant 0 - 6 mo; 7 mo - 2 y

Infant weightB

7 mo

Mother (400)

10

g

NA

Final 7600

7100, 8100

Diff -800

−2300, 700C

0.30

C

 

 

+infant (300)

 

 

 

 

 

 

 

 

 

 

Mother (6400)

9

 

NA

8400

7700, 9100

 

 

 

 

 

+infant (0)

 

 

 

 

 

 

 

 

 

Infant length

7 mo

Mother (400)

10

cm

NA

Final 65.5

64.4, 66.6

Diff −3.8

−7.8, 0.2C

0.06

 

 

 

 

+infant (300)

 

 

 

 

 

 

 

 

 

 

 

 

Mother (6400)

9

 

NA

69.3

67.4, 71.2

 

 

 

 

 

 

 

+infant (0)

 

 

 

 

 

 

 

 

Marya 198837

India

[3243609]

Pregnant women & infant 0-6 mo

Birth weight

Delivery

Vit D 1.2 mil

100

g

NA

Final 2990

2920, 3060

Diff +190

90, 290C

<0.001

C

 

 

IU total

 

 

 

 

 

 

 

 

 

 

No supplement

100

 

NA

2800

2730, 2870

 

 

 

 

 

Birth length

 

Vit D 1.2 mil

100

cm

NA

Final 50.06

49.7, 50.4

Diff +1.6

1.1, 2.1C

<0.001

 

 

 

 

IU total

 

 

 

 

 

 

 

 

 

 

 

 

No supplement

100

 

NA

48.45

48.1, 48.8

 

 

 

Marya 198141 [7239350]E

Pregnant women & infant 0-6 mo

Birth weight

Delivery

Vit D 1.2 mil

20

g

NA

Final 3140

2940, 3340

Diff +410

166, 654C

0.001

C

 

 

IU total

 

 

 

 

 

 

 

 

 

 

Vit D 1200 IU

25

g

NA

Final 2890

2760, 3020

Diff +160

0, 320C

0.05

 

 

 

+ 375 mg Ca (3rd trimester)

 

 

 

 

 

 

 

 

 

 

 

 

No supplement

75

 

NA

2730

2650, 2810

 

 

 

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author Year

Study Name [PMID]

Life Stage

Outcome

1°/2°

Mean Followup

Interventions, Daily Dose

No. Analyzed

Unit

Baseline

Change (SD)

Change 95% CI

Net Diff

Net Diff 95% Cl

P Btw

Study Quality

Mallet40 1986

France (48º N)

[3755517]

Pregnant women & infant 0-6 mo

Birth weight

delivery

Vit D 1000 IU

21D

g

NA

Final 3370 (80)

 

Diff +160

 

NS

C

 

 

 

 

Vit D 200,000 IU 1× dose

27D

 

NA

3210 (90)

 

 

 

 

 

A See Table 1 in original paper for complete results stratified by North vs. South China and birth in spring vs. fall

B See Table 3 in original paper for results on 1 mo and 4 mo

C Estimated from available data

D Estimated from number of mothers; number of infants not reported

E This is not an RCT; the supplemented groups were randomized, but not the control (non-supplemented group); data from comparisons between the supplemented groups not reported.

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Table 7. Vitamin D and growth outcomes: Results of cohort studies

Author Year

Study Name

PMID

Life Stage

Outcome (n/N; Incidence)

Followup Duration

Maternal 25(OH)D concentration, nmol/L

No. in Category

Final value

Final SD

P value

Study Quality

Morley 200643 Australia [16352684]

Pregnant women; infant 0-6 mo

Birth weight (N=374)

Delivery

<28 at 28-32 wk

27

3397 g

57

NS

B

 

 

≥28 at 28-32 wk

347

3555

52

 

 

Birth length (N=374)

Delivery

<28 at 28-32 wk

27

49.8 cm

2.7

NS

 

 

 

 

≥28 at 28-32 wk

347

50.4

2.4

 

Gale 200842 PAHSG, UK [17311057]

Pregnant women; infant 0-6 mo

Birth weight (N=466)

Delivery

<30 (Quartile)

nd

3.38 kg

0.46

0.25A

C

 

 

 

 

30-50

nd

3.40

0.56

 

 

 

 

50-75

nd

3.49

1.57

 

 

 

 

>75

nd

3.43

0.51

 

 

Weight at 9 mo (N=440)

9 mo

<30

nd

15.9

1.14

0.58

 

 

 

 

30-50

nd

15.8

1.26

 

 

 

 

50-75

nd

16.1

1.34

 

 

 

 

>75

nd

15.9

1.09

 

 

Weight at 9 y (N=178)

9 y

<30

nd

27.4 kg

1.19

0.10

 

 

 

 

30-50

nd

29.4

1.21

 

 

 

 

50-75

nd

30

1.20

 

 

 

 

>75

nd

29.3

1.19

 

Pregnant women; infant 0-6 mo

Birth length (N=466)

Delivery

<30

nd

50 cm

1.83

0.15

 

 

 

 

30-50

nd

50

2.29

 

 

 

 

50-75

nd

50.5

2.25

 

 

 

 

>75

nd

50.1

2.09

 

 

Length at 9 mo (N=440)

9 mo

<30

nd

71.2 cm

2.85

0.86

 

 

 

 

30-50

nd

71.4

2.60

 

 

 

 

50-75

nd

71.7

2.89

 

 

 

 

>75

nd

71.1

2.67

 

 

Height at 9 y (N=178)

9 y

<30

nd

129.6 cm

5.88

0.19

 

 

 

 

30-50

nd

131.5

6.66

 

 

 

 

50-75

nd

131.8

5.09

 

 

 

 

>75

nd

130.6

6.45

ANon-adjusted

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×
Vitamin D and cardiovascular disease

Synopsis

No qualified systematic reviews have evaluated the association between vitamin D intake or serum 25(OH)D concentrations and incidence of hypertension. One RCT of almost 2700 elderly British who received either vitamin D3 100,000 IU every 4 months or placebo for 5 years found no statistically significant difference in event rates for various cardiovascular outcomes, including total events and cardiovascular deaths. No effects were also found in subgroup analyses of men and women. Three cohort and one nested case-control studies have analyzed the association between serum 25(OH)D concentrations and cardiovascular outcomes (cardiovascular events, nonfatal myocardial infarction or fatal coronary heart disease, cardiovascular death, myocardial infarction, and stroke). Significant associations were found between progressively lower 25(OH)D concentration and progressively increased risk of cardiovascular events in two studies of people approximately 40 to 75 years old. No significant associations were found between serum 25(OH)D concentrations and cardiovascular death, myocardial infarction, or stroke in one studyeach.

Detailed presentation (Tables 8, 9, 10 & 11; Figure 6)
Total cardiovascular events

Total cardiovascular events were evaluated by an RCT,44 the Framingham Offspring Study (FOS),45 and a nested case-control study derived from the Health Professionals Follow-up Study (HPFS).46 The RCT found no significant effect of vitamin D; both cohort studies found significant negative associations between serum 25(OH)D concentrations and outcomes.

The RCT randomized almost 2700 elderly participants (65-85 years) from the general population in Ipswich, UK (52° N) to vitamin D3 100,000 IU every 4 months or placebo.44 After 5 years, 36 percent of the participants had a cardiac or cerebrovascular event, but there was no statistically significant difference between those taking vitamin D or placebo. Similar results were found in subgroups of men and women. The RCT was rated quality B primarily due to inadequate verification of outcomes.

The FOS cohort evaluated 1739 men and women with no history of cardiovascular disease and a mean age of 59 years (based on the standard deviation, with an approximate rage of 41 to 77 years).45 After 5.4 years, 6.9 percent had a cardiovascular event (including myocardial infarction, coronary insufficiency, angina, stroke, transient ischemic attack, claudication, and heart failure). Overall, the methodological quality of the study was A; though their secondary analysis of three categories of serum 25(OH)D concentrations (as opposed to two categories) was rated C due to incomplete reporting and lack of adjustment for important variables including season of blood draw. In their primary analysis, people with serum 25(OH)D concentrations less than 37.5 nmol/L were 70 percent more likely (P=0.02) to have a cardiovascular event. In their secondary analysis, those with 25(OH)D concentrations between 25 and 37.5 nmol/L were about 50 percent more likely (P=0.01) to have an event than those with higher concentrations. Furthermore, a multivariable analysis of continuous 25(OH)D concentrations suggested increased likelihoods of cardiovascular e vents in those with 25(OH)D concentrations below approximately 50 to 55 nmol/L.

In a nested case-control study of the HPFS, 454 men 40 to 75 years old with no cardiovascular history who had a nonfatal myocardial infarction or coronary heart disease death

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

over a 10 year period were matched with 1354 controls.46 The methodological quality of the analysis was A, although due to limitations on analyzable serum, the investigators had to use a case-control analysis instead of a complete analysis of all eligible men in the HPFS. Across four categories of men based on their serum 25(OH)D concentrations, lower concentrations were significantly associated with increased cardiovascular events (trend across categories P=0.02). Compared with men who had 25(OH)D concentrations above 75 nmol/L, those with 25(OH)D concentrations 56 to 75 nmol/L had an adjusted relative risk (RR) of 1.6 (95% CI 1.1, 2.3), those with 25(OH)D 37.5 to 56 nmol/L had an RR of 1.4 (95% CI 0.96, 2.1), and those with 25(OH)D below 37.5 nmol/L had an RR of 2.1 (95% CI 1.2, 3.5).

Cardiovascular death

The British RCT of vitamin D3 100,000 IU every 4 months versus placebo analyzed cardiovascular death as a primary outcome; 8 percent of the participants had cardiovascular deaths within 5 years.44 Fewer people taking vitamin D3 supplements had cardiovascular deaths (RR = 0.84), but this finding was not statistically significant (95% CI 0.65, 1.10). Similar results were found in subgroups of men and women.

An analysis of NHANES III (methodological quality C) evaluated cardiovascular death (due to hypertensive disease, ischemic heart disease, arrhythmia, heart failure, cerebrovascular disease, atherosclerosis or other disease of the arteries) in over 13,000 men and women regardless of baseline medical history.47 During almost 9 years of followup, 5.8 percent had a cardiovascular death. The analysis compared four categories of serum 25(OH)D concentrations ranging from less than 44.5 nmol/L to more than 80 nmol/L. No significant association was found between serum 25(OH)D concentration and cardiovascular death.

Ischemic heart disease

The RCT evaluated total ischemic heart disease.44 In this elderly British population, 17% had an ischemic heart disease event; no effect of vitamin D3 supplementation was found. Similar results were found in subgroups of men and women.

Ischemic heart disease death

The RCT evaluated total ischemic heart disease death as a primary outcome.44 In the trial, 3.4% had an ischemic heart disease event; no effect of vitamin D3 supplementation was found (RR = 0.84 [95% CI 0.56, 1.27]). Similar results were found in subgroups of men and women.

Myocardial infarction

In one small analysis, 755 elderly (age 65 to 99 years) Finnish men and women, regardless of cardiovascular history, were evaluated on the basis of myocardial infarction (methodological quality C due to lack of reporting of relevant data including information on the serum 25(OH)D or 1,25(OH)2D concentrations within the tertiles).48

During 10 years of followup, 17 percent of the participants had a myocardial infarction. Both analyses of serum 25(OH)D and 1,25(OH)2D concentrations found no significant association with risk of myocardial infarction.

Stroke

The RCT evaluated total cerebrovascular disease.44 In this elderly British population, 7.7% had a cerebrovascular event; no effect of vitamin D3 supplementation was found. Similar results were found in subgroups of men and women.

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Stroke was evaluated in the same small Finnish study. During 10 years of followup, 9.3 percent of the participants had a stroke. Both analyses of serum 25(OH)D and 1,25(OH)2D concentrations found no significant association with th risk of stroke.

Cerebrovascular death

The RCT evaluated cerebrovascular disease death as a primary outcome.44 In the trial, 2.0% had a fatal stroke; no effect of vitamin D3 supplementation was found. Similar results were found in subgroups of men and women.

Findings per vitamin D concentration

The RCT compared vitamin D3 supplementation 100,000 IU every 4 months with placebo, but found no effect on cardiovascular outcomes. Two cohort studies found a significant association between higher serum 25(OH)D concentrations and lower risk of combined cardiovascular events. Both found that those people in the highest 25(OH)D category analyzed within each study had the lowest risk. The FOS used a maximum threshold of 37.5 nmol/L; the HPFS used a maximum threshold of 75 nmol/L. The FOS provided a graphic representation of a multivariable regression of continuous 25(OH)D concentrations (Figure 2 in the study).45 The risk of cardiovascular events rose below 37 to 50 nmol/L serum 25(OH)D concentration. The Finnish cohort did not report the range of serum 25(OH)D and 1,25(OH)2D concentrations.48

Findings per age and sex

The single RCT included elderly people from the general population. No effects on various cardiovascular events were found. Subgroup analyses of men and women yielded similar findings. The four cohort studies included adults across the full age range. Three of the cohorts included about half men and women; one included only men. None evaluated potential differences in associations based on age or sex, but no differences were evident across studies.

Findings by life stage

  • 0 – 6 mo Not reviewed

  • 7 mo – 2 y Not reviewed

  • 3 – 8 y Not reviewed

  • 9 – 18 y Not reviewed

  • 19 – 50 y For cardiovascular events, only a minority of evaluated participants were within this life stage (almost all above 40 years). The NHANES III study, which found no association between serum 25(OH)D concentration and cardiovascular death, included largely people within this life stage.

  • 51 – 70 y The majority of people investigated for the association between serum 25(OH)D concentration and cardiovascular events were within this life stage. Significant negative associations were found between lower serum 25(OH)D concentrations and cardiovascular events, across a range of 25(OH)D concentrations. The NHANES III study likely included many people within this life stage; no association was found with cardiovascular death.

  • 71 y The majority of participants in the British RCT included men and women within this age group. Vitamin D supplementation was not found to have an effect on cardiovascular outcomes. Among the cohort studies, only the small Finnish study adequately evaluated people within this life stage. No significant associations were found between serum 25(OH)D or 1,25(OH)2D concentrations and either myocardial infarction or stroke, however, the absolute concentrations were not reported.

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×
  • Postmenopause Only the RCT provided data on a subgroup that included only postmenopausal women. No effect of vitamin D3 supplementation was found.

  • Pregnant & lactating women Not reviewed

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Table 8. Vitamin D and cardiovascular outcomes: Characteristics of RCTs

Author Year

Study Name

Location (Latitude)

[PMID]

Population

Background Calcium Intake & Vitamin D Data

Comparisons

Compliance

Comments

Trivedi 20044

Ipswich, UK (52°N)

[12609940]

• Health status

General population

742 mg/day (at 4 years, no difference by treatment allocation)

Vit D3 100,000 IU vs placebo every 4 months

76% with at least 80% compliance; 66% at last dose (80% if excluding deaths)

 

• Mean age (range), y

75(65-85)

 

 

• Male (%)

76%

 

 

 

 

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Table 9. Vitamin D and cardiovascular outcomes: Results of RCTs

Author Year

Study Name

[PMID]

Age Range, Sex (Subgp)

Outcome

1°/2°

Mean Followup

Interventions, Daily Dose

n Event

N Total

Outcome Metric (Comparison)

Result

95% CI

P Btw

Study Quality

Trivedi 20044 [12609940]

65-85 y, Both

CVD, total

5 y

Vit D3 100,000 IU every 4 mo

477

1345

Age adj RR (Vit D/Placebo)

0.90A

0.77, 1.06

0.22

B

 

 

 

 

 

Placebo

503

1341

 

 

 

 

 

 

IHD, total

 

Vit D3

224

1345

Age adj RR (Vit D/Placebo)

0.94A

0.77, 1.15

0.57

 

 

 

 

 

Placebo

233

1341

 

 

 

 

 

 

CeVD, total

 

Vit D3

105

1345

Age adj RR (Vit D/Placebo)

1.02A

0.77, 1.36

0.87

 

 

 

 

 

Placebo

101

1341

 

 

 

 

 

 

CVD death

 

Vit D3

101

1345

Age adj RR (Vit D/Placebo)

0.84A

0.65, 1.10

0.20

 

 

 

 

 

Placebo

117

1341

 

 

 

 

 

 

IHD death

 

Vit D3

42

1345

Age adj RR (Vit D/Placebo)

0.84A

0.56, 1.27

0.41

 

 

 

 

 

Placebo

49

1341

 

 

 

 

 

 

CeVD death

 

Vit D3

28

1345

Age adj RR (Vit D/Placebo)

1.04A

0.61, 1.20

0.89

 

 

 

 

 

Placebo

26

1341

 

 

 

 

A Similar results for subgroups of men and women

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Table 10. Vitamin D and cardiovascular outcomes: Characteristics of cohort studies

Author Year

Study Name

Location (Latitude)

[PMID]

Population

Vitamin D Concentration

Comparisons

Confounders/Effect Modifiers Adjusted

Specific CVD Outcomes

Nutrients

Demograph

Anthrop

Medical

UV exposure

Lifestyle

Wang 200845

Framingham Offspring

Framingham, MA (mostly) (42°N)

[18180395]

• Health status

No CVD

• Assay method

RIA (DiaSorin)

Outcome stratified by 2 or 3 categories

XA

X

X

X

XA

X

CVD event

• Mean age (SD), y

59 (9)

 

 

 

 

 

 

 

 

 

• Male (%)

45

• Season blood drawn

All

 

 

 

 

 

 

 

 

Giovannucci 200846

HPFS

US (various)

[18541825]

• Health status

No CVD

• Dietary assessment method

RIA (Hollis 1993)

Outcome stratified by 4 categoriesB

X

X

X

X

X

X

Nonfatal MI or fatal CHD

• Mean age (range), y

64 (40-75)

 

 

 

 

 

 

 

 

 

 

• Male (%)

100

• Internal validation? (y/n)

All

 

 

 

 

 

 

 

 

Melamed 200847

NHANES III

US (various)

[18695076]

• Health status

Any

• Assay method

RIA (DiaSorin)

Outcome stratified by 4 categories

X

X

X

X

X

X

CVD death

• Mean age (range), y

45 (≥20)

 

 

 

 

 

 

 

 

 

 

• Male (%)

46

• Season blood drawn

All (even distribution)

 

 

 

 

 

 

 

 

Marniemi 200548

Turku, Finland (60°N)

[15955467]

• Health status

Any

• Assay method

RIA (Incstar)

Outcome stratified by tertiles

 

X

 

 

 

X

MI Stroke

• Mean age (range), y

79 (65-99)

 

 

 

 

 

 

 

 

 

 

• Male (%)

48

• Season blood drawn

All

 

 

 

 

 

 

 

 

A Not in 3-category analysis

B Case-control study

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Table 11. Vitamin D and cardiovascular outcomes: Results of cohort studies

Author Year

Study Name

[PMID]

Age Range, Sex

Outcome (n/N; Incidence)

Followup Duration (Time to Dx)

Vit D Measure

Concentration, nmol/L

No. of Cases

No. in Category

Adjusted OR

95% CI

P for Trend

Study Quality

CVD Events

Both Sexes

Wang 200845

Framingham Offspring

[18180395]

Mean (SD) 59 (9), Both

CVD event (120/1739; 0.069)

5.4 y

25(OH)D

<37.5

50

481

1.70

1.08, 2.67*

0.02A

A

 

 

 

≥37.5

70

1258

1

Reference

 

 

 

 

 

 

 

<25

nd

nd

1.80

1.05, 3.08*

0.01

C

 

 

 

 

 

25-37.5

nd

nd

1.53

1.00, 2.36*

 

 

 

 

 

 

 

≥37.5

70

1258

1

Reference

 

 

Men

Giovannucci 200846

HPFS

[18541825]

40-75 y, Men

Nonfatal MI or fatal CHD (454 cases; 1354 controls)

10 y

25(OH)D

≤37.5

63

150

2.09

1.24, 3.54

0.02BC

A

 

 

 

 

37.5-56.25

156

463

1.43

0.96, 2.13

 

 

 

 

 

 

 

56.25-75

165

464

1.60

1.10, 2.32

 

 

 

 

 

 

 

>75

70

277

1

Reference

 

 

CVD Death

Both Sexes

Melamed 200847

NHANES III

[18695076]

≥20 y, Both

CVD death (777/13,331; 0.058)

8.7 y

25(OH)D

<44.5

nd

nd

1.20

0.87, 1.64

nd

C

 

 

 

 

 

44.5-60.75

nd

nd

0.88

0.69, 1.14

 

 

 

 

 

 

 

60.75-80.25

nd

nd

0.83

0.65, 1.07

 

 

 

 

 

 

 

>80.25

nd

nd

1

Reference

 

 

Myocardial Infarction

Both Sexes

Marniemi 200548

[15955467]

65-99 y, Both

MI (130/755; 0.172)

10 y

25(OH)D

nd

nd

~252

1

Reference

nd

C

 

 

 

 

nd

nd

~252

0.99

0.64, 1.53

 

 

 

 

 

 

 

nd

nd

~252

0.77

0.47, 1.27

 

 

 

 

 

 

1,25(OH)2D

nd

nd

~252

1

Reference

nd

 

 

 

 

 

 

nd

nd

~252

1.05

0.68, 1.62

 

 

 

 

 

 

 

nd

nd

~252

0.82

0.52, 1.30

 

 

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author Year

Study Name

[PMID]

Age Range, Sex

Outcome (n/N; Incidence)

Followup Duration (Time to Dx)

Vit D Measure

Concentration, nmol/L

No. of Cases

No. in Category

Adjusted OR

95% CI

P for Trend

Study Quality

Stroke

Both Sexes

Marniemi 200548

[15955467]

65-99 y, Both

Stroke (70/755; 0.093)

10 y

25(OH)D

nd

nd

~252

1

Reference

nd

C

 

 

 

 

nd

nd

~252

1.13

0.62, 2.05

 

 

 

 

 

 

 

nd

nd

~252

1.00

0.51, 1.94

 

 

 

 

 

 

1,25(OH)2D

nd

nd

~252

1

Reference

nd

 

 

 

 

 

 

nd

nd

~252

0.63

0.37, 1.09

 

 

 

 

 

 

 

nd

nd

~252

0.41

0.22, 0.77*

 

 

* Statistically significant (P<0.05)

A Multivariable Cox regression with continuous 25(OH)D and regression splines with nonlinear relationships suggests an increased hazard of CVD events at serum 25(OH)D concentrations below approximately 50-55 nmol/L. See Figure 2 on page 508 of article.

B Adjusted regression analyses found OR=0.98 (0.96, 0.998) per 2.5 nmol/L increase in 25(OH)D and risk reduction of −2.1% (−0.2%, −4.0%) per 2.5 nmol/L increase in serum 25(OH)D concentration.

C In a subgroup analysis of participants on no cholesterol lowering drugs at baseline, comparing the highest serum 25(OH)D concentration category (>75 nmol/L) to the lowest (37.5 nmol/L), adjusted RR=2.30 (1.33, 3.97)

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Figure 6. Cardiovascular outcomes risk stratified by vitamin D concentration

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×
Vitamin D and body weight

Synopsis

No qualified systematic reviews have evaluated the association between vitamin D intake or serum 25(OH)D concentrations and body weight in adults. No cohort studies evaluated serum vitamin D concentrations and weight changes. Three RCTs from Finland, Norway, and India compared different doses of vitamin D (300 IU daily, 20,000 or 40,000 IU weekly, or 120,000 IU every 2 weeks) to placebo, with or without supplemental calcium in both groups. The study participants also varied: they were postmenopausal women, obese men and women, or only obese men. In the Finnish and Norwegian studies, the participants on average, gained weight in all groups over 1 or 3 years; in the Indian study weight remained mostly stable over 6 weeks. All studies found no difference in weight change with or without vitamin D supplementation.

Detailed presentation (Tables 12 & 13)

Three RCTs of vitamin D reported body weight (or body mass index [BMI]) as an outcome. The Kuopio (Finland) Osteoporosis Risk Factor and Prevention Study (Kuopio ORFPS) included postmenopausal women in a four-arm study.49 Two of the study arms included hormone replacement treatment and are not further discussed here. The remaining two arms compared vitamin D3 300 IU (83 women) versus placebo (95 women), where all women were taking low dose calcium lactate 500 mg/d (equivalent to 93 mg Ca++/d). Women on cholesterol-lowering medication at anypoint during the trial were excluded. The primary outcome of the trial was the serum lipid profile. The women ranged in age from 47 to 56 years. After 3 years, women, on average, gained weight in both study arms (about 1-2 kg). Those in the placebo arm gained an absolute 1.5 percent more weight than those in the vitamin D arm, but the difference was not statistically significant. The study had a methodological quality of C due to an uneven distribution of body weights between study arms at baseline (means 71.5 and 67.6 kg) and an overall withdrawal r ate of over 30 percent.

The second trial was conducted in Norway among healthy overweight and obese women and men.50 The participants’ mean baseline serum 25(OH)D concentration was 53 nmol/L. The trial compared vitamin D2 40,000 IU weekly (116 participants completed), 20,000 IU weekly (106 participants), and placebo (112 participants). All study participants also took calcium carbonate 500 mg daily. Almost all participants complied with the vitamin D (or placebo). Changes in weight and BMI were primary outcomes. The participants ranged in age from 21 to 70 years. After 1 year, changes in weight were small (increases of 0.1-0.5 kg) in each trial group. Compared to the placebo group, those taking the larger dose of vitamin D had less weight gain than those taking the smaller dose, but none of the differences among study groups were statistically significant. The study was rated methodological quality B, primarily due to the high dropout rate (25 percent), which was not explained.

The third trial was conducted in New Delhi, India among healthy obese men.51 The participants’ mean baseline serum 25(OH)D concentration was about 33 nmol/L. The trial compared vitamin D3 120,000 given under supervised conditions every 2 weeks and placebo in 100 men, of whom 71 were analyzed; most dropouts occurred because of refusals for subsequent blood draws (to assess the primary outcome). After 6 weeks, weight in kg and BMI were essentially stable, with no difference in weight change between the interventions. The study was rated methodological quality B because of the high dropout rate; for weight (in kg), the study was of quality C because baseline weights were not reported.

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Findings per vitamin D dose

There was a lack of effect found across a range of doses from 300 IU to 8570 IU (prorated) daily.

Findings per age and sex

There was a lack of effect found in studies both of men mostly in their 40s, somewhat older people of both sexes, and postmenopausal women.

Findings by life stage

  • 0 – 6 mo Not reviewed

  • 7 mo – 2 y Not reviewed

  • 3 – 8 y Not reviewed

  • 9 – 18 y Not reviewed

  • 19 – 50 y No effect was found in one trial of men mostly within this life stage after 6 weeks.

  • 51 – 70 y The majority of people in the trials were within this life stage. No significant effect was found on weight from vitamin D supplementation for 1or 3 years.

  • 71 y No data

  • Postmenopause All the women in the Finnish trial were postmenopausal.

  • Pregnant & lactating women Not reviewed

Table 12. Vitamin D and weight: Characteristics of RCTs

Author Year

Study Name

Location (Latitude)

[PMID]

Population

Background Calcium Intake & Vitamin D Data

Comparisons

Compliance

Comments

Heikkinen 199749

Kuopio ORFPS Kuopio, Finland (63°N)

[9405029]

• Health status

All, post-menopause

nd

Vit D3 & Ca lactate vs Placebo & Ca lactate

nd

 

• Mean age (range), y

53 (47-56)

 

 

 

• Male (%)

0

 

 

 

 

Sneve 200850

Tromsø, Norway (70°N)

[19056900]

• Health status

Healthy overweight and obese

25(OH)D 53.1±16.9 nmol/L Ca intake 940±398 mg/d

Vit D3 40,000 IU per week vs Vit D3 20,000 IU per week vs Placebo All: Ca carbonate 500 mg/d

The compliance rate for cholecalciferol/placebo capsules were 95% in all 3 groups, and for the calcium tablets 81-85% across all 3 groups.

 

• Mean age (range), y

48 (21-70)

 

 

• Male (%)

36

 

 

 

Nagpal 200951

New Delhi, India (28.5°N)

[19125756]

• Health status

Healthy, obese

25(OH)D: 36.5 nmol/L (treatment group), 30.0 nmol/L (control group)

Vit D3 120,000 IU every 2 weeks vs Placebo

100% (implied); supervised home visits

Excluded subjects who refused subsequent blood draws

• Mean age (SD), y

44 (8)

 

• Male (%)

100%

 

 

 

 

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Table 13. Vitamin D and weight: Results of RCTs

Author Year

Study Name

[PMID]

Age Range, Sex (Subgp)

Outcome

1°/2°

Mean Followup

Interventions, Daily Dose

No. Analyzed

Unit

Baseline

Change

Change 95% CI

Net Diff

Net Diff 95% CI

P Btw

Study Quality

Isocaloric Diet

Heikkinen 199749

Kuopio ORFPS

[9405029]

47-56 y, Women

Weight

3 y

Vit D3 300 IU + Ca lactate 93 mg

83

kg

71.5

+1.84%

+0.43%, +3.25%

−1.5%

−3.6%, +0.6%A

NSB

C

Ca lactate 93 mg

95

 

67.6

+3.32%

+1.73%, 4.91%

 

 

 

Sneve 200850

[19056900]

21-70 y, Both

Weight

1 y

Vit D3 40,000 IU weekly+ Ca carbonate 500 mg

116

kg

101.0

+0.1

−0.6, +0.8

−0.4

−1.3, +0.5A

NS

B

Vit D3 20,000 IU weekly + Ca carbonate 500 mg

106

 

98.6

+0.3

−0.3, +0.9

−0.2

−1.1, +0.7A

NS

Ca carbonate 500 mg

112

 

100.6

+0.5

-0.2, +1.2

 

 

 

BMI

1 y

Vit D3 40,000 IU weekly + Ca carbonate 500 mg

116

BMI

35.0

0.0

−0.2, +0.2

−0.2

−0.6, +0.2A

NS

Vit D3 20,000 IU weekly + Ca carbonate 500 mg

106

 

34.4

+0.1

−0.1, +0.3

−0.1

−0.4, +0.2A

NS

Ca carbonate 500 mg

112

 

35.1

+0.2

−0.1, +0.5

 

 

 

Nagpal 200951

New Delhi, India

[19125756]

44 (8, SD) Men

Weight

6 wk

Vit D3 120,000 IU every 2 wk

35

kg

nd

+0.03

−0.6, +0.6

+0.42

−0.4, +1.2

NS

C

Placebo

36

 

nd

−0.38

−0.9, +0.2

 

 

 

BMI

6 wk

Vit D3 120,000 IU every 2 wk

35

BMI

26.7

−0.02

−0.2, +0.2

+0.02

−0.3, +0.3

NS

B

Placebo

36

 

26.0

−0.04

−0.3, +0.2

 

A Estimated from reported data

B Per estimated 95% confidence interval, P=0.17

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×
Vitamin D and cancer
Cancer from all causes and total cancer mortality

Synopsis

No qualified systematic reviews have evaluated relationships between vitamin D and total cancer incidence or mortality. One RCT showed no effect of combined vitamin D3 (1000 IU/d) and calcium (~1500 mg/d) supplementation versus calcium supplementation (~1500 mg/d) alone on the risk of total cancer in healthy postmenopausal women (>55 years old) living in Nebraska (latitude 41°N). Another RCT also found no difference in total cancer mortality or incidence between supplemental vitamin D3 (100,000 IU every 4 months) and placebo in elderly (71+ years old) men and women living in the United Kingdom (latitude 52° N). Both RCTs were rated B quality.

Analyses using NHANES III data (general adult populations living in the US) showed no significant association between baseline 25(OH)D concentrations and total cancer mortality.

Detailed presentation (Tables 14, 15, 16 & 17)

A 4-year population-based RCT,52 sampled from a 9 county, largely rural area in eastern Nebraska (latitude 41°N), aimed to determine the efficacy of vitamin D3 (1000 IU/d) plus calcium (either calcium citrate 1400 mg/d or calcium carbonate 1500 mg/d) or calcium alone (either calcium citrate 1400 mg/d or calcium carbonate 1500 mg/d) compared to placebo in reducing fracture incident. Only the comparison between the combined vitamin D and calcium versus the calcium alone groups is discussed here. The other comparisons are described in the calcium and combined vitamin D and calcium sections. This study was rated methodological quality B. Incidence of cancer was a secondary outcome of this trial. A total of 1179 postmenopausal women, aged more than 55 years old, were randomized. The mean 25(OH)D concentration at baseline was 72 nmol/L. The relative risk of developing cancer at the end of study was 0.76 (95% CI: 0.38, 1.55). On the hypothesis that cancers diagnosed early in the study would have been present, although unrecognized on entry, the analyses were restricted to women who were free of cancer at 1 year intervention. The relative risk of developing cancer at the end of study for the vitamin D3 plus calcium group changed to 0.55 (95% CI 0.24, 1.28).

Another 5-year RCT compared the effects of supplemental vitamin D3 (100,000 IU every 4 months) with placebo on total cancer mortality and incidence in 2686 elderly participants with a mean age of 75 years in the United Kingdom (latitude 52° N).44 Total cancer mortality and incidence were evaluated as two of multiple secondary endpoints. The primary endpoint was the prevention of fracture. At 5 years vitamin D3 supplementation had no significant effect on the prevention of total cancer mortality (HR 0.86; 95% CI 0.61, 1.20) or incidence (HR 1.09; 95% CI 0.86, 1.36). This trial was rated B because it did not report in sufficient detail the randomization method, and the outcome ascertainment was based on death certificates or self-reported data, not verified with another objective documents (e.g., medical records or pathology reports).

Reported in two publications (one was rated B and one was rated C), there was no association between baseline 25(OH)D concentrations and total cancer mortality in the total NHANES III study population47,53 or in subgroup analyses by either season or latitude after a median 9 years of followup.53

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Findings by age, sex and/or ethnicity

There were no differences in the total cancer mortality and incidence between men and women, reported in a 5-year RCT compared the effects of supplemental vitamin D3 (100,000 IU every 4 months) with placebo. In the NHANES III analysis, there was a suggestion of increased risk of total cancer mortality in men whose baseline 25(OH)D were in the two highest categories (80 to <100 nmol/L; ≥100 nmol/L) compared to the reference category (<50 nmol/L) [80 to <100 nmol/L: RR = 1.21, 95% CI 0.83 to 1.78; ≥100 nmol/L: RR = 1.35; 95% CI 0.78 to 2.31; P for trend=0.08]. However, this relationship was not seen in women (P for trend=0.12).53 When racial/ethnic groups were considered separately, there was also no association between baseline 25(OH)D concentrations and total cancer mortality in non-Hispanic whites (P for trend=0.80), non-Hispanic blacks (P for trend=0.14), or Mexican Americans (P for trend=0.37).

Findings Findings by life stage

  • 0 – 6 mo No data

  • 7 mo – 2 y No data

  • 3 – 8 y No data

  • 9 – 18 y No data

  • 19 – 50 y Analyses using NAHANES III data showed no significant association between baseline 25(OH)D concentrations and total cancer mortality. NHANES III included participants mostly within this life stage.

  • 51 – 70 y A proportion of participants in NHANES III were in this life stage, but no unique conclusions are possible for this life stage separate from those for people 19 to 50 years.

  • 71 y One RCT included elderly men and women mostly in this life stage. Thetrial found no difference in total cancer mortality or incidence between supplemental vitamin D3 (100,000 IU every 4 months) and placebo.

  • Postmenopause One RCT with healthy postmenopausal women showed no effect of vitamin D3 supplementation (1000 IU/d) on the risk of total cancer.

  • Pregnant & lactating women No Data

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Table 14. Vitamin D and total cancer: Characteristics of RCTs

Author Year

Study Name

Location (Latitude)

[PMID]

Population

Background Calcium Intake & Vitamin D Data

Comparisons

Compliance

Comments

Lappe 200752

Nebraska, US (41º N)

[17556697]

• Health status

Mentally and physically fit; postmenopause

25(OH)D: 71.8 nmol/L

Vit D3 1000 IU/d + Ca (citrate 1400 mg/d or carbonate 1500 mg/d) vs. Ca (citrate 1400 mg/d or carbonate 1500 mg/d) vs. placebo

nd

 

• Mean age (SD), y

67 (7.3)

 

 

 

 

• Male (%)

0

 

 

 

 

Trivedi 200344

Oxford, UK (52°N)

[12609940]

• Health status

General population

25(OH)D: 53.4 nmol/L

Vit D3 100,000 IU vs placebo every 4 months

Participants taking 80% of study medication: 76%A

Previous CVD: 28%, previous cancer: 6%, steroids user: 5%, and HRT taker: 7%.

• Mean age (range), y

75 (65-85)

Calcium intake= 742 mg/d (at 4 years, no difference by treatment allocation)

 

 

• Male (%)

76%

 

 

 

A No difference between the vitamin D and the placebo arm.

Table 15. Vitamin D and total cancer: Characteristics of cohort studies

Author Year

Study Name

Location (Latitude)

[PMID]

Population

Vitamin D Concentration

Comparisons

Confounders/Effect Modifiers Adjusted

Comments

Nutrients

Demograph

Anthrop

Medical

UV exposure

Lifestyle

Cohort

Freedman 200753

NHANES III

US (various)

[16481636]

• Health status

Any

• Assay method

RIA (DiaSorin)

Cancer mortality stratified by prespecified baseline 25(OH)D cut points

X

X

X

X

X

X

Final model includes sex, race/ethnicity, and smoking pattern. Other potential confounders were examined but not chosen.

• Mean age (range), y

44 (≥17)

 

 

 

 

 

 

 

 

 

• Male (%)

45

• Season blood drawn

All

 

 

 

 

 

 

Melamed 200847

NHANES III

US (various)

[18695076]

• Health status

DM 7.4%, history of CVD 7.9%, HTN 25%

• Assay method

RIA (DiaSorin)

Cancer mortality stratified by baseline 25(OH)D quartiles

X

X

X

X

X

X

 

 

• Mean age (range), y

45 (≥20)

 

 

 

 

 

 

 

 

 

 

 

• Male (%)

46

• Season blood drawn

All

 

 

 

 

 

 

 

 

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Table 16. Vitamin D and total cancer: Results of RCTs

Author Year

Study Name

Location (Latitude)

[PMID]

Life Stage

Outcome

1°/2°

Followup, y

Interventions, Daily Dose

n Event

N Total

Outcome Metric (Comparison)

Result

95% CI

P Btw

Study Quality

Lappe 200752

Postmenopausal women

Incident cancer (all causes)

4

Vit D3 1000 IU + Ca (citrate 1400 mg or carbonate 1500 mg)

13

446

RR (Vit D+Ca vs Ca)

0.76

0.38, 1.55

NS

B

Nebraska, US (41º N)

[17556697]

 

 

 

 

Ca (citrate 1400 mg or carbonate 1500 mg)

17

445

 

 

 

 

 

Postmenopausal women

Incident cancer restricted to subjects who were free of cancer at 1 y intervention)

4

Vit D3 1000 IU + Ca (citrate 1400 mg or carbonate 1500 mg)

8

403

RR (Vit D+Ca vs Ca)

0.55

0.24, 1.28

NS

B

 

 

 

 

Ca (citrate 1400 mg or carbonate 1500 mg)

15

416

 

 

 

 

Trivedi 200344

[12609940]

65-85 y, Both sexes

Incident cancer (all causes)

5

Vit D3 100,000 IU every 4 mo (~833 IU/d)

188

1345

HR (Vit D vs placebo)

1.09

0.86,

1.36

NS

B

 

 

 

 

 

Placebo

173

1341

 

 

 

 

 

 

Total cancer mortality

5

Vit D3 100,000 IU every 4 mo (~833 IU/d)

63

1345

HR (Vit D vs placebo)

0.86

0.61, 1.2

NS

 

 

 

 

 

 

Placebo

72

1341

 

 

 

 

 

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Table 17. Vitamin D and total cancer: Results of cohort studies

Author Year

Study Name

[PMID]

Life Stage

Outcome (n/N; Incidence)

Followup Duration (Time to Dx)

25(OH)D, nmol/L

No. of Cases

No. in Category

Adjusted HR

95% CI

P for Trend

Study Quality

Freedman 200753

NHANES III US

[16481636]

Adults, both sexes

Cancer mortality (536/16818; 0.032)

105 mo

<50

175

5744

1

Reference

0.65

B

 

 

 

 

50 to <62.5

103

3143

1.22

0.91, 1.64

 

 

 

 

 

 

62.5 to <80

117

3713

1.02

0.69, 1.50

 

 

 

 

 

 

80 to <100

80

4218 (total, ≥80 nmol/L)

1.00

0.71, 1.40

 

 

 

 

 

 

100 to <120

41

 

0.92

0.58, 1.46

 

 

 

 

 

 

120

20

 

1.49

0.85, 2.64

 

 

 

Adults, males

Cancer mortality (318/7632; 0.042)

105 mo

<50

88

1993

1

Reference

0.08

 

 

 

 

 

50 to <62.5

57

1461

1.03

0.73, 1.44

 

 

 

 

 

 

62.5 to <80

71

1845

0.99

0.57, 1.74

 

 

 

 

 

 

80 to <100

58

2333 (total, ≥80 nmol/L)

1.21

0.83, 1.78

 

 

 

 

 

 

≥100

44

 

1.35

0.78, 2.31

 

 

 

Adults, females

Cancer mortality (218/9163; 0.024)

105 mo

<50

87

3751

1

Reference

0.12

 

 

 

 

 

50 to <62.5

46

1682

1.40

0.94, 2.08

 

 

 

 

 

 

62.5 to <80

46

1845

1.02

0.62, 1.67

 

 

 

 

 

 

80 to <100

22

1885 (total, ≥80 nmol/L)

0.72

0.40, 1.26

 

 

 

 

 

 

≥100

17

 

0.78

0.40, 1.53

 

 

Melamed 200847

NHANES III

US (various)

[18695076]

Adults, both sexes

Cancer mortality (N=13331)

Median 8.7 (IQR 7.1-10.2) y

>80

nd

nd

1

Reference

nd

C

 

 

 

 

61-80

nd

nd

0.8

0.54, 1.19

 

 

 

 

 

 

44-60

nd

nd

1.08

0.8, 1.46

 

 

 

 

 

 

<44

nd

nd

0.91

0.63, 1.31

 

 

* Statistically significant (P<0.05)

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×
Prostate cancer

Synopsis

No qualified systematic reviews have evaluated the association between serum vitamin D concentrations and incidence of prostate cancer. Eight nested case-control studies (2B, 6C) found no association between baseline serum 25(OH)D concentrations and the risk of prostate cancer. One study rated C found a significant association between lower baseline serum 25(OH)D concentrations (<30 compared to >55 nmol/L) and higher risk of prostate cancer (adjusted OR 1.8, lowest compared to highest quartile). The same study found that the prostate cancer risk was increased in subjects less than 52 years at study entry and who had serum 25(OH)D concentration less than 40 nmol/L (adjusted OR 3.5). However, there was no difference in risk between low and high serum 25(OH)D concentration for those older than 51 years at study entry. A C study suggested an U-shaped association between baseline serum 25(OH)D concentrations and the risk of prostate cancer.

Detailed presentation (Tables 18 & 19; Figure 7)

A total of 12 nested case-control studies in 14 publications reported on the association between baseline serum 25(OH)D concentrations and the risk of prostate cancer.53-66 The number of cases ranged from 61 to 749. The latitudes of the studies ranged from 21º N to 60º N. The mean age of the subjects ranged from 44 to 68 years. Baseline serum concentrations of 25(OH)D in these studies ranged from 12.8 to 194 nmol/L. The time between blood drawn and the diagnosis of prostate cancer varied from 2 to 16 years. The methodological quality of three studies was rated B and nine studies were rated C.

19-50 years

Two studies provided data on younger subjects. Ahonen et al. analyzed subjects from 40 to 57 years of age.55 The study found that the prostate cancer risk was increased in subjects less than 52 years at study entry and had low serum 25(OH)D concentration (≤40 nmol/L) (adjusted OR 3.5, 95% CI 1.7, 7.0). The corresponding adjusted OR for those older than 51 years at study entrywas 1.2 and was not significant. This study adjusted for factors related to insulin resistance syndrome but not those potentially related to prostate cancer.

Freedman et al. analyzed data from NHANES III and reported on subjects with a mean age of 44 years and found that the adjusted relative risk of mortality from prostate cancer was 0.91 (95% CI 0.39, 2.14) in the group with baseline serum 25(OH)D concentration of at least 62.5 nmol/L compared to the group with less than 62.5 nmol/L.53

51-70 years

Ten studies reported data on subjects with a mean age ranged from 51 to 68 years. Eight studies did not find an association by trend analysis between baseline serum 25(OH)D concentrations and the risk of prostate cancer.54,56-63,66 One study found no association between baseline serum 25(OH)D concentrations and mortality from prostate cancer.58 One study found an association between lower baseline serum 25(OH)D concentrations (<30 compared to >55 nmol/L) and the risk of prostate cancer (P for trend = 0.01).55 The adjusted OR of the lowest compared to highest quartile was 1.8. The study also found that the prostate cancer risk was increased in subjects less than 52 years at study entry and had low serum 25(OH)D concentration (≤40 nmol/L) (adjusted OR 3.5, 95% CI 1.7, 7.0). However, there was no difference in risk (adjusted OR 1.2, P=NS) between low (≤40 nmol/L) and high (>40 nmol/L) serum 25(OH)D

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

concentration for those older than 51 years at study entry. This study did not adjust for factors potentially relevant to prostate cancer. One study reported an U-shaped association between baseline serum 25(OH)D concentrations and the risk of prostate cancer: the odds ratio in the group with 25(OH)D concentration of at least 80 nmol/L was 1.7 (95% CI 1.1, 2.4) compared to the group with a 25(OH)D concentration of 40-49 nmol/L; the odds ratio in the group with 25(OH)D concentration of no more than 19 nmol/L was 1.5 (95% CI 0.8, 2.7) compared to the group with a 25(OH)D concentration of 40 to 49 nmol/L.64 Even though this study used a conditional logistic regression in its analysis to maintain matching status, it was unclear if additional factors potentially relevant to prostate cancer were also entered into the regression analysis.

1,25(OH)2D

Five studies reported on the association between 1,25(OH)2D serum concentrations and the risk of prostate cancer. Four studies did not find an association.59,62,63,66 One study found that the risk of prostate cancer decreased with higher serum concentrations of 1,25(OH)2D in men with low serum concentrations of 25(OH)D (unadjusted OR 0.15, comparing 4th quartile of 1,25(OH)2D (104-211 pmol/L) to 1st quartile (13-68 pmol/L) in men with serum 25(OH)D concentrations that ranged from 7.5-45 nmol/L).58 When stratified by age and race, this association was only found in men above the median age of 57 years at time of blood drawn but not in younger men; the association was similar in black and white men.

Findings by life stage

  • 0 – 6 mo not applicable

  • 7 mo – 2 y not applicable

  • 3 – 8 y not applicable

  • 9 – 18 y not reviewed

  • 19 – 50 y One study found that the prostate cancer risk was highest in subjects less than 52 years at study entry and had low serum 25(OH)D concentration (≤40 nmol/L) (adjusted OR 3.5, 95% CI 1.7, 7.0). Another study analyzed data from NHANES III and reported on subjects with a mean age of 44 years and found that the adjusted relative risk of mortality from prostate cancer was 0.91 (95% CI 0.39, 2.14) in the group with baseline serum 25(OH)D concentration of at least 62.5 nmol/L compared to the group with less than 62.5 nmol/L.

  • 51 – 70 y Eight studies did not find an association by P for trend analysis between baseline serum 25(OH)D concentrations and the risk of prostate cancer. One study found an inverse association of baseline serum 25(OH)D concentrations (<30 compared to >55 nmol/L) and the risk of prostate cancer (adjusted OR 1.8, lowest compared to highest quartile, P for trend = 0.01). This study found that the prostate cancer risk was increased in subjects less than 52 years at studyentryand had low serum 25(OH)D concentration (≤40 nmol/L) (adjusted OR 3.5, 95% CI 1.7, 7.0). However, there was no difference in risk (adjusted OR 1.2, P=NS) between low (≤40 nmol/L) and high (>40 nmol/L) serum 25(OH)D concentration for those older than 51 years at studyentry. One studyreported an U-shaped association between baseline serum 25(OH)D concentrations and the risk of prostate cancer: the odds ratio in the group with 25(OH)D concentration of at least 80 nmol/L was 1.7 (95% CI 1.1, 2.4) compared to the group with a 25(OH)D concentration of 40-49 nmol/L; the odds ratio in the group with 25(OH)D concentration of no more

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

than 19 nmol/L was 1.5 (95% CI 0.8, 2.7) compared to the group with a 25(OH)D concentration of 40 to 49 nmol/L.

  • 71 y No study specifically targeted men older than 70 years.

  • Postmenopause Not applicable

  • Pregnant & lactating women Not applicable

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Table 18. Vitamin D and prostate cancer: Characteristics of nested case-control studies

Author Year

Study Name

Location (Latitude)

[PMID]

Population

25(OH)D

Comparisons

Confounders/Effect Modifiers Adjusted

Comments

Nutrients

Demographic

Anthrop

Medical

UV exposure

Life styles

Ahn 200854

PLCO

US (21ºN to 44ºN)

[18505967]

Health status

8% current smoker

Assay

RIA (Heartland)

Prostate cancer risk stratified baseline 25(OH)D quintiles

X

 

X

X

 

X

 

Mean age range/SD), y

67.8 (5.3)

 

 

 

 

 

 

 

 

 

Male (%)

100

Season blood drawn

nd

 

 

 

 

 

 

 

Platz 200463

Mikhak 200761

HPFS US (multiple latitudes)

[15090720]

[17440943]

Health status

Smoked 18%; DM 3.6%

Assay

RIA

Prostate cancer risk stratified by baseline 25(OH)D quartiles

X

X

X

X

X

X

6% nonwhite

Mean age range/SD), y

66 (7)

 

 

 

 

 

 

 

 

 

Male (%)

100

Season blood drawn

nd

 

 

 

 

 

 

 

Freedman 200753

NHANES III US (multiple latitudes)

[17971526]

Health status

28% current smoker

Assay

RIA

Prostate cancer mortality stratified by 2 baseline 25(OH)D categories

X

X

X

X

X

X

71% white; 14% black; 6% Hispanics

Mean age range/SD), y

44

 

 

 

 

 

 

 

 

Male (%)

100

Season blood drawn

South: Nov to Mar; North: Apr to Oct

 

 

 

 

 

 

 

Tuohimaa 200464

Helsinki Heart Vasterbotten; Janus Project;

Finland (60°N)

[14618623]

Health status

Gemfibrozil vs. placebo subjects

Assay

RIA (Incstar)

Prostate cancer risk stratified by 5 baseline 25(OH)D categories

 

X

 

 

X

 

 

Mean age range/SD), y

<40 to >60

 

 

 

 

 

 

 

 

 

Male (%)

100

Season blood drawn

nd

 

 

 

 

 

 

 

Li 200760

Gann 199666

PHS US (multiple latitudes)

[17388667]

[8850273]

Health status

on ASA, β-carotene, placebo trial; 9% current smoker

Assay

RIA (Bruce Hollis)

Prostate cancer risk stratified by baseline 25(OH)D quartiles

 

X

 

 

X

94% white

Mean age (range/SD), y

58.9 (8.3)

 

 

 

 

 

 

 

 

 

 

Male (%)

100

Season blood drawn

24% spring winter

 

 

 

 

 

 

 

Corder 199358

San Francisco US (37ºN)

[8220092]

Health status

nd

Assay

Competitive protein-binding (Hadded, 1971)

Prostate cancer risk compared by baseline 25(OH)D

 

X

 

 

X

 

50% black; 50% white

Mean age range/SD), y

57 (38-81)

 

 

 

 

 

 

 

 

 

Male (%)

100

Season blood drawn

nd

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author Year

Study Name

Location (Latitude)

[PMID]

Population

25(OH)D

Comparisons

Confounders/Effect Modifiers Adjusted

Comments

Nutrients

Demographic

Anthrop

Medical

UV exposure

Life styles

Ahonen 200055

Helsinki Heart

Finland (60°N)

[11075874]

Health status

Gemfibrozil vs. placebo subjects

Assay

RIA (Incstar)

Prostate cancer risk stratified baseline 25(OH)D quartiles

 

X

X

X

X

X

 

Mean age range/SD), y

40-57

 

 

 

 

 

 

 

 

 

Male (%)

100

Season blood drawn

Jan-Feb; Mar-May; Sep

 

 

 

 

 

 

 

Nomura 199862

Honolulu Heart US (21ºN)

[9794175]

Health status

64% smoked

Assay

Protein-binding

Prostate cancer risk stratified baseline 25(OH)D quartiles

 

X

 

 

X

X

100% Japanese Americans

Mean age range/SD), y

58 (49-70)

 

 

 

 

 

 

 

 

Male (%)

100

Season blood drawn

nd

 

 

 

 

 

 

 

Tuohimaa 200765

Helsinki Heart

Finland (60°N)

17301263

Health status

Gemfibrozil vs. placebo subjects

Assay

RIA (Incstar)

Prostate cancer risk stratified 3 baseline 25(OH)D categories

 

X

X

X

 

 

 

Mean age range/SD), y

51 (3.7)

 

 

 

 

 

 

 

 

 

Male (%)

100

Season blood drawn

Most in winter

 

 

 

 

 

 

 

Jacobs 200459

NPC Eastern US (25º46’N to 41ºN)

[15225833]

Health status

Selenium vs. placebo subjectsA

Assay

RIA

Prostate cancer risk stratified baseline 25(OH)D tertiles

 

X

X

X

X

X

100% white

Mean age range/SD), y

68 (nd)

 

 

 

 

 

 

 

 

 

Male (%)

100

Season blood drawn

nd

 

 

 

 

 

 

 

Braun 199557

WCC, MD

US (39°N)

[7612803]

Health status

nd

Assay

RIA (Bruce Hollis, 1993)

Prostate cancer risk stratified baseline 25(OH)D quintiles

 

X

 

 

 

 

 

Mean age (range/SD), y

<45-75+

 

 

 

 

 

 

 

 

 

Male (%)

100

Season blood drawn

Aug through Nov

 

 

 

 

 

 

 

Baron 200556

CPP US (multiple latitudes)

[15767334]B

Health status

had >1 colon adenoma removal

Assay

Competitive protein-binding (Quest)

Prostate cancer risk stratified baseline 25(OH)D tertiles

X

X

 

 

X

 

5% black

Mean age range/SD),

62 (8.7)

 

 

 

 

 

 

 

 

 

 

Male (%)

100

Season blood drawn

nd

 

 

 

 

 

 

 

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author Year

Study Name

Location (Latitude)

[PMID]

Population

25(OH)D

Comparisons

Confounders/Effect Modifiers Adjusted

Comments

Nutrients

Demographic

Anthrop

Medical

UV exposure

Life styles

Braun 199557

WCC, MD

US (39°N)

[7612803]

Health status

nd

Assay

RIA (Bruce Hollis, 1993)

Prostate cancer risk stratified by baseline 25(OH)D quintiles

 

X

 

 

 

 

100% white

Mean age (range/SD), y

<45-75+

 

 

 

 

 

 

 

 

 

Male (%)

100

Season blood drawn

Aug through Nov

 

 

 

 

 

 

 

Baron 200556

CPP

US (multiple latitudes)

[15767334]B

Health status

had >1 colon adenoma removal

Assay

Competitive protein-binding (Quest)

Prostate cancer risk stratified by baseline 25(OH)D tertiles

X

X

 

 

X

 

5% black

Mean age (range/SD), y

62 (8.7)

 

 

 

 

 

 

 

 

 

 

Male (%)

100

Season blood drawn

nd

 

 

 

 

 

 

 

A For prevention of recurrence of non-melanoma skin cancer

B This is a cohort study, not a nested case-control study.

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Table 19. Vitamin D and prostate cancer: Results of nested case-control studies

Author Year

Study Name

PMID

Life Stage (male), y

Outcome (no. of cases; no. of control)

Time to diagnosis, y

25(OH)D concentration, nmol/L

No. of cases

No. of control

Adjusted OR

95% CI

P for trend

Study Quality

Ahn 200854

PLCO

[8505967]

51-70

Prostate cancer (741; 781)

2-8

12.8-42.5

119

157

1

Reference

0.20

B

 

 

 

42.5-51.

125

156

1.10

0.78, 1.56

 

 

 

 

 

51.4-60.5

190

157

1.53

1.10, 2.13*

 

 

 

 

 

 

60.6-71.7

167

156

1.33

0.95, 1.86

 

 

 

 

 

 

71.8-129.5

148

155

1.18

0.83, 1.68

 

 

Platz 200463

Mikhak 200761 HPFS

[15090720]

[17440943]

51-70

Prostate cancer (460; 460)

2.2 (mean)

Quartile 1A

109

114

1

Reference

0.59

B

 

 

 

Quartile 2

115

113

1.00

0.67, 1.49

 

 

 

 

 

Quartile 3

94

120

0.77

0.51, 1.15

 

 

 

 

 

Quartile 4

142

113

1.19

0.79, 1.79

 

 

Freedman 200753

NHANES III

[17971526]

19-50

Mortality prostate cancer

nd

<62.5

22

nd

1

Reference

0.95

B

 

 

 

≥62.5

25

nd

0.91

0.39, 2.14

 

 

Tuohimaa 200464 Helsinki

Heart [14618623]

19-50

51-70

Prostate cancer (622; 1451)

≤9 ->14 (range)

≤19

19

nd

1.5

0.8, 2.7

 

C

 

 

 

20-39

169

nd

1.3

0.98, 1.6

 

 

 

 

 

40-59

229

nd

1

Reference

 

 

 

 

 

 

60-79

138

nd

1.2

0.9, 1.5

 

 

 

 

 

 

≥80

67

nd

1.7

1.1, 2.4*

 

 

Li 200760

PHS

[17388667]

19-50

51-70

Prostate cancer (492; 664)

11 (median)

Quartile 1B

nd

nd

1.01

0.71, 1.44

0.91

C

 

 

 

Quartile 2

nd

nd

1.26

0.89, 1.80

 

 

 

 

 

 

Quartile 3

nd

nd

1.00

0.71, 1.41

 

 

 

 

 

 

Quartile 4

nd

nd

1

Reference

 

 

Gann 199666 PHS

[8850273]

19-50

51-70

Prostate cancer (232; 414)

6 (mean)

15.7-53.3

nd

nd

1.00

nd

0.82

C

 

 

 

53.4-70.9

nd

nd

1.10

nd

 

 

 

 

 

 

71-93.5

nd

nd

1.16

nd

 

 

 

 

 

 

93.6-194

nd

nd

0.92

0.56, 1.50

 

 

 

Prostate cancer; age ≤61 y

 

15.7-53.3

nd

nd

1.00

nd

 nd

 

 

 

 

 

53.4-70.9

nd

nd

1.19

nd

 

 

 

 

 

 

71-93.5

nd

nd

1.75

nd

 

 

 

 

 

 

93.6-194

nd

nd

1.48

0.73, 2.98

 

 

 

Prostate cancer; age >61 y

 

15.7-53.3

nd

nd

1.00

nd

nd

 

 

 

 

 

53.4-70.9

nd

nd

1.00

nd

 

 

 

 

 

 

71-93.5

nd

nd

0.82

nd

 

 

 

 

 

 

93.6-194

nd

nd

0.76

0.39, 1.47

 

 

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author Year

Study Name

PMID

Life Stage (male), y

Outcome (no. of cases; no. of control)

Time to diagnosis, y

25(OH)D concentration, nmol/L

No. of cases

No. of control

Adjusted OR

95% CI

P for trend

Study Quality

Corder 199358

[8220092]

19-50

51-70

Prostate cancer (181; 181)

>5 (mode)

60.0 (case) vs. 50.5 (control) (est.)

181

181

-

-

-

C

 

Mortality prostate cancer

 

nd

51

nd

-

-

-

 

Ahonen 200055

Helsinki Heart

[11075874]

19-50

51-70

Prostate cancer (149; 566)

8-14 (mode)

< 30C

48

131

1.8

1.0, 3.2*

0.01

C

 

 

 

31-40

41

143

1.4

0.8, 2.4

 

 

 

 

 

 

41-54

26

148

0.8

0.5, 1.5

 

 

 

 

 

 

> 55

34

144

1

Reference

 

 

 

 

Prostate cancer in those <52 years old at entry

 

≤40

nd

nd

3.5

1.7, 7.0*

 

 

 

 

 

 

>40

nd

nd

1

 

 

 

 

Prostate cancer in those >51 years old at entry

 

≤40

nd

nd

1.2

0.7, 2.1

 

 

 

 

>40

nd

nd

1

 

 

Nomura 199862

Honolulu Heart

[9794175]

19-50

51-70

Prostate cancer (136; 136)

16 (mean)

<85D

38

34

1

Reference

0.68

C

 

 

 

85-101

35

36

0.8

0.4, 1.8

 

 

 

 

 

102-119

30

32

0.8

0.4, 1.7

 

 

 

 

 

≥120

33

34

0.8

0.4, 1.8

 

 

Tuohimaa 200765 Helsinki

Heart [17301263]

19-50

51-70

Prostate cancer (132; 456)

10.8 (mean)

<40

-

-

1.88

1.15, 3.08*

 

C

 

 

 

40-59

-

-

1

Reference

 

 

 

≥60

-

-

1.25

0.64, 2.43

 

 

Jacobs 200459

NPC

[15225833]

51-70

Prostate cancer (83; 166)

5.1 (mean)

20-63.3

26

58

1

Reference

0.51

C

 

 

 

63.4-81.9

33

49

1.71

0.68, 4.34

 

 

 

82-149

24

59

0.75

0.29, 1.91

 

 

Braun 199557 WCC

[7612803]

19-50

51-70

Prostate cancer (61; 122)

14 (mean)

<60.1

7

24

1

Reference

0.60

C

 

 

 

60.1-73.8

17

25

2.3

0.7, 7.8

 

 

 

 

 

 

73.9-88.5

16

24

2.3

0.7, 7.7

 

 

 

 

 

 

88.6-103

4

25

0.6

0.1, 2.5

 

 

 

 

>103

17

24

2.4E

0.8, 8.2

 

 

Baron 200556

CPP

[15767334]F

19-50

51-70

Prostate cancer (70 cases in a total of 672)F

<4 (34%)

<62.9

nd

NA

1

Reference

0.70

C

 

 

 

62.9-84.9

nd

NA

1.22

0.66, 2.26

 

 

 

 

 

 

85

nd

NA

0.32

0.72, 2.43

 

 

*Statistically significant (P<0.05)

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

A Cut points separated by analytical run; season, distributions among control (see Table 3 in original study

B Cut points based on control standardized by season of collection

C Cut points based on total original cohort

D Cut points based on control frequency

E Unadjusted

F This is a cohort study, not a nested case-control study

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Figure 7. Prostate cancer risk stratified by vitamin D concentration

Figure 7. Prostate cancer risk stratified by vitamin D concentration
Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×
Colorectal cancer

Synopsis

No qualified systematic reviews have evaluated the association between 25(OH)D concentrations and colorectal cancer mortality or incidence. One B quality RCT of elderly population reported no significant difference in colorectal cancer mortality or incidence between supplemental vitamin D3 and no supplements. One B quality cohort study found an inverse association between higher 25(OH)D concentrations and the risk of colorectal cancer mortality (HR 0.28, highest compared to lowest tertile). Two B quality nested case-control studies of women found a trend between higher 25(OH)D serum concentrations and lower risk of colorectal cancer incidence (trend analysis). Another two B quality nested case-control studies of men, and one B quality and two C quality nested case-control studies of both sexes reported no significant association between 25(OH)D concentrations and risk of colorectal cancer or colon cancer.

Detailed presentation of supplemental vitamin D and colorectal caner (Tables 20 & 21)

An RCT compared supplemental vitamin D3 (100,000 IU every 4 months) with placebo in 2686 elderly participants with a mean age of 75 years in the United Kingdom (latitude 52° N).44 Colorectal cancer mortality and incidence were evaluated as two of multiple secondary endpoints. The primary endpoint was the prevention of fracture. At 5 years vitamin D3 supplementation had no significant effect on the prevention of colorectal cancer mortality (P=0.33) or incidence (P=0.94). This trial was rated B because it did not report in sufficient detail the randomization method, and the outcome ascertainment was based on death certificates or self-reported data, not verified with another objective documents (e.g., medical records or pathology reports).

Findings per age and sex

The same British trial reported no significant difference in colorectal caner mortality or incidence between the vitamin D supplements group and the placebo at 5 years in men (P=0.96 and 0.59, respectively). In women, the trial also found no significant difference in colorectal cancer incidence between the two groups (P=0.32), whereas the risk of colorectal cancer mortality in the supplements group was significantly decreased compared to the placebo (0/326 deaths vs. 4/323 deaths; HR, not reported; P=0.04).

Findings per special populations

No subgroup data were available regarding special populations (e.g., obese participants, smokers, ethnic groups, or users of contraceptives).

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Table 20. Vitamin D and colorectal cancer: Characteristics of RCTs

Author Year

Study Name

Location (Latitude)

[PMID]

Population

Background Calcium Intake & Vitamin D Data

Comparisons

Compliance

Comments

Trivedi 200344

Oxford, UK (52°N)

[12609940]

• Health status

General population

25(OH)D: 53.4 nmol/L

Vit D3 100,000 IU vs placebo every 4 months

Participants taking ≥80% of study medication: 76%A

Previous CVD: 28%, previous cancer: 6%, steroids user: 5%, and HRT taker: 7%.

• Mean age (range), y

75 (65-85)

Calcium intake= 742 mg/day (at 4 years, no difference by treatment allocation)

 

• Male (%)

76%

 

 

 

CVD = cardiovascular disease; HRT = hormone replacement therapy.

A No difference between the vitamin D and the placebo arm.

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Table 21. Vitamin D and colorectal cancer: Results of RCTs

Author Year

Study Name

[PMID]

Age Range, Sex (Subgp)

Outcome

1°/2°

Mean Followup

Interventions, Daily Dose

n Event

N Total

Outcome Metric (Comparison)

Result

95% CI

P Btw

Study Quality

Trivedi 200344

[12609940]

65-85 y, Both sexes

CRC, mortality

5 y

Vit D3 100,000 IU every 4 mo

7

1345

Age adj HR (Vit D/Placebo)

0.62

0.24, 1.60

0.33

B

 

 

 

 

 

Placebo

11

1341

 

 

 

 

 

 

 

CRC, incidence

 

Vit D3

28

1345

Age adj HR (Vit D/Placebo)

1.02

0.60, 1.74

0.94

 

 

 

 

 

 

Placebo

27

1341

 

 

 

 

 

 

65-85 y, Men

CRC, mortality

5 y

Vit D3

7

1019

Age adj HR (Vit D/Placebo)

0.97

0.34, 2.78

0.96

 

 

 

 

 

 

Placebo

7

1018

 

 

 

 

 

 

 

CRC, incidence

 

Vit D3

25

1019

Age adj HR (Vit D/Placebo)

1.18

0.65, 2.12

0.59

 

 

 

 

 

 

Placebo

21

1018

 

 

 

 

 

 

65-85 y, Women

CRC, mortality

5 y

Vit D3

0

326

Age adj HR (Vit D/Placebo)

NA

NA

0.04

 

 

 

 

 

 

Placebo

4

323

 

 

 

 

 

 

 

CRC, incidence

 

Vit D3

3

326

Age adj HR (Vit D/Placebo)

0.49

0.12, 1.98

0.32

 

 

 

 

 

 

Placebo

6

323

 

 

 

 

 

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Detailed presentation of 25(OH)D concentrations and colorectal cancer (Tables 22 & 23; Figures 8, 9, & 10)

A total of seven nested case-control studies evaluated the associations between 25(OH)D concentrations and risk of colorectal cancer67-71 or colon cancer.72,73 The number of pairs of cases and controls in these studies ranged from 101 to 588. Another cohort study comprising 16,818 adult community volunteers from the NHANES III53 assessed the association between 25(OH)D concentrations and colorectal cancer mortality. The mean age of the subjects ranged from 44 to 66 years. Locations of the studies ranged from 20° N to 60° N. Baseline 25(OH)D concentrations ranged from 10 nmol/L to 227.5 nmol/L. No studies reported followup 25(OH)D concentrations. Time between blood drawn and the diagnosis of colorectal cancer incidence or mortality ranged from less than 1 year to 17 years. None of the studies reported power calculations. Methodological quality of five nested case-control studies67-71 were rated B and two were rated C.72,73 Common reasons for downgrading the quality ratings included exclusion of participants without available blood samples, no verification of cancer diagnosis, and lack of adequate statistical adjustments. The cohort study53 was rated B because it was unclear whether cases were verified and there was no statistical adjustment for family history.

Findings per age and sex

The NHANES III53 analyzed data for both sexes combined. An adjusted analysis found an inverse association between 25(OH)D concentrations and the risk of colorectal cancer mortality (HR: 0.28, highest [≥80 nmol/L] compared to lowest tertile [<50 nmol/L]; P for trend = 0.02). Two studies from WCC reported colon cancer incidence for both sexes combined.72,73 One study reported a significantly lower 25(OH)D concentrations in colon cancer cases than controls (58.9 nmol/L vs. 86.6 nmol/L; P<0.001).73 Both studies reported no significant association between 25(OH)D concentrations and colon cancer risk by trend analysis.

Three studies, from the Japan PHC, HPFS, and ATBC respectively, provided data on adult men.67-69 None of the studies found an association between 25(OH)D concentrations and colorectal cancer risk. Although all three studies provided data on colon cancer and rectal cancer as subgroup analysis, only HPFS reported a significant negative trend between 25(OH)D concentrations and risk of colon cancer (OR 0.46, highest [median 97.0 nmol/L] compared to lowest quartile [median 48.3 nmol/L]; P for trend = 0.005).69 The HPFS also reported a subgroup analysis on men aged 65 years or older.69 No significant association was reported between 25(OH)D concentrations and colorectal cancer risk by trend analysis.

The Japan PHC and HPFS compared 25(OH)D concentrations between colorectal cancer cases and controls.68,69 Neither reported a significant difference. One study explored subgroup analyses. Only the rectal cancer cases had significantly lower 25(OH)D concentrations compared to the controls (55 nmol/L for cases vs. 110 nmol/L for controls; P = 0.005).68

Two nested case-control studies from the NHS and Japan PHC provided data on adult women.68,70 The NHS reported a negative trend between 25(OH)D concentrations and colorectal cancer risk (OR 0.53, highest [median 99.1 nmol/L] compared to lowest quintile [median 40.2 nmol/L]; P for trend = 0.02).70 This trend remained significant in a subgroup analysis of women age 60 years or older (OR 0.35 between the highest quintiles [median 99.1 nmol/L] and lowest [median 40.2 nmol/L]; P for trend = 0.006) or in rectal cancer alone (OR 0.31, highest [median 92.4 nmol/L] compared to lowest tertile [median 44.4 nmol/L]; P for trend = 0.03).70 The WHI focused on postmenopausal women.71 A significant negative trend was reported between

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

25(OH)D concentrations and colorectal cancer risk (OR 2.53, between highest [≥58.4 nmol/L] and lowest quintiles [<31.0 nmol/L]; P for Trend end = 0.02).

The Japan PHC compared 25(OH)D concentrations between cases and controls; no significant difference was reported.68

Findings per special populations

No subgroup data were available regarding the association between 25(OH)D concentrations and colorectal cancer risk in obese persons. One study exclusively included male smokers aged between 50 and 69 years,67 and reported no significant association between 25(OH)D concentrations and colorectal cancer risk by trend analysis. Another study that exclusively included white population also found no association.72 In addition, another study that focused on women who were taking hormone replacement therapy reported no significant association between 25(OH)D and colorectal cancer.70

Findings excluding early cases

Three studies performed sensitivity analyses on the association between 25(OH)D concentrations and colorectal cancer risk by excluding cases diagnosed within the first 1 to 2 years after blood draw.67,69,70 One study found a significant negative association between 25(OH)D concentrations and colon cancer risk (OR 0.3, between highest [>48.2 nmol/L] and lowest quartiles [≤ 24.5 nmol/L]; P for Trend = 0.04), which was not significant in main analysis.67 Otherwise, the results were not materially different from the main analysis.

Findings on 1,25-Dihydroxyvitamin D

A total of three studies evaluated the associations between 1,25(OH)2D concentrations and colorectal cancer risk67,70 or colon cancer.73 None of the studies found a significant association by trend analysis. One study reported no significant association between 1,25(OH)2D concentrations and rectal cancer risk.67

Findings by life stage

  • 0 – 6 mo Not reviewed

  • 7 mo – 2 y Not reviewed

  • 3 – 8 y Not reviewed

  • 9 – 18 y Not reviewed

  • 19 – 50 y The analysis of the NHANES III with a mean age of 44 years included participants mostly within this life stage. The study found an inverse association between 25(OH)D and colorectal cancer mortality.

  • 51 – 70 y The seven nested case-control studies included people with a mean age ranged from 55 to 66 years. A negative trend between 25(OH)D concentrations and colorectal cancer risk was found in two studies of women. Out of five studies that separately assessed the risk of colon cancer and rectal cancer, only one study of men and another study of women found a negative trend in colon cancer risk and rectal cancer risk, respectively. Otherwise, no association was found between 25(OH)D concentrations and cancer risk.

  • 71 y One RCT with a mean age of 75 included participants mostly within this life stage. The trial found no difference in colorectal cancer mortality or incidence between supplemental vitamin D and no supplements.

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×
  • Postmenopause One study and a subgroup analysis in another study focused on postmenopausal women. A negative trend between 25(OH)D concentrations and colorectal cancer risk was found in these two studies.

  • Pregnant & lactating women Not reviewed

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Table 22. Vitamin D and colorectal cancer: Characteristics of observational studiesA

Author Year

Study Name

Location (Latitude)

[PMID]

Population

Vitamin D Concentration

Comparisons

Confounders/Effect Modifiers Adjusted

Comments

Nutrients

Demograph

Anthrop

Medical

UV exposure

Lifestyle

Cohort

Freedman 200753

NHANES III

US (various)

[16481636]

• Health status

Any

• Assay method

RIA (DiaSorin)

Colorectal cancer mortality stratified by prespecified baseline

X

X

X

X

X

X

White: 71%; Black: 14%; Hispanic: 6%; Others: 9%

• Mean age (range), y

44 (≥17)

 

 

 

 

 

 

 

 

 

• Male (%)

45

• Season blood drawn

All

25(OH)D cut points

 

 

 

 

 

 

 

Nested case-control

 

 

 

 

 

 

 

 

 

 

 

 

Braun 199573

WCC

Maryland, US (38°N)

[329893]

• Health status

Any

• Assay method

RIA (Horris 1993)

• 25(OH)D levels between cases and controls

 

X

 

 

X

 

 

• Mean age (range), y

55 (nd)

 

 

 

 

 

 

 

 

 

 

• Male (%)

nd

• Season blood drawn

Fall

• Colon cancer risk stratified by baseline 25(OH)D quintiles

 

 

 

 

 

 

 

Feskanich 200470

NHS

US (various)

[15342452]

• Health status

Any

• Assay method

RIA (Horris 1997)

Colorectal cancer risk stratified by baseline 25(OH)D quintiles

X

X

X

X

X

X

Aspirin user (>10 y): 10%; Hormone replacement therapy: 34%

 

• Mean age (range), y

60 (43-70)

 

 

 

 

 

 

 

 

 

• Male (%)

0

• Season blood drawn

All

 

 

 

 

 

 

 

Garland 198972

WCC

Maryland, US (38°N)

[2572900]

• Health status

Any

• Assay method

HPLA (Clemens 1982)

• 25(OH)D levels between cases and controls

 

X

 

 

X

 

White: 100%

• Mean age (range), y

63 (nd)

 

 

 

 

 

 

 

 

 

 

• Male (%)

50

• Season blood drawn

Fall

• Colon cancer risk stratified by baseline 25(OH)D quintiles

 

 

 

 

 

 

 

Otani 200768

Japan PHC

Japan (various)

[17622244]

• Health status

Any

• Assay method

CPBA (Haddad 1971)

• 25(OH)D levels between cases and controls

X

X

X

X

X

X

 

• Mean age (range), y

Men: 57 (40-69);

Women: 56 (40-69)

 

 

 

 

 

 

 

 

 

 

• Male (%)

 

• Season blood drawn

All

• Colorectal cancer risk stratified by baseline 25(OH)D quartiles

 

 

 

 

 

 

 

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author Year

Study Name

Location (Latitude)

[PMID]

Population

Vitamin D Concentration

Comparisons

Confounders/Effect Modifiers Adjusted

Comments

Nutrients

Demograph

Anthrop

Medical

UV exposure

Lifestyle

Tangrea 199767

ATBC

Finland (~60°N)

[9242478]

• Health status

SmokerB

• Assay method

RIA (Horris 1993)

Colorectal cancer risk stratified by baseline 25(OH)D quartiles

X

X

X

 

X

X

 

• Mean age (range), y

60 (50-69)

 

 

 

 

 

 

 

 

 

• Male (%)

100

• Season blood drawn

All

 

 

 

 

 

 

 

 

Wactawski-Wende 200671

WHI

US (various)

[16481636]

• Health status

Postmenopausal womenC

• Assay method

RIA (DiaSorin)

Colorectal cancer risk stratified by baseline 25(OH)D quartiles

 

X

X

X

 

X

White: 83%; Black: 9%; Hispanic: 4% Others: 4%

• Mean age (range), y

nd (50-79)

 

 

 

 

 

 

 

 

 

• Male (%)

0

• Season blood drawn

All

 

 

 

 

 

 

 

 

Wu 200769

HPFS

US (various)

[17623801]

• Health status

Smoker 5%

• Assay method

RIA (Horris 1997)

• 25(OH)D levels between cases and controls

X

X

X

X

X

X

Aspirin user in 1994: 40%; Current smoker: 5%

• Mean age (range), y

66 (nd)

 

 

 

 

 

 

 

 

 

• Male (%)

100

• Season blood drawn

All

• Colorectal cancer risk stratified by baseline 25(OH)D quintiles

 

 

 

 

 

 

 

A This table is ordered alphabetically by study author.

B Participants of a lung cancer prevention 2 by 2 RCT of alpha-tocopherol and beta-carotene.

C Participants of a hip fracture prevention RCT of vitamin D3 and calcium

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Table 23. Vitamin D and colorectal cancer: Results of observational studies

Author Year

Study Name

[PMID]

Life Stage

Outcome

(n/N; Incidence)

Followup Duration (Time to Dx)

25(OH)D Concentration, nmol/L

No. of Cases

No. in Category

Adjusted OR

95% CI

P for Trend

Study Quality

Cohort study

Colorectal cancer mortality

Women

Freedman 200753

[17971526]

19-50†

51-70

≥71

Colorectal Cancer Mortality

(66/16818; 0.004)

nd

<50

28

~5606

1

Reference

0.02

B

 

 

 

 

50-80

24

~5606

0.44

0.20, 0.95*

 

 

 

 

 

 

≥80

14

~5606

0.28

0.11, 0.68*

 

 

Nested case-control study

Colorectal cancer

Men

Otani 200768

Japan PHC

[17622244]

19-50

51-70†

Colorectal cancer

(N=196 cases; 392 controls)

1-13

<57.2

43

74

1

Reference

0.39

B

 

 

 

 

57.2-69.0

40

85

0.76

0.42, 1.4

 

 

 

 

 

 

69.0-80.2

36

85

0.76

0.39, 1.5

 

 

 

 

 

 

≥80.2

44

80

0.73

0.35, 1.5

 

 

Wu 200769

HPFS

[17623801]

19-50

51-70†

≥71

Colorectal cancer

(179 cases; 356 controls)

1-9

46, median

45

71

1

Reference

0.24A

B

 

 

 

 

62.5

44

71

0.97

0.55, 1.70

 

 

 

 

 

 

72.8

30

68

0.66

0.35, 1.24

 

 

 

 

 

 

83.3

23

74

0.51

0.27, 0.97*

 

 

 

 

 

 

98.5

37

72

0.83

0.45, 1.52

 

 

 

19-50

51-70†

Colorectal cancer, age <65

 

48.2, median

25

34

1

Reference

0.13

 

 

 

 

 

66.8

15

28

1.03

0.36, 2.91

 

 

 

 

 

 

80.0

9

30

0.38

0.12, 1.26

 

 

 

 

 

 

97.0

14

36

0.45

0.15, 1.40

 

 

 

51-70†

≥71

Colorectal cancer, age ≥65

 

48.2, median

34

55

1

Reference

0.34

 

 

 

 

 

66.8

36

61

0.97

0.50, 1.87

 

 

 

 

 

 

80.0

19

58

0.56

0.27, 1.15

 

 

 

 

 

 

97.0

27

54

0.83

0.39, 1.75

 

 

Tangrea 199767

ATBC

[9242478]

19-50

51-70†

Colorectal cancer

(146 cases; 292 controls)

1-8

≤24.5

46

72

1

Reference

0.13

B

 

 

 

 

24.5-34.7

35

73

0.7

0.4, 1.3

 

 

 

 

 

 

34.7-48.2

36

73

0.8

0.4, 1.3

 

 

 

 

 

 

>48.2

29

72

0.6

0.3, 1.1

 

 

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author Year

Study Name

[PMID]

Life Stage

Outcome (n/N; Incidence)

Followup Duration (Time to Dx)

25(OH)D Concentration, nmol/L

No. of Cases

No. in Category

Adjusted OR

95% CI

P for Trend

Study Quality

Women

Wactawski-Wende 200671

WHI

[16481636]

Post-menopausal women

Colorectal cancer (306 cases; 306 controls)

1-12

<31.0

88

67

2.53

1.49, 4.32

0.02

B

 

 

 

 

31.0-42.3

80

73

1.96

1.18, 3.24*

 

 

 

 

 

 

42.4-58.3

78

73

1.95

1.18, 3.24*

 

 

 

 

 

 

≥58.4

60

93

1

Reference

 

 

Feskanich 200470

NHS

[15342452]

19-50

51-70†

Colorectal cancer (192 cases; 384 controls)

1-11

40.2, median

53

77

1

Reference

0.02B

B

 

 

 

 

55.1

47

79

0.93

0.53, 1.63

 

 

 

 

 

 

66.7

35

75

0.79

0.44, 1.40

 

 

 

 

 

 

77.5

29

77

0.58

0.31, 1.07

 

 

 

 

 

 

99.1

29

75

0.53

0.27, 1.04

 

 

Otani 200768

Japan PHC

[17622244]

19-50

51-70†

Colorectal cancer (179 cases; 358 controls)

1-13

<57.2

41

77

1

Reference

0.74

B

 

 

 

 

57.2-69.0

34

73

1.0

0.55, 1.9

 

 

 

 

 

 

69.0-80.2

44

71

1.2

0.65, 2.3

 

 

 

 

 

 

≥80.2

41

76

1.1

0.50, 2.3

 

 

Colon cancer

Both sexes

Braun 199573

WCC

[329893]

19-50

51-70†

≥71

Colon cancer (57 cases; 114 controls)

1-17

<43

nd

nd

1

Reference

0.57

C

 

 

 

 

43.0-51.5

nd

nd

0.3

0.1, 1.0

 

 

 

 

 

 

51.5-61.8

nd

nd

0.5

0.2, 1.5

 

 

 

 

 

 

61.8-75.3

nd

nd

0.7

0.2, 2.0

 

 

 

 

 

 

≥75.3

nd

nd

0.4

0.1, 1.4

 

 

Garland 198972

WCC

[2572900]

19-50

51-70†

≥71

Colon cancer (34 cases; 67 controls)

1-9

10 to <50

9

8

1

Reference

0.41

C

 

 

 

 

50.0-67.5

7

13

0.48

0.13, 1.80

 

 

 

 

 

 

67.5-82.5

5

18

0.25

0.06, 0.98*

 

 

 

 

 

 

82.5-105

4

17

0.21

0.05, 0.89*

 

 

 

 

 

 

105-227.5

9

11

0.73

0.20, 2.66

 

 

Men

Otani 200768

Japan PHC

[17622244]

19-50

51-70†

Colon cancer (141 cases; 282 controls)

1-13

<57.2

25

54

1

Reference

0.70

B

 

 

 

 

57.2-69.0

27

55

0.98

0.48, 2.0

 

 

69.0-80.2

29

66

1.0

0.48, 2.3

 

 

 

 

≥80.2

38

62

1.2

0.51, 2.7

 

 

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author Year

Study Name

[PMID]

Life Stage

Outcome (n/N; Incidence)

Followup Duration (Time to Dx)

25(OH)D Concentration, nmol/L

No. of Cases

No. in Category

Adjusted OR

95% CI

P for Trend

Study Quality

Wu 200769

HPFS

[17623801]

19-50

51-70†

≥71

Colon cancer (139 cases; 276 controls)

1-9

48.3, median

49

66

1

Reference

0.005C

B

 

 

 

 

66.8

44

68

0.74

0.42, 1.33

 

 

 

 

 

 

80.0

17

68

0.29

0.14, 0.59*

 

 

 

 

 

 

97.0

29

74

0.46

0.24, 0.89*

 

 

Tangrea 199767

ATBC

[9242478]

19-50

51-70†

Colon cancer (91 cases; 182 controls)

1-8

≤24.5

30

47

1

Reference

0.69D

B

 

 

 

 

24.5-34.7

18

47

0.6

0.3, 1.2

 

 

 

 

 

 

34.7-48.2

22

45

0.8

0.4, 1.6

 

 

 

 

 

 

>48.2

21

42

0.8

0.4, 1.6

 

 

Women

Feskanich 200470

NHS

[15342452]

19-50

51-70†

Colon cancer (148 cases; 296 controls)

1-11

41.2, median

41.2

75

1

Reference

0.17

B

 

 

 

 

59.7

59.7

71

1.03

0.56, 1.89

 

 

 

 

 

 

73.3

73.3

77

0.54

0.28, 1.03

 

 

 

 

 

 

98.1

98.1

72

0.70

0.35, 1.38

 

 

Otani 200768

Japan PHC

[17622244]

19-50

51-70†

Colon cancer (115 cases; 230 controls)

1-13

<57.2

21

53

1

Reference

0.12

B

 

 

 

 

57.2-69.0

27

48

1.7

0.78, 3.6

 

 

 

 

 

 

69.0-80.2

27

41

2.1

0.90, 4.7

 

 

 

 

 

 

≥80.2

31

53

2.1

0.78, 5.6

 

 

Rectal cancer

Men

Otani 200768

Japan PHC

[17622244]

19-50

51-70†

Rectal cancer (55 cases; 110 controls)

1-13

<57.2

18

20

1

Reference

0.06

B

 

 

 

 

57.2-69.0

13

30

0.17

0.02, 1.2

 

 

 

 

 

 

69.0-80.2

7

19

0.25

0.05, 1.3

 

 

 

 

 

 

≥80.2

6

18

0.075

0.005, 0.99

 

 

Tangrea 199767

ATBC

[9242478]

19-50

51-70†

Rectal cancer (55 cases; 110 controls)

1-8

≤24.5

16

25

1

Reference

0.06E

B

 

 

 

 

24.5-34.7

17

26

0.9

0.4, 2.4

 

 

 

 

 

 

34.7-48.2

14

28

0.8

0.3, 2.0

 

 

 

 

 

 

>48.2

8

30

0.4

0.1, 1.1

 

 

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author Year

Study Name

[PMID]

Life Stage

Outcome (n/N; Incidence)

Followup Duration (Time to Dx)

25(OH)D Concentration, nmol/L

No. of Cases

No. in Category

Adjusted OR

95% CI

P for Trend

Study Quality

Wu 200769

HPFS

[17623801]

19-50

51-70F

≥71

Rectal cancer (40 cases; 80 controls)

1-9

53.0, median

11

30

1

Reference

0.08

B

 

 

 

 

73.3

15

28

1.74

0.61, 5.00

 

 

 

 

 

 

93.5

14

22

3.32

0.87, 12.69

 

 

Women

 

 

 

 

 

 

 

 

 

 

Otani 200768

Japan PHC

[17622244]

19-50

51-70†

Rectal cancer (64 cases; 128 controls)

1-13

<57.2

20

24

1

Reference

0.17

B

 

 

 

 

57.2-69.0

7

25

0.26

0.07, 1.0

 

 

 

 

 

 

69.0-80.2

17

30

0.46

0.15, 14

 

 

 

 

 

 

≥80.2

10

23

0.33

0.08, 1.3

 

 

Feskanich 200470

NHS

[15342452]

19-50

51-70†

Rectal cancer (44 cases; 88 controls)

1-11

44.4, median

24

31

1

Reference

0.03

B

 

 

 

 

66.2

10

26

0.52

0.14, 1.93

 

 

92.4

10

31

0.31

0.08, 1.31

 

 

* Statistically significant (P<0.05)

A P for trend = 0.31 when cases diagnosed within 2 years of blood collection were excluded.

B Results were not notably changed when cases diagnosed within the first year after blood collection were excluded (P for trend not reported). Subgroup analyses per age were also reported as follows: Age ≥ 60, OR = 0.35 (95% CI 0.14, 0.87) between the lowest and highest quintiles; P for trend = 0.006. Age < 60, OR = 1.36 (95% CI 0.48, 3.92) between the lowest and highest quintiles; P for trend = 0.70.

C P for trend = 0.008 when cases diagnosed within 2 years of blood collection were excluded.

D P for trend = 0.58 when cases diagnosed within 2 years of blood collection were excluded.

E P for trend = 0.04 when cases diagnosed within 2 years of blood collection were excluded.

F Most representative life stage

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Figure 8. Colorectal cancer risk stratified by vitamin D concentration

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Figure 9. Colon cancer risk stratified by vitamin D concentration

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Figure 10. Rectal cancer risk stratified by vitamin D concentration

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×
Colorectal adenoma

Synopsis

No systematic reviews have evaluated the association between 25(OH)D concentrations and the risk of colorectal adenoma. One B quality nested case-control study in women found no significant association between 25(OH)D concentrations and the risk of colorectal adenoma.

Detailed presentation (Tables 24 & 25)

One nested case-control study within the NHS evaluated the relationship between 25(OH)D concentrations and the risk of colorectal adenoma in women.74 At 5 years, an adjusted analysis found no significant association between 25(OH)D concentrations and the incidence of colorectal adenoma by trend analysis. Subgroup analyses also found no significant association between 25(OH)D concentrations and the incidence of colon or rectal adenoma. No subgroup data were available regarding age or other special populations (e.g., obese, smokers, ethnic groups, or users of contraceptives). This study was rated B because it excluded more than 50 percent of participants of the original cohort because their blood samples were not available.

Findings by life stage

  • 0 – 6 mo Not reviewed

  • 7 mo – 2 y Not reviewed

  • 3 – 8 y Not reviewed

  • 9 – 18 y Not reviewed

  • 19 – 50 y A proportion of participants in the NHS was in this life stage. No unique conclusions are possible for this life stage separate from those for people 51 to 70 years.

  • 51 – 70 y The analysis of the NHS included female participants mostly within this life stage. The study found no association between 25(OH)D and the incidence of colorectal adenoma.

  • ≥71 y A proportion of participants in the NHS was in this life stage. No unique conclusions are possible for this life stage separate from those for people 51 to 70 years.

  • Postmenopause The analysis of NHS partially included postmenopausal women. However, no unique conclusions are possible for this life stage separate from those for people 51 to 70 years.

  • Pregnant & lactating women Not reviewed

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Table 24. Vitamin D and colorectal adenoma: Characteristics of observational studies

Author Year

Study Name

Location (Latitude)

[PMID]

Population

Vitamin D Concentration

Comparisons

Confounders/Effect Modifiers Adjusted

Comments

Nutrients

Demograph

Anthrop

Medical

UV exposure

Lifestyle

Nested case-control 

 

 

 

 

 

 

 

 

 

 

 

 

Platz 200074

NHS

US (various)

[11045788]

• Health status

Any

• Assay method

RIA (Horris 1993)

• Colorectal adenoma risk stratified by baseline 25(OH)D quartiles

X

X

X

X

X

X

Aspirin user: 26%; Hormone replacement therapy: 36%

• Mean Age

59 (7)

 

 

 

 

 

 

 

• Male %

0

• Season blood drawn

All

 

 

 

 

 

 

 

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Table 25. Vitamin D and colorectal adenoma: Results of observational studies

Author Year

Study Name

[PMID]

Life Stage

Outcome (n/N; Incidence)

Followup Duration (Time to Dx)

25(OH)D Concentration, nmol/L

No. of Cases

No. in Category

Adjusted OR

95% CI

P for Trend

Study Quality

Nested case-control study

Colorectal adenoma

 

 

 

 

 

 

 

 

 

 

Women

 

 

 

 

 

 

 

 

 

 

Platz 200074

19-50

Colorectal adenoma (326 cases; 326 controls)

5

16.3, median

103

82

1

Reference

1.0

B

NHS

51-70†

 

 

 

 

 

 

 

 

[11045788]

≥71

 

 

 

 

 

 

 

 

 

 

 

 

22.6

62

80

0.64

0.41, 1.00

 

 

 

 

 

 

28.3

61

82

0.58

0.36, 0.95

 

 

 

 

 

 

38.0

100

82

1.04

0.66, 1.66

 

 

Colon adenoma

 

 

 

 

 

 

 

 

 

 

Women

 

 

 

 

 

 

 

 

 

 

Platz 200074

19-50

Colon adenoma (261 cases; 261 controls)

5

16.3, median

79

64

1

Reference

1.0

B

NHS

51-70A

 

 

 

 

 

 

 

 

[11045788]

≥71

 

 

 

 

 

 

 

 

 

 

 

 

22.6

55

64

0.71

0.43, 1.18

 

 

 

 

 

 

28.3

51

69

0.60

0.35, 1.02

 

 

 

 

 

 

38.0

76

64

1.02

0.60, 1.73

 

 

Rectal adenoma

 

 

 

 

 

 

 

 

 

 

Women

 

 

 

 

 

 

 

 

 

 

Platz 200074

19-50

Rectal adenoma (65 cases; 65 controls)

5

16.3, median

24

18

1

Reference

0.9

B

NHS

51-70†

 

 

 

 

 

 

 

 

[11045788]

≥71

 

 

 

 

 

 

 

 

 

 

 

 

22.6

7

16

0.38

0.12, 0.19

 

 

 

 

 

 

28.3

10

13

0.34

0.08, 1.42

 

 

 

 

 

 

38.0

24

18

1.59

0.50, 5.03

 

 

* Statistically significant (P<0.05)

A Most representative life stage

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×
Breast cancer

Synopsis

No qualified systematic reviews evaluated the association between vitamin D and calcium intake or serum 25(OH)D concentration and risk of breast cancer. One cohort study compared serum 25(OH)D concentrations and the risk of breast cancer-specific mortality,53 and two nested case-control studies compared 25(OH)D concentrations and the risk of breast cancer.75,76 The cohort study utilizing NHANES III data found significant decrease in breast cancer-specific mortality during 9 years of followup in those with serum concentration of 25(OH)D greater than 62 nmol/L. The Nurses’ Health Study and Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, however, found no significant relationship between serum concentration of 25(OH) D and risk of breast cancer diagnosis in either pre- or postmenopausal women during 7 to 12 years of followup.75,76 All three studies were rated B quality.

Detailed presentation (Tables 26 & 27)

The NHANES III study followed 16,818 adults with a mean age of 44 years with a background calcium intake on average of about 812 mg/day (from diet and supplements). 53 The study included 71% non-Hispanic white, 14% non-Hispanic black, 6% Mexican American, and 9% from other races. During 9 years of followup, women with serum concentration of 25(OH) D greater than 62 nmol/L had a hazard ratio of 0.28 for breast cancer-specific mortality compared to those with 62 nmol/L or lower (95% CI 0.08-0.93). The breast cancer-specific mortality was one of many cancer-specific mortality outcomes reported in this study.

Two nested case-control studies of women with a mean age of 57 years and 67 years, respectively, found no relationship between serum 25(OH)D concentrations and risk of breast cancer.75,76 However, in the second study, when compared with the lowest quintile, quintiles 3 to 5 were associated with nonsignificantly elevated risks. In multivariable adjusted analyses, the risk associated with 25(OH)D levels below 15 ng/mL compared with higher levels was 0.81 (95% CI 0.59, 1.12).76

Findings by age and sex

In the one nested case-control study (methodological quality B) including both premenopausal and postmenopausal women, no relationship was found between vitamin D levels and risk of breast cancer. However, in this study, there was a statistically significant trend towards decreased risk of breast cancer among women older than 60 years of age with serum concentration of 25(OH)D greater than 62 nmol/L.

Findings by life stage

  • 0 – 6 mo Not applicable

  • 7 mo – 2 y Not applicable

  • 3 – 8 y Not applicable

  • 9 – 18 y Not applicable

  • 19 – 50 y A followup study of NHANES III including women with a mean age of 44 years found a decreased mortality (hazard ratio 0.28) due to breast cancer among those with serum concentration of 25(OH)D greater than 62 nmol/L.

  • 51 – 70 y Two nested case-control studies of women with a mean age of 57 years and 67 years, respectively, found no relationship between vitamin D levels and risk of

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

breast cancer. However, in one of these studies, there was a statistically significant trend towards decreased risk of breast cancer among women older than 60 years of age with serum concentration of 25(OH)D greater than 62 nmol/L.

  • ≥71 y Not reviewed

  • Postmenopause Not reviewed

  • Pregnant & lactating women Not reviewed

Table 26. Vitamin D and breast cancer: Characteristics of observational studies

Author Year

Study Name

Location (Latitude)

[PMID]

Population

Vitamin D Concentration

Comparisons

Confounders/Effect Modifiers Adjusted

Comments

Nutrients

Demograph

Anthrop

Medical

UV exposure

Lifestyle

Cohort

 

 

 

 

 

 

 

 

 

 

 

 

Freedman 200753

NHANES III

US (38º N)

[17971526]

• Health status

Noninstitutionalized

• Assay method

RIA

Breast cancer risks: Quintile 1 vs. Quintile 2

X

X

X

 

X

X

 

• Mean age (range/SD), y

44 (ND)

 

 

 

 

 

 

 

 

 

 

 

• Season blood drawn

All year

 

 

 

 

 

 

 

 

Nested Case-Control

 

 

 

 

 

 

 

 

 

 

 

 

Bertone-Johnson 200575

NHS

US (38º N)

[16103450]

• Health status

No Cancer

• Assay method

RIA

Breast cancer risks: Quintile 1 vs. Quintile 2, 3, 4, 5

X

X

X

X

 

X

 

• Mean age (range/SD), y

57 (7.0)

 

 

 

 

 

 

 

 

 

 

 

• Season blood drawn

All year

 

 

 

 

 

 

 

 

Freedman 200876

PLCO Trial

US (38º N)

[18381472]

• Health status

No Cancer

• Assay method

RIA

Breast cancer risks: Quintile 1 vs. Quintile 2, 3, 4, 5

X

X

X

X

 

X

 

• Mean age (range/SD), y

67 (ND)

 

 

 

 

 

 

 

 

 

 

 

• Season blood drawn

Dec- Sep

 

 

 

 

 

 

 

 

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Table 27. Vitamin D and breast cancer: Results of observational studies

Author Year

Study Name

[PMID]

Life Stage

Outcome (n/N; Incidence)

Followup Duration (Time to Dx)

Vit D Measure

Concentration, nmol/L

No. of Cases

No. in Category

Adjusted RR

95% CI

P for Trend

Study Quality

Cohort

 

 

 

 

 

 

 

 

 

 

 

Freedman 200753

NHANES III

[17971526]

All Adults

Breast cancer mortality (28/ND)A

105 mo

25(OH)D

<63

20

ND

1

Reference

NS

B

 

 

 

 

≥63

8

ND

HR 0.28

0.08, 0.93*

 

 

Nested Case- Control

 

 

 

 

 

 

 

 

 

 

 

Bertone-Johnson 200575

NHS

[16103450]

Pre- and Post-menopausal

Breast cancer (701/1425)

<1-82 mo

25(OH)D

≤50 (1st batch)

159

297

1

Reference

nd

B

 

 

≤70 (2nd batch)

 

 

 

 

 

 

 

 

 

 

≤45 (3rd batch)

 

 

 

 

 

 

 

 

 

 

 

51 - 70

149

278

0.95

0.66, 1.36

 

 

 

 

 

 

 

72 - 85

 

 

 

 

 

 

 

 

 

 

 

47 to 60

 

 

 

 

 

 

 

 

 

 

 

72 - 82

125

266

0.74

0.51, 1.06

 

 

 

 

 

 

 

87 - 97

 

 

 

 

 

 

 

 

 

 

 

62 - 72

 

 

 

 

 

 

 

 

 

 

 

85 - 97

144

296

0.80

0.58, 1.11

 

 

 

 

 

 

 

100 - 117

 

 

 

 

 

 

 

 

 

 

 

75 - 90

 

 

 

 

 

 

 

 

 

 

 

≥100

124

265

0.73

0.49, 1.07

 

 

 

 

 

 

 

≥120

 

 

 

 

 

 

 

 

 

 

 

≥92

 

 

 

 

 

 

 

 

Breast cancer

<60 y (701/1425)

 

 

 

97

191

1

Reference

NS

 

 

 

 

 

 

 

84

170

0.96

0.62, 1.49

 

 

 

 

 

 

 

 

77

164

0.80

0.51, 1.26

 

 

 

 

 

 

 

 

90

192

0.85

0.55, 1.32

 

 

 

 

 

 

 

 

70

146

0.92

0.57, 1.48

 

 

 

 

Breast cancer

≥60 y (701/1425)

 

 

 

62

109

1

Reference

0.03

 

 

 

 

 

 

 

65

114

1.07

0.60, 1.92

 

 

 

 

 

 

 

 

48

105

0.64

0.35, 1.16

 

 

 

 

 

 

 

 

54

99

0.68

0.38, 1.24

 

 

 

 

 

 

 

 

54

125

0.57

0.31-1.04

 

 

Suggested Citation:"Appendix D: Methods and Results from the AHRQ-Tufts Evidence-Based Report on Vitamin D and Calcium." Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. doi: 10.17226/13050.
×

Author Year

Study Name

[PMID]

Life Stage

Outcome (n/N; Incidence)

Fol