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Cochrane Database of Systematic Reviews

Vitamin D supplementation for prevention of cancer in adults

Information

DOI:
https://doi.org/10.1002/14651858.CD007469.pub2Copy DOI
Database:
  1. Cochrane Database of Systematic Reviews
Version published:
  1. 23 June 2014see what's new
Type:
  1. Intervention
Stage:
  1. Review
Cochrane Editorial Group:
  1. Cochrane Metabolic and Endocrine Disorders Group

Copyright:
  1. Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Authors

  • Goran Bjelakovic

    Correspondence to: Department of Internal Medicine, Medical Faculty, University of Nis, Nis, Serbia

    [email protected]

    The Cochrane Hepato‐Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

  • Lise Lotte Gluud

    Gastrounit, Medical Division, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark

  • Dimitrinka Nikolova

    The Cochrane Hepato‐Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

  • Kate Whitfield

    Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

  • Goran Krstic

    Fraser Health Authority, Environmental Health Services, New Westminster, Canada

  • Jørn Wetterslev

    Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

  • Christian Gluud

    The Cochrane Hepato‐Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

Contributions of authors

Goran Bjelakovic (GB): initiated the review, drafted the protocol, performed the literature search, data extraction, and statistical analyses, and drafted the review.
Lise Lotte Gluud (LLG): revised the protocol, performed data extraction, and revised the review.
Dimitrinka Nikolova (DN): revised the protocol, performed data extraction, and revised the review.
Kate Whitfield (KW): developed the search strategy, revised the protocol, performed data extraction, and revised the review.
Goran Krstic (GK): joined the team of authors during the preparation of the review, performed data extraction, and revised the review.
Jørn Wetterslev (JW): revised the protocol, performed data extraction, and revised the review.
Christian Gluud (CG): revised the protocol, acted as arbiter for disagreements, and revised the review.

Sources of support

Internal sources

  • The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Denmark.

External sources

  • Ministry of Education, Science and Technological Development of the Republic of Serbia, Serbia.

Declarations of interest

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.

Acknowledgements

We extend our gratitude to all participants and investigators who took part in the randomised clinical trials. We are grateful to the many authors who kindly responded to our requests for further information on the trials they were involved in. We thank the individual trial authors in our Characteristics of included studies tables. We thank Sarah Louise Klingenberg, the Cochrane Hepato‐Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark, for her help with paper copies of publications.

Version history

Published

Title

Stage

Authors

Version

2014 Jun 23

Vitamin D supplementation for prevention of cancer in adults

Review

Goran Bjelakovic, Lise Lotte Gluud, Dimitrinka Nikolova, Kate Whitfield, Goran Krstic, Jørn Wetterslev, Christian Gluud

https://doi.org/10.1002/14651858.CD007469.pub2

2008 Oct 08

Vitamin D supplementation for prevention of cancer in adults

Protocol

Goran Bjelakovic, Lise Lotte Gluud, Dimitrinka Nikolova, Kate Whitfield, Jørn Wetterslev, Christian Gluud

https://doi.org/10.1002/14651858.CD007469

Differences between protocol and review

1. Methods section. Criteria for considering studies for this review. Types of participants. We have now added the following categories of participants, which were excluded in order to be more precise: people with secondary induced osteoporosis (for example, glucocorticoid‐induced osteoporosis, thyroidectomy, primary hyperparathyroidism, chronic kidney disease, liver cirrhosis, Crohn's disease, and gastrointestinal bypass surgery). Firstly, all of these conditions are accompanied by deranged vitamin D metabolism, and by an increase in bone resorption and by a decrease in bone formation. Secondly, we decided to follow exclusion criteria applied in our previous Cochrane review on vitamin D supplementation for prevention of mortality (Bjelakovic 2014).
2. Methods section. Criteria for considering studies for this review. Types of interventions. We have now deleted the following types of interventions: in combination with other vitamins or trace elements; in combination with calcium and other vitamins and trace elements. Our intention was to eliminate the influence of other co‐interventions on our results. We wanted to obtain results that would reflect the pure influence of vitamin D on the outcome measures.
3. We changed QUORUM (Moher 1999) into PRISMA (Moher 2009) as the guideline was updated.
4. Data collection and analysis. Assessment of risk of bias in included studies. We have now added the following risk of bias domains: incomplete outcome data; selective outcome reporting; for‐profit bias; and risk of other bias as the guidelines for risk of bias were updated.
5. Data collection and analysis. Data synthesis. We also planned to conduct trial sequential analyses with diversity‐adjusted required information size instead of heterogeneity‐adjusted required information size. The reason is that the diversity‐adjusted required information size seems to give less biased estimates of the required information size than the inconsistency‐adjusted required information size (Wetterslev 2009).
6. Data collection and analysis. Dealing with missing data. Regarding the primary outcomes, we included participants with incomplete or missing data in sensitivity analyses by imputing them according to the extreme case analysis favouring the experimental intervention ('best‐worst' case scenario): none of the dropouts/participants lost from the experimental arm, but all of the dropouts/participants lost from the control arm experienced the outcome, including all randomised participants in the denominator, and extreme case analysis favouring the control ('worst‐best' case scenario): all dropouts/participants lost from the experimental arm, but none from the control arm experienced the outcome, including all randomised participants in the denominator.
7. Data collection and analysis. Subgroup analysis. We have decided against performing the following subgroup analysis: "trials without risk of for‐profit bias compared to trials with risk of for‐profit bias", due to the introduction of this source of bias in the review.
8. Data collection and analysis. Sensitivity analysis. We have now decided against performing the following sensitivity analyses: repeating the analysis excluding unpublished trials; repeating the analysis excluding trials using the following filters: diagnostic criteria, language of publication, country. The reason is that all included trials used the same diagnostic criteria. We did not find unpublished trials. All included trials came from high‐income countries and were published in the English language.
9. Goran Krstic joined the team of authors during the preparation of the review.

Keywords

MeSH

PICOs

Population
Intervention
Comparison
Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

Study flow diagram.
Figures and Tables -
Figure 1

Study flow diagram.

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figures and Tables -
Figure 2

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
Figures and Tables -
Figure 3

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

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.
Figures and Tables -
Figure 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.

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.
Figures and Tables -
Figure 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.

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.
Figures and Tables -
Figure 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.

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 1 Cancer occurrence in trials with a low or high risk of bias.
Figures and Tables -
Analysis 1.1

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 1 Cancer occurrence in trials with a low or high risk of bias.

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 2 Cancer occurrence and risk of for‐profit bias.
Figures and Tables -
Analysis 1.2

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 2 Cancer occurrence and risk of for‐profit bias.

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 3 Cancer occurrence in primary and secondary prevention trials.
Figures and Tables -
Analysis 1.3

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 3 Cancer occurrence in primary and secondary prevention trials.

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 4 Cancer occurrence and vitamin D status.
Figures and Tables -
Analysis 1.4

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 4 Cancer occurrence and vitamin D status.

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 5 Cancer occurrence ('best‐worst case' and 'worst‐best case' scenario).
Figures and Tables -
Analysis 1.5

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 5 Cancer occurrence ('best‐worst case' and 'worst‐best case' scenario).

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 6 Cancer occurrence in trials using vitamin D₃ (cholecalciferol).
Figures and Tables -
Analysis 1.6

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 6 Cancer occurrence in trials using vitamin D₃ (cholecalciferol).

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 7 Cancer occurrence in trials using vitamin D₃ singly or combined with calcium.
Figures and Tables -
Analysis 1.7

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 7 Cancer occurrence in trials using vitamin D₃ singly or combined with calcium.

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 8 Lung cancer occurrence in trials using vitamin D₃ (cholecalciferol).
Figures and Tables -
Analysis 1.8

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 8 Lung cancer occurrence in trials using vitamin D₃ (cholecalciferol).

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 9 Breast cancer occurrence in trials using vitamin D₃ (cholecalciferol).
Figures and Tables -
Analysis 1.9

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 9 Breast cancer occurrence in trials using vitamin D₃ (cholecalciferol).

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 10 Colorectal cancer occurrence in trials using vitamin D₃ (cholecalciferol).
Figures and Tables -
Analysis 1.10

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 10 Colorectal cancer occurrence in trials using vitamin D₃ (cholecalciferol).

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 11 Pancreatic cancer occurrence in trials using vitamin D₃ (cholecalciferol).
Figures and Tables -
Analysis 1.11

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 11 Pancreatic cancer occurrence in trials using vitamin D₃ (cholecalciferol).

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 12 Prostate cancer occurrence in trials using vitamin D₃ (cholecalciferol).
Figures and Tables -
Analysis 1.12

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 12 Prostate cancer occurrence in trials using vitamin D₃ (cholecalciferol).

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 13 Uterine cancer occurrence in trials using vitamin D₃ (cholecalciferol).
Figures and Tables -
Analysis 1.13

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 13 Uterine cancer occurrence in trials using vitamin D₃ (cholecalciferol).

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 14 Ovarian cancer occurrence in trials using vitamin D₃ (cholecalciferol).
Figures and Tables -
Analysis 1.14

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 14 Ovarian cancer occurrence in trials using vitamin D₃ (cholecalciferol).

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 15 Oesophageal cancer occurrence in trials using vitamin D₃ (cholecalciferol).
Figures and Tables -
Analysis 1.15

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 15 Oesophageal cancer occurrence in trials using vitamin D₃ (cholecalciferol).

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 16 Stomach cancer occurrence in trials using vitamin D₃ (cholecalciferol).
Figures and Tables -
Analysis 1.16

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 16 Stomach cancer occurrence in trials using vitamin D₃ (cholecalciferol).

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 17 Liver cancer occurrence in trials using vitamin D₃ (cholecalciferol).
Figures and Tables -
Analysis 1.17

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 17 Liver cancer occurrence in trials using vitamin D₃ (cholecalciferol).

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 18 Cancer occurrence in trials using vitamin D₂ (ergocalciferol).
Figures and Tables -
Analysis 1.18

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 18 Cancer occurrence in trials using vitamin D₂ (ergocalciferol).

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 19 Cancer occurrence in trials using calcitriol.
Figures and Tables -
Analysis 1.19

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 19 Cancer occurrence in trials using calcitriol.

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 20 Breast cancer occurrence in trials using calcitriol.
Figures and Tables -
Analysis 1.20

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 20 Breast cancer occurrence in trials using calcitriol.

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 21 Uterine cancer occurrence in trials using calcitriol.
Figures and Tables -
Analysis 1.21

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 21 Uterine cancer occurrence in trials using calcitriol.

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 22 Stomach cancer occurrence in trials using calcitriol.
Figures and Tables -
Analysis 1.22

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 22 Stomach cancer occurrence in trials using calcitriol.

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 23 All‐cause mortality in trials with a low or high risk of bias.
Figures and Tables -
Analysis 1.23

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 23 All‐cause mortality in trials with a low or high risk of bias.

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 24 All‐cause mortality ('best‐worst case' and 'worst‐best case' scenario).
Figures and Tables -
Analysis 1.24

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 24 All‐cause mortality ('best‐worst case' and 'worst‐best case' scenario).

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 25 Cancer mortality.
Figures and Tables -
Analysis 1.25

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 25 Cancer mortality.

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 26 Cancer mortality ('best‐worst case' and 'worst‐best case' scenario).
Figures and Tables -
Analysis 1.26

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 26 Cancer mortality ('best‐worst case' and 'worst‐best case' scenario).

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 27 Adverse events.
Figures and Tables -
Analysis 1.27

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 27 Adverse events.

Summary of findings for the main comparison. Vitamin D versus placebo or no intervention for prevention of cancer in adults

Vitamin D versus placebo or no intervention for prevention of cancer in adults

Patient or population: healthy participants or recruited among the general population; individuals diagnosed with a specific disease in a stable phase or with vitamin D deficiency

Settings: outpatients
Intervention: vitamin D versus placebo or no intervention

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

Vitamin D versus placebo or no intervention

Cancer occurrence

Follow‐up: 0.5 to 7 years

Study population

RR 1.00
(0.94 to 1.06)

50623
(18)

⊕⊕⊕⊝

moderatea

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.

77 per 1000

77 per 1000
(72 to 81)

Moderate

28 per 1000

28 per 1000
(26 to 30)

Cancer occurrence in trials using vitamin D₃ (cholecalciferol)

Follow‐up: 0.5 to 7 years

Study population

RR 1.00
(0.94 to 1.06)

49891
(14)

⊕⊕⊕⊝

moderatea

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.

77 per 1000

77 per 1000
(73 to 82)

Moderate

28 per 1000

28 per 1000
(26 to 30)

All‐cause mortality

Follow‐up: 0.5 to 7 years

Study population

RR 0.93
(0.88 to 0.98)

49866
(15)

⊕⊕⊝⊝

lowb

Trial sequential analysis of all trials irrespective of bias risks showed that the required information size had not yet been reached and that the cumulative Z‐curve did not cross the trial sequential monitoring boundary for benefit.

80 per 1000

75 per 1000
(71 to 79)

Moderate

16 per 1000

15 per 1000
(14 to 16)

Cancer mortality in trials using vitamin D(cholecalciferol)

Follow‐up: 5 to 7 years

Study population

RR 0.88
(0.78 to 0.98)

44492
(4)

⊕⊕⊝⊝

lowb

Trial sequential analysis of all trials irrespective of bias risks showed that the required information size had not yet been reached and that the cumulative Z‐curve did not cross the trial sequential monitoring boundary for benefit.

29 per 1000

25 per 1000
(22 to 28)

Moderate

37 per 1000

33 per 1000
(29 to 36)

Adverse events: nephrolithiasis in trials using vitamin D(cholecalciferol) combined with calcium

Follow‐up: 0.5 to 7 years

Study population

RR 1.17
(1.03 to 1.34)

42753
(3)

⊕⊕⊝⊝

lowb

Trial sequential analysis of all trials irrespective of bias risks showed that the required information size had not yet been reached and that the cumulative Z‐curve did not cross the trial sequential monitoring boundary for benefit.

18 per 1000

21 per 1000
(18 to 24)

Moderate

1 per 1000

1 per 1000
(1 to 1)

Health‐related quality of life

See comment

Not investigated.

Health economics

See comment

Not investigated.

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

aDowngraded by one level because of risk of attrition bias

bDowngraded by two levels because of risk of attrition bias and imprecision

Figures and Tables -
Summary of findings for the main comparison. Vitamin D versus placebo or no intervention for prevention of cancer in adults
Table 1. Overview of study populations

Characteristic

Intervention(s) and comparator(s)

Screened/eligible
[N]

Randomised
[N]

ITT
[N]

Finishing study
[N]

Randomised finishing study
[%]

(1) Avenell 2012

 

 

I1: vitamin D₃

15,024

1343

1343

1813

68

I2: vitamin D₃ plus calcium

1306

1306

C1: calcium

1311

1311

1762

67

C2: matched placebo tablets

1332

1332

total:

5292

5292

3575

68

(2) Bolton‐Smith 2007

 

 

I1: vitamin D₃ plus calcium

62

62

50

81

C1: matched placebo

61

61

56

92

total:

123

123

106

86

(3) Brunner 2011

 

 

I1: vitamin D₃ plus calcium

68,132

18,176

18,176

16,936

93

C1: matched placebo

18,106

18,106

16,815

93

total:

36,282

36,282

33,751

93

(4) Daly 2008

 

 

I1: calcium‐vitamin D₃‐fortified milk plus calcium

422

85

85

76

89

C1: usual diet

82

82

73

89

total:

167

167

149

89

(5) Gallagher 2001

 

 

I1: calcitriol

1905

123

123

101

82

C1: matched placebo

123

123

112

91

total:

246

246

213

87

(6) Glendenning 2012

 

 

I1: cholecalciferol

2110

353

353

331

94

C1: placebo vitamin D

333

333

307

92

total:

686

686

638

93

(7) Grady 1991

 

 

I1: calcitriol

98

50

50

49

98

C1: placebo vitamin D

48

48

48

100

total:

98

50

97

99

(8) Janssen 2010

 

 

I1: vitamin D₃ plus calcium

91

36

36

18

50

C1:placebo vitamin D₃ plus calcium

34

34

31

91

total:

70

70

49

70

(9) Komulainen 1999

 

 

I1: vitamin D₃ plus calcium

13,100

116

116

112

97

C1: placebo

116

116

115

99

total:

232

232

227

98

(10) Lappe 2007

 

 

I1: vitamin D₃ plus calcium

1180

446

446

403

90

C1: vitamin D₃ placebo plus calcium

445

445

416

93

C2: vitamin D₃ placebo plus calcium placebo

288

288

266

92

total:

1179

1179

1085

92

(11) Larsen 2012

I1: vitamin D₃

136

65

65

55

85

C1: vitamin D placebo

65

65

57

88

total:

130

130

112

86

(12) Murdoch 2012

I1: vitamin D₃

351

161

161

148

92

C1: vitamin D placebo

161

161

146

91

total:

322

322

294

91

(13) Ott 1989

 

 

I1: calcitriol plus calcium

43

43

39

91

C1: placebo vitamin D plus calcium

43

43

37

86

total:

86

86

76

88

(14) Prince 2008

 

 

I1: vitamin D₂ plus calcium

827

151

151

144

95

C1: placebo vitamin D plus calcium

151

151

145

96

total:

302

302

289

95

(15) Sanders 2010

 

 

I1: vitamin D₃

7204

1131

1131

1015

90

C1: vitamin D placebo

1127

1127

1017

90

total:

2258

2258

2032

90

(16) Trivedi 2003

 

 

I1: vitamin D₃

1345

1345

1262

94

C1:placebo vitamin D

1341

1341

1264

94

total:

2686

2686

2526

94

(17) Witham 2013

I1: vitamin D₃

341

80

80

73

91

C1: placebo vitamin D

79

79

69

87

total:

159

159

142

89

(18) Wood 2012

I1: vitamin D₃

424

102

102

84

82

I2: vitamin D₃

101

101

90

89

C1: placebo vitamin D

102

102

91

89

total:

305

305

265

87

Grand total

All interventions

25,275

22,799

90

All controls

25,348

22,827

90

All interventions and controls

50,623

45,626

90

"‐" denotes not reported
ITT: intention‐to‐treat

Figures and Tables -
Table 1. Overview of study populations
Comparison 1. Vitamin D versus placebo or no intervention

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Cancer occurrence in trials with a low or high risk of bias Show forest plot

18

50623

Risk Ratio (M‐H, Random, 95% CI)

1.00 [0.94, 1.06]

1.1 Trials with low risk of bias

2

2991

Risk Ratio (M‐H, Random, 95% CI)

1.08 [0.89, 1.31]

1.2 Trials with high risk of bias

16

47632

Risk Ratio (M‐H, Random, 95% CI)

0.99 [0.93, 1.05]

2 Cancer occurrence and risk of for‐profit bias Show forest plot

18

50623

Risk Ratio (M‐H, Random, 95% CI)

1.00 [0.94, 1.06]

2.1 Trials without risk of for‐profit bias

2

2991

Risk Ratio (M‐H, Random, 95% CI)

1.08 [0.89, 1.31]

2.2 Trials with risk of for‐profit bias

16

47632

Risk Ratio (M‐H, Random, 95% CI)

0.99 [0.93, 1.05]

3 Cancer occurrence in primary and secondary prevention trials Show forest plot

18

50623

Risk Ratio (M‐H, Random, 95% CI)

1.00 [0.94, 1.06]

3.1 Primary prevention trials

16

50334

Risk Ratio (M‐H, Random, 95% CI)

1.00 [0.94, 1.06]

3.2 Secondary prevention trials

2

289

Risk Ratio (M‐H, Random, 95% CI)

1.33 [0.26, 6.96]

4 Cancer occurrence and vitamin D status Show forest plot

18

50623

Risk Ratio (M‐H, Random, 95% CI)

1.00 [0.94, 1.06]

4.1 Vitamin D insufficiency

7

44668

Risk Ratio (M‐H, Random, 95% CI)

0.99 [0.93, 1.05]

4.2 Vitamin D adequacy

9

4544

Risk Ratio (M‐H, Random, 95% CI)

1.12 [0.94, 1.34]

4.3 Unknown vitamin status

2

1411

Risk Ratio (M‐H, Random, 95% CI)

0.59 [0.33, 1.05]

5 Cancer occurrence ('best‐worst case' and 'worst‐best case' scenario) Show forest plot

17

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

5.1 'Best‐worst' case scenario

17

49444

Risk Ratio (M‐H, Random, 95% CI)

0.41 [0.31, 0.54]

5.2 'Worst‐best' case scenario

17

49444

Risk Ratio (M‐H, Random, 95% CI)

2.76 [1.97, 3.86]

6 Cancer occurrence in trials using vitamin D₃ (cholecalciferol) Show forest plot

14

49891

Risk Ratio (M‐H, Random, 95% CI)

1.00 [0.94, 1.06]

6.1 Vitamin D₃ trials with low risk of bias

2

2991

Risk Ratio (M‐H, Random, 95% CI)

1.08 [0.89, 1.31]

6.2 Vitamin D₃ trials with high risk of bias

12

46900

Risk Ratio (M‐H, Random, 95% CI)

0.99 [0.93, 1.05]

7 Cancer occurrence in trials using vitamin D₃ singly or combined with calcium Show forest plot

14

49870

Risk Ratio (M‐H, Random, 95% CI)

0.98 [0.92, 1.04]

7.1 Vitamin D₃ singly

8

9200

Risk Ratio (M‐H, Random, 95% CI)

1.03 [0.90, 1.17]

7.2 Vitamin D₃ combined with calcium

7

40670

Risk Ratio (M‐H, Random, 95% CI)

0.97 [0.91, 1.04]

8 Lung cancer occurrence in trials using vitamin D₃ (cholecalciferol) Show forest plot

5

45509

Risk Ratio (M‐H, Random, 95% CI)

0.86 [0.69, 1.07]

9 Breast cancer occurrence in trials using vitamin D₃ (cholecalciferol) Show forest plot

7

43669

Risk Ratio (M‐H, Random, 95% CI)

0.97 [0.86, 1.09]

10 Colorectal cancer occurrence in trials using vitamin D₃ (cholecalciferol) Show forest plot

5

45598

Risk Ratio (M‐H, Random, 95% CI)

1.11 [0.92, 1.34]

11 Pancreatic cancer occurrence in trials using vitamin D₃ (cholecalciferol) Show forest plot

2

36405

Risk Ratio (M‐H, Random, 95% CI)

0.91 [0.57, 1.46]

12 Prostate cancer occurrence in trials using vitamin D₃ (cholecalciferol) Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

13 Uterine cancer occurrence in trials using vitamin D₃ (cholecalciferol) Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

14 Ovarian cancer occurrence in trials using vitamin D₃ (cholecalciferol) Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

15 Oesophageal cancer occurrence in trials using vitamin D₃ (cholecalciferol) Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

16 Stomach cancer occurrence in trials using vitamin D₃ (cholecalciferol) Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

17 Liver cancer occurrence in trials using vitamin D₃ (cholecalciferol) Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

18 Cancer occurrence in trials using vitamin D₂ (ergocalciferol) Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

19 Cancer occurrence in trials using calcitriol Show forest plot

3

430

Risk Ratio (M‐H, Random, 95% CI)

1.45 [0.52, 4.06]

20 Breast cancer occurrence in trials using calcitriol Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

21 Uterine cancer occurrence in trials using calcitriol Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

22 Stomach cancer occurrence in trials using calcitriol Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

23 All‐cause mortality in trials with a low or high risk of bias Show forest plot

15

49866

Risk Ratio (M‐H, Random, 95% CI)

0.93 [0.88, 0.98]

23.1 Trials with low risk of bias

1

2686

Risk Ratio (M‐H, Random, 95% CI)

0.90 [0.77, 1.07]

23.2 Trials with high risk of bias

14

47180

Risk Ratio (M‐H, Random, 95% CI)

0.93 [0.88, 0.99]

24 All‐cause mortality ('best‐worst case' and 'worst‐best case' scenario) Show forest plot

14

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

24.1 'Best‐worst' case scenario

14

48687

Risk Ratio (M‐H, Random, 95% CI)

0.43 [0.31, 0.60]

24.2 'Worst‐best' case scenario

14

48687

Risk Ratio (M‐H, Random, 95% CI)

2.03 [1.47, 2.80]

25 Cancer mortality Show forest plot

4

44492

Risk Ratio (M‐H, Random, 95% CI)

0.88 [0.78, 0.98]

26 Cancer mortality ('best‐worst case' and 'worst‐best case' scenario) Show forest plot

4

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

26.1 'Best‐worst' case scenario

4

44492

Risk Ratio (M‐H, Random, 95% CI)

0.48 [0.33, 0.70]

26.2 'Worst‐best' case scenario

4

44492

Risk Ratio (M‐H, Random, 95% CI)

1.69 [1.04, 2.75]

27 Adverse events Show forest plot

15

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

27.1 Hypercalcaemia in trials using supplemental forms of vitamin D

4

5879

Risk Ratio (M‐H, Random, 95% CI)

1.41 [0.64, 3.09]

27.2 Hypercalcaemia in trials using active forms of vitamin D

2

332

Risk Ratio (M‐H, Random, 95% CI)

4.03 [0.56, 29.22]

27.3 Nephrolithiasis in trials using vitamin D₃ combined with calcium

3

42753

Risk Ratio (M‐H, Random, 95% CI)

1.17 [1.03, 1.34]

27.4 Nephrolithiasis in trials using calcitriol

1

246

Risk Ratio (M‐H, Random, 95% CI)

0.33 [0.01, 8.10]

27.5 Hypercalciuria

1

98

Risk Ratio (M‐H, Random, 95% CI)

12.49 [0.72, 215.84]

27.6 Renal insufficiency

3

5549

Risk Ratio (M‐H, Random, 95% CI)

0.65 [0.23, 1.82]

27.7 Cardiovascular disorders

8

4938

Risk Ratio (M‐H, Random, 95% CI)

0.95 [0.86, 1.05]

27.8 Gastrointestinal disorders

7

1624

Risk Ratio (M‐H, Random, 95% CI)

1.19 [0.88, 1.59]

27.9 Psychiatric disorders

2

332

Risk Ratio (M‐H, Random, 95% CI)

1.42 [0.46, 4.38]

Figures and Tables -
Comparison 1. Vitamin D versus placebo or no intervention