Final Evidence Summary
Other Supporting Document for Vitamin D and Calcium to Prevent Fractures: Preventive Medication
Vitamin D With or Without Calcium Supplementation for Prevention of Cancer and Fractures
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 D1. 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 D2, 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 cells4. These functions suggest a possible role of vitamin D in cancer prevention.
This review is based in part on our 2009 evidence report5 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 calcium6. 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 methods7, 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 calcium5 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 20078. In the current review, we present a focused update of these 2 systematic reviews5, 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 elsewhere5. 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 report5 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 poor9. For RCTs, we applied quality items described in the CONSORT (Consolidated Standards of Reporting Trials) statement10. For observational studies, we applied quality items described in the STROBE (Strengthening the Reporting of Observational studies in Epidemiology) statement11, 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-analysis12 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 only13.
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 RCTs16, 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 RCT18, 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 RCT16 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 comparison16, 17. Dose and regimen of vitamin D3 supplementation were 100,000 IU every 4 months in the trial conducted in the United Kingdom17 and 1100 IU daily in the trial conducted in Nebraska16. 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 16 enrolled a total of 37,016 postmenopausal women, 98% of whom were from the Women's Health Initiative trial18, 19. Daily dose and regimen of vitamin D3 (plus calcium) supplementation were 400 IU (plus 1500 mg) in the Women's Health Initiative trial18, 19 and 1100 IU (plus 1400 to 1500 mg) in the trial in Nebraska16. 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 incidence18, 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 RCTs17, 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 women17, 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 persons21-26, 29, 30, 32-34, mostly (69%) postmenopausal women from the Women's Health Initiative trial33. 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 cancer35-37 or colorectal19, 38-45, prostate46-56, or breast57-61 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 women35-37, 86% of whom were from 1 study36 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 36. 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 outcome19, 38-45, 11 reported a prostate cancer outcome46-56, and 5 reported a breast cancer outcome57-61. 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-analyses48, 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-analyses61. 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).
Effects of Vitamin D With or Without Calcium on Changes in Vitamin D Status
In our 2009 evidence report5, 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 report5 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 findings64-66. Others have suspected that the adverse outcomes of renal and urinary stones were associated with excess calcium intake from both diet and calcium supplements67. 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 events68, 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 fracture31. 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.
Copyright and Source Information
Source: This article was first published in Annals of Internal Medicine (Ann Intern Med 2011;155:827-838; http://www.annals.org)
Acknowledgment: The authors thank 6 additional investigators who participated in the design, implementation, and writing of the Tufts Evidence-based Practice Center evidence report on vitamin D and calcium5, including abstract screening, but were not primarily responsible for the re-mapping of analytic framework or updated analyses and did not participate in writing this manuscript: Stanley Ip, MD; Gowri Raman, MD, MS; Athina Tatsioni, MD, PhD; Kamal Patel, MPH, MS; Alice H. Lichtenstein, DSc; and Ethan M. Balk, MD, MPH. None of these investigators discloses any conflict of interest. Jenny Lamont, MS, edited a draft of this manuscript; she takes no responsibility for the content of this manuscript.
Grant Support: By Agency for Healthcare Research and Quality contract HHSA 290-2007-10055-I.
Potential Conflicts of Interest: Drs. Chung, Lee, and Trikalinos: Grant (money to institution): AHRQ Effective Health Care Program, under contract with Tufts Evidence-based Practice Center. Dr. Lau: Grant (money to institution): AHRQ. Disclosures can be also viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M11-1328.
Requests for Single Reprints: Mei Chung, PhD, MPH, Tufts Evidence-based Practice Center, Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Box 63, 800 Washington Street, Boston, MA 02111; e-mail, email@example.com.
Current author addresses and author contributions are available at http://www.annals.org.>
Appendix Figure 2. Summary of evidence search and selection.
KQ = key question; RCT = randomized, controlled trial.
* A total of 16,733 citations were screened for a wide array of clinical outcomes. The 3971 citations refer to those specifically from the cancer and bone health search, but potentially relevant citations from searches for other outcomes were also screened for cancer and bone health outcomes.
† A total of 584 full-text articles were retrieved for review for a wide array of clinical outcomes, including cancer and bone health outcomes.
‡ Reasons for exclusion are in the 2009 evidence report5.
Appendix Figure 6. Quality assessment of observational studies examining the associations between baseline vitamin D status and risk for cancer.
Quality item “<20% loss to follow-up” was applicable only to prospective cohort studies (total cancer outcome). A. Three prospective cohort studies reporting total cancer outcome. B. Nine nested case–control studies reporting colorectal cancer outcome. C. Eleven nested case–control studies reporting prostate cancer outcome. D. Five nested case–control studies reporting breast cancer outcome.
Appendix Figure 7. Effects of vitamin D with or without calcium supplementation on the net changes in serum 25-(OH)D concentrations.
We explored the dose–response relationships between the doses of vitamin D (with or without calcium) and net changes in serum 25-(OH)D concentrations graphically, using a scatterplot where the observed net changes in 25-(OH)D concentration were plotted against the doses of vitamin D3 supplementation. Studies were included only if they reported sufficient data to estimate both mean net change and SE of the net change. Calculations of mean net change and SE of the net change were described elsewhere5. Each circle represents an RCT. The size of the circle is proportional to the sample size of the RCT. A total of 26 RCTs were included21, 23, 34, 75–97.
(OH)D = 25-hydroxyvitamin D; RCT = randomized, controlled trial.
Table 1. Key Questions and Summary of Evidence Reviewed
|KQs and Comparisons of Interest||Outcomes||Studies (Total
|Methodologic Quality||Follow-up Duration||Main Findings||Supplement or Appendix Figure Providing Details|
|KQ 1: What are the effects of vitamin D with or without calcium supplements on the clinical outcomes of cancer and fractures in RCTs? (overarching question)|
|Vitamin D supplementation vs. placebo*||Total cancer||2 RCTs (n = 3577)||2 fair||4–5 y||1 RCT in elderly men and women, aged ≥71 y (n = 2686)
Incidence: HR, 1.09 (95% CI, 0.86–1.36)
Mortality: HR, 0.86 (CI, 0.61–1.20)
1 RCT in postmenopausal women, aged >55 y (n = 891)†
|Colorectal cancer||1 RCT (n = 2686)||1 fair||5 y||Incidence: HR, 1.02 (CI, 0.60–1.74)
Mortality: HR, 0.62 (CI, 0.24–1.60)
|Breast cancer||1 RCT (n = 2686)||1 fair||5 y||Incidence: HR, 0.99 (CI, 0.25–4.0)
|Fracture||5 RCTs (n = 14,583)||1 good
|7 mo–5 y||Meta-analysis of 5 RCTs in elderly men and women (n = 14,583)
Overall: RR, 1.03 (CI, 0.84–1.26)
Institutionalized: RR, 0.99 (CI, 0.72–1.34)
Community-dwelling: RR, 1.06 (CI, 0.77–1.46)
|Combined vitamin D and calcium supplementation vs. placebo||Total cancer||2 RCTs (n = 37,016)||1 good
|4–7 y||1 RCT in postmenopausal women, aged >55 y (n = 734)†
Incidence: RR, 0.40 (CI, 0.20–0.82)‡
Mortality: RR, 0.23 (CI, 0.09–0.60)‡
1 RCT in postmenopausal women (n = 36,282)
|1 RCT (n = 36,282)||1 good||7 y||Incidence: HR, 1.08 (CI, 0.86–1.34)
Mortality: HR, 0.82 (CI, 0.52–1.29)
|Breast cancer||1 RCT (n = 36,282)||1 good||7 y||Incidence: HR, 0.96 (CI, 0.86–1.07)
Mortality: HR, 0.99 (CI, 0.55–1.76)
|Fracture||11 RCTs (n = 52,915)||2 good
|1–7 y||Meta-analysis of 11 RCTs in mostly (69%) postmenopausal women (n = 52,915)
Overall: RR, 0.88 (CI, 0.79–0.99)‡
Institutionalized: RR, 0.71 (CI, 0.57–0.89)‡
Community-dwelling: RR, 0.89 (CI, 0.76–1.04)
Community-dwelling with history of fracture: RR, 1.02 (CI, 0.89–1.16)
|KQ 2: What are the associations between vitamin D status and the clinical outcomes of cancer and fractures in observational studies?|
|Dose–response relationship between 25-(OH)D concentration at baseline and risk for cancer||Total cancer||3 prospective cohort studies (n = 19,503)||1 good
|Mean, 7–14 y||Higher 25-(OH)D concentrations were associated with increased risk for total cancer mortality in men, but the ranges of 25-(OH)D concentrations varied across studies
One study found that baseline blood 25-(OH)D concentration was not associated with risk for total cancer mortality in adult women (n = 8914)
|Colorectal cancer||9 nested case–control studies (3136 cases)||8 fair
|NA||Linear dose–response meta-analysis of 9 studies
Pooled adjusted OR, 0.94 (CI, 0.91–0.97)‡ per 10-nmol/L increase in 25-(OH)D concentration
|Prostate cancer||11 nested case–control studies (4005 cases)||4 fair
|NA||Linear dose–response meta-analysis of 8 studies
Pooled adjusted OR, 1.01 (CI, 0.99–1.04) per 10-nmol/L increase in 25-(OH)D concentration
|Breast cancer||5 nested case–control studies (3128 cases)||3 fair
|NA||Linear dose–response meta-analysis of 4 studies
Pooled adjusted OR, 0.99 (CI, 0.97–1.01) per 10-nmol/L increase in 25-(OH)D concentration
|Fracture||15 studies (3 prospective cohorts and 12 case–control studies) were reviewed in the University of Ottawa Evidence-based Practice Center evidence report8||Overall, there is inconsistent evidence for an association between serum 25-(OH)D concentrations and the risk for fractures.
One of 3 cohorts reported an inverse association between blood 25-(OH)D concentrations and fracture rates, and 9 of 12 case–control studies found significantly lower 25-(OH)D concentrations in cases vs. controls.
|KQ 3: What are the effects of vitamin D with or without calcium supplements on the net changes in vitamin D status in RCTs?|
|Dose of vitamin D supplement||Net changes in blood 25-(OH)D concentration||26 RCTs included in our 2009 evidence report5||Clear relationship between increasing dose of vitamin D3 and increasing net change in blood 25-(OH)D concentration||Appendix Figure 7|
|KQ 4: What are the adverse outcomes associated with vitamin D and calcium supplements in RCTs?|
|Vitamin D with or without calcium supplementation vs. placebo||Adverse events||All 63 RCTs included in our 2009 evidence report5 and 19 RCTs included in the focused update||The majority of RCTs did not provide information on adverse events and were not adequately powered to detect adverse events.
1 RCT in postmenopausal women (n = 36,282)
25-(OH)D = 25-hydroxyvitamin D; HR = hazard ratio; KQ = key question; NA = not applicable; NR = not reported; OR = odds ratio; RCT = randomized, controlled trial; RR = risk ratio.
* We considered the comparison of combined vitamin D and calcium supplementation vs. calcium supplementation alone to be equivalent to vitamin D supplementation vs. placebo.
† Sample size is specific to the comparison. This 3-group RCT enrolled a total of 1179 postmenopausal women.
‡ Statistically significant (P < 0.05).
Table 2. Results of Linear Mixed-Effects Meta-Regression to Examine the Dose–Response Relationships Between Each 10-nmol/L Increase in Prediagnosis Blood 25-Hydroxyvitamin D Concentration and the Risks for Colorectal, Prostate, and Breast Cancer in Nested Case–Control Studies
|Outcomes||Studies (Reference)||Methodologic Quality||Case-Patients and Controls, n*||Pooled Adjusted
OR (95% CI)†
|Colorectal cancer||9 nested case–control studies19, 38–45||8 fair, 1 poor||1127 case-patients
|Prostate cancer||8 nested case–control studies46, 47, 49, 50, 52–55||4 fair, 4 poor||2399 case-patients
|Female breast cancer||4 nested case–control studies57–60||3 fair, 1 poor||2363 case-patients
OR = odds ratio.
* Effective counts of case-patients and controls. Go to the Appendix for methods used for the dose–response meta-analyses.
† Different covariates were adjusted across studies.
A total of 33 publications met our eligibility criteria for KQ 2 (the associations between vitamin D status and the clinical outcomes of cancer), but 5 publications were excluded because they were superseded by later publications in the same cohort with more cancer cases70-73. Many cohorts had multiple publications reporting different cancer outcomes of interest. There was no overlap in study populations in each cancer outcome in our systematic review and in each dose–response meta-regression.
We performed linear dose–response meta-regressions to examine the associations between blood 25-(OH)D concentrations and the risk for prostate and colorectal cancers by using a mixed-effect logistic regression model. Specifically, we fitted a mixed-effects meta-regression (with fixed intercepts and random slopes) using the exact binomial likelihood, which explicitly models between-study variability in the strength of the dose–response relationship. For each study, we back-calculated the “effective counts” of events in each category of 25-(OH)D concentration based on the pertinent adjusted log odds ratios (vs. a reference exposure category), their variance, and the total number of participants per exposure category and by solving a set of nonlinear equations74. The effective counts of events are such that when used in a logistic regression with the exposure categories as the sole predictors, they result in the same log odds ratios (coefficients), variances, and covariances as those from the original adjusted model. The mean value per exposure category of 25-(OH)D concentration is also needed for dose–response meta-regressions. When it was not reported, the midpoint between exposure category thresholds was selected, and for the open categories, we imputed a mean intake 20% lower for the lowest quintile threshold or 20% higher for the highest quintile threshold, respectively.
To show the individual study results in Figure 3, we calculate the adjusted probability of cancer (odds/[1 + odds]) by using the effective numbers of case-patients and controls and plotted against the mean value of each exposure category of 25-(OH)D concentration.
Figure 2. Results of random-effects model meta-analysis of the effects of combined vitamin D and calcium supplementation as compared with placebo on total fracture in randomized, controlled trials.
NS = not specified; NV = nonvertebral.
* Equally allocated groups.
† Unequally allocated groups; 2 women were randomly assigned to the control group for every 1 woman randomly assigned to the treatment group.
Figure 3. Relationships between prediagnosis blood 25-(OH)D concentrations and risks for colorectal, prostate, and breast cancer in individual nested case–control studies included in the dose–response meta-analyses.
Circle size is proportional to the number of cancer cases relative to all other studies included in the same panel. Go to the Appendix for methods used for the dose–response meta-analyses. 25-(OH)D = 25-hydroxyvitamin D.
* Men. † Women. ‡ Both men and women.
- Norman AW. A vitamin D nutritional cornucopia: new insights concerning the serum 25-hydroxyvitamin D status of the US population [Editorial]. Am J Clin Nutr. 2008;88:1455-6. [PMID: 19064502]
- Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266-81. [PMID: 17634462]
- DeLuca HF. Overview of general physiologic features and functions of vitamin D. Am J Clin Nutr. 2004;80:1689S-96S. [PMID: 15585789]
- Norman AW, Bouillon R. Vitamin D nutritional policy needs a vision for the future. Exp Biol Med (Maywood). 2010;235:1034-45. [PMID: 20667908]
- Chung M, Balk EM, Brendel M, Ip S, Lau J, Lee J, et al. Vitamin D and Calcium: A Systematic Review of Health Outcomes. Evidence Report No. 183. (Prepared by the Tufts Evidence-based Practice Center under contract HHSA 290-2007-10055-I.) AHRQ Publication No. 09-E105. Rockville, MD: Agency for Healthcare Research and Quality; 2009. Accessed at http://www.ahrq.gov/research/findings/evidence-based-reports/vitadcal.pdf on 19 September 2013.
- Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academies Press; 2011.
- Harris RP, Helfand M, Woolf SH, Lohr KN, Mulrow CD, Teutsch SM, et al; Methods Work Group, Third US Preventive Services Task Force. Current methods of the US Preventive Services Task Force: a review of the process. Am J Prev Med. 2001;20:21-35. [PMID: 11306229]
- Cranney A, Horsley T, O’Donnell S, Weiler H, Puil L, Ooi D, et al. Effectiveness and Safety of Vitamin D in Relation to Bone Health. Evidence Report/Technology Assessment No. 158 (Prepared by the University of Ottawa Evidence-based Practice Center under contract 290-02-0021). AHRQ Publication No. 07-E013. Rockville, MD: Agency for Healthcare Research and Quality; 2007. Accessed at archive.ahrq.gov/downloads/pub/evidence/pdf/vitamind/vitad.pdf on 19 September 2013.
- Agency for Healthcare Research and Quality. Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews, version 1.0, 2007. Rockville, MD: U.S. Department of Health and Human Services, Agency for Healthcare Research and Quality; 2007. Accessed at http://effectivehealthcare.ahrq.gov/repFiles/2007_10DraftMethodsGuide.pdf on 12 November 2011.
- Moher D, Schulz KF, Altman D; CONSORT Group (Consolidated Standards of Reporting Trials). The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomized trials. JAMA. 2001;285:1987-91. [PMID: 11308435]
- von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP; STROBE Initiative. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Ann Intern Med. 2007;147:573-7. [PMID: 17938396]
- DerSimonian R, Laird N. Meta-Analysis in clinical trials. Control Clin Trials. 1986;7:177-88. [PMID: 3802833]
- Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557-60. [PMID: 12958120]
- Berkey CS, Hoaglin DC, Mosteller F, Colditz GA. A random-effects regression model for meta-analysis. Stat Med. 1995;14:395-411. [PMID: 7746979]
- Knapp G, Hartung J. Improved tests for a random effects meta-regression with a single covariate. Stat Med. 2003;22:2693-710. [PMID: 12939780]
- Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr. 2007;85:1586-91. [PMID: 17556697]
- Trivedi DP, Doll R, Khaw KT. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial. BMJ. 2003;326:469. [PMID: 12609940]
- Chlebowski RT, Johnson KC, Kooperberg C, Pettinger M, Wactawski-Wende J, Rohan T, et al; Women’s Health Initiative Investigators. Calcium plus vitamin D supplementation and the risk of breast cancer. J Natl Cancer Inst. 2008;100:1581-91. [PMID: 19001601]
- Wactawski-Wende J, Kotchen JM, Anderson GL, Assaf AR, Brunner RL, O’Sullivan MJ, et al; Women’s Health Initiative Investigators. Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med. 2006;354:684-96. [PMID: 16481636]
- Lyons RA, Johansen A, Brophy S, Newcombe RG, Phillips CJ, Lervy B, et al. Preventing fractures among older people living in institutional care: a pragmatic randomised double blind placebo controlled trial of vitamin D supplementation. Osteoporos Int. 2007;18:811-8. [PMID: 17473911]
- Chapuy MC, Arlot ME, Duboeuf F, Brun J, Crouzet B, Arnaud S, et al. Vitamin D3 and calcium to prevent hip fractures in the elderly women. N Engl J Med. 1992;327:1637-42. [PMID: 1331788]
- Chapuy MC, Pamphile R, Paris E, Kempf C, Schlichting M, Arnaud S, et al. Combined calcium and vitamin D3 supplementation in elderly women: confirmation of reversal of secondary hyperparathyroidism and hip fracture risk: the Decalyos II study. Osteoporos Int. 2002;13:257-64. [PMID: 11991447]
- Dawson-Hughes B, Harris SS, Krall EA, Dallal GE. Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. N Engl J Med. 1997;337:670-6. [PMID: 9278463]
- Flicker L, MacInnis RJ, Stein MS, Scherer SC, Mead KE, Nowson CA, et al. Should older people in residential care receive vitamin D to prevent falls? Results of a randomized trial. J Am Geriatr Soc. 2005;53:1881-8. [PMID: 16274368]
- Grant AM, Avenell A, Campbell MK, McDonald AM, MacLennan GS, McPherson GC, et al; RECORD Trial Group. Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial. Lancet. 2005;365:1621-8. [PMID: 15885294]
- Komulainen MH, Kröger H, Tuppurainen MT, Heikkinen AM, Alhava E, Honkanen R, et al. HRT and Vit D in prevention of non-vertebral fractures in postmenopausal women; a 5 year randomized trial. Maturitas. 1998;31:45-54. [PMID: 10091204]
- Law M, Withers H, Morris J, Anderson F. Vitamin D supplementation and the prevention of fractures and falls: results of a randomised trial in elderly people in residential accommodation. Age Ageing. 2006;35:482-6. [PMID: 16641143]
- Lips P, Graafmans WC, Ooms ME, Bezemer PD, Bouter LM. Vitamin D supplementation and fracture incidence in elderly persons. A randomized, placebo-controlled clinical trial. Ann Intern Med. 1996;124:400-6. [PMID: 8554248]
- Porthouse J, Cockayne S, King C, Saxon L, Steele E, Aspray T, et al. Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care. BMJ. 2005;330:1003. [PMID: 15860827]
- Salovaara K, Tuppurainen M, Kärkkäinen M, Rikkonen T, Sandini L, Sirola J, et al. Effect of vitamin D(3) and calcium on fracture risk in 65- to 71-year-old women: a population-based 3-year randomized, controlled trial—the OSTPRE-FPS. J Bone Miner Res. 2010;25:1487-95. [PMID: 20200964]
- Sanders KM, Stuart AL, Williamson EJ, Simpson JA, Kotowicz MA, Young D, et al. Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA. 2010;303:1815-22. [PMID: 20460620]
- Harwood RH, Sahota O, Gaynor K, Masud T, Hosking DJ; Nottingham Neck of Femur (NONOF) Study. A randomised, controlled comparison of different calcium and vitamin D supplementation regimens in elderly women after hip fracture: the Nottingham Neck of Femur (NONOF) Study. Age Ageing. 2004;33:45-51. [PMID: 14695863]
- Jackson RD, LaCroix AZ, Gass M, Wallace RB, Robbins J, Lewis CE, et al; Women’s Health Initiative Investigators. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med. 2006;354:669-83. [PMID: 16481635]
- Pfeifer M, Begerow B, Minne HW, Abrams C, Nachtigall D, Hansen C. Effects of a short-term vitamin D and calcium supplementation on body sway and secondary hyperparathyroidism in elderly women. J Bone Miner Res. 2000;15:1113-8. [PMID: 10841179]
- Cawthon PM, Parimi N, Barrett-Connor E, Laughlin GA, Ensrud KE, Hoffman AR, et al; Osteoporotic Fractures in Men (MrOS) Research Group. Serum 25-hydroxyvitamin D, parathyroid hormone, and mortality in older men. J Clin Endocrinol Metab. 2010;95:4625-34. [PMID: 20631024]
- Freedman DM, Looker AC, Abnet CC, Linet MS, Graubard BI. Serum 25-hydroxyvitamin D and cancer mortality in the NHANES III study (1988-2006). Cancer Res. 2010;70:8587-97. [PMID: 20847342]
- Michaëlsson K, Baron JA, Snellman G, Gedeborg R, Byberg L, Sundström J, et al. Plasma vitamin D and mortality in older men: a community-based prospective cohort study. Am J Clin Nutr. 2010;92:841-8. [PMID: 20720256]
- Feskanich D, Ma J, Fuchs CS, Kirkner GJ, Hankinson SE, Hollis BW, et al. Plasma vitamin D metabolites and risk of colorectal cancer in women. Cancer Epidemiol Biomarkers Prev. 2004;13:1502-8. [PMID: 15342452]
- Garland CF, Comstock GW, Garland FC, Helsing KJ, Shaw EK, Gorham ED. Serum 25-hydroxyvitamin D and colon cancer: eight-year prospective study. Lancet. 1989;2:1176-8. [PMID: 2572900]
- Jenab M, Bueno-de-Mesquita HB, Ferrari P, van Duijnhoven FJ, Norat T, Pischon T, et al. Association between pre-diagnostic circulating vitamin D concentration and risk of colorectal cancer in European populations: a nested case-control study. BMJ. 2010;340:b5500. [PMID: 20093284]
- Otani T, Iwasaki M, Sasazuki S, Inoue M, Tsugane S; Japan Public Health Center-Based Prospective Study Group. Plasma vitamin D and risk of colorectal cancer: the Japan Public Health Center-Based Prospective Study. Br J Cancer. 2007;97:446-51. [PMID: 9242478]
- Tangrea J, Helzlsouer K, Pietinen P, Taylor P, Hollis B, Virtamo J, et al. Serum levels of vitamin D metabolites and the subsequent risk of colon and rectal cancer in Finnish men. Cancer Causes Control. 1997;8:615-25. [PMID: 9242478]
- Weinstein SJ, Yu K, Horst RL, Ashby J, Virtamo J, Albanes D. Serum 25-hydroxyvitamin D and risks of colon and rectal cancer in Finnish men. Am J Epidemiol. 2011;173:499-508. [PMID: 21248311]
- Woolcott CG, Wilkens LR, Nomura AM, Horst RL, Goodman MT, Murphy SP, et al. Plasma 25-hydroxyvitamin D levels and the risk of colorectal cancer: the multiethnic cohort study. Cancer Epidemiol Biomarkers Prev. 2010; 19:130-4. [PMID: 20056631]
- Wu K, Feskanich D, Fuchs CS, Willett WC, Hollis BW, Giovannucci EL. A nested case control study of plasma 25-hydroxyvitamin D concentrations and risk of colorectal cancer. J Natl Cancer Inst. 2007;99:1120-9. [PMID: 17623801]
- Ahn J, Peters U, Albanes D, Purdue MP, Abnet CC, Chatterjee N, et al; Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Project Team. Serum vitamin D concentration and prostate cancer risk: a nested case-control study. J Natl Cancer Inst. 2008;100:796-804. [PMID: 18505967]
- Ahonen MH, Tenkanen L, Teppo L, Hakama M, Tuohimaa P. Prostate cancer risk and prediagnostic serum 25-hydroxyvitamin D levels (Finland). Cancer Causes Control. 2000;11:847-52. [PMID: 11075874]
- Baron JA, Beach M, Wallace K, Grau MV, Sandler RS, Mandel JS, et al. Risk of prostate cancer in a randomized clinical trial of calcium supplementation. Cancer Epidemiol Biomarkers Prev. 2005;14:586-9. [PMID: 15767334]
- Braun MM, Helzlsouer KJ, Hollis BW, Comstock GW. Prostate cancer and prediagnostic levels of serum vitamin D metabolites (Maryland, United States). Cancer Causes Control. 1995;6:235-9. [PMID: 7612803]
- Jacobs ET, Giuliano AR, Martínez ME, Hollis BW, Reid ME, Marshall JR. Plasma levels of 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and the risk of prostate cancer. J Steroid Biochem Mol Biol. 2004;89-90:533-7. [PMID: 15225833]
- Li H, Stampfer MJ, Hollis JB, Mucci LA, Gaziano JM, Hunter D, et al. A prospective study of plasma vitamin D metabolites, vitamin D receptor polymorphisms, and prostate cancer. PLoS Med. 2007;4:e103. [PMID: 17388667]
- Mikhak B, Hunter DJ, Spiegelman D, Platz EA, Hollis BW, Giovannucci E. Vitamin D receptor (VDR) gene polymorphisms and haplotypes, interactions with plasma 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, and prostate cancer risk. Prostate. 2007;67:911-23. [PMID: 17440943]
- Nomura AM, Stemmermann GN, Lee J, Kolonel LN, Chen TC, Turner A, et al. Serum vitamin D metabolite levels and the subsequent development of prostate cancer (Hawaii, United States). Cancer Causes Control. 1998;9:425-32. [PMID: 9794175]
- Park SY, Cooney RV, Wilkens LR, Murphy SP, Henderson BE, Kolonel LN. Plasma 25-hydroxyvitamin D and prostate cancer risk: the multiethnic cohort. Eur J Cancer. 2010;46:932-6. [PMID: 20064705]
- Travis RC, Crowe FL, Allen NE, Appleby PN, Roddam AW, Tjønneland A, et al. Serum vitamin D and risk of prostate cancer in a case-control analysis nested within the European Prospective Investigation into Cancer and Nutrition (EPIC). Am J Epidemiol. 2009;169:1223-32. [PMID: 19359375]
- Tuohimaa P, Tenkanen L, Ahonen M, Lumme S, Jellum E, Hallmans G, et al. Both high and low levels of blood vitamin D are associated with a higher prostate cancer risk: a longitudinal, nested case-control study in the Nordic countries. Int J Cancer. 2004;108:104-8. [PMID: 14618623]
- Almquist M, Bondeson AG, Bondeson L, Malm J, Manjer J. Serum levels of vitamin D, PTH and calcium and breast cancer risk-a prospective nested case-control study. Int J Cancer. 2010;127:2159-68. [PMID: 20112341]
- Bertone-Johnson ER, Chen WY, Holick MF, Hollis BW, Colditz GA, Willett WC, et al. Plasma 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D and risk of breast cancer. Cancer Epidemiol Biomarkers Prev. 2005;14:1991-7. [PMID: 16103450]
- Freedman DM, Chang SC, Falk RT, Purdue MP, Huang WY, McCarty CA, et al. Serum levels of vitamin D metabolites and breast cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Cancer Epidemiol Biomarkers Prev. 2008;17:889-94. [PMID: 18381472]
- McCullough ML, Stevens VL, Patel R, Jacobs EJ, Bain EB, Horst RL, et al. Serum 25-hydroxyvitamin D concentrations and postmenopausal breast cancer risk: a nested case control study in the Cancer Prevention Study-II Nutrition Cohort. Breast Cancer Res. 2009;11:R64. [PMID: 19715600]
- Rejnmark L, Tietze A, Vestergaard P, Buhl L, Lehbrink M, Heickendorff L, et al. Reduced prediagnostic 25-hydroxyvitamin D levels in women with breast cancer: a nested case-control study. Cancer Epidemiol Biomarkers Prev. 2009;18:2655-60. [PMID: 19789365]
- Wallace RB, Wactawski-Wende J, O’Sullivan MJ, Larson JC, Cochrane B, Gass M, et al. Urinary tract stone occurrence in the Women’s Health Initiative (WHI) randomized clinical trial of calcium and vitamin D supplements. Am J Clin Nutr. 2011;94:270-7. [PMID: 21525191]
- Lyman GH, Kuderer NM. The strengths and limitations of meta-analyses based on aggregate data. BMC Med Res Methodol. 2005;5:14. [PMID: 15850485]
- Forman MR, Levin B. Calcium plus vitamin D3 supplementation and colorectal cancer in women [Editorial]. N Engl J Med. 2006;354:752-4. [PMID: 16481644]
- Holick MF. Calcium plus vitamin D and the risk of colorectal cancer [Letter]. N Engl J Med. 2006;354:2287-8. [PMID: 16723623]
- Finkelstein JS. Calcium plus vitamin D for postmenopausal women—bone appétit? [Editorial]. N Engl J Med. 2006;354:750-2. [PMID: 16481643]
- Favus MJ. The risk of kidney stone formation: the form of calcium matters [Editorial]. Am J Clin Nutr. 2011;94:5-6. [PMID: 21633076]
- Guallar E, Miller ER 3rd, Ordovas JM, Stranges S. Vitamin D supplementation in the age of lost innocence [Editorial]. Ann Intern Med. 2010;152:327-9. [PMID: 20194240]
- Braun MM, Helzlsouer KJ, Hollis BW, Comstock GW. Colon cancer and serum vitamin D metabolite levels 10-17 years prior to diagnosis. Am J Epidemiol. 1995;142:608-11. [PMID: 7653469]
- Freedman DM, Looker AC, Chang SC, Graubard BI. Prospective study of serum vitamin D and cancer mortality in the United States. J Natl Cancer Inst. 2007;99:1594-602. [PMID: 17971526]
- Gann PH, Ma J, Hennekens CH, Hollis BW, Haddad JG, Stampfer MJ. Circulating vitamin D metabolites in relation to subsequent development of prostate cancer. Cancer Epidemiol Biomarkers Prev. 1996;5:121-6. [PMID: 8850273]
- Platz EA, Leitzmann MF, Hollis BW, Willett WC, Giovannucci E. Plasma 1,25-dihydroxy- and 25-hydroxyvitamin D and subsequent risk of prostate cancer. Cancer Causes Control. 2004;15:255-65. [PMID: 15090720]
- Tuohimaa P, Tenkanen L, Syvälä H, Lumme S, Hakulinen T, Dillner J, et al. Interaction of factors related to the metabolic syndrome and vitamin D on risk of prostate cancer. Cancer Epidemiol Biomarkers Prev. 2007;16:302-7. [PMID: 17301263]
- Hamling J, Lee P, Weitkunat R, Ambühl M. Facilitating meta-analyses by deriving relative effect and precision estimates for alternative comparisons from a set of estimates presented by exposure level or disease category. Stat Med. 2008;27:954-70. [PMID: 17676579]
- Björkman M, Sorva A, Risteli J, Tilvis R. Vitamin D supplementation has minor effects on parathyroid hormone and bone turnover markers in vitamin D-deficient bedridden older patients. Age Ageing. 2008;37:25-31. [PMID: 17965037]
- Blum M, Dallal GE, Dawson-Hughes B. Body size and serum 25 hydroxy vitamin D response to oral supplements in healthy older adults. J Am Coll Nutr. 2008;27:274-9. [PMID: 18689559]
- Bunout D, Barrera G, Leiva L, Gattas V, de la Maza MP, Avendanõ M, et al. Effects of vitamin D supplementation and exercise training on physical performance in Chilean vitamin D deficient elderly subjects. Exp Gerontol. 2006;41:746-52. [PMID: 16797903]
- Chel V, Wijnhoven HA, Smit JH, Ooms M, Lips P. Efficacy of different doses and time intervals of oral vitamin D supplementation with or without calcium in elderly nursing home residents. Osteoporos Int. 2008;19:663-71. [PMID: 17874029]
- Deroisy R, Collette J, Albert A, Jupsin I, Reginster JY. Administration of a supplement containing both calcium and vitamin D is more effective than calcium alone to reduce secondary hyperparathyroidism in postmenopausal women with low 25(OH)vitamin D circulating levels. Aging Clin Exp Res. 2002;14:13-7. [PMID: 12027147]
- Himmelstein S, Clemens TL, Rubin A, Lindsay R. Vitamin D supplementation in elderly nursing home residents increases 25(OH)D but not 1,25(OH)2D. Am J Clin Nutr. 1990;52:701-6. [PMID: 2403063]
- Kenny AM, Biskup B, Robbins B, Marcella G, Burleson JA. Effects of vitamin D supplementation on strength, physical function, and health perception in older, community-dwelling men. J Am Geriatr Soc. 2003;51:1762-7. [PMID: 14687355]
- Krieg MA, Jacquet AF, Bremgartner M, Cuttelod S, Thiébaud D, Burckhardt P. Effect of supplementation with vitamin D3 and calcium on quantitative ultrasound of bone in elderly institutionalized women: a longitudinal study. Osteoporos Int. 1999;9:483-8. [PMID: 10624454]
- Pfeifer M, Begerow B, Minne HW, Nachtigall D, Hansen C. Effects of a short-term vitamin D(3) and calcium supplementation on blood pressure and parathyroid hormone levels in elderly women. J Clin Endocrinol Metab. 2001;86:1633-7. [PMID: 11297596]
- Sorva A, Risteli J, Risteli L, Välimäki M, Tilvis R. Effects of vitamin D and calcium on markers of bone metabolism in geriatric patients with low serum 25-hydroxyvitamin D levels. Calcif Tissue Int. 1991;49 (Suppl):S88-9. [PMID: 1933612]
- Zhu K, Devine A, Dick IM, Wilson SG, Prince RL. Effects of calcium and vitamin D supplementation on hip bone mineral density and calcium-related analytes in elderly ambulatory Australian women: a five-year randomized controlled trial. J Clin Endocrinol Metab. 2008;93:743-9. [PMID: 18089701]
- Barnes MS, Robson PJ, Bonham MP, Strain JJ, Wallace JM. Effect of vitamin D supplementation on vitamin D status and bone turnover markers in young adults. Eur J Clin Nutr. 2006;60:727-33. [PMID: 16391584]
- Bolton-Smith C, McMurdo ME, Paterson CR, Mole PA, Harvey JM, Fenton ST, et al. Two-year randomized controlled trial of vitamin K1 (phylloquinone) and vitamin D3 plus calcium on the bone health of older women. J Bone Miner Res. 2007;22:509-19. [PMID: 17243866]
- Harris SS, Dawson-Hughes B. Plasma vitamin D and 25OHD responses of young and old men to supplementation with vitamin D3. J Am Coll Nutr. 2002;21:357-62. [PMID: 12166534]
- Heaney RP, Davies KM, Chen TC, Holick MF, Barger-Lux MJ. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr. 2003;77:204-10. [PMID: 12499343]
- Heikkinen A, Parviainen MT, Tuppurainen MT, Niskanen L, Komulainen MH, Saarikoski S. Effects of postmenopausal hormone replacement therapy with and without vitamin D3 on circulating levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D. Calcif Tissue Int. 1998;62:26-30. [PMID: 9405729]
- Honkanen R, Alhava E, Parviainen M, Talasniemi S, Mönkkönen R. The necessity and safety of calcium and vitamin D in the elderly. J Am Geriatr Soc. 1990;38:862-6. [PMID: 2387950]
- Jensen C, Holloway L, Block G, Spiller G, Gildengorin G, Gunderson E, et al. Long-term effects of nutrient intervention on markers of bone remodeling and calciotropic hormones in late-postmenopausal women. Am J Clin Nutr. 2002;75:1114-20. [PMID: 12036821]
- Nelson ML, Blum JM, Hollis BW, Rosen C, Sullivan SS. Supplements of 20 microg/d cholecalciferol optimized serum 25-hydroxyvitamin D concentrations in 80% of premenopausal women in winter. J Nutr. 2009;139:540-6. [PMID: 19158226]
- Orwoll ES, Weigel RM, Oviatt SK, McClung MR, Deftos LJ. Calcium and cholecalciferol: effects of small supplements in normal men. Am J Clin Nutr. 1988;48:127-30. [PMID: 2839025]
- Patel R, Collins D, Bullock S, Swaminathan R, Blake GM, Fogelman I. The effect of season and vitamin D supplementation on bone mineral density in healthy women: a double-masked crossover study. Osteoporos Int. 2001;12:319-25. [PMID: 11420782]
- Riis B, Christiansen C, Rodbro P. The effect of different vitamin D treatments on serum vitamin D levels in early postmenopausal women. Acta Vitaminol Enzymol. 1984;6:77-82. [PMID: 6093487]
- Trang HM, Cole DE, Rubin LA, Pierratos A, Siu S, Vieth R. Evidence that vitamin D3 increases serum 25-hydroxyvitamin D more efficiently than does vitamin D2. Am J Clin Nutr. 1998;68:854-8. [PMID: 9771862]
Internet Citation: Final Evidence Summary: Vitamin D and Calcium to Prevent Fractures: Preventive Medication. U.S. Preventive Services Task Force. August 2014.