You Are Here:
An Updated Meta-Analysis for the U.S. Preventive Services Task Force
Release Date: December 2011
By Mei Chung, PhD, MPH; Jounghee Lee, PhD; Teruhiko Terasawa, MD, PhD; Joseph Lau, MD; and Thomas A. Trikalinos, MD, PhD
The information in this article is intended to help clinicians, employers, policymakers, and others make informed decisions about the provision of health care services. This article is intended as a reference and not as a substitute for clinical judgment.
This article may be used, in whole or in part, as the basis for the development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied.
This article was first published in Annals of Internal Medicine on December 20, 2011 (Ann Intern Med 2011;155:827-838; http://www.annals.org).
Background: Studies suggest that vitamin D supplementation may reduce cancer and fracture risks.
Purpose: To examine the benefits and harms of vitamin D with or without calcium supplementation on clinical outcomes of cancer and fractures in adults.
Data Sources: English-language studies identified from MEDLINE and the Cochrane Central Register of Controlled Trials through July 2011.
Study Selection: Randomized, controlled trials (RCTs), prospective cohort studies, and nested case-control studies reporting incidence of or death from cancer and fracture outcomes.
Data Extraction: Multiple reviewers extracted details about participant characteristics, including baseline vitamin D status and use of supplements; details of statistical analyses, including adjustments for confounding; and methodological quality. Differences were resolved by consensus.
Data Synthesis: 19 RCTs (3 for cancer and 16 for fracture outcomes) and 28 observational studies (for cancer outcomes) were analyzed. Limited data from RCTs suggested that high-dose (1000 IU/d) vitamin D supplementation can reduce the risk for total cancer, and data from observational studies suggested that higher blood 25-hydroxyvitamin D (25-[OH]D) concentrations might be associated with increased risk for cancer. Mixed-effects dose-response meta-analyses showed that each 10-nmol/L increase in blood 25-(OH)D concentration was associated with a 6% (95% CI, 3% to 9%) reduced risk for colorectal cancer but no statistically significant dose-response relationships for prostate and breast cancer. Random-effects model meta-analysis showed that combined vitamin D and calcium supplementation reduced fracture risk (pooled relative risk, 0.88 [CI, 0.78 to 0.99]) in older adults, but the effects differed according to study setting: institution (relative risk, 0.71 [CI, 0.57 to 0.89]) versus community-dwelling (relative risk, 0.89 [CI, 0.76 to 1.04]). One RCT showed adverse outcomes associated with supplementation, including increased risk for renal and urinary tract stones.
Limitations: Most trial participants were older (aged ≥65 years) postmenopausal women. Observational studies were heterogeneous and were limited by potential confounders.
Conclusion: Combined vitamin D and calcium supplementation can reduce fracture risk, but the effects may be smaller among community-dwelling older adults than among institutionalized elderly persons. Appropriate dose and dosing regimens, however, require further study. Evidence is not sufficiently robust to draw conclusions regarding the benefits or harms of vitamin D supplementation for the prevention of cancer.
Primary Funding Source: Agency for Healthcare Research and Quality.
One of the major biological functions of vitamin D is to regulate bone mineralization. Many tissues besides bone are also influenced by vitamin D (1). There are 2 forms of vitamin D: D3 (cholecalciferol) and D2 (ergocalciferol). Both forms are biologically activated in humans by hydroxylation first in the liver, to form 25-hydroxyvitamin D (25-[OH]D), and subsequently in the kidneys, to form 1,25-dihydroxyvitamin D (1,25-[OH]2D). Although 25-(OH)D has low biological activity, it is the major form of vitamin D that circulates in the bloodstream. Thus, blood 25-(OH)D concentrations are generally thought to reflect nutritional status regarding vitamin D (2, 3). In addition to indirectly affecting bone mineralization, 1,25-(OH)2D has further, diverse biological effects. For example, as recently noted, 1,25-(OH)2D inhibits parathyroid hormone secretion and promotes insulin secretion, inhibits adaptive immunity and promotes innate immunity, and inhibits proliferation and stimulates differentiation of cells (4). These functions suggest a possible role of vitamin D in cancer prevention.
This review is based in part on our 2009 evidence report (5) on the relationship of vitamin D and calcium, with 17 health outcomes, that was produced to inform an Institute of Medicine committee charged to update the Dietary Reference Intakes for vitamin D and calcium (6). Here, we updated and reanalyzed part of our broad systematic review to support the U.S. Preventive Services Task Force (USPSTF) recommendations on vitamin D with or without calcium supplements for preventing cancer and fractures. Following USPSTF methods (7), we used an analytic framework (Appendix Figure 1) that maps the 4 key questions (KQs) evaluated in the current review: KQ 1 addresses the effects of vitamin D supplementation on cancer and fracture outcomes, KQ 2 addresses the associations between vitamin D status and cancer and fracture outcomes, KQ 3 addresses the effects of vitamin D supplementation on changes in vitamin D status, and KQ 4 addresses the adverse events associated with supplementation (go to Table 1 for full KQs).
Our 2009 evidence report on vitamin D and calcium (5) included a systematic review of primary studies for cancer outcomes and updated a previous systematic review by the University of Ottawa Evidence-based Practice Center on fractures, published in 2007 (8). In the current review, we present a focused update of these 2 systematic reviews (5, 8).
Data Sources and Searches
In our 2009 evidence report, we searched MEDLINE and the Cochrane Central Register of Controlled Trials through April 2009 for primary studies of any design. Search terms included vitamin D, 25-hydroxyvitamin D, calcium, and text terms and Medical Subject Heading terms related to cancer or neoplasms, fracture, and bone mineral density. We limited searches to articles about human participants published in English-language journals. The complete search strategies have been published elsewhere (5). We updated specific searches for cancer and fracture outcomes through July 2011.
Study Selection and Outcomes of Interest
For cancer, clinical outcomes of interest included incidence of or death from prostate, colorectal, or breast cancer or from all types of cancer combined (total cancer). For fractures, clinical outcomes of interest included incidence of any fracture at any site (for example, hip, spine, or wrist). We recorded whether the cancer or fracture outcomes were primary or secondary end points in the original article.
For benefits and harms of vitamin D supplementation (KQs 1 and 4), we included randomized, controlled trials (RCTs) of generally healthy adults (<20% of study participants had major chronic diseases, such as diabetes or cardiovascular disease, at baseline) that compared vitamin D supplementation with or without calcium against no supplementation or placebo for the outcomes of interest. For the purpose of our review, we excluded studies that enrolled pregnant women only or measured vitamin D status only during pregnancy and RCTs comparing different dosages of vitamin D supplementation without a control group that did not receive vitamin D supplementation. To include available data on elderly persons (aged ≥65 years), we also accepted RCTs of older ambulatory adults with any disease other than cancer. We excluded short-term (<1 month) RCTs and trials that used synthetic vitamin D analogues (for example, oxacalcitriol or paricalcitol).
For associations between vitamin D status and outcomes (KQ 2), we included prospective cohort or nested case-control studies of adults that investigated the associations of vitamin D status (as measured by blood 25-[OH]D) with cancer outcomes of interest. In contrast to cancer outcomes, for which only a limited number of RCTs were eligible, a large number of RCTs reporting fracture outcomes met our eligibility criteria; therefore, we decided not to update the observational studies of the associations of vitamin D status and fracture outcomes, instead referring to the Ottawa evidence report (which is current up to 2005) (8) for this question.
For effects of vitamin D supplementation on changes in vitamin D status (KQ 3), we adopted the results from our 2009 evidence report (5) and did not update the search.
Data Extraction and Quality Assessment
For all eligible RCTs and observational studies in the present update, we extracted data on study characteristics, participant characteristics, details on vitamin D and calcium supplements, baseline vitamin D status (including assay used, definition of outcomes, and study results). For RCTs, the number of events and total number of participants in each group were extracted to calculate effect sizes.
For observational studies, we selected the results from the full statistical model that adjusted for the largest number of potential confounders and recorded the number of cases and total number at risk (for cohort studies) or controls (for nested case-control studies) for each blood 25-(OH)D category, if reported. All quantitative data were verified by a second reviewer. For observational studies, we also listed the confounders adjusted for in the study design (for example, matching factors) or analyses.
We used the Agency for Healthcare Research and Quality Methods Reference Guide for Effectiveness Reviews criteria to grade study methodologic quality as good, fair, or poor (9). For RCTs, we applied quality items described in the CONSORT (Consolidated Standards of Reporting Trials) statement (10). For observational studies, we applied quality items described in the STROBE (Strengthening the Reporting of Observational studies in Epidemiology) statement (11), and specific items concerning the background vitamin D exposure, adjustment for potential confounding factors, and clarity of reporting of vitamin D status assessments and statistical analyses. For each included study, 1 reviewer rated study quality, which was confirmed by at least 1 other reviewer. Disagreements were resolved by consensus.
For analyses of RCTs included for KQ 1, we used the DerSimonian-Laird random-effects model meta-analysis (12) to examine the effects of vitamin D with or without calcium supplements on fractures. Most of these studies reported more than 1 fracture outcome. We selected 1 fracture outcome from each study to be included in our meta-analyses based on the descending order of most reported outcomes: total fracture, hip fracture, and nonvertebral fracture. We tested for heterogeneity with the Cochran Q statistic (considered significant when the P value was less than 0.10) and quantified the extent of heterogeneity with the I2 index. We defined low, moderate, and high heterogeneity as I2 values of 25%, 50%, and 75%, respectively. These cutoffs are arbitrary and were used for descriptive purposes only (13).
We reported the effects of combined vitamin D and calcium supplementation separately from vitamin D supplementation alone on cancer and fracture outcomes. Subgroup analyses were performed to evaluate the influences of study populations (that is, institutionalized or community-dwelling adults) on the pooled effect estimates. The Z test was used to test the difference in estimates of pooled effects between subgroups. We also used random-effects meta-regression (fitted with restricted maximum likelihood) (14, 15) to explore whether the effects of vitamin D supplementation on fracture outcomes depends on 2 factors: daily dose of vitamin D supplementation and baseline blood 25-(OH)D concentration.
For the analyses of observational studies included for KQ 2, we performed mixed-effects logistic regression to assess the dose-response relationships of blood 25-(OH)D concentrations with colorectal, prostate, and breast cancer risks by using adjusted results from full multivariable models (go to Appendix for details).
Analyses were conducted by using Stata SE 11 software (StataCorp, College Station, Texas). All P values were 2-tailed, and a P value less than 0.05 was considered to indicate a significant difference, unless otherwise specified.
Role of the Funding Source
The Agency for Healthcare Research and Quality funded this focused update under a contract to support the USPSTF. The funding source had no role in study selection, quality assessment, or data synthesis, although they provided project oversight and reviewed the draft evidence synthesis.
We included 137 studies in this review: 19 RCTs for KQ 1 (3 for cancer outcomes and 16 for fracture outcomes), 28 observational studies and 1 systematic review for KQ 2, 26 RCTs for KQ 3, and 63 RCTs for KQ 4. Appendix Figure 2 shows the summary results from evidence searches and study selection. Table 1 provides an overview of the numbers of studies and participants, methodological quality, and main findings of the included studies.
Effects of Vitamin D, With or Without Calcium, on Cancer and Fracture Outcomes
Three RCTs reported effects of vitamin D with or without calcium supplements on clinical cancer outcomes (Supplement 1, available at www.annals.org) . Cancer outcomes were secondary end points in all 3 RCTs. Of these, 2 RCTs (16, 17) were rated as fair quality because of a high rate of loss to follow-up (>10%) or unclear reporting of randomization and allocation concealment. The third RCT (18, 19) was rated as good quality (Appendix Figure 3). Although all 3 RCTs enrolled older adults, they focused on distinct populations: two enrolled generally healthy postmenopausal women, and 1 enrolled elderly men and women (aged ≥71 years). These RCTs lasted 4 to 7 years and were heterogeneous in the dose and regimen of vitamin D3 supplementation. The results from these 3 RCTs are summarized in Table 1. Of note, 1 RCT (16) provided data for 2 comparisons: vitamin D supplementation versus placebo and combined vitamin D and calcium supplementation versus placebo.
Vitamin D Supplementation Versus Placebo. Two fair-quality RCTs contributed information to this comparison (16, 17). Dose and regimen of vitamin D3 supplementation were 100,000 IU every 4 months in the trial conducted in the United Kingdom (17) and 1100 IU daily in the trial conducted in Nebraska (16). A total of 2686 elderly men and women and 891 healthy postmenopausal women were evaluated. The hazard or risk ratios for the incidence and mortality of colorectal, breast, or total cancer ranged from 0.55 to 1.09 (<1.0 favors vitamin D3 supplementation), with wide CIs (Table 1). On the basis of the CIs, one cannot rule out the possibility of clinically important effects in risk in either direction (for example, a protective effect of at least 14% reduction in risk or a harmful effect of at least 20% increase in risk).
Combined Vitamin D and Calcium Supplementation Versus Placebo. Two RCTs (1 of good quality [18, 19] and 1 of fair quality ) enrolled a total of 37,016 postmenopausal women, 98% of whom were from the Women's Health Initiative trial (18, 19). Daily dose and regimen of vitamin D3 (plus calcium) supplementation were 400 IU (plus 1500 mg) in the Women's Health Initiative trial (18, 19) and 1100 IU (plus 1400 to 1500 mg) in the trial in Nebraska (16). The Women's Health Initiative trial showed hazard ratios of total cancer or any specific cancer (including colorectal and breast) ranging from 0.96 to 1.08, with narrow CIs, for cancer incidence (18, 19). In contrast, the smaller trial conducted in Nebraska reported a 60% (CI, 18% to 80%) reduction in the risk for total cancer incidence (Table 1) (16).
Sixteen RCTs (17, 20-34) examined the effects of vitamin D with or without calcium supplements on fracture outcomes (Supplement 2, available at www.annals.org) . Of these, 3 RCTs were of good quality, 7 were of fair quality, and 4 were of poor quality (Appendix Figure 4). Fracture outcomes were primary end points in 13 (81%) of the 16 RCTs. Eight of the RCTs reported an outcome of fracture at any site, 5 reported data on hip fracture, 2 reported nonvertebral fracture, and 1 did not define the fracture outcome.
Vitamin D Supplementation Versus Placebo. Five RCTs compared supplemental vitamin D (400 to 1370 IU/d) with placebo in a total of 14,583 elderly men and women (17, 20, 27, 28, 31), with follow-up ranging from 7 months to 5 years. Of these, 1 RCT was of good quality, 3 were of fair quality, and 1 was of poor quality. Common limitations among the fair- or poor-quality RCTs were unclear reporting of randomization and outcome assessment and lack of allocation concealment. The overall random-effects meta-analysis found that vitamin D supplementation alone did not reduce fracture risk (pooled relative risk, 1.03 [CI, 0.84 to 1.26]), with high heterogeneity across studies (I2 = 60%; P = 0.02). The subgroup meta-analysis results according to setting (that is, institution vs. community) were similar to the overall effect estimate (Figure 1).
Combined Vitamin D and Calcium Supplementation Versus Placebo. Eleven RCTs compared the combination of vitamin D (300 to 1000 IU/d) and calcium (500 to 1200 mg/d) supplementation with placebo in a total of 52,915 persons (21-26, 29, 30, 32-34), mostly (69%) postmenopausal women from the Women's Health Initiative trial (33). Of these, 2 RCTs were of good quality, 5 were of fair quality, and 4 were of poor quality. Common limitations among the fair- or poor-quality RCTs were a high rate of loss to follow-up (>10%) and unclear reporting of randomization, allocation concealment, and outcome assessment. Follow-up ranged from 1 to 7 years among these RCTs.
Our random-effects meta-analysis showed that combined vitamin D and calcium supplementation reduced the risk for total fracture as compared with placebo (pooled relative risk, 0.88 [CI, 0.78 to 0.99]), with moderate heterogeneity across studies (I2 = 36%; P = 0.11). Subgroup meta-analysis results showed that the pooled effect estimates differed according to setting (P = 0.07): there was a significant risk reduction among institutionalized elderly persons (relative risk, 0.71 [CI, 0.57 to 0.89]). The risk reduction was smaller in community-dwelling elderly persons or postmenopausal women (relative risk, 0.89 [CI, 0.76 to 1.04]) and no risk reduction among community-dwelling women with history of fracture (relative risk, 1.02 [CI, 0.89 to 1.16]) (Figure 2).
Meta-regression analyses did not show differential effects depending on the daily dose of vitamin D supplementation (16 studies included; risk ratio per 100-IU increase in dose, 1.01 [CI, 0.97 to 1.07]) or the baseline blood 25-(OH)D concentration (12 studies included; risk ratio per 100-IU increase in concentration, 1.02 [CI, 0.86 to 1.2]).
Associations Between Vitamin D Status and Cancer and Fracture Outcomes
We included 28 observational studies: Three prospective cohort and 25 nested case-control studies evaluated the associations between baseline vitamin D status and risk for total cancer (35-37) or colorectal (19, 38-45), prostate (46-56), or breast (57-61) cancer (Supplement 3, available at www.annals.org) . One (4%), 17 (61%), and 10 (36%) of the 28 studies were of good, fair, and poor quality, respectively (Appendix Figure 5). Common limitations among the fair- or poor-quality observational studies were lack of adjustment of family history of cancer in the analyses, lack of justification of final statistical models, and unclear reporting of blinding of exposure or outcome assessors (Appendix Figure 6).
Three prospective cohorts (1 of good quality; 2 of fair quality) examined the associations between baseline vitamin D status and risk for total cancer mortality in 19,503 men and women (35-37), 86% of whom were from 1 study (36) in the United States (only this study included women). The mean follow-up ranged from 7 to 14 years, and the incidence of total cancer deaths ranged from 53 to 158 per 1000 persons. All studies observed higher baseline blood 25-(OH)D concentrations with increased risks for total cancer mortality among men, but this association was not found among women (reported in 1 study ). The ranges of blood 25-(OH)D concentrations and the shapes of the dose-response relationships varied across studies (Supplement 4, available at www.annals.org).
Of the 25 nested case-control studies included, 9 reported a colorectal cancer outcome (19, 38-45), 11 reported a prostate cancer outcome (46-56), and 5 reported a breast cancer outcome (57-61). The cancer outcomes were self-reported, with verification against medical records or linkage data from cancer registries in most studies; all stages of cancer were included.
For colorectal cancer, most studies found an inverse relationship with prediagnosis blood 25-(OH)D concentration (Figure 3, top). Our dose-response meta-analysis of 9 nested case-control studies showed that each 10-nmol/L increase in prediagnosis blood 25-(OH)D concentration was associated with a 6% (CI, 3% to 9%) reduction in risk for colorectal cancer (Table 2).
For prostate cancer, 3 poor-quality studies (with a total of 1147 cases) provided insufficient data for our dose-response meta-analyses (48, 51, 56). Findings from individual studies were mixed, and some studies suggested a nonlinear relationship (Figure 3, middle). Our dose-response meta-analysis of 8 nested case-control studies showed that each 10-nmol/L increase in prediagnosis blood 25-(OH)D concentration was not associated with risk for prostate cancer (Table 2).
For the female breast cancer outcome, 1 poor-quality study (of 142 cases) provided insufficient data for our dose-response meta-analyses (61). Only this study (not shown in the figure) and 1 of the remaining 4 studies found that higher prediagnosis blood 25-(OH)D was associated with a lower risk for breast cancer (Figure 3, bottom). Our dose-response meta-analysis of the 4 nested case-control studies showed that each 10-nmol/L increase in prediagnosis blood 25-(OH)D concentration was not associated with risk for breast cancer (Table 2).
A brief summary of the findings of the relationships between vitamin D status and fracture risk from the University of Ottawa Evidence-based Practice Center evidence report (8) is presented in Table 1.
Effects of Vitamin D With or Without Calcium on Changes in Vitamin D Status
In our 2009 evidence report (5), we used a scatter-plot to evaluate the net changes in blood 25-(OH)D concentration (that is, between-group differences in the change from baseline) against the doses of vitamin D supplementation using data from 26 RCTs of adults (Appendix Figure 7). The plot showed a clear relationship between increasing dose of vitamin D3 and increasing net change in blood 25-(OH)D concentration.
Adverse Events Associated With Vitamin D With or Without Calcium
The Women's Health Initiative trial found an increase in the risk for renal and urinary tract stones with supplementation (hazard ratio, 1.17 [CI, 1.02 to 1.34] for both outcomes) (18, 19, 62). No other identified study evaluated the effects of vitamin D with or without calcium supplements on renal outcomes.
Most of the RCTs included in our 2009 evidence report (5) and from our update did not provide information on adverse events and were not adequately powered to detect adverse events. Other RCTs reported a few cases of gastrointestinal disruption (such as constipation, diarrhea, or upset stomach), musculoskeletal soreness, primary hyperparathyroidism, hypercalcemia, and renal calculi. However, these adverse events may or may not be associated with the vitamin D or calcium supplements.
On the basis of the aggregate internal validity of the body of evidence for each key question—in turn based on the number, methodological quality, and size of studies; consistency of results between studies; and directness of evidence—we concluded that combined vitamin D (300 to 1100 IU/d) and calcium supplementation (500 to 1200 mg/d), but not vitamin D supplementation alone, can reduce the fracture risk in older adults. However, the effects may vary according to setting, with smaller effects in community-dwelling elderly persons or postmenopausal women than in institutionalized elderly persons. The evidence is not sufficiently robust to draw a conclusion about the benefits or harms of vitamin D supplementation for cancer prevention. Direct evidence from RCTs for the effects of vitamin D (with or without calcium) supplementation on cancer outcomes is limited and does not agree with data from observational studies. Limited data from RCTs suggest that a high dosage (1000 IU/d) of vitamin D can reduce the risk for total cancer.
Although data from observational studies suggest that higher blood 25-(OH)D concentrations may be associated with increased risks for total cancer, the threshold of a “safe” concentration remains unclear. Observational studies also suggest that the relationship between blood 25-(OH)D concentrations and risk for cancer may be site-specific and can vary across different populations. For example, our analyses showed that higher blood 25-(OH)D concentrations were associated with a reduced risk for colorectal cancer but not breast or prostate cancer. These results, however, are limited by the methodological quality of the included observational studies, particularly regarding the potential for residual confounding. Other issues that must be considered in interpreting the results from observational studies include shifts in methodological approaches to measure serum 25-(OH)D concentrations, the latitude or study location, and the time of year when blood was sampled.
Because of these issues, as well as the limitations of study-level meta-analysis (such as ecologic and publication bias) (63), the results of our dose-response meta-analyses must be interpreted with caution. One cannot predict the effects on the pooled effect estimates if these biases exist.
The Women's Health Initiative trial is the largest RCT included in the current review. This trial was rated as a good-quality effectiveness trial (in contrast with a more standardized efficacy trial) on the basis of supporting decision making about whether to actively recommend supplementation for an individual woman in the real-world setting. Critics of this study have pointed to the “low dosage” (400 IU/d) of vitamin D supplementation, lack of blood 25-(OH)D measurement, poor adherence, low baseline risk of the study population, and off-study use of additional vitamin D and calcium supplements during the trial as factors that could explain the null findings (64-66). Others have suspected that the adverse outcomes of renal and urinary stones were associated with excess calcium intake from both diet and calcium supplements (67). These concerns raise many important issues regarding the design and conduct of future trials of dietary supplements, which need to consider the myriad differences between nutrients and drugs, especially when the background exposure to a nutrient (such as vitamin D) cannot be reliably ascertained.
Current understanding of the benefits and harms of vitamin D (with or without calcium) supplements in the general population is chiefly limited by the difficulties in evaluating true vitamin D status. No methods are currently available to quantify the contribution of endogenous vitamin D synthesis resulting from sun exposure on an individual or a group, and serious limitations remain in accurately estimating dietary vitamin D intake because of the incompleteness of nutrient databases for both vitamin D-fortified food and vitamin D supplements. Moreover, the addition of vitamin D supplements to vitamin D taken in through all other means may exceed the safe level, resulting in harmful events (68, 69). This caution is supported by the recent finding from a randomized, double-blind, placebo-controlled trial examining the effects of a single annual megadose of vitamin D3 (500,000 IU, equivalent to approximately 1370 IU/d) on fall and fracture outcomes in community-dwelling elderly women with a history of fall or fracture (31). This RCT used the highest daily dose of vitamin D3 of all included RCTs and demonstrated that the megadose increased the risk for fractures and falls. Future study is needed to evaluate the appropriate dose and dosing regimens of vitamin D supplementation for bone health outcomes.