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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 FREE

Mei Chung, PhD, MPH; Jounghee Lee, PhD; Teruhiko Terasawa, MD, PhD; Joseph Lau, MD; and Thomas A. Trikalinos, MD, PhD
[+] Article and Author Information

From Tufts Evidence-based Practice Center, Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, Massachusetts, and Department of Medicine, Fujita Health University School of Medicine, Tsu, Japan.


Disclaimer: The opinions expressed are those of the authors and do not reflect the official position of the Agency for Healthcare Research and Quality or the U.S. Preventive Services Task Force.

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 calcium (5), 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, mchung1@tuftsmedicalcenter.org.

Current Author Addresses: Drs. Chung, Lau, and Trikalinos: Tufts Evidence-based Practice Center, Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Box 63, 800 Washington Street, Boston, MA 02111.

Dr. Lee: Nutrition Education, Graduate School of Education, Kyonggi University, Suwon, Gyeonggi-do 443-760, Republic of Korea.

Dr. Terasawa: Department of Medicine, Fujita Health University Nanakuri Sanatorium, 424-1 Odoricho, Tsu, Mie, Japan.

Author Contributions: Conception and design: M. Chung, T. Terasawa, J. Lau, T.A. Trikalinos.

Analysis and interpretation of the data: M. Chung, J. Lee, T. Terasawa, T.A. Trikalinos.

Drafting of the article: M. Chung, T. Terasawa.

Critical revision of the article for important intellectual content: M. Chung, T. Terasawa, T.A. Trikalinos.

Final approval of the article: M. Chung, J. Lee, T. Terasawa, J. Lau, T.A. Trikalinos.

Statistical expertise: M. Chung, T.A. Trikalinos.

Obtaining of funding: J. Lau.

Administrative, technical, or logistic support: J. Lau.

Collection and assembly of data: M. Chung, J. Lee, T. Terasawa.


Ann Intern Med. 2011;155(12):827-838. doi:10.7326/0003-4819-155-12-201112200-00005
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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.

Editors' Notes
Context

  • People want to know about potential benefits and harms of vitamin D supplementation.

Contribution

  • This review of 19 trials and 28 observational studies reports the following: Combined vitamin D and calcium supplementation reduce fracture risk in older persons; optimum dosing regimens are unclear; effects of vitamin D supplementation on cancer risk are uncertain; and supplementation may increase the risk for renal and urinary tract stones.

Caution

  • Most trials involved older women. Observational studies were limited by confounding factors.

Implication

  • Vitamin D supplementation can reduce fracture risk, but optimal doses and effects on cancer risk are uncertain.

—The Editors

Editor's Note: The related draft recommendation statement will soon be available for public comment at www.uspreventiveservicestaskforce.org. The USPSTF will consider all submitted comments when it finalizes its recommendation. To sign up for notification about the posting of draft recommendation statements, please visit the USPSTF Web site.

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 (23). 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 (see Table 1 for full KQs).

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Appendix Figure 1.
Analytic framework and study questions.

KQ = key question.

* See “Study Selection” section for detailed population of interest.

† Blood 25-hydroxyvitamin D concentration was used as the indicator of vitamin D status.

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Table Jump PlaceholderTable 1.  Key Questions and Summary of Evidence Reviewed

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.

Data Synthesis

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) (1415) 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 (see the 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.

Search Results

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.

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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 report (5).

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Effects of Vitamin D, With or Without Calcium, on Cancer and Fracture Outcomes
Cancer

Three RCTs reported effects of vitamin D with or without calcium supplements on clinical cancer outcomes (Supplement 1). Cancer outcomes were secondary end points in all 3 RCTs. Of these, 2 RCTs (1617) 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 (1819) 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.

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Appendix Figure 3.
Quality assessment of 3 RCTs examining the effects of vitamin D with or without calcium supplementation on cancer outcomes.

NR = not reported; RCT = randomized, controlled trial.

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Vitamin D Supplementation Versus Placebo. Two fair-quality RCTs contributed information to this comparison (1617). 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 [1819] and 1 of fair quality [16]) enrolled a total of 37 016 postmenopausal women, 98% of whom were from the Women's Health Initiative trial (1819). Daily dose and regimen of vitamin D3 (plus calcium) supplementation were 400 IU (plus 1500 mg) in the Women's Health Initiative trial (1819) 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 (1819). 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).

Fracture

Sixteen RCTs (17, 2034) examined the effects of vitamin D with or without calcium supplements on fracture outcomes (Supplement 2). 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.

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Appendix Figure 4.
Quality assessment of 16 RCTs examining the effects of vitamin D with or without calcium supplementation on fracture outcomes.

NR = not reported; RCT = randomized, controlled trial.

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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, 2728, 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).

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Figure 1.
Results of random-effects meta-analysis of the effects of vitamin D supplementation compared with placebo on total fracture in randomized, controlled trials.
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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 (2126, 2930, 3234), 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).

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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.

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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
Cancer

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 (3537) or colorectal (19, 3845), prostate (4656), or breast (5761) cancer (Supplement 3). 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).

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Appendix Figure 5.
Distribution of quality rating in 3 prospective cohort and 25 nested case–control studies evaluating the associations between baseline vitamin D status and risks for any cancer, as well as colorectal, prostate, or breast cancer.

Numbers on the bars indicate the number of studies.

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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.

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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 (3537), 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 [36]). The ranges of blood 25-(OH)D concentrations and the shapes of the dose–response relationships varied across studies (Supplement 4).

Of the 25 nested case–control studies included, 9 reported a colorectal cancer outcome (19, 3845), 11 reported a prostate cancer outcome (4656), and 5 reported a breast cancer outcome (5761). 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).

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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. See the Appendix for methods used for the dose–response meta-analyses. 25-(OH)D = 25-hydroxyvitamin D.

* Men.

† Women.

‡ Both men and women.

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Table Jump PlaceholderTable 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

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).

Fractures

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.

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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 elsewhere (5). 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 included (21, 23, 34, 7597). 25-(OH)D = 25-hydroxyvitamin D; RCT = randomized, controlled trial.

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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) (1819, 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 (6466). 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 (6869). 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.

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Appendix

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 cases (7073). 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 equations (74). 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.

Figures

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Appendix Figure 1.
Analytic framework and study questions.

KQ = key question.

* See “Study Selection” section for detailed population of interest.

† Blood 25-hydroxyvitamin D concentration was used as the indicator of vitamin D status.

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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 report (5).

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Appendix Figure 3.
Quality assessment of 3 RCTs examining the effects of vitamin D with or without calcium supplementation on cancer outcomes.

NR = not reported; RCT = randomized, controlled trial.

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Appendix Figure 4.
Quality assessment of 16 RCTs examining the effects of vitamin D with or without calcium supplementation on fracture outcomes.

NR = not reported; RCT = randomized, controlled trial.

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Figure 1.
Results of random-effects meta-analysis of the effects of vitamin D supplementation compared with placebo on total fracture in randomized, controlled trials.
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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.

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Appendix Figure 5.
Distribution of quality rating in 3 prospective cohort and 25 nested case–control studies evaluating the associations between baseline vitamin D status and risks for any cancer, as well as colorectal, prostate, or breast cancer.

Numbers on the bars indicate the number of studies.

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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.

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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. See the Appendix for methods used for the dose–response meta-analyses. 25-(OH)D = 25-hydroxyvitamin D.

* Men.

† Women.

‡ Both men and women.

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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 elsewhere (5). 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 included (21, 23, 34, 7597). 25-(OH)D = 25-hydroxyvitamin D; RCT = randomized, controlled trial.

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Tables

Table Jump PlaceholderTable 1.  Key Questions and Summary of Evidence Reviewed
Table Jump PlaceholderTable 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

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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.
PubMed
 
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.
PubMed
 
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:SupplS88-9.
PubMed
 
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.
PubMed
 
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.
PubMed
 
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.
PubMed
 
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.
PubMed
 
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.
PubMed
 
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.
PubMed
 
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.
PubMed
 
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.
PubMed
 
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.
PubMed
 
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.
PubMed
 
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.
PubMed
 
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.
PubMed
 
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.
PubMed
 

Letters

NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Comments

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Follow-up period affects results of observational studies of cancer incidence
Posted on December 22, 2011
William B.Grant, Director, Epidemiologist
Sunlight, Nutrition and Health Research Center
Conflict of Interest: None Declared

The paper by Chung et al. (1) found a 6% (95% CI, 3%-9%) reduction in risk of colorectal cancer for a 10-nmol/L increase in serum 25- hydroxyvitmin D [25(OH)D] concentration but no statistically significant reduction for breast or colorectal cancer. The findings for colorectal and prostate cancer agree with other recent meta-analyses (2,3) but the finding for breast cancer differs. The reason for the difference for breast cancer is that the other two meta-analyses included case-control studies while (1) did not. The reason this is an important difference is that the usefulness of a single serum 25(OH)D concentration value from the time of enrollment in a cohort study decreases with time. A study in Norway found that the correlation coefficient for serum draws 14 years apart was 0.42 (4). For breast cancer, the adjusted probability of incidence decreases fairly rapidly with increasing follow-up time. When four case-control study results and five nested case-control study results were plotted vs. follow-up period, it was found that all five studies with follow-up period less than three years found significantly reduced relative risks for a 50-nmol/L change in 25(OH)D concentration, but none of those with longer follow-up periods did (5). The data were fit with a linear function that increased from 0.62 at zero years to 0.95 for seven years of follow up.

For colorectal cancer, there were statistically significant inverse correlations of incidence with respect to serum 25(OH)D concentration out to follow-up periods of 14 years (5).

All four studies (1-3,5) agree that there is no significant correlation between prediagnostic serum 25(OH)D concentration and incidence of prostate cancer out to follow-up times of 28 years. In (5) the linear fit to the relative risk declined from 1.09 at 3 years to 0.93 at 28 years. Prostate cancer is a very slow growing cancer, and it could be that risk of prostate cancer related to vitamin D occurs early in life.

Thus, the differences in findings from observational studies could be due to differences in rate of cancer development, from rapid for breast cancer to slow for prostate cancer.

As discussed in (2) and (5), the observational results for breast and colorectal cancer with respect to serum 25(OH)D concentration are consistent with findings from ecological studies based on indices of solar ultraviolet-B doses and corrected for confounding factors. Ecological studies also find inverse correlations for about 15 other types of cancer incidence and/or mortality rate.

References

1. Chung M, Lee J, Terasawa T, Lau J, Trikalinos TA. 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. Ann Intern Med. 2011;155:827-38.

2. Grant WB. Relation between prediagnostic serum 25-hydroxyvitamin D level and incidence of breast, colorectal, and other cancers. J Photochem Photobiol B. 2010;101:130-6.

3. Gandini S, Boniol M, Haukka J, Byrnes G, Cox B, Sneyd MJ, et al. Meta- analysis of observational studies of serum 25-hydroxyvitamin D levels and colorectal, breast and prostate cancer and colorectal adenoma. Int J Cancer. 2011;128:1414-24.

4. Jorde R, Sneve M, Hutchinson M, Emaus N, Figenschau Y, Grimnes G. Tracking of serum 25-hydroxyvitamin D levels during 14 years in a population-based study and during 12 months in an intervention study. Am J Epidemiol. 2010;171:903-8.

5. Grant WB. Effect of interval between serum draw and follow-up period on relative risk of cancer incidence with respect to 25-hydroxyvitamin D level; implications for meta-analyses and setting vitamin D guidelines, Deramato-Endocrinology. 2011;3:3:199-204.

Conflict of Interest:

I receive funding from the UV Foundation (McLean, VA), Bio-Tech-Pharmacal (Fayetteville, AR), the Vitamin D Council (San Luis Obispo, CA), and the Vitamin D Society (Canada).

Plasma 25-Hydroxyvitamin D3 vs. 1,25-Dihydroxyvitamin D3
Posted on December 23, 2011
GoranKrstic, PhD, Human Health Risk Assessment Specialist
Fraser Health
Conflict of Interest: None Declared

Taking into consideration that "observational studies were heterogeneous and were limited by potential confounders", Chung et al. [1] concluded that "evidence is not sufficiently robust to draw conclusions regarding the benefits or harms of vitamin D supplementation for the prevention of cancer". However, with the exception of breast cancer in the combined vitamin D and calcium supplementation group, the summary of evidence on the basis of the Supplement 1 presented in Table 1 of this study shows that mortality hazard ratios (HR) and relative risks (RR) are consistently lower for the cancer mortality when compared to the cancer incidence rates. Apparently, vitamin D supplementation may have a beneficial effect for improving prognosis and reducing cancer mortality in the elderly population. This is one of the important findings of the study which should be highlighted in the overall conclusion.

There is evidence in the published literature that incidence/mortality rates for some of the most common cancer types are negatively associated with regional insolation [2-5], suggesting that latitudinal variation in annual ultraviolet (UV-B) irradiation may play a role in the observed relationship through the production of vitamin D in the skin. In addition, a meta-analysis of vitamin D receptor (VDR) polymorphisms and cancer risk shows that two most studied VDR polymorphisms (Fok1 and Bsm1) could be involved in modulating the risks from breast, skin and prostate cancers [6], and the polymorphism on the loci for the genes encoding vitamin D activating enzyme 1-alpha hydroxylase (CYP27B1) is associated with the variation in colon cancer risk [7]. In their high-resolution map of VDR binding sites with influence on the immune and other functional pathways, Ramagopalan et al. [8] discuss the observed significant enrichment in regions near cancer- associated genes.

The presented meta-analysis by Chung et al. [1] depends inevitably on the accuracy of the observed vitamin D status which is measured in the studied elderly population(s) as a function of plasma 25-Hydroxyvitamin D3 (25[OH]D3 or calcidiol) concentration. However, the active form of vitamin D required for both the bone health and the functional immune system is 1,25-Dihydroxyvitamin D3 (1,25[OH]2D3 or calcitriol) [9-11], which could be low in individuals with insufficient or missing enzymes for the transformation of vitamin D precursors to the active 1,25[OH]2D3. In such individuals, one may observe "normal" or even higher than usual plasma levels of 25[OH]D3 which could prompt a potentially misleading conclusion that vitamin D has no effect on cancer prognosis/mortality or that higher levels in the circulation are associated with an elevated cancer risk [12]. For example, a recent study by Ramagopalan et al. [13] shows a causative role for CYP27B1 gene variants in multiple sclerosis (MS). Due to a lack of 1-alpha hydroxylase, even extremely high daily doses of vitamin D3 supplementation are not expected to improve the functional 1,25[OH]2D3 status in some MS patients and they may require a direct treatment with calcitriol [14].

When compared to the control groups, one may expect to observe a higher prevalence of impaired vitamin D metabolism/transformation among the cases of cancer or other diseases associated with vitamin D deficiency which may introduce a significant bias into a comparative epidemiological study. Hence, the upcoming new studies on the role/value of vitamin D in the prevention/treatment of cancer or other diseases should focus on the functional/active form of vitamin D (i.e., 1,25[OH]2D3) rather than to rely on its metabolic precursors as perhaps cost-effective and/or convenient proxies. As it is the case in all epidemiological studies, the quality of the output and the conclusions should be expected to reflect the quality of input data.

References

1. Chung M, Lee J, Terasawa T, Lau J, Trikalinos TA. 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. Ann Intern Med. 2011;155:827-838.

2. Garland CF, Garland FC, Gorham ED, Lipkin M, Newmark H, Mohr SB et al. The role of vitamin D in cancer prevention. Am J Public Health. 2006;96:252-261.

3. Grant WB. An ecological study of cancer incidence and mortality rates in France with respect to latitude, an index for vitamin D production. Dermatoendocrinol. 2010;2(2):62-67.

4. Boscoe FP, Schymura MJ. Solar ultraviolet-B exposure and cancer incidence and mortality in the United States, 1993-2002. BMC Cancer. 2006;6:264.

5. Giovannucci E. The epidemiology of vitamin D and cancer incidence and mortality: a review (United States). Cancer Causes Control. 2005;16(2):83-95.

6. Raimondi S, Johansson H, Maisonneuve P, Gandini S. Review and meta -analysis on vitamin D receptor polymorphisms and cancer risk. Carcinogenesis. 2009;30(7):1170-1180.

7. Dong LM, Ulrich CM, Hsu L, Duggan DJ, Benitez DS et al. Vitamin D related genes, CYP24A1 and CYP27B1, and colon cancer risk. Cancer Epidemiol Biomarkers Prev. 2009;18(9):2540-8.

8. Ramagopalan SV, Heger A, Berlanga AJ, Maugeri NJ, Lincoln MR, Burrell A, et al. A ChIP-seq defined genome-wide map of vitamin D receptor binding: associations with disease and evolution. Genome Res. 2010;20(10):1352-1360.

9. Sutton ALM, MacDonald PN. Vitamin D: More than a "Bone-a-Fide" hormone. Molecular Endocrinology. 2003;17(5):777-791.

10. Cutolo M. Vitamin D and autoimmune rheumatic diseases. 478 Rheumatology. 2009;48:210-212.

11. Bikle D. Nonclassic actions of vitamin D. J Clin Endocrinol Metab. 2009;94:26-34.

12. Krsti? G. Re: "Circulating 25-hydroxyvitamin D and risk of pancreatic cancer". Am J Epidemiol. 2011;173(4): 476.

13. Ramagopalan SV, Dyment DA, Cader MZ, Morrison KM, Disanto G, Morahan JM et al. Rare variants in the CYP27B1 gene are associated with multiple sclerosis. Ann Neurol. 2011;70(6):881-886.

14. Wingerchuk DM, Lesaux J, Rice GP, Kremenchutzky M, Ebers GC. A pilot study of oral calcitriol (1,25-dihydroxyvitamin D3) for relapsing- remitting multiple sclerosis. J Neurol Neurosurg Psychiatry. 2005;76(9):1294-6.

Conflict of Interest:

None declared

Regulation of the Metabolic Steps Fairly Complex
Posted on December 27, 2011
Arthur B.Chausmer, MD, PhD, FACP, FACE, FACN, CNS
Johns Hopkins University School of Medicine, Endocrinology, Diabates, and Metabolism
Conflict of Interest: None Declared

In the December 20th issue of the Annals there were two articles regarding vitamin D. The actual information was about the 25 hydroxycalciferol (25 OHD) intermediate metabolite and there are some other important points to consider when reading and assessing these articles. Among them is to remember that the regulation of the metabolic steps in this pathway are fairly complex involving at least phosphorus, calcium, PTH as well as hepatic and renal functionality. These, and other limitations, must all be considered when assessing any discussion of the vitamin D pathways and intermediates. Since the total body load of any of the D metabolites has yet to be quantitatively assessed, there is no way of knowing if there is a deficiency state or not; what relationship, if any, exists between blood levels and the total body stores; or what the relationship between the active and inactive metabolites might be. These are key points. The other key point to at least be remembered is that no matter how strong a statistical correlation may be, it in no way infers causality.

The popular, and wrong, interpretation of low serum 25 hydroxycholecalciferol (25 OHD) is that this reflects a vitamin D deficiency state. No one has any idea what the actual total body stores of 25 OHD or 1,25 dihydroxycholecalciferol (1,25 OHD) are. Therefore one cannot say the stores of either metabolite are low or anything about the relationship of the 25 OHD to 1,25 OHD, which is the active metabolite. 25 OHD is inactive for all practical purposes and measurements of this metabolite are of questionable physiologic significance. The extrapolations of indirect data on which some of the basic assumptions have been made are, at best, supposition and cannot be considered proof on which clinical decisions should be made. 25 OHD is an intermediate which is the result of 25 hydroxylation of calciferol in the liver. It is no more an index of whole body D status, or even 25 OHD status, than a low serum Na reflects total body Na stores in edema or lowserum K reflects intracellular K stores until there is profound depletion. The total body stores of D can be high, as it is a fat soluble vitamin, and the serum level low if the 25 hydroxylase is relatively inactive. The stores can be low and the circulating 250HD high if the 25 hydroxylase has been stimulated. These are but one set of examples. There are, of course, several other scenarios in which there is a less than acceptable correlation.

While there may be some suggestive evidence of non calcium activity for 25 OHD, it must still be considered physiologically inactive for all practical purposes. There has been no evidence other than suggestive correlations for these, and even those studies are arguable.

These points suggest a critical, and even skeptical, approach to the studies presented before any clinical actions are taken based on these data. These, of course, represent my own views and not necessarily of any organization with which I am affiliated.

Interpretation of the effects of calcium and vitamin D supplements
Posted on January 15, 2012
Mark JBolland, Senior Research Fellow, Andrew Grey, Ian R Reid
University of Auckland
Conflict of Interest: None Declared

It is surprising that Chung and colleagues did not address the issue of the potential increased cardiovascular risk of calcium supplements when considering effects of co-administered calcium and vitamin D on fracture risk (1). Previously, we reported that co-administered calcium and vitamin D increased the risk of myocardial infarction by 21%, stroke by 20%, and that the cardiovascular risks of calcium supplements outweighed their benefits on fracture prevention (2).

Chung and colleagues concluded that '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.' However, the relative risk of fracture with co-administered calcium and vitamin D for community dwelling individuals was 0.89 (0.76- 1.04) which was not statistically significant (1). Similarly, in a recent meta-analysis in this journal, Wang and colleagues concluded that "... vitamin D supplements at moderate to high doses may reduce CVD risk, whereas calcium supplements seem to have minimal cardiovascular effects" (3). In those analyses, the relative risk of cardiovascular events with vitamin D supplements was 0.90 (0.77-1.05) and with calcium supplements was 1.14 (0.92-1.41). Thus, for 3 statistically non-significant results of the same magnitude (10-15% increase or decrease in risk), 3 different conclusions were reported: 'small reductions in risk', N'may reduce risk', and 'no effect'. Inconsistent interpretations of statistically non- significant results for the effects of vitamin D and calcium supplements continue to create confusion for researchers, clinicians, patients, and the media, and possibly reflect the preconceptions of the authors as much as the analyses themselves.

References

1. Chung M, Lee J, Terasawa T, Lau J, Trikalinos TA. 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. Ann Intern Med. 2011;155(12):827-38.

2. Bolland MJ, Grey A, Avenell A, Gamble GD, Reid IR. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women's Health Initiative limited access dataset and meta-analysis. BMJ. 2011;342:d2040.

3. Wang L, Manson JE, Song Y, Sesso HD. Systematic review: Vitamin D and calcium supplementation in prevention of cardiovascular events. Ann Intern Med. 2010;152(5):315-23.

Conflict of Interest:

None declared

Vitamin D supplementation in cancer prevention; a solution?
Posted on February 7, 2012
Syed A.Hussain, Medical Physician, Adil Sheikh
Aga Khan University Hospital,Karachi,Pakistan
Conflict of Interest: None Declared

Chung et al in his article titled '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'has discussed the role of vitamin D and calcium supplementation in reduction of fracture risk and prevention of cancer(1).The authors while taking into account various RCTs and observational studies, could not reach a concrete conclusion on whether vitamin D supplementation can reduce cancer risk. Vitamin D along with its proven role in maintaining bone health has also been implicated to have tumor suppressor properties as seen in preclinical models (2).Pakistan has a significant cancer burden, the Karachi Cancer Registry (KCR) data shows a high prevalence of lung cancer and breast cancer along with a rising incidence for oral cavity, prostrate,gynecological and colorectal malignancies(3).Malignancies responsible for 7% of total mortality in Pakistan as per the WHO health report released in 2011.

In a survey conducted in Karachi a city harboring 9% of the Pakistan's population,where we looked at serum 25-hydroxy vitamin D levels of asymptomatic individuals age 30 and above from the community(4), 58% had vitamin D deficiency(<20 ng/dL) while 26% had vitamin D insufficiency(20-29 ng/dL).Only 25% reported daily use of vitamin D supplements and mean 25(OH) vitamin D levels were significantly higher in those using vitamin D supplements (23 vs 19 ng/dL p=0.021). Our study results paint a grim picture , showing that more than 80% of our urban community dwelling asymptomatic adults have low levels of vitamin D(<30ng/dL) , and more than 75% of this subset do not follow the recommendations of the 2011 Institute of Medicine(IOM) report on vitamin D supplementation.

The gross national income per capita in Pakistan is US$2590 and total health expenditure is 2.6% of GDP with approximately eight physicians per 10,000 people. Keeping in view the prevailing lack of health care services and resources, a cost effective program is required to fully utilize the benefits which can be obtained from vitamin D. Government support in the form of policies of food fortification with vitamin D, education regarding adequate sun exposure and highlighting benefits of supplementation of vitamin D in improving serum levels, may all prove to be astute strategies to combat the common finding of low levels of vitamin D in our population.

REFERENCES

1. Chung M, Lee J, Terasawa T, Lau J, Trikalinos TA. 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. Ann Intern Med. 2011 Dec 20;155(12):827-38.

2. Krishnan AV, Trump DL, Johnson CS, Feldman D. The role of vitamin D in cancer prevention and treatment. Endocrinol Metab Clin North Am. 2010 Jun;39(2):401-18, table of contents.

3. Bhurgri Y, Bhurgri A, Nishter S, Ahmed A, Usman A, Pervez S, et al. Pakistan--country profile of cancer and cancer control 1995-2004. J Pak Med Assoc. 2006 Mar;56(3):124-30.

4. Sheikh A, Saeed Z, Jafri S A, Yazdani I, Hussain S. Vitamin D levels in asymptomatic adults-a population survey in Karachi,Pakistan. Under peer review. 2012.

Conflict of Interest:

None declared

Vitamin D Status vs. Cancer Survival/Prognosis
Posted on June 25, 2012
Goran Krstic, PhD
Fraser Health, New Westminster, BC
Conflict of Interest: None Declared

In the current (June 2012) summary of recommendations and evidence regarding Vitamin D and Calcium Supplementation to Prevent Cancer and Osteoporotic Fractures in Adults, the U.S. Preventive Services Task Force (USPSTF) indicates that “the current evidence is insufficient to assess the balance of the benefits and harms of vitamin D supplementation, with or without calcium, for the primary prevention of cancer in adults.” and that “There is inadequate evidence to determine the effect of vitamin D supplementation, with or without calcium, on overall cancer incidence and mortality in adults.”

 Although vitamin D and calcium are often discussed as related supplements, it should be emphasized that an assessment of the effects of 400 IU of vitamin D3 combined with 1,000 mg of calcium carbonate supplementation on cancer incidence and/or mortality is not the same as, for example, 2,000 IU vitamin D3 supplementation without calcium carbonate vs. cancer mortality, survival rate and/or prognosis. Hence, vitamin D and calcium carbonate supplementations should be considered as two separate treatments requiring two separate evidence-based recommendations. A role of vitamin D in the immune system modulation should be recognized in light of the current evidence in the published literature [1-4]. Cancer patients should have their vitamin D status checked and those with an established vitamin D deficiency/insufficiency should be advised to take steps to improve their vitamin D status ether by supplementation or by spending more time outdoors exposed to sunlight.A statement by the USPSTF regarding renal stones that “There is adequate evidence that supplementation with ≤400 IU of vitamin D3 and 1,000 mg of calcium carbonate increases the incidence of renal stones.” is correct. However, it should be emphasized for the reader that the observed higher incidence of renal stone formation in the treatment when compared to the control group is associated with the calcium carbonate (not vitamin D) supplementation. A ≤400 IU of vitamin D3 supplementation is probably not sufficient to have a significant impact on the vitamin D status in the studied population. For example, a dose of 250 µg vitamin D/day (10,000 IU) for up to 5 months is not expected to elevate circulating 25(OH)D to the concentrations greater than 90 ng/mL (225 nmol/L), while doses < 25 µg vitamin D/day (<1,000 IU) are inadequate for maintaining physiologically normal circulating 25(OH)D concentrations of 15 to 80 ng/mL (37 to 200 nmol/L) [5].

Taking into consideration that “observational studies were heterogeneous and were limited by potential confounders”, Chung et al. [6] concluded that “evidence is not sufficiently robust to draw conclusions regarding the benefits or harms of vitamin D supplementation for the prevention of cancer”. However, with the exception of breast cancer in the combined vitamin D and calcium supplementation group, the summary of evidence on the basis of the Supplement 1 presented in Table 1 of this study shows that hazard ratios (HR) and risk ratios (RR) are consistently lower for the cancer mortality when compared to the cancer incidence rates. Apparently, vitamin D supplementation may have a beneficial effect for improving prognosis and reducing cancer mortality in the elderly population. This is one of the important findings of the study which should be highlighted in the overall conclusion.There is evidence in the published literature that incidence/mortality rates for some of the most common cancer types are negatively associated with regional insolation [7-10], suggesting that latitudinal variation in annual ultraviolet (UV-B) irradiation may play a role in the observed relationship through the production of vitamin D in the skin. In addition, a meta-analysis of vitamin D receptor (VDR) polymorphisms and cancer risk shows that two most studied VDR polymorphisms (Fok1 and Bsm1) could be involved in modulating the risks from breast, skin and prostate cancers [11], and the polymorphism on the loci for the genes encoding vitamin D activating enzyme 1-alpha hydroxylase (CYP27B1) is associated with the variation in colon cancer risk [12]. In their high-resolution map of VDR binding sites with influence on the immune and other functional pathways, Ramagopalan et al. [13] discuss the observed significant enrichment in regions near cancer-associated genes.

The presented meta-analysis by Chung et al. [6] depends inevitably on the accuracy of the observed vitamin D status which is measured in the studied elderly population(s) as a function of plasma 25-Hydroxyvitamin D3 (25[OH]D3 or calcidiol) concentration. However, the active form of vitamin D required for both the bone health and the functional immune system is 1,25-Dihydroxyvitamin D3 (1,25[OH]2D3 or calcitriol) [4,14,15], which could be low in individuals with insufficient or missing enzymes for the transformation of vitamin D precursors to the active 1,25[OH]2D3. In such individuals, one may observe “normal” or even higher than usual plasma levels of 25[OH]D3 which could prompt a potentially misleading conclusion that vitamin D has no effect on cancer prognosis/mortality or that higher levels in the circulation are associated with an elevated cancer risk [16]. For example, a recent study by Ramagopalan et al. [17] shows a causative role for CYP27B1 gene variants in multiple sclerosis (MS). Due to a lack of 1-alpha hydroxylase, even extremely high daily doses of vitamin D3 supplementation are not expected to improve the functional 1,25[OH]2D3 status in some MS patients and they may require a direct treatment with calcitriol [18].When compared to the control groups, one may expect to observe a higher prevalence of impaired vitamin D metabolism/transformation among the cases of cancer or other diseases associated with vitamin D deficiency which may introduce a significant bias into a comparative epidemiological study. Hence, the upcoming new studies on the role/value of vitamin D in the prevention/treatment of cancer or other diseases should focus on the functional/active form of vitamin D (i.e., 1,25[OH]2D3) rather than to rely on its metabolic precursors as perhaps cost-effective and/or convenient proxies. As it is the case in all epidemiological studies, the quality of the output and the conclusions should be expected to reflect the quality of input data.

References

1. Baeke F, Takiishi T, Korf H, Gysemans C, Mathieu C. Vitamin D: modulator of the immune system. Curr Opin Pharmacol. 2010;10(4):482-96.

2. Kamen DL, Tangpricha V. Vitamin D and molecular actions on the immune system: modulation of innate and autoimmunity. J Mol Med (Berl). 2010;88(5): 441–450.

3. Mead MN. Benefits of sunlight: A bright spot for human health. Environ Health Perspect. 2008;116(4):A160-A167.

4. Cutolo M. Vitamin D and autoimmune rheumatic diseases. Rheumatology 2009;48:210-212.

5. Hollis BW and Wagner CL. Assessment of dietary vitamin D requirements during pregnancy and lactation. Am J Clin Nutr. 2004;79(5):717-726.

6. Chung M, Lee J, Terasawa T, Lau J, Trikalinos TA. 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. Ann Intern Med. 2011;155:827-838.

7. Garland CF, Garland FC, Gorham ED, Lipkin M, Newmark H, Mohr SB et al. The role of vitamin D in cancer prevention. Am J Public Health. 2006;96:252–261.

8. Grant WB. An ecological study of cancer incidence and mortality rates in France with respect to latitude, an index for vitamin D production. Dermatoendocrinol. 2010;2(2):62-67.

9. Boscoe FP, Schymura MJ. Solar ultraviolet-B exposure and cancer incidence and mortality in the United States, 1993-2002. BMC Cancer. 2006;6:264.

10. Giovannucci E. The epidemiology of vitamin D and cancer incidence and mortality: a review (United States). Cancer Causes Control. 2005;16(2):83-95.

11. Raimondi S, Johansson H, Maisonneuve P, Gandini S. Review and meta-analysis on vitamin D receptor polymorphisms and cancer risk. Carcinogenesis. 2009;30(7):1170–1180.

12. Dong LM, Ulrich CM, Hsu L, Duggan DJ, Benitez DS et al. Vitamin D related genes, CYP24A1 and CYP27B1, and colon cancer risk. Cancer Epidemiol Biomarkers Prev. 2009;18(9):2540-8.

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