Vitamin D supplementation for prevention of mortality in adults

Goran Bjelakovic; Lise Lotte Gluud; Dimitrinka Nikolova; Kate Whitfield; Jørn Wetterslev; Rosa G Simonetti; Marija Bjelakovic; Christian Gluud

doi:10.1002/14651858.CD007470.pub3

Cochrane Database of Systematic Reviews

Vitamin D supplementation for prevention of mortality in adults

Information

DOI:

https://doi.org/10.1002/14651858.CD007470.pub3 Copy DOI

Database:

Cochrane Database of Systematic Reviews

Version published:

10 January 2014see what's new

Type:

Intervention

Stage:

Review

Cochrane Editorial Group:

Cochrane Metabolic and Endocrine Disorders Group

Copyright:

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
Jørn Wetterslev

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

U.O. di Medicina 2, Ospedali Riuniti Villa Sofia‐Cervello, Palermo, Italy
Marija Bjelakovic

Institute of Anatomy, Medical Faculty, University of Nis, Nis, Serbia
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): performed the literature search, data extraction and statistical analyses and drafted the review.
Lise Lotte Gluud (LLG): performed data extraction and revised the review.
Dimitrinka Nikolova (DN): performed data extraction and revised the review.
Kate Whitfield (KW): developed the search strategy, performed data extraction and revised the review.
Jørn Wetterslev (JW): performed data extraction and revised the review.
Rosa G Simonetti (RGS): performed data extraction and revised the review.
Marija Bjelakovic (MB) performed data extraction and revised the review.
Christian Gluud (CG): initiated the systematic review, 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 Science Republic of Serbia, Serbia.

Declarations of interest

None known.

Acknowledgements

We extend our gratitude to all participants and investigators in the randomised clinical trials. We are grateful to the many authors of publications who kindly responded to our requests for further information on the trials in which they were involved.

Version history

Published

Title

Stage

Authors

Version

2014 Jan 10

Vitamin D supplementation for prevention of mortality in adults

Review

Goran Bjelakovic, Lise Lotte Gluud, Dimitrinka Nikolova, Kate Whitfield, Jørn Wetterslev, Rosa G Simonetti, Marija Bjelakovic, Christian Gluud

https://doi.org/10.1002/14651858.CD007470.pub3

2011 Jul 06

Vitamin D supplementation for prevention of mortality in adults

Review

Goran Bjelakovic, Lise Lotte Gluud, Dimitrinka Nikolova, Kate Whitfield, Jørn Wetterslev, Rosa G Simonetti, Marija Bjelakovic, Christian Gluud

https://doi.org/10.1002/14651858.CD007470.pub2

2008 Oct 08

Vitamin D supplementation for prevention of mortality in adults

Protocol

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

https://doi.org/10.1002/14651858.CD007470

Differences between protocol and review

Difference between the last published review version and the present review version

We interpreted our results much more conservatively as the result of extensive discussion of the validity of our results among the review authors.

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

Adolescent; Adult; Aged; Aged, 80 and over; Female; Humans; Male; Middle Aged; Young Adult;

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.

Figure 1

Study flow diagram.

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Figure 2

Risk of bias according to bias domains in the 56 randomised clinical trials on vitamin D and mortality.

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Figure 3

Risk of bias in the included 56 randomised clinical trials on vitamin D and mortality.

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Trial sequential analysis on mortality in 38 vitamin D3 trials   The diversity‐adjusted required information size (RIS) was calculated based on mortality in the control group of 10%; relative risk reduction of 5% in the experimental group; type I error of 5%; and type II error of 20% (80% power). No diversity was noted. The required information size was 110,505 participants. The cumulative Z‐curve (blue line) crossed the trial sequential monitoring boundaries for benefit (red inward sloping line) after the 22nd trial. Accordingly, the risk of random error in the finding seems acceptable according to the O'Brien Fleming stopping rule for an individual trial interim analysis. Subsequently, 16 trials have been published.

Figure 4

Trial sequential analysis on mortality in 38 vitamin D₃ trials
The diversity‐adjusted required information size (RIS) was calculated based on mortality in the control group of 10%; relative risk reduction of 5% in the experimental group; type I error of 5%; and type II error of 20% (80% power). No diversity was noted. The required information size was 110,505 participants. The cumulative Z‐curve (blue line) crossed the trial sequential monitoring boundaries for benefit (red inward sloping line) after the 22nd trial. Accordingly, the risk of random error in the finding seems acceptable according to the O'Brien Fleming stopping rule for an individual trial interim analysis. Subsequently, 16 trials have been published.

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Trial sequential analysis on mortality in the 13 trials that administered low dose of vitamin D3 (i.e. a dose less than 800 IU per day)   The diversity‐adjusted required information size (RIS) was calculated based on mortality in the control group of 10%; relative risk reduction of 5% in the experimental group; type I error of 5%; and type II error of 20% (80% power). No diversity was noted. The required information size was 110,505 participants. The cumulative Z‐curve (blue line) did not cross the trial sequential monitoring boundaries for benefit (red line) at any time. Accordingly, the crossing of the conventional statistical 5% boundary (the horizontal brown line) may be due to random errors.

Figure 5

Trial sequential analysis on mortality in the 13 trials that administered low dose of vitamin D₃ (i.e. a dose less than 800 IU per day)
The diversity‐adjusted required information size (RIS) was calculated based on mortality in the control group of 10%; relative risk reduction of 5% in the experimental group; type I error of 5%; and type II error of 20% (80% power). No diversity was noted. The required information size was 110,505 participants. The cumulative Z‐curve (blue line) did not cross the trial sequential monitoring boundaries for benefit (red line) at any time. Accordingly, the crossing of the conventional statistical 5% boundary (the horizontal brown line) may be due to random errors.

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Trial sequential analysis of mortality in 12 vitamin D2 trials   The diversity‐adjusted required information size (RIS) was conducted based on 10% mortality in the control group; relative risk reduction of 10% in the experimental group; type I error of 5%; and type II error of 20% (80% power). No diversity was noted. The required information size was 27,585 participants. The cumulative Z‐curve (blue line) crossed the trial sequential monitoring boundaries for futility (red outward sloping line) after the eighth trial.

Figure 6

Trial sequential analysis of mortality in 12 vitamin D₂ trials
The diversity‐adjusted required information size (RIS) was conducted based on 10% mortality in the control group; relative risk reduction of 10% in the experimental group; type I error of 5%; and type II error of 20% (80% power). No diversity was noted. The required information size was 27,585 participants. The cumulative Z‐curve (blue line) crossed the trial sequential monitoring boundaries for futility (red outward sloping line) after the eighth trial.

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Analysis 1.1

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

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Analysis 1.2

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 2 All‐cause mortality in individually randomised and cluster‐randomised trials.

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Analysis 1.3

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 3 All‐cause mortality in placebo‐controlled and no intervention trials.

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Analysis 1.4

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 4 All‐cause mortality and risk of industry bias.

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Analysis 1.5

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 5 All‐cause mortality in primary and secondary prevention trials.

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Analysis 1.6

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 6 All‐cause mortality and vitamin D status.

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Analysis 1.7

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 7 All‐cause mortality in ambulatory and institutionalised participants.

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Analysis 1.8

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 8 All‐cause mortality ('best‐worst case' and 'worst‐best case' scenario).

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Comparison 1 Vitamin D versus placebo or no intervention, Outcome 9 All‐cause mortality in trials using vitamin D3 (cholecalciferol).

Analysis 1.9

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 9 All‐cause mortality in trials using vitamin D₃ (cholecalciferol).

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Comparison 1 Vitamin D versus placebo or no intervention, Outcome 10 All‐cause mortality in trials using vitamin D3 singly or combined with calcium.

Analysis 1.10

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 10 All‐cause mortality in trials using vitamin D₃ singly or combined with calcium.

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Comparison 1 Vitamin D versus placebo or no intervention, Outcome 11 All‐cause mortality in trials using low or high dose of vitamin D3.

Analysis 1.11

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 11 All‐cause mortality in trials using low or high dose of vitamin D₃.

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Comparison 1 Vitamin D versus placebo or no intervention, Outcome 12 All‐cause mortality in trials applying vitamin D3 daily or intermittently.

Analysis 1.12

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 12 All‐cause mortality in trials applying vitamin D₃ daily or intermittently.

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Comparison 1 Vitamin D versus placebo or no intervention, Outcome 13 All‐cause mortality in trials using vitamin D3 and vitamin D status.

Analysis 1.13

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 13 All‐cause mortality in trials using vitamin D₃ and vitamin D status.

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Comparison 1 Vitamin D versus placebo or no intervention, Outcome 14 All‐cause mortality in trials using vitamin D3 according to the participant's sex.

Analysis 1.14

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 14 All‐cause mortality in trials using vitamin D₃ according to the participant's sex.

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Comparison 1 Vitamin D versus placebo or no intervention, Outcome 15 All‐cause mortality in trials using vitamin D2 (ergocalciferol).

Analysis 1.15

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 15 All‐cause mortality in trials using vitamin D₂ (ergocalciferol).

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Comparison 1 Vitamin D versus placebo or no intervention, Outcome 16 All‐cause mortality in trials using vitamin D2 singly or combined with calcium.

Analysis 1.16

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 16 All‐cause mortality in trials using vitamin D₂ singly or combined with calcium.

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Comparison 1 Vitamin D versus placebo or no intervention, Outcome 17 All‐cause mortality in trials using low or high dose of vitamin D2.

Analysis 1.17

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 17 All‐cause mortality in trials using low or high dose of vitamin D₂.

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Comparison 1 Vitamin D versus placebo or no intervention, Outcome 18 All‐cause mortality in trials applying vitamin D2 daily or intermittently.

Analysis 1.18

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 18 All‐cause mortality in trials applying vitamin D₂ daily or intermittently.

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Comparison 1 Vitamin D versus placebo or no intervention, Outcome 19 All‐cause mortality in trials using vitamin D2 and vitamin D status.

Analysis 1.19

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 19 All‐cause mortality in trials using vitamin D₂ and vitamin D status.

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Analysis 1.20

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 20 All‐cause mortality in trials using alfacalcidol (1α‐hydroxyvitamin D).

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Analysis 1.21

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 21 All‐cause mortality in trials using alfacalcidol and vitamin D status.

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Analysis 1.22

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 22 All‐cause mortality in trials using calcitriol (1,25‐dihydroxyvitamin D).

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Analysis 1.23

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 23 All‐cause mortality in trials using calcitriol and vitamin D status.

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Analysis 1.24

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 24 Cancer mortality.

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Analysis 1.25

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

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Analysis 1.26

Comparison 1 Vitamin D versus placebo or no intervention, Outcome 26 Adverse events.

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Summary of findings for the main comparison. Vitamin D supplementation for prevention of mortality in adults

Vitamin D supplementation for prevention of mortality in adults
Population: adults Settings: any Intervention: vitamin D Comparison: 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
	Placebo or no intervention	Vitamin D
All‐cause mortality in trials using vitamin D₃ (cholecalciferol) (Follow‐up: 0.08 to 7 years)	Study population		RR 0.94 (0.91 to 0.98)	75,927 (38)	⊕⊕⊕⊝ moderate^a	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 crossed the trial sequential monitoring boundary for benefit. If this is correct, the intervention effect corresponds to a number needed to treat for a beneficial outcome (NNTB) of 150 participants over five years to save one additional life
	114 per 1000	107 per 1000 (104 to 112)
	Moderate risk
	46 per 1000	43 per 1000 (42 to 45)
Cardiovascular mortality in trials using vitamin D₃ (cholecalciferol) (Follow‐up: 0.31 to 6.2 years)	Study population		RR 0.98 (0.90 to 1.07)	47,267 (10)	⊕⊕⊝⊝ low^b	Trial sequential analysis showed that the cumulative Z‐curve did not cross the conventional monitoring boundary for benefit. The required information size was 2,539,845 participants
	42 per 1000	41 per 1000 (38 to 45)
	Moderate risk
	13 per 1000	11 per 1000 (12 to 15)
Cancer mortality in trials using vitamin D₃ (cholecalciferol) (Follow‐up: 5 to 7 years)	Study population		RR 0.88 (0.78 to 0.98)	44,492 (4)	⊕⊕⊕⊝ moderate^a	Trial sequential analysis showed that the cumulative Z‐curve did not cross the conventional monitoring boundary for benefit. The required information size was 66,724 participants
	29 per 1000	25 per 1000 (22 to 31)
	Moderate risk
	21 per 1000	19 per 1000 (16 to 21)
Adverse events: nephrolithiasis in trials using vitamin D₃ combined with calcium (Follow‐up: 1.25 to 7 years)	Study population		RR 1.17 (1.02 to 1.34)	42,876 (4)	⊕⊕⊕⊝ moderate^a
	18 per 1000	21 per 1000 (18 to 24)
	Moderate risk
	9 per 1000	11 per 1000 (9 to 12)
Adverse events: hypercalcaemia in trials using the active forms of vitamin D (alfacalcidol and calcitriol) (Follow‐up: 0.75 to 3 years)	Study population		RR 3.18 (1.17 to 8.68)	710 (3)	⊕⊕⊝⊝ low^b
	23 per 1000	72 per 1000 (27 to 197)
	Moderate risk
	11 per 1000	15 per 1000 (4 to 23)
Health‐related quality of life (Follow‐up: 0.38 years)	See comment	See comment	Not estimable	105 (1)	See comment	Insufficient information: significant worsening in disease‐specific quality of life in the vitamin D₂ group compared with the placebo group was reported. The between‐group difference at 20 weeks was 5.3 (0.5 to 10.2), and the minimally important difference (MID) is estimated to be 5 points in either direction
Health economics (Follow‐up: 4 years)	See comment	See comment	Not estimable	3270 (1)	See comment	Insufficient information: authors reported that vitamin D₃ and calcium supplementation prevented 46 hip fractures in every 1000 women treated
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; RRR: relative risk reduction
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

Summary of findings for the main comparison. Vitamin D supplementation for prevention of mortality in adults

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Table 1. Characteristics of included trials (I)

Characteristic Study ID	Design	Arms	Bias risk	Blinding	Participants [N]	Women [%]	Mean age [years]
Aloia 2005	Parallel	2	Low	PL	208	100	60
Avenell 2004	2 × 2	4	High	NI	134	83	77
Avenell 2012	2 × 2	4	Low	PL	5292	85	77
Baeksgaard 1998	Parallel	3	High	PL	240	100	62.5
Bischoff 2003	Parallel	2	High	PL	122	100	85.3
Bjorkman 2007	Parallel	3	Low	PL	218	82	84.5
Bolton‐Smith 2007	2 × 2	4	Low	PL	244	100	68
Brazier 2005	Parallel	2	High	PL	192	100	74.6
Broe 2007	Parallel	5	Low	PL	124	73	89
Brohult 1973	Parallel	2	High	PL	50	68	52
Burleigh 2007	Parallel	2	Low	PL	205	59	83
Campbell 2005	2 × 2	4	High	NI	391	68	83.6
Chapuy 1992	Parallel	2	High	PL	3270	100	84
Chapuy 2002	Parallel	3	High	PL	610	100	85
Chel 2008	Parallel	6	High	PL	338	77	84
Cherniack 2011	Parallel	2	High	PL	46	2	80
Cooper 2003	Parallel	2	Low	PL	187	100	56
Corless 1985	Parallel	2	High	PL	65	78	82.4
Daly 2008	Parallel	2	High	NI	167	0	61.9
Dawson‐Hughes 1997	Parallel	2	Low	PL	389	55	71
Dukas 2004	Parallel	2	Low	PL	378	51	71
Flicker 2005	Parallel	2	Low	PL	625	95	83.4
Gallagher 2001	2 × 2	4	Low	PL	489	100	71.5
Glendenning 2012	Parallel	2	Low	PL	686	100	76.7
Grady 1991	Parallel	2	High	PL	98	54	79.1
Grimnes 2011	Parallel	2	Low	PL	104	49	52
Harwood 2004	Parallel	4	High	NI	150	100	81.2
Jackson 2006	Parallel	2	Low	PL	36,282	100	62.4
Janssen 2010	Parallel	2	Low	PL	70	100	80.8
Komulainen 1999	2 × 2	4	Low	PL	464	100	52.7
Krieg 1999	Parallel	2	High	NI	248	100	84.5
Kärkkäinen 2010	Parallel	2	High	NI	3139	100	67
Lappe 2007	Parallel	3	High	PL	1179	100	66.7
Larsen 2004	2 × 2	4	High	NI	9605	60	75
Latham 2003	2 × 2	4	Low	PL	243	53	79.5
Law 2006	Parallel	2	High	NI	3717	76	85
Lehouck 2012	Parallel	2	Low	PL	181	20	68
Lips 1996	Parallel	2	Low	PL	2578	74	80
Lips 2010	Parallel	2	Low	PL	226	NR	78
Lyons 2007	Parallel	2	Low	PL	3440	76	84
Meier 2004	Parallel	2	High	NI	55	65	56.5
Mochonis 2006	Parallel	3	High	NI	112	100	60.3
Ooms 1995	Parallel	2	Low	PL	348	100	80.3
Ott 1989	Parallel	2	High	PL	86	100	67.5
Porthouse 2005	Parallel	2	High	NI	3314	100	76.8
Prince 2008	Parallel	2	Low	PL	302	100	77.2
Sanders 2010	Parallel	2	Low	PL	2258	100	76.0
Sato 1997	Parallel	2	High	PL	64	45	68.5
Sato 1999a	Parallel	2	High	PL	86	78	70.6
Sato 1999b	Parallel	3	High	NI	103	56	70.7
Sato 2005a	Parallel	2	Low	PL	96	100	74.1
Schleithoff 2006	Parallel	2	Low	PL	123	17	51
Smith 2007	Parallel	2	Low	PL	9440	54	79.1
Trivedi 2003	Parallel	2	Low	PL	2686	24	74.7
Witham 2010	Parallel	2	Low	PL	105	34	79.7
Zhu 2008	Parallel	3	Low	PL	120	100	75
NI: no intervention; NR: not reported; PL: placebo

Table 1. Characteristics of included trials (I)

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Table 2. Characteristics of included trials (II)

Characteristic Study ID	Participants	Outcome Measures	Country	Sponsor
Aloia 2005	Black postmenopausal African‐American women	Bone mineral density	USA	No
Avenell 2004	Elderly people with an osteoporotic fracture within the past 10 years	Recruitment, compliance and retention within a randomised trial	UK	Yes
Avenell 2012	Elderly people with low‐trauma osteoporotic fracture in the previous 10 years	Fractures	UK	Yes
Baeksgaard 1998	Postmenopausal women	Bone mineral density	Denmark	Yes
Bischoff 2003	Elderly women living in institutional care	Falls	Switzerland	Yes
Bjorkman 2007	Chronically bedridden patients	Parathyroid function and bone mineral density	Finland	Yes
Bolton‐Smith 2007	Elderly non‐osteoporotic women	Bone mineral density	UK	Yes
Brazier 2005	Elderly vitamin D–insufficient women	Bone mineral density	France	Yes
Broe 2007	Nursing home residents	Falls	USA	Yes
Brohult 1973	Patients with rheumatoid arthritis	Objective and subjective improvement	Sweden	Yes
Burleigh 2007	Older geriatric inpatients	Falls	UK	Yes
Campbell 2005	Elderly people with visual impairment	Numbers of falls and injuries resulting from falls	New Zealand	No
Chapuy 1992	Healthy ambulatory women	Fractures	France	Yes
Chapuy 2002	Elderly people living in institutional care	Biochemical variables of calcium homeostasis, femoral neck bone mineral density and hip fracture risk	France	Yes
Chel 2008	Nursing home residents	Vitamin D status	Netherlands	Yes
Cherniack 2011	Elderly people	Vitamin D status	USA	Yes
Cooper 2003	Postmenopausal women	Bone mineral density	Australia	Yes
Corless 1985	Elderly patients from the geriatric wards	Abilities to carry out basic activities of daily life	UK	Yes
Daly 2008	Healthy ambulatory men	Bone mineral density	Australia	Yes
Dawson‐Hughes 1997	Healthy ambulatory participants	Bone mineral density	USA	Yes
Dukas 2004	Elderly people	Falls	Switzerland	Yes
Flicker 2005	Elderly people living in institutional care	Falls and fractures	Australia	No
Gallagher 2001	Elderly women	Bone mineral density	USA	No
Glendenning 2012	Elderly community‐dwelling ambulatory women	Falls, muscular strength and mobility	Australia	No
Grady 1991	Elderly people	Muscle strength	USA	Yes
Grimnes 2011	Healthy people with a low vitamin D status	Insulin sensitivity and secretion	Norway	No
Harwood 2004	Elderly women following surgery for hip fracture	Bone mineral density, falls and fractures	UK	Yes
Jackson 2006	Postmenopausal women	Fractures	USA	Yes
Janssen 2010	Elderly vitamin D–insufficient women	Muscle strength, power and functional mobility	Netherlands	Yes
Komulainen 1999	Postmenopausal women	Bone mineral density	Finland	Yes
Krieg 1999	Elderly institutionalised women	Bone mineral density	Switzerland	Yes
Kärkkäinen 2010	Postmenopausal women	Falls	Finland	Yes
Lappe 2007	Healthy postmenopausal white women	Fractures	USA	Yes
Larsen 2004	Older community‐dwelling residents	Falls	Denmark	Yes
Latham 2003	Frail elderly people	Self‐rated physical health and falls	New Zealand	No
Law 2006	Nursing home residents	Falls and fractures	UK	No
Lehouck 2012	Patients with chronic obstructive pulmonary disease	Time to first exacerbation	Belgium	Yes
Lips 1996	Elderly people	Fractures	Netherlands	Yes
Lips 2010	Elderly people with vitamin D insufficiency	Postural stability, muscle strength and safety	Netherlands	No
Lyons 2007	Older people living in institutional care	Fractures	UK	No
Meier 2004	Healthy volunteers	Bone mineral density	Germany	No
Mochonis 2006	Postmenopausal women	Bone mineral density	Greece	Yes
Ooms 1995	Elderly people	Bone mineral density	Netherlands	Yes
Ott 1989	Postmenopausal women	Bone mass	USA	Yes
Porthouse 2005	Elderly women with one or more risk factors for hip fracture	Fractures	UK	Yes
Prince 2008	Elderly women with a history of falling and vitamin D insufficiency	Falls	Australia	Yes
Sanders 2010	Elderly women at high risk of fracture	Falls and fractures	Australia	Yes
Sato 1997	Outpatients with hemiplegia after stroke	Bone mineral density and fractures	Japan	No
Sato 1999a	Elderly patients with Parkinson's disease	Fractures	Japan	No
Sato 1999b	Outpatients with hemiplegia after stroke	Bone mineral density	Japan	Yes
Sato 2005a	Hospitalised elderly women with post‐stroke hemiplegia	Falls	Japan	No
Schleithoff 2006	Patients with congestive heart failure	Mortality	Germany	Yes
Smith 2007	Elderly people	Fractures	UK	No
Trivedi 2003	Elderly people	Mortality, fractures	UK	No
Witham 2010	Patients with systolic heart failure	Exercise capacity	UK	No
Zhu 2008	Elderly women	Bone mineral density	Australia	No

Table 2. Characteristics of included trials (II)

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Table 3. Characteristics of included trials (III)

Characteristic Study ID	D₃ [IU]	D₂ [IU]	1α(OH)D [µg]	1,25(OH)₂D [µg]	Ca [mg]	Regimen	Route	Treatment [years]	Follow‐up [years]
Aloia 2005	800 2000				1200‐1500^a	Daily	Oral	3	3
Avenell 2004	800				1000^b	Daily	Oral	1	1
Avenell 2012	800				500^b	Daily	Oral	3.75	6.2
Baeksgaard 1998	560				1000	Daily	Oral	2	2
Bischoff 2003	800				1200^a	Daily	Oral	0.25	0.25
Bjorkman 2007	400 1200				500^a	Daily	Oral	0.5	0.5
Bolton‐Smith 2007	400				1000	Daily	Oral	2	2
Brazier 2005	800				1000	Daily	Oral	1	1
Broe 2007		200 400 600 800				Daily	Oral	0.42	0.42
Brohult 1973	100,000					Daily	Oral	1	1
Burleigh 2007	800				1200^a	Daily	Oral	0.08	0.08
Campbell 2005	50,000 100,000					Monthly	Oral	1	1
Chapuy 1992	800				1200	Daily	Oral	1.5	4
Chapuy 2002	800				1200	Daily	Oral	2	2
Chel 2008	600 4200 18.000				800 1600	Daily Weekly Monthly	Oral	0.33	0.33
Cherniack 2011	2000				1200^a	Daily	Oral	0.5	0.5
Cooper 2003		10,000			1000^a	Weekly	Oral	2	2
Corless 1985		9000				Daily	Oral	0.75	0.75
Daly 2008	800				1000	Daily	Oral	2	3.5
Dawson‐Hughes 1997	700				500	Daily	Oral	3	3
Dukas 2004			1			Daily	Oral	0.75	0.75
Flicker 2005		1000 10,000			600^a	Daily Weekly	Oral	2	2
Gallagher 2001				0.5		Daily	Oral	3	5
Glendenning 2012	150,000					Three‐monthly	Oral	0.5	0.75
Grady 1991				0.5		Daily	Oral	0.5	0.5
Grimnes 2011	20,000					Twice weekly	Oral	0.5	0.5
Harwood 2004	800	300,000			1000	Single dose daily	Intramuscular Oral	1	1
Jackson 2006	400				1000	Daily	Oral	7	7
Janssen 2010	400				500^a	Daily	Oral	0.5	0.5
Komulainen 1999	300				500	Daily	Oral	5	5
Krieg 1999	880				1000	Daily	Oral	2	2
Kärkkäinen 2010	800				1000	Daily	Oral	3	3
Lappe 2007	1000				1400‐1500^b	Daily	Oral	4	4
Larsen 2004	400				1000	Daily	Oral	3.5	3.5
Latham 2003	300,000					Single dose	Oral	0.003	0.5
Law 2006		100,000				Four‐monthly	Oral	0.83	0.83
Lehouck 2012	100,000					Monthly	Oral	1	1
Lips 1996	400					Daily	Oral	3.5	3.5
Lips 2010	8400				500^a	weekly	Oral	0.31	0.31
Lyons 2007		100,000				Four‐monthly	Oral	3	3
Meier 2004	500				500	Daily	Oral	0.5	1
Mochonis 2006	300				1200^b	Daily	Oral	1	1
Ooms 1995	400					Daily	Oral	2	2
Ott 1989				0.5 2	1000^a	Daily	Oral	2	2
Porthouse 2005	800				1000	Daily	Oral	2	2
Prince 2008		1000			1000^a	Daily	Oral	1	1
Sanders 2010	500,000					Yearly	Oral	2.96	2.96
Sato 1997			1		300^a	Daily	Oral	0.5	0.5
Sato 1999a			1			Daily	Oral	1.5	1.5
Sato 1999b			1			Daily	Oral	1	1
Sato 2005a		1000				Daily	Oral	2	2
Schleithoff 2006	2000				500^a	Daily	Oral	0.75	1.25
Smith 2007		300,000				Yearly	Intramuscular	3	3
Trivedi 2003	100,000					Four‐monthly	Oral	5	5
Witham 2010		100,000				10‐weekly	Oral	0.38	0.38
Zhu 2008		1000			1200^b	Daily	Oral	5	5
^aEqual dose of calcium was administered to a control group ^bCalcium was tested singly in one arm of the trial as well as combined with vitamin D; placebo or no intervention group of the trial was not supplemented with calcium 1α(OH)D: alfacalcidol; 1,25(OH)₂D: calcitriol; IU: international units; µg: microgram

Table 3. Characteristics of included trials (III)

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Table 4. Overview of study populations

Characteristic Study ID	Intervention(s) and control(s)	[N] screened / eligible	[N] randomised	[N] ITT	[N] finishing study	[%] of randomised participants finishing study
1. Aloia 2005	I: vitamin D₃ plus calcium	322	104	104	74	71
1. Aloia 2005	C: placebo	322	104	104	74	71
total:			208	208	148	71
2. Avenell 2004	I: vitamin D₃	180	70	70	‐	‐
2. Avenell 2004	C: no intervention	180	64	64	‐	‐
total:			134	134	‐	‐
3. Avenell 2012	I: vitamin D₃	15,024	2649	2649	1813	68
3. Avenell 2012	C: matched placebo tablets	15,024	2643	2643	1762	67
total:			5292	5292	3575	68
4. Baeksgaard 1998	I: vitamin D₃ plus calcium	‐	80	80	65	81
4. Baeksgaard 1998	C: matched placebo tablets	‐	80	80	64	80
total:			160	160	129	80
5. Bischoff 2003	I: vitamin D₃ plus calcium	130	62	62	‐	‐
5. Bischoff 2003	C: calcium	130	60	60	‐	‐
total:			122	122	89	73
6. Bjorkman 2007	I: vitamin D₃ plus calcium	1215	150	150	123	82
6. Bjorkman 2007	C: calcium	1215	68	68	59	87
total:			218	218	182	83
7. Bolton‐Smith 2007	I: vitamin D₃ plus calcium	‐	62	62	50	81
7. Bolton‐Smith 2007	C: matched placebo	‐	61	61	56	92
total:			123	123	106	86
8. Brazier 2005	I: vitamin D₃ plus calcium	360	95	95	74	78
8. Brazier 2005	C: matched placebo tablets	360	97	97	68	70
total:			192	192	142	74
9. Broe 2007	I: vitamin D₂	126	99	99	96	97
9. Broe 2007	C: matched placebo tablets	126	25	25	25	100
total:			124	124	121	98
10. Brohult 1973	I: vitamin D₃	‐	25	25	24	96
10. Brohult 1973	C: placebo	‐	25	25	25	100
total:			50	50	49	98
11. Burleigh 2007	I: vitamin D₃ plus calcium	515	101	101	98	97
11. Burleigh 2007	C: placebo	515	104	104	101	97
total:			205	205	199	97
12. Campbell 2005	I: home safety assessment and modification programme	391	195	195	177	91
12. Campbell 2005	C: social visits	391	196	196	184	94
total:			391	391	361	92
13. Chapuy 1992	I: vitamin D₃ plus calcium	‐	1634	1634	1590	97
13. Chapuy 1992	C: double placebo	‐	1636	1636	1573	96
total:			3270	3270	3163	96
14. Chapuy 2002	I: vitamin D₃ plus calcium	639	393	393	‐	‐
14. Chapuy 2002	C: double placebo	639	190	190	‐	‐
total:			583	583	‐	‐
15. Chel 2008	I: vitamin D₃	1006	166	166	139	84
15. Chel 2008	C: matched placebo tablets	1006	172	172	137	80
total:			338	338	276	82
16. Cherniack 2011	I: vitamin D₃ plus calcium	52	23	23	17	74
16. Cherniack 2011	C: matched placebo plus calcium	52	23	23	17	74
total:			46	46	34	74
17. Cooper 2003	I: vitamin D₂ plus calcium	‐	93	93	73	78
17. Cooper 2003	C: calcium	‐	94	94	80	85
total:			187	187	153	82
18. Coreless 1985	I: vitamin D₂	320	32	32	8	25
18. Coreless 1985	C: placebo	320	33	33	17	51
total:			65	65	25	38
19. Daly 2006	I: calcium‐vitamin D₃–fortified milk plus calcium	422	85	85	76	89
19. Daly 2006	C: no intervention	422	82	82	73	89
total:			167	167	149	89
20. Dawson‐Hughes 1997	I: vitamin D₃ plus calcium	545	187	187	148	79
20. Dawson‐Hughes 1997	C: placebo	545	202	202	170	84
total:			389	389	318	82
21. Dukas 2004	I: alfacalcidol	410	192	192	‐	‐
21. Dukas 2004	C: placebo	410	186	186	‐	‐
total:			378	378	‐	‐
22. Flicker 2005	I: vitamin D₃ plus calcium	1767	313	313	269	86
22. Flicker 2005	C: calcium	1767	312	312	271	87
total:			625	625	540	86
23. Gallagher 2001	I: calcitriol	1905	123	123	101	82
23. Gallagher 2001	C: matched placebo	1905	123	123	112	91
total:			246	246	213	87
24. Glendenning 2012	I: cholecalciferol 150,000 three‐monthly	2110	353	353	331	94
24. Glendenning 2012	C: placebo vitamin D		333	333	307	92
total:			686	686	638	93
25. Grady 1991	I: calcitriol	98	50	50	49	98
25. Grady 1991	C: placebo vitamin D	98	48	48	47	98
total:			98	98	96	98
26. Grimnes 2011	I: vitamin D₃	108	51	51	49	96
26. Grimnes 2011	C: placebo	108	53	53	45	85
total:			104	104	94	90
27. Harwood 004	I: vitamin D plus calcium	208	113	113	‐	‐
27. Harwood 004	C: no intervention	208	37	37	‐	‐
total:			150	150	‐	‐
28. Jackson 2006	I: vitamin D₃ plus calcium	68,132	18,176	18,176	16,936	93
28. Jackson 2006	C: matched placebo	68,132	18,106	18,106	16,815	93
total:			36,282	36,282	33,751	93
29. Janssen 2010	I: vitamin D₃ plus calcium	91	36	36	18	50
29. Janssen 2010	C: matched placebo vitamin D₃ plus calcium	91	34	34	31	91
total:			70	70	49	70
30. Komulainen 1999	I: oestradiol valerate and cyproterone acetate	13,100	116	116	‐	‐
30. Komulainen 1999	C: placebo	13,100	116	116	‐	‐
total:			232	232	‐	‐
31. Krieg 1999	I: vitamin D₃ plus calcium	‐	124	124	50	40
31. Krieg 1999	C: no treatment	‐	124	124	53	43
total:			248	248	103	41
32. Kärkkäinen 2010	I: vitamin D₃ plus calcium	5407	1718	1718	1566	91
32. Kärkkäinen 2010	C: no treatment		1714	1714	1573	92
total:			3432	3432	3139	91
33. Lappe 2007	I: vitamin D₃ plus calcium	1180	446	446	‐	‐
33. Lappe 2007	C: calcium plus placebo tablets		733	733	‐	‐
total:			1179	1179	‐	‐
34. Larsen 2004	I: home safety inspection, vitamin D₃ plus calcium	62,000	4957	4957	‐	‐
34. Larsen 2004	C: no intervention	62,000	4648	4648	‐	‐
total:			9605	9605	‐	‐
35. Latham 2003	I: vitamin D₃	3,028	121	121	108	89
35. Latham 2003	C: matched placebo tablets	3,028	122	122	114	93
total:			243	243	222	91
36. Law 2006	I: vitamin D₂	‐	1762	1762	1366	77
36. Law 2006	C: no intervention	‐	1955	1955	1569	80
total:			3717	3717	2935	79
37. Lehouck 2012	I: vitamin D₃	419	91	91	72	79
37. Lehouck 2012	C: matched placebo	419	91	91	78	86
total:			182	182	150	82
38. Lips 1996	I: vitamin D₃	‐	1291	1291	1061	82
38. Lips 1996	C: matched placebo	‐	1287	1287	1029	80
total:			2578	2578	2090	81
39. Lips 2010	I: vitamin D₃	593	114	114	105	92
39. Lips 2010	C: matched placebo	593	112	112	97	87
total:			226	226	202	89
40. Lyons 2007	I: vitamin D₂	5745	1725	1725	778	45
40. Lyons 2007	C: matched placebo tablets	5745	1715	1715	762	44
total:			3440	3440	1540	44
41. Meier 2004	I: vitamin D₃	‐	30	30	27	90
41. Meier 2004	C: no intervention	‐	25	25	16	64
total:			55	55	43	78
42. Mochonis 2006	I: vitamin D₃ plus calcium	‐	72	72	65	90
42. Mochonis 2006	C: no intervention	‐	40	40	36	90
total:			112	112	101	90
43. Ooms 1995	I: vitamin D₃	‐	177	177	126	71
43. Ooms 1995	C: matched placebo	‐	171	171	118	69
total:			348	348	244	70
44. Ott 1989	I: vitamin D₃ plus calcium	‐	43	43	39	91
44. Ott 1989	C: matched placebo vitamin D plus calcium	‐	43	43	37	86
total:			86	86	76	88
45. Porthouse 2005	I: vitamin D₃ plus calcium	11,022	1321	1321	1212	92
45. Porthouse 2005	C: no intervention	11,022	1993	1993	1862	93
total:			3454	3454	3074	92
46. Prince 2008	I: vitamin D₂ plus calcium	827	151	151	144	95
46. Prince 2008	C: matched placebo tablets of vitamin D plus calcium	827	151	151	145	96
total:			302	302	289	95
47. Sanders 2010	I: vitamin D₃	7204	1131	1131	1015	90
47. Sanders 2010	C: matched placebo tablets		1127	1127	1017	90
total:			2258	2258	1032	90
48. Sato 1997	I: vitamin D (alfacalcidol) plus calcium	‐	45	45	30	67
48. Sato 1997	C: matched placebo tablets of vitamin D and calcium		39	39	34	87
total:			84	84	64	76
49. Sato 1999a	I: vitamin D (alfacalcidol)	‐	43	43	40	93
49. Sato 1999a	C: matched placebo tablets of vitamin D	‐	43	43	40	93
total:			86	86	80	93
50. Sato 1999b	I: vitamin D (alfacalcidol)	‐	34	34	32	94
50. Sato 1999b	C: matched placebo tablet of vitamin D	‐	35	35	32	91
total:			69	69	64	93
51. Sato 2005a	I: vitamin D₂	‐	48	48	43	90
51. Sato 2005a	C: matched placebo tablets of vitamin D	‐	48	48	42	87
total:			96	96	85	88
52. Schleithoff 2006	I: vitamin D₃ plus calcium	‐	61	61	42	69
52. Schleithoff 2006	C: matched placebo vitamin D plus calcium	‐	62	62	51	82
total:			103	103	93	90
53. Smith 2007	I: vitamin D₂	13,487	4727	4727	2304	49
53. Smith 2007	C: matched placebo intramuscular injection	13,487	4713	4713	2266	48
total:			9440	9440	4570	48
54. Trivedi 2003	I: vitamin D₃	‐	1345	1345	1262	94
54. Trivedi 2003	C: matched placebo vitamin D	‐	1341	1341	1264	94
total:			2696	2696	2526	94
55. Witham 2010	I: vitamin D₂	173	53	53	48	91
55. Witham 2010	C: matched placebo tablets	173	52	52	48	91
total:			105	105	96	91
56. Zhu 2008	I: vitamin D₂ plus calcium	‐	39	39	33	85
56. Zhu 2008	C: matched placebo vitamin D and calcium	‐	81	81	74	91
total:			120	120	107	89
*Grand total*	*All interventions*		*47,472*		*45,351*
	*All controls*		*47,814*		*45,278*
	*All interventions and controls*		*95,286*		*90,629^a*
"‐" denotes not reported ^aNumbers not available for all studies C: control; I: intervention; ITT: intention‐to‐treat

Table 4. Overview of study populations

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Comparison 1. Vitamin D versus placebo or no intervention

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All‐cause mortality in trials with low or high risk of bias Show forest plot	56	95286	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.94, 0.99]

1.1 Trials with low risk of bias	30	67516	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.92, 0.99]
1.2 Trials with high risk of bias	26	27770	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.92, 1.06]
2 All‐cause mortality in individually randomised and cluster‐randomised trials Show forest plot	56	95286	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.94, 0.99]

2.1 Individually randomised trials	54	81964	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.93, 0.99]
2.2 Cluster‐randomised trials	2	13322	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.82, 1.34]
3 All‐cause mortality in placebo‐controlled and no intervention trials Show forest plot	56	95286	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.94, 0.99]

3.1 Placebo in the control group	44	73892	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.93, 0.99]
3.2 No intervention in the control group	12	21394	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.91, 1.21]
4 All‐cause mortality and risk of industry bias Show forest plot	56	95286	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.94, 0.99]

4.1 Trials without risk of industry bias	7	7372	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.92, 1.03]
4.2 Trials with risk of industry bias	49	87914	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.93, 1.00]
5 All‐cause mortality in primary and secondary prevention trials Show forest plot	56	95286	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.94, 0.99]

5.1 Primary prevention trials	48	94491	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.94, 0.99]
5.2 Secondary prevention trials	8	795	Risk Ratio (M‐H, Random, 95% CI)	1.31 [0.73, 2.35]
6 All‐cause mortality and vitamin D status Show forest plot	56	95286	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.94, 0.99]

6.1 Vitamin D insufficiency	26	56697	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.91, 0.99]
6.2 Vitamin D adequacy	19	16283	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.87, 1.05]
6.3 Unknown vitamin D status	11	22306	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.92, 1.13]
7 All‐cause mortality in ambulatory and institutionalised participants Show forest plot	56	95286	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.94, 0.99]

7.1 Ambulatory participants	45	86071	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.92, 0.98]
7.2 Institutionalised participants	11	9215	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.92, 1.13]
8 All‐cause mortality ('best‐worst case' and 'worst‐best case' scenario) Show forest plot	53		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

8.1 'Best‐worst' case scenario	53	84418	Risk Ratio (M‐H, Random, 95% CI)	0.40 [0.32, 0.51]
8.2 'Worst‐best' case scenario	53	84418	Risk Ratio (M‐H, Random, 95% CI)	2.78 [2.13, 3.63]
9 All‐cause mortality in trials using vitamin D₃ (cholecalciferol) Show forest plot	38	75927	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.91, 0.98]

9.1 Vitamin D3 trials with low risk of bias	20	52645	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.89, 0.98]
9.2 Vitamin D3 trials with high risk of bias	18	23282	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.91, 1.00]
10 All‐cause mortality in trials using vitamin D₃ singly or combined with calcium Show forest plot	38		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

10.1 Vitamin D3 singly	13	12609	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.85, 1.00]
10.2 Vitamin D3 combined with calcium	27	63051	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.92, 0.99]
11 All‐cause mortality in trials using low or high dose of vitamin D₃ Show forest plot	38		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

11.1 Low dose of vitamin D3 (< 800 IU a day)	13	50437	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.87, 0.97]
11.2 High dose of vitamin D3 (≥ 800 IU a day)	26	25558	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.92, 1.00]
12 All‐cause mortality in trials applying vitamin D₃ daily or intermittently Show forest plot	38		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

12.1 Vitamin D3 daily	31	69168	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.91, 0.98]
12.2 Vitamin D3 intermittently	8	6871	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.77, 1.03]
13 All‐cause mortality in trials using vitamin D₃ and vitamin D status Show forest plot	38	75927	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.91, 0.98]

13.1 Vitamin D insufficiency	20	55883	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.91, 0.99]
13.2 Vitamin D adequacy	10	4979	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.80, 1.07]
13.3 Unknown vitamin D status	8	15065	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.78, 1.16]
14 All‐cause mortality in trials using vitamin D₃ according to the participant's sex Show forest plot	38	75927	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.91, 0.98]

14.1 Vitamin D3 trialsincluding only women	19	53062	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.84, 1.03]
14.2 Vitamin D3 trials including men and women	19	22865	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.89, 0.98]
15 All‐cause mortality in trials using vitamin D₂ (ergocalciferol) Show forest plot	12	18349	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.96, 1.08]

15.1 Vitamin D2 trials with low risk of bias	9	14439	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.93, 1.04]
15.2 Vitamin D2 trials with high risk of bias	3	3910	Risk Ratio (M‐H, Random, 95% CI)	1.20 [1.05, 1.37]
16 All‐cause mortality in trials using vitamin D₂ singly or combined with calcium Show forest plot	12		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

16.1 Vitamin D2 singly	8	17079	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.96, 1.12]
16.2 Vitamin D2 combined with calcium	5	1307	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.64, 1.57]
17 All‐cause mortality in trials using low or high dose of vitamin D₂ Show forest plot	12		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

17.1 Low dose of vitamin D2	1	101	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.17, 3.98]
17.2 High dose of vitamin D2	12	18273	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.95, 1.10]
18 All‐cause mortality in trials applying vitamin D₂ daily or intermittently Show forest plot	12		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

18.1 Vitamin D2 daily	6	1349	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.68, 1.12]
18.2 Vitamin D2 intermittently	6	17000	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.95, 1.18]
19 All‐cause mortality in trials using vitamin D₂ and vitamin D status Show forest plot	12	18349	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.96, 1.08]

19.1 Vitamin D insufficiency	6	4413	Risk Ratio (M‐H, Random, 95% CI)	1.20 [1.05, 1.37]
19.2 Vitamin D adequacy	5	10496	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.86, 1.10]
19.3 Unknown vitamin D status	1	3440	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.93, 1.05]
20 All‐cause mortality in trials using alfacalcidol (1α‐hydroxyvitamin D) Show forest plot	4	617	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.22, 4.15]

21 All‐cause mortality in trials using alfacalcidol and vitamin D status Show forest plot	4	617	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.22, 4.15]

21.1 Vitamin D insufficiency	2	155	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.11, 9.52]
21.2 Vitamin D adequacy	1	378	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.06, 15.37]
21.3 Unknown vitamin D status	1	84	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.06, 13.40]
22 All‐cause mortality in trials using calcitriol (1,25‐dihydroxyvitamin D) Show forest plot	3	430	Risk Ratio (M‐H, Random, 95% CI)	1.37 [0.27, 7.03]

23 All‐cause mortality in trials using calcitriol and vitamin D status Show forest plot	3	430	Risk Ratio (M‐H, Random, 95% CI)	1.37 [0.27, 7.03]

23.1 Vitamin D insufficiency	1	86	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.01, 7.96]
23.2 Vitamin D adequacy	2	344	Risk Ratio (M‐H, Random, 95% CI)	2.28 [0.34, 15.39]
24 Cancer mortality Show forest plot	4	44492	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.78, 0.98]

25 Cardiovascular mortality Show forest plot	10	47267	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.90, 1.07]

26 Adverse events Show forest plot	35		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

26.1 Hypercalcemia in trials using supplemental forms of vitamin D	15	11323	Risk Ratio (M‐H, Random, 95% CI)	1.36 [0.85, 2.18]
26.2 Hypercalcemia in trials using active forms of vitamin D	3	710	Risk Ratio (M‐H, Random, 95% CI)	3.18 [1.17, 8.68]
26.3 Nephrolithiasis in trials using vitamin D3 combined with calcium	4	42876	Risk Ratio (M‐H, Random, 95% CI)	1.17 [1.02, 1.34]
26.4 Nephrolithiasis in trials using calcitriol	1	246	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.01, 8.10]
26.5 Hypercalciuria	3	695	Risk Ratio (M‐H, Random, 95% CI)	4.64 [0.99, 21.76]
26.6 Renal insufficiency	3	5495	Risk Ratio (M‐H, Random, 95% CI)	1.70 [0.27, 10.70]
26.7 Cardiovascular disorders	8	4495	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.86, 1.05]
26.8 Gastrointestinal disorders	16	9702	Risk Ratio (M‐H, Random, 95% CI)	1.36 [0.87, 2.13]
26.9 Psychiatric disorders	3	580	Risk Ratio (M‐H, Random, 95% CI)	1.44 [0.56, 3.73]
26.10 Skin disorders	2	3810	Risk Ratio (M‐H, Random, 95% CI)	3.27 [0.17, 62.47]
26.11 Cancer	14	49707	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.94, 1.06]

Comparison 1. Vitamin D versus placebo or no intervention

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Vitamin D supplementation for prevention of mortality in adults

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