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Meta-Analysis
. 2014 Jun 23;2014(6):CD007469.
doi: 10.1002/14651858.CD007469.pub2.

Vitamin D supplementation for prevention of cancer in adults

Goran Bjelakovic  1 , Lise Lotte Gluud, Dimitrinka Nikolova, Kate Whitfield, Goran Krstic, Jørn Wetterslev, Christian Gluud
Affiliations
Meta-Analysis

Vitamin D supplementation for prevention of cancer in adults

Goran Bjelakovic et al. Cochrane Database Syst Rev. .

Abstract

Background: The evidence on whether vitamin D supplementation is effective in decreasing cancers is contradictory.

Objectives: To assess the beneficial and harmful effects of vitamin D supplementation for prevention of cancer in adults.

Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, LILACS, Science Citation Index Expanded, and the Conference Proceedings Citation Index-Science to February 2014. We scanned bibliographies of relevant publications and asked experts and pharmaceutical companies for additional trials.

Selection criteria: We included randomised trials that compared vitamin D at any dose, duration, and route of administration versus placebo or no intervention in adults who were healthy or were recruited among the general population, or diagnosed with a specific disease. Vitamin D could have been administered as supplemental vitamin D (vitamin D₃ (cholecalciferol) or vitamin D₂ (ergocalciferol)), or an active form of vitamin D (1α-hydroxyvitamin D (alfacalcidol), or 1,25-dihydroxyvitamin D (calcitriol)).

Data collection and analysis: Two review authors extracted data independently. We conducted random-effects and fixed-effect model meta-analyses. For dichotomous outcomes, we calculated the risk ratios (RRs). We considered risk of bias in order to assess the risk of systematic errors. We conducted trial sequential analyses to assess the risk of random errors.

Main results: Eighteen randomised trials with 50,623 participants provided data for the analyses. All trials came from high-income countries. Most of the trials had a high risk of bias, mainly for-profit bias. Most trials included elderly community-dwelling women (aged 47 to 97 years). Vitamin D was administered for a weighted mean of six years. Fourteen trials tested vitamin D₃, one trial tested vitamin D₂, and three trials tested calcitriol supplementation. Cancer occurrence was observed in 1927/25,275 (7.6%) recipients of vitamin D versus 1943/25,348 (7.7%) recipients of control interventions (RR 1.00 (95% confidence interval (CI) 0.94 to 1.06); P = 0.88; I² = 0%; 18 trials; 50,623 participants; moderate quality evidence according to the GRADE instrument). Trial sequential analysis (TSA) of the 18 vitamin D trials shows that the futility area is reached after the 10th trial, allowing us to conclude that a possible intervention effect, if any, is lower than a 5% relative risk reduction. We did not observe substantial differences in the effect of vitamin D on cancer in subgroup analyses of trials at low risk of bias compared to trials at high risk of bias; of trials with no risk of for-profit bias compared to trials with risk of for-profit bias; of trials assessing primary prevention compared to trials assessing secondary prevention; of trials including participants with vitamin D levels below 20 ng/mL at entry compared to trials including participants with vitamin D levels of 20 ng/mL or more at entry; or of trials using concomitant calcium supplementation compared to trials without calcium. Vitamin D decreased all-cause mortality (1854/24,846 (7.5%) versus 2007/25,020 (8.0%); RR 0.93 (95% CI 0.88 to 0.98); P = 0.009; I² = 0%; 15 trials; 49,866 participants; moderate quality evidence), but TSA indicates that this finding could be due to random errors. Cancer occurrence was observed in 1918/24,908 (7.7%) recipients of vitamin D₃ versus 1933/24,983 (7.7%) in recipients of control interventions (RR 1.00 (95% CI 0.94 to 1.06); P = 0.88; I² = 0%; 14 trials; 49,891 participants; moderate quality evidence). TSA of the vitamin D₃ trials shows that the futility area is reached after the 10th trial, allowing us to conclude that a possible intervention effect, if any, is lower than a 5% relative risk reduction. Vitamin D₃ decreased cancer mortality (558/22,286 (2.5%) versus 634/22,206 (2.8%); RR 0.88 (95% CI 0.78 to 0.98); P = 0.02; I² = 0%; 4 trials; 44,492 participants; low quality evidence), but TSA indicates that this finding could be due to random errors. Vitamin D₃ combined with calcium increased nephrolithiasis (RR 1.17 (95% CI 1.03 to 1.34); P = 0.02; I² = 0%; 3 trials; 42,753 participants; moderate quality evidence). TSA, however, indicates that this finding could be due to random errors. We did not find any data on health-related quality of life or health economics in the randomised trials included in this review.

Authors' conclusions: There is currently no firm evidence that vitamin D supplementation decreases or increases cancer occurrence in predominantly elderly community-dwelling women. Vitamin D₃ supplementation decreased cancer mortality and vitamin D supplementation decreased all-cause mortality, but these estimates are at risk of type I errors due to the fact that too few participants were examined, and to risks of attrition bias originating from substantial dropout of participants. Combined vitamin D₃ and calcium supplements increased nephrolithiasis, whereas it remains unclear from the included trials whether vitamin D₃, calcium, or both were responsible for this effect. We need more trials on vitamin D supplementation, assessing the benefits and harms among younger participants, men, and people with low vitamin D status, and assessing longer duration of treatments as well as higher dosages of vitamin D. Follow-up of all participants is necessary to reduce attrition bias.

PubMed Disclaimer

Conflict of interest statement

Goran Bjelakovic (GB): None known. Lise Lotte Gluud (LLG): None known. Dimitrinka Nikolova (DN): None known. Kate Whitfield (KW): None known. Goran Krstic (GK): None known. Jørn Wetterslev (JW): None known. Christian Gluud (CG): None known.

Figures

1
1
Study flow diagram.
2
2
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
4
4
Funnel plot of comparison: 1 Vitamin D versus placebo or no intervention, outcome: 1.1 Cancer occurrence in trials with a low or high risk of bias.
5
5
Trial sequential analysis on cancer occurrence in the 18 vitamin D trials was performed based on cancer occurrence of 10% in the control group, a relative risk reduction of 5% with vitamin D supplementation, a type I error of 5%, and a type II error of 20% (80% power). There was no diversity. This resulted in a required information size of 110,505 participants. Trial sequential analysis of all vitamin D trials suggests that the futility area is reached after the 10th trial allowing us to conclude that any possible intervention effect, if any, is lower than a 5% relative risk reduction. The blue line represents the cumulative Z‐score of the meta‐analysis. The green lines represent the conventional statistical boundaries. The red inward sloping lines represent the trial sequential monitoring boundaries.
6
6
Trial sequential analysis on cancer mortality in the four vitamin D trials was performed based on cancer mortality of 3% in the control group, a relative risk reduction of 10% with vitamin D₃ supplementation, a type I error of 5%, and a type II error of 20% (80% power). There was no diversity. The required information size was 110,505 participants. The cumulative Z‐curve (blue line) did not cross the trial sequential monitoring boundary (red line) after the fourth trial. The blue line represents the cumulative Z‐score of the meta‐analysis. The green lines represent the conventional statistical boundaries. The red inward sloping lines represent the trial sequential monitoring boundaries.
1.1
1.1. Analysis
Comparison 1 Vitamin D versus placebo or no intervention, Outcome 1 Cancer occurrence in trials with a low or high risk of bias.
1.2
1.2. Analysis
Comparison 1 Vitamin D versus placebo or no intervention, Outcome 2 Cancer occurrence and risk of for‐profit bias.
1.3
1.3. Analysis
Comparison 1 Vitamin D versus placebo or no intervention, Outcome 3 Cancer occurrence in primary and secondary prevention trials.
1.4
1.4. Analysis
Comparison 1 Vitamin D versus placebo or no intervention, Outcome 4 Cancer occurrence and vitamin D status.
1.5
1.5. Analysis
Comparison 1 Vitamin D versus placebo or no intervention, Outcome 5 Cancer occurrence ('best‐worst case' and 'worst‐best case' scenario).
1.6
1.6. Analysis
Comparison 1 Vitamin D versus placebo or no intervention, Outcome 6 Cancer occurrence in trials using vitamin D₃ (cholecalciferol).
1.7
1.7. Analysis
Comparison 1 Vitamin D versus placebo or no intervention, Outcome 7 Cancer occurrence in trials using vitamin D₃ singly or combined with calcium.
1.8
1.8. Analysis
Comparison 1 Vitamin D versus placebo or no intervention, Outcome 8 Lung cancer occurrence in trials using vitamin D₃ (cholecalciferol).
1.9
1.9. Analysis
Comparison 1 Vitamin D versus placebo or no intervention, Outcome 9 Breast cancer occurrence in trials using vitamin D₃ (cholecalciferol).
1.10
1.10. Analysis
Comparison 1 Vitamin D versus placebo or no intervention, Outcome 10 Colorectal cancer occurrence in trials using vitamin D₃ (cholecalciferol).
1.11
1.11. Analysis
Comparison 1 Vitamin D versus placebo or no intervention, Outcome 11 Pancreatic cancer occurrence in trials using vitamin D₃ (cholecalciferol).
1.12
1.12. Analysis
Comparison 1 Vitamin D versus placebo or no intervention, Outcome 12 Prostate cancer occurrence in trials using vitamin D₃ (cholecalciferol).
1.13
1.13. Analysis
Comparison 1 Vitamin D versus placebo or no intervention, Outcome 13 Uterine cancer occurrence in trials using vitamin D₃ (cholecalciferol).
1.14
1.14. Analysis
Comparison 1 Vitamin D versus placebo or no intervention, Outcome 14 Ovarian cancer occurrence in trials using vitamin D₃ (cholecalciferol).
1.15
1.15. Analysis
Comparison 1 Vitamin D versus placebo or no intervention, Outcome 15 Oesophageal cancer occurrence in trials using vitamin D₃ (cholecalciferol).
1.16
1.16. Analysis
Comparison 1 Vitamin D versus placebo or no intervention, Outcome 16 Stomach cancer occurrence in trials using vitamin D₃ (cholecalciferol).
1.17
1.17. Analysis
Comparison 1 Vitamin D versus placebo or no intervention, Outcome 17 Liver cancer occurrence in trials using vitamin D₃ (cholecalciferol).
1.18
1.18. Analysis
Comparison 1 Vitamin D versus placebo or no intervention, Outcome 18 Cancer occurrence in trials using vitamin D₂ (ergocalciferol).
1.19
1.19. Analysis
Comparison 1 Vitamin D versus placebo or no intervention, Outcome 19 Cancer occurrence in trials using calcitriol.
1.20
1.20. Analysis
Comparison 1 Vitamin D versus placebo or no intervention, Outcome 20 Breast cancer occurrence in trials using calcitriol.
1.21
1.21. Analysis
Comparison 1 Vitamin D versus placebo or no intervention, Outcome 21 Uterine cancer occurrence in trials using calcitriol.
1.22
1.22. Analysis
Comparison 1 Vitamin D versus placebo or no intervention, Outcome 22 Stomach cancer occurrence in trials using calcitriol.
1.23
1.23. Analysis
Comparison 1 Vitamin D versus placebo or no intervention, Outcome 23 All‐cause mortality in trials with a low or high risk of bias.
1.24
1.24. Analysis
Comparison 1 Vitamin D versus placebo or no intervention, Outcome 24 All‐cause mortality ('best‐worst case' and 'worst‐best case' scenario).
1.25
1.25. Analysis
Comparison 1 Vitamin D versus placebo or no intervention, Outcome 25 Cancer mortality.
1.26
1.26. Analysis
Comparison 1 Vitamin D versus placebo or no intervention, Outcome 26 Cancer mortality ('best‐worst case' and 'worst‐best case' scenario).
1.27
1.27. Analysis
Comparison 1 Vitamin D versus placebo or no intervention, Outcome 27 Adverse events.
See this image and copyright information in PMC

Update of

  • doi: 10.1002/14651858.CD007469

References

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References to studies excluded from this review

Anderson 2010 {published data only}
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Chadha 2010 {published data only}
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References to ongoing studies

ACTRN12611000402943 {published data only}
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ISRCTN17873085 {published data only}
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