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Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet]. York (UK): Centre for Reviews and Dissemination (UK); 1995-.

Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet].

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

M Chung, J Lee, T Terasawa, J Lau, and TA Trikalinos.

Review published: 2011.

Link to full article: [Journal publisher]

CRD summary

The authors concluded that combined vitamin D and calcium supplementation can reduce fracture risk in adults. There was insufficient evidence to draw conclusions on cancer prevention. The authors' conclusion reflects the evidence presented and seems largely reliable.

Authors' objectives

To update on the effects of vitamin D supplementation (with or without calcium supplementation) on cancer and fracture outcomes in adults. The review also included an analysis of adverse events by supplementing new data to studies included in a previous review conducted by the authors (see Other Publications of Related Interest).

Searching

MEDLINE and Cochrane Central Register of Controlled Trials (CENTRAL) were searched to July 2011 for published articles in English. Search terms were reported. The original review also searched bibliographies.

Study selection

Randomised controlled trials (RCTs) of generally healthy adults (less than 20% with major chronic disease at baseline) that compared vitamin D supplementation (with or without calcium) with no supplementation or placebo in adults were eligible for inclusion. Trials of older ambulatory adults (≥65 years) with any disease except cancer were included. Cancer outcomes were incidence or death from all types of cancer and prostate, breast and colorectal cancer. Fracture outcomes were incidence of fracture at any site. Trials were excluded where: duration was less than one month; pregnant women were the only participants; vitamin D status was measured only during pregnancy; and synthetic vitamin D analogues were used.

Included studies in the update were conducted worldwide; several were in the UK. Most studies included male and female elderly participants or postmenopausal women located in hospitals, residential care or the community. Mean age ranged from 52.7 years to 85 years. Various intervention doses were reported in the paper. Intervention duration ranged from eight weeks to seven years.

[A: Two reviewers were involved in the selection of studies.]

Assessment of study quality

Trial quality was assessed for randomisation, allocation concealment, blinding, baseline similarity of groups, loss to follow-up, use of intention-to-treat analysis, adjustment for confounding and use of appropriate statistical analysis.

The authors stated that multiple reviewers carried out the quality assessment. Disagreements were resolved by consensus.

Data extraction

Data were extracted to enable calculation of hazard ratios (HR) or risk ratios (RR), with 95% confidence intervals (CI).

Data were extracted by one reviewer and checked by a second reviewer. Disagreements were resolved by consensus.

Methods of synthesis

Trials of cancer outcomes were combined in a narrative synthesis. For the analysis of fracture outcomes, effect sizes were pooled in a random-effects meta-analysis (DerSimonian and Laird). Random-effects meta-regression explored the influence of daily dose and baseline 25-(OH) D concentration. Statistical heterogeneity was assessed with the Q and I2 statistics (I2=25% was considered low heterogeneity, 50% moderate and 75% high). For cancer and fracture outcomes, results for combined vitamin D and calcium supplementation were reported separately from vitamin D supplementation alone. Subgroup analysis explored the effect of population setting (institutionalised or community-dwelling).

Results of the review

The authors reported that 19 RCTs were included for clinical outcome: three RCTs for cancer outcomes and 16 RCTs for fracture outcomes. Study quality was rated largely fair or good. Adjustment for confounders, loss to follow-up, unclear reporting of randomisation and allocation concealment were of concern in some studies. Follow-up ranged from seven months to seven years. It appeared that 35 studies were included for adverse events, but this was unclear.

Fracture outcomes (16 RCTs): Pooled analysis of combined Vitamin D and calcium supplementation versus placebo showed a statistically significant reduction in overall fracture risk (RR 0.88, 95% CI 0.79 to 0.99, I2=36%; 11 RCTs). This estimate was influenced by population setting, with a higher and statistically significant risk reduction in institutionalised elderly patients (RR 0.71, 95% CI 0.57 to 0.89, I2=0%; three RCTs) compared with patients who lived in the community.. There was no risk reduction in community-based women with a history of fracture (two RCTs). Pooled analysis showed no statistically significant effect on overall fracture risk in patients who received vitamin D supplementation versus placebo (five RCTs, I2=66%). Subgroup and meta-regression analyses did not reveal any influences on this finding.

Cancer outcomes (three RCTs): There were no statistically significant outcomes for cancer incidence or mortality in patients who received vitamin D supplementation versus placebo (two RCTs). Confidence intervals were wide in some cases, which suggested that clinically important effects in either direction could be possible. One trial (734 patients) assessed combined Vitamin D and calcium supplementation versus placebo and found significantly reductions in cancer incidence (RR 0.40, 95% CI 0.20 to 0.82) and mortality (RR 0.23, 95% CI 0.09 to 0.60). A second larger trial showed hazard ratios that ranged from 0.96 to 1.08 for cancer incidence, with narrow CIs for a range of cancer sites; none were statistically significant. .

Adverse events (apparently 35 RCTs): The authors reported that most studies did not supply sufficient information and were inadequately powered to detect adverse events. One RCT reported in detail (36,282 patients) in postmenopausal women who received vitamin D with or without calcium supplementation found a significantly increased risk for renal or urinary tract stones (HR 1.17, 1.02 to 1.34 for each outcome) compared with placebo.

Authors' conclusions

Combined vitamin D and calcium supplementation can reduce fracture risk, but the effects may be smaller in older adults who are community-dwelling than in those who are institutionalised. There was insufficient evidence to draw conclusions on the benefits and harms of vitamin D supplementation for the prevention of cancer.

CRD commentary

The review question was clear. Inclusion criteria were sufficiently replicable. Data sources included two large electronic databases. The restriction to published studies in English meant that relevant studies might have been overlooked and language and publication biases could not be ruled out. The review process was conducted with attempts to achieve transparency and rigour.

Quality assessment criteria were relevant to the included study designs and the results of this assessment were used in the discussion of the review findings. Study details were presented; the number of trials that reported on adverse events was unclear. Some discrepancies were noted between tables and text in the paper and between the paper and the full report.

The authors' conclusion reflects the evidence presented and seems largely reliable.

Implications of the review for practice and research

Practice: The authors did not state any implications for practice.

Research: The authors stated that appropriate dose and dosing regimens for vitamin D supplementation required further research.

Funding

Agency for Healthcare Research and Quality.

Bibliographic details

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 Annals of Internal Medicine 2011; 155(12): 827-838. [PubMed: 22184690]

Other publications of related interest

Chung M, Balk EM, Brendel M, Ip S, Lau J, Lee J, Lichtenstein A, Patel K, Raman G, Tatsioni A, Terasawa T, Trikalinos TA. Vitamin D and calcium: a systematic review of health outcomes. Rockville, MD, USA: Agency for Healthcare Research and Quality. Evidence Report/Technology Assessment; 183. 2009.

Indexing Status

Subject indexing assigned by NLM

MeSH

25-Hydroxyvitamin D 2 /blood; Advisory Committees; Age Factors; Calcium /administration & dosage /adverse effects; Dietary Supplements /adverse effects; Fractures, Bone /prevention & control; Humans; Neoplasms /prevention & control; Sex Factors; United States; Urinary Calculi /etiology; Vitamin D /administration & dosage /adverse effects

AccessionNumber

12012000003

Database entry date

25/01/2012

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.

CRD has determined that this article meets the DARE scientific quality criteria for a systematic review.

Copyright © 2014 University of York.

PMID: 22184690

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