Skip to content

Advertisement

  • Research article
  • Open Access
  • Open Peer Review

Assessment of research waste part 2: wrong study populations- an exemplar of baseline vitamin D status of participants in trials of vitamin D supplementation

BMC Medical Research Methodology201818:101

https://doi.org/10.1186/s12874-018-0555-1

  • Received: 3 December 2017
  • Accepted: 10 September 2018
  • Published:
Open Peer Review reports

Abstract

Background

Research waste can occur when trials are conducted in the wrong populations. Vitamin D deficient populations are most likely to benefit from vitamin D supplementation. We investigated waste attributable to randomised controlled trials (RCTs) of supplementation in populations that were not vitamin D deficient.

Methods

In December 2015, we searched Pubmed, recent systematic reviews, and three trial registries for RCTs of vitamin D with clinical endpoints in adults, and 25-hydroxvitamin D (25OHD) survey data relevant to large (N ≥ 1000) RCTs. We investigated the proportion of RCTs that studied vitamin D deficient populations, temporal trends in baseline 25OHD, and whether investigators in large RCTs considered relevant 25OHD survey data or systematic reviews in their trial justifications.

Results

Of 137 RCTs of vitamin D with clinical endpoints, 118 (86%) reported baseline mean/median 25OHD, which was < 25, 25–49, 50–74, and ≥ 75 nmol/L in 12 (10%), 62 (53%), 36 (31%), and 8 (7%) RCTs, respectively. In 70% of RCTs, baseline 25OHD was > 40 nmol/L. Baseline 25OHD increased over time. Before 2006, 38%, 62%, 0% and 0% of RCTs had baseline 25OHD < 25, 25–49, 50–74, and ≥ 75 nmol/L respectively; in 2011–15, the respective proportions were 9%, 49%, 37%, and 6%. Of 12 RCTs with baseline 25OHD < 25 nmol/L, 8 had neutral findings. Of 25 large RCTs (18 completed, 7 ongoing), 1 was undertaken in a vitamin D deficient population, 3 in vitamin D insufficient populations, and 17 had, or probably will have, baseline 25OHD > 40 nmol/L. 44% (8/18) of large completed RCTs cited relevant prior population 25OHD data, and only 3/10 (30%) relevant prior systematic reviews.

Conclusions

Up to 70% of RCTs of vitamin D with clinical endpoints, 71% of large completed RCTs, and 100% of ongoing large RCTs could be considered research waste because they studied cohorts that were not vitamin D deficient.

Keywords

  • Vitamin D
  • Deficiency
  • Sufficiency
  • Randomized controlled trials
  • Research waste
  • Fracture
  • Cardiovascular disease
  • Cancer
  • Mortality

Background

Chalmers and Glasziou estimated that 85% of clinical research is wasteful, with 50% of studies having design or major methodological weaknesses [1]. In these companion reports, we assessed research waste in a single field - calcium and vitamin D research. In the first report [2], we focused on redundant research characterized by the undertaking and publication of uninformative observational studies and randomised controlled trials (RCTs) with surrogate endpoints long after the need for large RCTs with ‘hard’ clinical endpoints was established. In this second report, we address waste characterised by conducting RCTs in poorly targeted population groups.

Clinical guidelines disagree on the serum 25-hydroxyvitamin D (25OHD) concentrations that constitute vitamin D sufficiency. The Institute of Medicine recommends ≥50 nmol/L to ensure adequate 25OHD for 97.5% of the population, with a median target value of 40 nmol/L [3], whereas the Endocrine Society recommends ≥75 nmol/L [4]. However despite this disagreement, there is general agreement that 25OHD < 25 nmol/L indicates deficiency, and recent UK guidance on vitamin D supplementation is based on maintaining 25OHD above this threshold [5]. Mildly low 25OHD is often termed vitamin D insufficiency, and moderately low 25OHD vitamin D deficiency. Throughout the text, we have used vitamin D deficiency to refer to 25OHD < 25 nmol/L, and insufficiency to 25OHD < 50 nmol/L [6]. Intuitively, supplementing populations that are vitamin D deficient is more likely to produce benefits than supplementing populations with higher 25OHD [7]. Potential benefits of vitamin D could be obscured if a high proportion of participants in RCTs are vitamin D sufficient. Thus, RCTs in cohorts that are vitamin D sufficient are unlikely to show benefits of vitamin D supplementation and could be considered research waste. Recent systematic reviews of RCTs of vitamin D supplementation have not shown benefits on skeletal or non-skeletal endpoints [811]. We set out to determine what proportion of RCTs of vitamin D supplementation with clinical endpoints has been conducted in vitamin D deficient populations, and whether baseline 25OHD in such RCTs have changed over time. We then focused on large RCTs either already completed or in progress, identified data on target population vitamin D status available prior to the trial, and determined whether the investigators reported relevant data on vitamin D status. We also determined whether investigators reported relevant systematic reviews in their trial justification, as recommended [1, 12].

Methods

Literature searches

In December 2015, we searched Pubmed for RCTs of vitamin D in adults (>18y) (Additional file 1: Table S1) and for recent systematic reviews on clinical conditions and major surrogate endpoints that were the primary endpoints in identified RCTs (Additional file 1: Tables S2 and S3). We included trials with an untreated or placebo group, trials comparing different vitamin D doses, trials with or without calcium supplements, and trials with multiple interventions provided that 2 study arms differed only by the use of vitamin D. We included quasi-randomized trials but excluded trials where the method of allocation was sequential or unreported, trials where vitamin D was administered routinely post-thyroidectomy, and trials of hydroxylated vitamin D analogues. The flow of articles is shown in Additional file 1: Figure S1.

In December 2015, we also searched ClinicalTrials.gov (https://clinicaltrials.gov/), the International Standard Randomised Controlled Trial Number (ISRCTN) registry (http://www.isrctn.com/) and the Australian New Zealand Clinical Trials Registry (ANZCTR) (http://www.anzctr.org.au/) for completed and ongoing trials, using vitamin D as the search term.

Finally, we obtained vitamin D status survey data from published systematic reviews [1317]. supplemented by Medline, Embase, and Google searches using our vitamin D search strategy and text words for the countries of interest, and checked citations in reference lists.

Trial classification

We categorised each RCT according to whether clinical or surrogate endpoints were reported in the Abstract (or full-text where there was no Abstract), using the Institute of Medicine definition of surrogate outcomes as “biomarker[s] intended to substitute for a clinical endpoint [and] expected to predict clinical benefit (or harm. ..) based on epidemiologic, therapeutic, pathophysiologic, or other scientific evidence” [18]. Where multiple endpoints were reported, we recorded the most relevant clinical endpoint, and if there were no clinical endpoints, the most clinically relevant surrogate endpoint. Where there were multiple publications from the same RCT, we included the study with the most relevant clinical endpoint or the most clinically relevant surrogate endpoint.

Vitamin D status survey data

For large (N ≥ 1000) completed and ongoing RCTs, we identified surveys of vitamin D status undertaken in the same country and most similar population group, based on age and sex, prior to the trial being undertaken. We preferentially sought data from the five years before trial inception or 10 years before trial completion/publication, but used older data if we could not locate such data.

Analyses

A single author (MB or AA) extracted relevant data. One author (MB) classified trials as having clinical or surrogate endpoints, and a second author (AG) checked the classifications. We report the proportions of trials with mean/median baseline 25OHD < 25, 25–49, 50–74, ≥75 nmol/L over time. In trials with mean/median baseline 25OHD < 25 nmol/L and trials that reported a subgroup analysis based on baseline 25OHD, two authors (MB, AG) independently assessed whether the results of the trial or subgroup analysis were beneficial, neutral, or harmful and disagreements were resolved by consensus.

We examined primary trial publications, and trial protocols (where available), for large RCTs (N ≥ 1000) and assessed whether trial investigators discussed prior relevant evidence on vitamin D status of the intended trial population in their justification for the trial. We also examined whether trial investigators discussed systematic reviews of randomised trials relevant to the primary endpoint that were available before trial recruitment commenced in the Introduction section of the primary publication.

Early 25OHD competitive binding protein (CBP) assays overestimated 25OHD concentrations [19]. As an approximation, we used an adjustment factor of 0.54 for CBP assays in papers published before 2000 [19]. and 0.76 to adjust for overestimation from the Nicholls’ immunoassay [20]. We have presented the RCT and survey data in Tables 3 and 4 corrected for these overestimations.

Results

Baseline 25OHD in randomised controlled trials

From 4682 unique Pubmed records and 38 systematic reviews, we identified 779 publications from 547 RCTs of vitamin D, of which 137 (111,976 participants) reported a clinical endpoint in the Abstract (Additional file 1: Tables S1, S2, S3 and Figure S1). Figure 1a shows that the rate of publication of RCTs has increased markedly, with 11 RCTs in 2001–5, 28 in 2006–10, and 88 in 2011–15. Mean/median baseline 25OHD was reported in 118/137 (86%) RCTs (Fig. 1b), with 62%, 82%, and 93% of RCTs reporting baseline 25OHD before 2006, in 2006–10, and in 2011–15 respectively. Overall, mean/median baseline 25OHD was < 25, 25–49, 50–74, and ≥ 75 nmol/L in 12 (10%), 62 (53%), 36 (31%), and 8 (7%) RCTs, respectively. In 70% of RCTs, baseline 25OHD was > 40 nmol/L. Of 12 RCTs with baseline 25OHD < 25 nmol/L, 8 had neutral findings (Table 1).
Fig. 1
Fig. 1

Panel a shows the number of randomized controlled trials (RCTs) of vitamin D with clinical endpoints in the Abstract published over time by year (bars) and cumulatively (line). Panel b shows the distribution of mean/median baseline 25-hydroxyvitamin D (25OHD) concentrations in these RCTs. Panel c shows the 25OHD concentrations plotted against year of publication with a line of best fit. Panel d shows the proportion of trials with mean/median baseline 25OHD < 25, 25–49, 50–74 and ≥ 75 nmol/L by year of publication. Above each bar is the number of trials

Table 1

Characteristics of 12 randomised controlled trials of vitamin D supplements in populations with mean/median 25OHD < 25 nmol/L and clinical endpoints reported in abstract

Study

Clinical endpoint

Endpoint type

Study Size (N)

25OHD Assay

Mean/Median 25OHD (SD) (nmol/L)a

Result of Trialb

Brooke 1980 [44]

Newborn outcomes

Secondary

126

CBP

11 (1)

Benefit

Chapuy 1994 [21]

Fracture

Primary

3270

CBP

20 (14)

Benefit

Pfeifer 2000 [45]

Risk of fall

Secondary

148

Nicholls

19 (10)

Neutral

Chapuy 2002 [46]

Fracture

Secondary

583

Incstar

22 (16)

Neutral

Bischoff 2003 [47]

Risk of fall

Primary

122

Nicholls

23 (N/A)

Neutral

Martineau 2011 [48]

Tuberculosis sputum culture conversion

Primary

126

LCMS/MS

21 (20)

Neutral

Mosayebi 2011 [49]

Multiple sclerosis disability score

Primary

59

IDS

25 (7)

Neutral

Amestejani 2012 [50]

Atopic dermatitis

Primary

60

Biosource

24 (5)

Benefit

Schreuder 2012 [51]

Pain

Primary

84

Diasorin

20 (10)

Neutral

Mozaffari-Khosravi 2013 [52]

Depression score

Primary

120

IDS

23 (N/A)

Benefit

Hossain 2014 [53]

Pregnancy outcomes

Primary

200

Immunoassay

13 (N/A)

Neutral

Bhan 2015 [54]

All-cause mortality

Secondary

105

LCMS/MS

22 (7)

Neutral

aAdjusted for assay- see text for details

bBased on intention-to-treat analysis of all randomized participants for relevant endpoint. Assessed independently by two authors (MB, AG)

Studies are listed in Additional file 1: Table S3 and the Additional file 1: Reference list

Abbreviations: 25OHD 25-hydroxyvitamin D, SD standard deviation, N/A not available. CBP competitive binding protein; LCMS/MS- liquid chromatography tandem mass-spectrometry

Figure 1c and d show that mean/median baseline 25OHD has increased over time. Before 2006, 38% of RCTs had 25OHD < 25 nmol/L, 62% between 25 and 49 nmol/L, and none ≥50 nmol/L. In 2006–10 and 2011–15, 0% and 9% respectively of RCTs had 25OHD < 25 nmol/L, while 61% and 49% respectively had 25OHD 25–49 nmol/L, 26% and 37% respectively had 25OHD 50–74 nmol/L, and 13% and 6% respectively had 25OHD ≥75 nmol/L.

Of 118 RCTs that reported mean/median baseline 25OHD, 19 (16%) reported a subgroup analysis for baseline 25OHD (Table 2). The 25OHD thresholds used in these analyses ranged from 20 to 80 nmol/L, with 5 analyses based on thresholds ≤25 nmol/L and 16 on thresholds ≤50 nmol/L. Table 2 shows that 17 RCTs reported similar results in the subgroup analysis and the main analysis for the primary endpoint (16 both analyses neutral, and 1 both analyses showed benefit for vitamin D). Three of these 17 RCTs reported a benefit for vitamin D for a secondary endpoint in a subgroup analysis. Another RCT did not report the result of the subgroup analysis for the primary endpoint, but reported a benefit for vitamin D for a secondary endpoint. Lastly, one RCT had co-primary endpoints and neutral results in the main analyses, but in the subgroup analyses there was a benefit for vitamin D for one endpoint and neutral results for the other. Four of the five RCTs that reported subgroup analyses with a 25OHD threshold of ≤25 nmol/L had neutral results for the primary endpoint in the main analysis, and none of these 4 RCTs reported beneficial effects for the primary endpoint in the subgroup analysis.
Table 2

Results of 18 randomised controlled trials of vitamin D supplements reporting subgroup analyses for baseline 25-hydroxyvitamin D

Study

25OHD threshold (nmol/L)

Subgroup Resulta

Comparison to primary analysisa

Jackson 2006 [33]

32.2

Neutral

Same

Jorde 2008 [55]

40

NR

N/Ab

Wejse 2009 [56]

75

Neutral

Same

Martineau 2011 [48]

20

Neutral

Same

Rastelli 2011 [57]

50

Neutral

Samec

Kjaergaard 2012 [58]

25

Neutral

Same

Lehouck 2012 [59]

25

Neutral

Sameb

Murdoch 2012 [60]

50

Neutral

Same

Abou-Raya 2013 [61]

25

Benefit

Same

McAlindon 2013 [62]

37.5

Neutral

Same

Amrein 2014 [63]

30

Neutral

Sameb

Lopez-Torres Hidalgo 2014 [64]

80

Neutral

Same

Tran 2014 [65]

50

Neutral

Same

Turner 2014 [66]

50

Neutral

Same

Baron 2015 [36]

57.9

Neutral

Same

Martineau 2015 [67]

50

Benefit

Differentd

Miskulin 2015 [68]

37.5

Neutral

Same

Sandoughi 2015 [69]

50

Neutral

Same

Tukvadze 2015 [70]

25

Neutral

Same

a Assessed independently by two authors (MB, AG)

b Benefit for secondary endpoint in subgroup analysis

c Primary endpoint not specified. Benefits in subgroup analyses for some but not all reported endpoints

d Two co-primary endpoints. Benefit in subgroup analysis for one co-primary endpoints. For other co-primary endpoint, subgroup analysis was neutral. In primary analyses, results for both co-primary endpoints were neutral

Studies are listed in Additional file 1: Table S3 and Reference list

Abbreviations: 25OHD 25-hydroxyvitamin D, NR not reported; N/A not applicable

Large randomised controlled trials and prior 25OHD surveys

Tables 3 and 4 show 18 published RCTs of vitamin D with ≥1000 participants (101,383 participants), and 7 planned and ongoing trials (79,939 intended participants). We included the pilot stage for the UK VIDAL trial with 1600 participants, which aimed to continue and recruit 20,000 participants, but has not yet received funding for the full roll out. All trials were/are conducted exclusively in North America, Europe, Australia or New Zealand, except for two multinational trials with countries from South America, Asia and Africa. 22/25 trials were in single countries: we did not examine prior 25OHD surveys for the 3 multinational trials.
Table 3

Large randomised controlled trials of vitamin D supplements with relevant prior 25-hydroxyvitamin D surveys

Trial

Survey identified

Reference/ Country

Trial characteristixcs

Baseline 25OHD

(nmol/L) /Assaya

Cites Prior 25OHD

Survey (S)/ Prior SR (PSR) /Any SR (ASR)

Recruit-ment started

Survey Date

Group surveyed

25OHD

[mean (SD)]

(nmol/L)/Assaa

Survey Referenceb

Chapuy 1994 [21]

France

N = 3270

100% Female

Mean age 84y

Subg 20

CPB

S:Yes Chapuy 1987

PSR:Noe

ASR:No

NS

1984

Men and women

Mean age 74-75y

CPB

Chapuy 1987 [71]

Outpatients

23 (10)

Long stay hospital

11 (6)

Lips 1996 [22]

Netherlands

N = 2578

74% Female

Mean age 80y

Subg 27

HPLC

S:Yes Lips 1987

PSR:Noe

ASR:No

1988

NS

Men and women

Mean age 76y

CPB

Lips 1987 [72]

Hip fracture patients

10.0 (5.7)

Apartment dwellers

17.8 (7.3)

     

1984–5

 

CPB

Lowik 1990 [73]

Men 65-79y

21.6 (10.3)

Women 65-79y

20.5 (8.6)

     

NS

Men and women

Mean age 81-84y

CPB

Lips 1988 [74]

Nursing home

12.7 (4.8)

Aged people home

12.9 (7.2)

Meyer 2002 [23]

Norway

N = 1144

76% Female

Mean age 85y

Subg 49

HPLC

S:Yes Mowe 1998

PSR:Noe

ASR:Yes

1995

1989

Men and women

Mean age 78-80y

Hospital patients

HPLC

Mowe 1998 [75]

Men

40.4 (23.2)

Women

37.5 (22.6)

Home-living

 

Men

59.6 (28.9)

Women

48.5 (20.3)

     

1989

 

CPB

Nes 1993 [76]

Men 75-76y

24.1 (10.1)

Women 75-76y

25.9 (11.2)

Trivedi 2003 [37]

UK

N = 2686

24% Female

Mean age 75y

ND

S:No

PSR:Noe

ASR:No

1996

1994-5

Men and women

Incstar

Finch 1998 [77]

Free-living 65y+

55.5 (26.9)

Institution 65+

32.8 (15.7)

Larsen 2004 [24]

Denmark

N = 9605

60% Female

Mean age 75y

Subg 36

Diasorin

S:Yes Lund 1979

PSR:Noe

ASR:Yes

1995

Pre 1979

Men and women

CPB

Lund 1979 [78]

61-93y

26.8 (12.4)

     

1989

Men and women

CPB

van der Wielen 1995 [14]

75-81y

Men 24

Women 22

Grant 2005 [29]

UK

N = 5292

85% Female

Mean age 77y

Subg 38

HPLC

S:No

PSR:Yes

ASR:Yes

1999

1994–5

Men and women

Incstar

Finch 1998 [77]

Free-living 65y+

55.5 (26.9)

Institution 65+

32.8 (15.7)

Porthouse

2005 [38]

UK

N = 3314

100% Female

Mean age 77y

ND

S:No

PSR:No

ASR:No

2001

1994–5

Women

Incstar

Finch 1998 [77]

Free-living 65y+

51.7 (24.7)

Institution 65+

32.5 (15.5)

Jackson 2006 [33]

USA

N = 36,282

100% Female

Mean age 62y

Subg 48

Liaison

S:No

PSR:Noe

ASR:Yes

1995

1988-94

Men and women

LC-MS/MS equivalent

Schleicher 2016c [79]

40-59y

60.1 (58.7,61.5)

≥60y

58.4 (57.4,59.5)

All females

59.2 (57.9,60.6)

Law 2006 [34]

UK

N = 3717

76% Female

Mean age 85y

Subg 47

IDS

S:No

PSR:No

ASR:No

2000

1994–5

Men and women

Incstar

Finch 1998 [77]

Institution 65+

32.8 (15.7)

Lyons 2007 [39]

UK

N = 3440

76% Female

Mean age 84y

ND

S:No

PSR:No

ASR:Yes

1999

1994–5

Men and women

Incstar

Finch 1998 [77]

Institution 65+

32.8 (15.7)

Smith 2007 [35]

UK

N = 9440

54% Female

Mean age 79y

Subg 43

Nicholls

S:No

PSR:No

ASR:Yes

1998

1994–5

Men and women

Incstar

Finch 1998 [77]

Free-living 65y+

55.5 (26.9)

Institution 65+

32.8 (15.7)

Lappe 2008 [25]

USA

N = 5201

100% Female

Median age 19y

ND

S:Yes Gordon 2004

PSR:No

ASR:No

2001

2001–3

Boys and girls

Nichols

Gordon 2004 [80]

11-18y

 

Summer

49.8 (21.3)

Winter

38.2 (18.8)

     

2001–2

Males and females

LC-MS/MS equivalent

Schleicher 2016 [79]

12-19y

63.0 (60.8,65.2)

20-39y

62.8 (60.6,64.9)

     

1988–94

Males and females

LC-MS/MS equivalent

Schleicher 2016c [79]

12-19y

66.2 (64.1,68.4)

20-39y

64.4 (62.8,66.0)

Salovaara 2010 [30]

Finland

N = 3432

100% Female

Mean age 67y

Subg 50

Diasorin

S:No

PSR:No

ASR:Yes

2002

2000–1

Women

Incstar

Kauppi 2009 [81]

Mean age 53y

Age range 30-97y

45.2 (26.4)

Sanders 2010 [26]

Australia

N = 2258

100% Female

Mean age 76y

Subg 50

Diasorin

S:Yes Pasco 2001

PSR:No

ASR:Yes

2003

1994–7

Women

Incstar

Pasco 2001 [82]

60-79y

62 (31.7)

80y+

53 (26.8)

Punthakee 2012 [42]

Multinational

N = 1221

41% Female

Mean age 67y

ND

S: No

PSR: Yes

ASR:Yes

2009

    

Baron 2015 [36]

USA

N = 2259

37% Female

Mean age 58y

61

IDS

S:No

PSR:Noe

ASR:Yes

2004

2001-2

Men and women

LC-MS/MS equivalent

Schleicher 2016c [79]

40-59y

62.4 (59.9,64.8)

≥60y

60.4 (58.0,62.9)

Cooper 2016 [27]d

UK

N = 1134

100% Female

Mean age 31y

47

Liaison

S:Yes Javaid 2006

PSR:Noe

ASR:Yes

2008

1991-2

Pregnant women

IDS

Javaid 2006 [83]

Mean 27y

18% < 26.5

31% 26.5–50

52% > 50

     

2008–12

Women

19 - 64y

Liaison

47.3

National Diet and Nutrition Survey 2014. [84]

ViDA 2017 [28]d

New Zealand

N = 5110

42% Female

Mean age 66y

63 LCMS/MS

S:Yes Rockwell 2006

PSR:Yes

ASR:Yes

2011

1996–7

Men 45-64y/65y+

52/55

Rockell 2006 [85]

Women 45-64y/65y+

45/43

Diasorin

     

2008–9

Men and women

61/63/66/62

Adult nutrition survey 2009 [86]

45-54y/55-64y/65-74y/≥75y

LCMS/MS

Table 4

Planned and ongoing large randomised controlled trials of vitamin D supplements with relevant prior 25-hydroxyvitamin D surveys

Trial

Survey identified

Trial/Country

Trial details

Cites 25OHD

Survey (S)/

Systematic

Review (SR)

Recruitment started

Survey Date

Group surveyed

25OHD[mean/median(SD)]

(nmol/L)/Assay

Survey Referencea

D-Health

Australia

N = 21,315, 5y

60,000 IU D3 monthly v placebo

Men/women 60-84y

ACTRN12613000743763

S:Yes Tran 2012 pilot

PSR:Yes

ASR:Yes

2014

2010–1

Men and women

41.7 (13.5)

Tran 2012 [87]

Waterhouse 2015 [88]

Mean age 72y

Liaison

   

2011–2

Men and Women

68.9/69.8/68.6

Australian health survey 2011–2 [89]

55-64y/65-74y/>75y

LCMS/MS

DO-HEALTH

5 countries in Europe

N = 2152, 3y

2000 IU/d D3 v placebo

Men/women ≥70y

NCT01745263

S:NDA

PSR:NDA

ASR: NDA

2012

    

FIND Finland

N = 2495, 5y

1600 IU/d D3 v 3200 IU/d D3 v placebo

Men ≥60y, women ≥65y

NCT01463813

S:Yes Hurskainen 2012

PSR:No

ASR:Yes

2012

1998-

2001

Men and women

43.4 (17.6)

Hurskainen 2012 [90]

Mean age 62.9y

HPLC

Recruitment stopped early had aimed for 18,000

  

2003–5

Men and women

64.8 (17.4)

Salminen 2015 [91]

Mean age 73.5y

IDS

   

2011–2

Men and women

58.6 (9.3)

Carlberg 2013 [92]

Mean age 66.6y

HPLC

TIPS-3

10 countries in Africa, Asia, South/ North America

N = 5000, 5y

60,000 IU D3 3 monthly v placebo

Men ≥55y, women ≥60y

NCT01646437

S:NDA

PSR:NDA

ASR:NDA

2012

    

VIDAL

UK

N = 1600, 2y

100,000 IU D3 monthly v placebo

Men and women 65-84y

ISRCTN46328341

Feasibility trial. Full trial (n = 20,000) not funded

S:Yes Hirani 2005

PSR:Yes

ASR:Yes

2012

2000

Private households

Diasorin

Hirani 2005 [93]

Men 65-79y/80+

58 (27)/48 (24)

Women 65-79y/80+

49 (25)/45 (20)

Institutions

 

Men 65-79y/80+

40 (24)/37 (20)

Women 65-79y/80+

37 (18)/37 (19)

VITAL

US

N = 25,874, 5y

2000 IU/d D3 v placebo

Men ≥50y, women ≥55y

NCT01169259

S:Yes Looker 2002

PSR:Yes

ASR:Yes

2010

1988–1994

Winter, lower latitude

Diasorin

Looker 2002 [94]

Women 40-80y+

61.6–59.6

Men 40-80y+

70.6–68.7

Summer, higher latitude

 

Women 40-80y+

68.6–61.8

Men 40-80y+

78.8–69.5

   

2005–2010

Men and women

LC-MS/MS equivalent

Schleicher 2016b [79]

40-59y

60.1–68.7

≥60y

59.4–72.6

   

1988–1994

Men and women

LC-MS/MS equivalent

Schleicher 2016b [79]

40-59y

60.1 (58.7,61.5)

≥60y

58.4 (57.4,59.5)

CAPS

US

N = 2303, 5y

2000 IU D3 and 1500 mg calcium daily v calcium

Women ≥55y

NCT01052051

S:NDA

PSR:NDA

ASR:NDA

2009

2005–2010

Men and women

LC-MS/MS equivalent

Schleicher 2016b [79]

40-59y

60.1–68.7

≥60y

59.4–72.6

All females

60.9–69.1

Table 3 shows that only 8 [2128] of the 18 completed trials (44%) cited the vitamin D status of a population similar to the recruited cohort in the primary publication. One further trial [29] discussed survey data in the trial paper’s introduction, but this was not used in the grant application. Investigators from two of these trials [21, 22] had undertaken prior relevant 25OHD surveys. Four of the eight trials cited old survey data, from at least 16 years [24, 27] and 6–9 years [23, 26] before trial recruitment. A trial from Finland that studied older adults (mean age 62y) cited survey data that lacked relevance, being from the USA and from young Finnish adults (mean age 38y) [30].

Table 4 shows that all four ongoing trials with accessible documents discuss the vitamin D status of their intended trial population. One trial in Australia conducted a pilot study that included assessment of vitamin D status. The US VITAL trial which started recruitment in 2010, used NHANES III (1988–94) data in its rationale and design paper justification [31, 32].

Table 3 shows that baseline 25OHD in large completed RCTs and relevant survey 25OHD data were comparable, apart from one Norwegian trial, where one survey indicated considerably worse vitamin D status than was observed in trial participants [23]. Only one [21] of the completed trials was conducted in a population that was clearly vitamin D deficient, based on trial (mean baseline 25OHD 20 nmol/L) and survey data (mean 11–23 nmol/L). Three trials [22, 24, 29] were undertaken in populations comprised largely of participants with vitamin D insufficiency. Of the remaining 13 single country trials with baseline 25OHD or relevant survey data, five trials [23, 27, 3335] had mean baseline 25OHD ≥40 nmol/L and four trials 25OHD ≥50 nmol/L [26, 28, 30, 36]. Four trials [25, 3739] did not report baseline 25OHD, but surveys and data from similar RCTs suggest that baseline 25OHD in the RCT would have been ≥40 nmol/L in three of these trials [25, 37, 38]. In these 13 trials, a substantial proportion of participants would have had 25OHD ≥50 nmol/L, consistent with the IOM definition of vitamin D sufficiency [3].

Table 4 shows that, based on survey data from the relevant population, all the ongoing single country trials are likely to recruit participants in whom the mean/median baseline 25OHD will be > 40–50 nmol/L, and none describe specific strategies for recruiting participants with 25OHD < 25 nmol/L.

Large randomised controlled trials and citation of prior systematic reviews of randomised controlled trials

We identified a relevant systematic review on vitamin D and fracture [40] published prior to trial recruitment starting for 8 completed large RCTs, and on mortality [41] for 2 RCTs, but no prior systematic reviews on colorectal adenoma or neonatal bone mineral content for two RCTs (Table 3). Thus, systematic reviews capable of informing the trial justification and design were available before trial recruitment in 10/18 (56%) of completed large RCTs. Only three [28, 29, 42] of the 10 RCTs (30%) cited such a systematic review in their primary publication. Nine trials (50%) cited systematic reviews that would have occurred after the decision had been made to undertake the trial. Four of the seven planned or ongoing trials with accessible relevant documents discuss systematic reviews in their protocols or publications: for three of the trials, the systematic reviews predate trial recruitment.

Discussion

Our results suggest a high proportion of research waste in RCTs of vitamin D supplementation. The recent proliferation of vitamin D RCTs was accompanied by increasing baseline 25OHD concentrations and therefore a declining proportion of RCTs conducted in vitamin D deficient cohorts. Only 10% of trials were carried out in populations that would be widely accepted as vitamin D deficient, in which benefits of vitamin D supplementation still have not been unequivocally established (Table 1). Because many participants in recent trials were vitamin D sufficient, they would be unlikely to benefit from vitamin D. Further, their inclusion could have obscured potential benefits from vitamin D for those participants who were vitamin D deficient. This issue applies to RCTs with mean/median baseline 25OHD in ranges variously defined as sufficient (7% with 25OHD ≥75 nmol/L, 37% with 25OHD ≥50 nmol/L). It likely also applies to the 33% of trials with baseline 25OHD 40–49 nmol/L in which a substantial proportion of participants will have had 25OHD ≥50 nmol/L. Thus, 7–37% of trials can be considered research waste, because they were conducted in the wrong population, but this proportion is as high as 70% if a 25OHD threshold for sufficiency of 40 nmol/L was applied, based on the Institute of Medicine’s target median value.

Very importantly, research waste was prevalent in large RCTs that were designed to inform clinical practice. Only 1 such trial was carried out in a vitamin D deficient population and another 3 in populations with vitamin D insufficiency. Twelve (71%) of the remaining completed and 5 (100%) ongoing single country trials had, or are likely to have, mean baseline 25OHD > 40 nmol/L, and based on survey and other trial data, we estimate that about 50% would have 25OHD ≥50 nmol/L. Failure to incorporate key available data during protocol development may have contributed to the high prevalence of waste. Few (44%) of the large completed RCTs cited or undertook prior relevant surveys of vitamin D status in their intended trial population. Only 56% of large completed RCTs had a relevant systematic review of randomised trials published prior to trial recruitment starting and, of these, only 30% cited such a review. When systematic reviews of randomised trials were discussed, they tended to have been published after the trial had commenced or been completed. Collectively, this suggests that these large, costly RCTs were not optimally designed to address the question of benefits of vitamin D supplements.

An important strength of this study assessing research waste is that we analysed the complete set of RCTs of vitamin D published over 30 years. The results from this single research area might not apply to other research fields, and waste may be more prevalent in mature as opposed to emerging areas of research. In assessing whether trials cited 25OHD surveys or relevant systematic reviews, we examined primary publications and protocols where available. Our results may have changed if we were able to examine grant applications and trial protocols, but protocols were often not available, and we had access to only one grant application [29]. Early 25OHD assays tended to overestimate 25OHD- we used 25OHD concentrations corrected for these overestimates. The corrected values are approximations, but nevertheless lower than the original values in the relevant trials and surveys, and therefore the proportions of participants with vitamin D deficiency in our analyses are higher than in the original publications. Very few RCTs reported the season when 25OHD measurements were obtained. Although seasonal changes in 25OHD will occur in all treatment arms, it is possible that seasonal effects of 25OHD might confound some trial results. A limitation of this study is that the literature search was conducted in December 2015.

The implications of this research are that the current body of RCTs of vitamin D with clinical endpoints, including large RCTs with ≥1000 participants, is largely conducted in populations that are not vitamin D deficient. Recent, large systematic reviews of these RCTs report no benefits of vitamin D [811]. In trials included in these meta-analyses reporting 25OHD, 72–75% had baseline 25OHD < 50 nmol/L [10, 43], consistent with Fig. 1d showing that the majority of trials prior to 2011 had baseline 25OHD < 50 nmol/L. Thus, it is reasonable to conclude that current evidence is sufficient to exclude benefits from vitamin D supplementation for unselected community-dwelling individuals with 25OHD > 30–40 nmol/L. Relatively few trials, including only 5003 participants (Table 1), have been carried out in populations with lower baseline 25OHD and their results are inconsistent, with only 33% of such trials reporting beneficial results from vitamin D. Subgroup analyses of participants with lower 25OHD at baseline were frequently undertaken but their results were invariably similar to the results of the main analyses for the primary endpoint, even when the subgroup was restricted to people with 25OHD ≤25 nmol/L. Therefore, it is uncertain whether vitamin D supplementation benefits people with clearly low 25OHD. Based on data from relevant 25OHD surveys, the large RCTs currently underway will not test the effects of vitamin D supplementation in deficient populations and therefore are unlikely to address this knowledge gap. Instead of continuing to spend resources on trials in vitamin D sufficient populations, investigators should focus on vitamin D deficient populations. Food fortification policies [15, 16], together with independent action by food manufacturers and new advice on supplementation [5], make it even less likely that future trials in deficient populations will be possible.

Our analyses suggest that up to 70% of RCTs with clinical endpoints, 71% of large (N ≥ 1000) completed RCTs, and 100% of ongoing large RCTs could be considered research waste because they studied cohorts with a high proportion of vitamin D sufficiency. In our companion paper [2], we reported that 69% of RCTs of vitamin D conducted since 2005 with skeletal endpoints of bone mineral density or fracture were research waste because they lacked novelty or did not add to existing clinical knowledge. Taken together, these findings support the very high proportions (> 85%) for research waste estimated by Chalmers and Glasziou [1].

Conclusions

We identified a very high proportion of research waste in RCTs of vitamin D with clinical endpoints. Few RCTs were carried out in vitamin D deficient populations most likely to benefit from vitamin D supplementation, and conversely most RCTs were carried out in populations unlikely to benefit from supplementation. Few large RCTs appeared to consider systematic reviews in their design. Ongoing large RCTs share the same weaknesses of previous trials. Strategies to improve the design of RCTs should be introduced and studied to determine whether they can reduce research waste.

Abbreviations

25OHD: 

25-hydroxyvitamin D

CBP: 

Competitive binding protein

RCT: 

Randomised controlled trial

Declarations

Acknowledgements

We thank the following for providing further information about their trial or survey: Paul Atyeo, Australian Bureau of Statistics, Australia; Anne Looker, Centers for Disease Control and Prevention, USA; Briony Romero and Rachel Neale, Queensland Institute of Medical Research, Berghofer Medical Research Institute, Australia. We also thank David Cooper, HSRU, University of Aberdeen, UK, for statistical advice; Shaun Treweek, HSRU, and Hilde Stromme, Norwegian Knowledge Centre for the Health Services, Oslo, for help locating a Norwegian publication.

Funding

No specific funding was received for this study. MB receives salary support from the Health Research Council of New Zealand. The Health Services Research Unit is funded by the Chief Scientist Office of the Scottish Government Health and Social Care Directorates. The funders had no role in the study design; collection, analysis, and interpretation of the data; writing of the report; and in the decision to submit the paper for publication.

Availability of data and materials

All data generated or analysed during this study are included in this published article and its supplementary information file.

Authors’ contributions

MB, AG and AA designed the research. MB and AA performed the literature searches and extracted the data. MB, AA and AG reviewed the studies. MB and AA performed the analyses. MB drafted the paper. All authors critically reviewed and improved it. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

MB, AG, and AA have all published randomised controlled trials and systematic reviews in the fields of calcium and vitamin D but otherwise have no competing interests to declare.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Department of Medicine, Bone and Joint Research Group, University of Auckland, Private Bag 92 019, Auckland, 1142, New Zealand
(2)
Health Services Research Unit, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, Scotland

References

  1. Chalmers I, Glasziou P. Avoidable waste in the production and reporting of research evidence. Lancet. 2009;374:86–9.View ArticleGoogle Scholar
  2. Bolland MJ, Avenell A, Grey A. Assessment of research waste part 1: an exemplar from examining study design, surrogate and clinical endpoints in studies of calcium intake and vitamin D supplementation. BMC Med Res Methodol. https://doi.org/10.1186/s12874-018-0556-0
  3. IOM (Institute of Medicine). Dietary reference intakes for calcium and vitamin D. Washington, DC: The National Academies Press; 2011.Google Scholar
  4. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96:1911–30.View ArticleGoogle Scholar
  5. Scientific Advisory Committee on Nutrition (SACN). Vitamin D and Health. 2016:Available on line at https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/537616/SACN_Vitamin_D_and_Health_report.pdf (Accessed 25 July 2016).
  6. Lips P. Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications. Endocr Rev. 2001;22:477–501.View ArticleGoogle Scholar
  7. Heaney RP. Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev. 2014;72:48–54.View ArticleGoogle Scholar
  8. Autier P, Boniol M, Pizot C, Mullie P. Vitamin D status and ill health: a systematic review. Lancet Diabetes Endocrinol. 2014;2:76–89.View ArticleGoogle Scholar
  9. Avenell A, Mak JC, O'Connell D. Vitamin D and vitamin D analogues for preventing fractures in post-menopausal women and older men. Cochrane Database Syst Rev. 2014;4:CD000227.Google Scholar
  10. Bolland MJ, Grey A, Gamble GD, Reid IR. The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis. Lancet Diabetes Endocrinol. 2014;2:307–20.View ArticleGoogle Scholar
  11. Theodoratou E, Tzoulaki I, Zgaga L, Ioannidis JP. Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials. BMJ. 2014;348:g2035.View ArticleGoogle Scholar
  12. Lund H, Brunnhuber K, Juhl C, Robinson K, Leenaars M, Dorch BF, et al. Towards evidence based research. BMJ. 2016;355:i5440.View ArticleGoogle Scholar
  13. McKenna MJ. Differences in vitamin D status between countries in young adults and the elderly. Am J Med. 1992;93:69–77.View ArticleGoogle Scholar
  14. van der Wielen RP, Lowik MR, van den Berg H, de Groot LC, Haller J, Moreiras O, et al. Serum vitamin D concentrations among elderly people in Europe. Lancet. 1995;346:207–10.View ArticleGoogle Scholar
  15. Hilger J, Friedel A, Herr R, Rausch T, Roos F, Wahl DA, et al. A systematic review of vitamin D status in populations worldwide. Br J Nutr. 2014;111:23–45.View ArticleGoogle Scholar
  16. Spiro A, Buttriss JL. Vitamin D: an overview of vitamin D status and intake in Europe. Nutr Bull. 2014;39:322–50.View ArticleGoogle Scholar
  17. Cashman KD, Dowling KG, Skrabakova Z, Gonzalez-Gross M, Valtuena J, De Henauw S, et al. Vitamin D deficiency in Europe: pandemic? Am J Clin Nutr. 2016;103:1033–44.View ArticleGoogle Scholar
  18. IOM (Institute of Medicine). Evaluation of biomarkers and surrogate endpoints in chronic disease. Washington (DC): National Academies Press (US); 2010.Google Scholar
  19. Lips P, Chapuy MC, Dawson-Hughes B, Pols HA, Holick MF. An international comparison of serum 25-hydroxyvitamin D measurements. Osteoporos Int. 1999;9:394–7.View ArticleGoogle Scholar
  20. Carter GD, Carter R, Jones J, Berry J. How accurate are assays for 25-hydroxyvitamin D? Data from the international vitamin D external quality assessment scheme. Clin Chem. 2004;50:2195–7.View ArticleGoogle Scholar
  21. Chapuy MC, Arlot ME, Delmas PD, Meunier PJ. Effect of calcium and cholecalciferol treatment for three years on hip fractures in elderly women. BMJ. 1994;308:1081–2.View ArticleGoogle Scholar
  22. Lips P, Graafmans WC, Ooms ME, Bezemer PD, Bouter LM. Vitamin D supplementation and fracture incidence in elderly persons. A randomized, placebo-controlled clinical trial. Ann Intern Med. 1996;124:400–6.View ArticleGoogle Scholar
  23. Meyer HE, Smedshaug GB, Kvaavik E, Falch JA, Tverdal A, Pedersen JI. Can vitamin D supplementation reduce the risk of fracture in the elderly? A randomized controlled trial. J Bone Miner Res. 2002;17:709–15.View ArticleGoogle Scholar
  24. Larsen ER, Mosekilde L, Foldspang A. Vitamin D and calcium supplementation prevents osteoporotic fractures in elderly community dwelling residents: a pragmatic population-based 3-year intervention study. J Bone Miner Res. 2004;19:370–8.View ArticleGoogle Scholar
  25. Lappe J, Cullen D, Haynatzki G, Recker R, Ahlf R, Thompson K. Calcium and vitamin d supplementation decreases incidence of stress fractures in female navy recruits. J Bone Miner Res. 2008;23:741–9.View ArticleGoogle Scholar
  26. Sanders KM, Stuart AL, Williamson EJ, Simpson JA, Kotowicz MA, Young D, et al. Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA. 2010;303:1815–22.View ArticleGoogle Scholar
  27. Cooper C, Harvey NC, Bishop NJ, Kennedy S, Papageorghiou AT, Schoenmakers I, et al. Maternal gestational vitamin D supplementation and offspring bone health (MAVIDOS): a multicentre, double-blind, randomised placebo-controlled trial. Lancet Diabetes Endocrinol. 2016;4:393–402.View ArticleGoogle Scholar
  28. Scragg R, Stewart AW, Waayer D, Lawes CMM, Toop L, Sluyter J, et al. Effect of monthly high-dose vitamin D supplementation on cardiovascular disease in the vitamin D assessment study a Randomized Clinical Trial. JAMA Cardiol. 2017;2:608–16.View ArticleGoogle Scholar
  29. Grant AM, Avenell A, Campbell MK, McDonald AM, MacLennan GS, McPherson GC, et al. Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (randomised evaluation of calcium or vitamin D, RECORD): a randomised placebo-controlled trial. Lancet. 2005;365:1621–8.View ArticleGoogle Scholar
  30. Salovaara K, Tuppurainen M, Karkkainen M, Rikkonen T, Sandini L, Sirola J, et al. Effect of vitamin D(3) and calcium on fracture risk in 65- to 71-year-old women: a population-based 3-year randomized, controlled trial--the OSTPRE-FPS. J Bone Miner Res. 2010;25:1487–95.View ArticleGoogle Scholar
  31. Manson JE, Bassuk SS, Lee IM, Cook NR, Albert MA, Gordon D, et al. The VITamin D and OmegA-3 TriaL (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease. Contemp Clin Trials. 2012;33:159–71.View ArticleGoogle Scholar
  32. Bassuk SS, Manson JE, Lee IM, Cook NR, Christen WG, Bubes VY, et al. Baseline characteristics of participants in the VITamin D and OmegA-3 TriaL (VITAL). Contemp Clin Trials. 2016;47:235–43.View ArticleGoogle Scholar
  33. Jackson RD, LaCroix AZ, Gass M, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med. 2006;354(7):669–83.Google Scholar
  34. Law M, Withers H, Morris J, Anderson F. Vitamin D supplementation and the prevention of fractures and falls: results of a randomised trial in elderly people in residential accommodation. Age Ageing. 2006;35:482–6.View ArticleGoogle Scholar
  35. Smith H, Anderson F, Raphael H, Maslin P, Crozier S, Cooper C. Effect of annual intramuscular vitamin D on fracture risk in elderly men and women--a population-based, randomized, double-blind, placebo-controlled trial. Rheumatology (Oxford). 2007;46:1852–7.View ArticleGoogle Scholar
  36. Baron JA, Barry EL, Mott LA, et al. A Trial of Calcium and Vitamin D for the Prevention of Colorectal Adenomas. N Engl J Med. 2015;373(16):1519–30.View ArticleGoogle Scholar
  37. Trivedi DP, Doll R, Khaw KT. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial. BMJ. 2003;326:469.View ArticleGoogle Scholar
  38. Porthouse J, Cockayne S, King C, Saxon L, Steele E, Aspray T, et al. Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care. BMJ. 2005;330:1003.View ArticleGoogle Scholar
  39. Lyons RA, Johansen A, Brophy S, Newcombe RG, Phillips CJ, Lervy B, et al. Preventing fractures among older people living in institutional care: a pragmatic randomised double blind placebo controlled trial of vitamin D supplementation. Osteoporos Int. 2007;18:811–8.View ArticleGoogle Scholar
  40. Gillespie WJ, Henry DA, O'Connell DL, Robertson J. Vitamin D, vitamin D analogues and calcium in prevention of fractures in involutional and postmenopausal osteoporosis. Cochrane Database Syst Rev. 1996;3:18.Google Scholar
  41. Autier P, Gandini S. Vitamin D supplementation and Total mortality: a meta-analysis of randomized controlled trials. Arch Intern Med. 2007;167:1730–7.View ArticleGoogle Scholar
  42. Punthakee Z, Bosch J, Dagenais G, Diaz R, Holman R, Probstfield J, et al. Design, history and results of the thiazolidinedione intervention with vitamin D evaluation (TIDE) randomised controlled trial. Diabetologia. 2012;55:36–45.View ArticleGoogle Scholar
  43. Bolland MJ, Grey A, Gamble GD, Reid IR. Vitamin D supplementation and falls: a trial sequential meta-analysis. Lancet Diabetes Endocrinol. 2014;2:573–80.View ArticleGoogle Scholar
  44. Brooke OG, Brown IR, Bone CD, et al. Vitamin D supplements in pregnant Asian women: effects on calcium status and fetal growth. Br Med J. 1980;280(6216):751–54.View ArticleGoogle Scholar
  45. Pfeifer M, Begerow B, Minne HW, Abrams C, Nachtigall D, Hansen C. Effects of a short-term vitamin D and calcium supplementation on body sway and secondary hyperparathyroidism in elderly women. J Bone Miner Res. 2000;15(6):1113–18.View ArticleGoogle Scholar
  46. Chapuy MC, Pamphile R, Paris E, et al. Combined calcium and vitamin D3 supplementation in elderly women: confirmation of reversal of secondary hyperparathyroidism and hip fracture risk: the Decalyos II study. Osteoporos Int. 2002;13(3):257–64.View ArticleGoogle Scholar
  47. Bischoff HA, Stahelin HB, Dick W, et al. Effects of vitamin D and calcium supplementation on falls: a randomized controlled trial. J Bone Miner Res. 2003;18(2):343–51.View ArticleGoogle Scholar
  48. Martineau AR, Timms PM, Bothamley GH, et al. High-dose vitamin D(3) during intensive-phase antimicrobial treatment of pulmonary tuberculosis: a double-blind randomised controlled trial. Lancet. 2011;377(9761):242–50.Google Scholar
  49. Mosayebi G, Ghazavi A, Ghasami K, Jand Y, Kokhaei P. Therapeutic effect of vitamin D3 in multiple sclerosis patients. Immunol Invest. 2011;40(6):627–39.View ArticleGoogle Scholar
  50. Amestejani M, Salehi BS, Vasigh M, et al. Vitamin D supplementation in the treatment of atopic dermatitis: a clinical trial study. J Drugs Dermatol. 2012;11(3):327–30.Google Scholar
  51. Schreuder F, Bernsen RM, van der Wouden JC. Vitamin D supplementation for nonspecific musculoskeletal pain in non-Western immigrants: a randomized controlled trial. Ann Fam Med. 2012;10(6):547–55.View ArticleGoogle Scholar
  52. Mozaffari-Khosravi H, Nabizade L, Yassini-Ardakani SM, Hadinedoushan H, Barzegar K. The effect of 2 different single injections of high dose of vitamin D on improving the depression in depressed patients with vitamin D deficiency: a randomized clinical trial. J Clin Psychopharmacol. 2013;33(3):378–85.View ArticleGoogle Scholar
  53. Hossain N, Kanani FH, Ramzan S, et al. Obstetric and neonatal outcomes of maternal vitamin D supplementation: results of an open-label, randomized controlled trial of antenatal vitamin D supplementation in Pakistani women. J Clin Endocrinol Metab. 2014;99(7):2448–55.View ArticleGoogle Scholar
  54. Bhan I, Dobens D, Tamez H, et al. Nutritional vitamin D supplementation in dialysis: a randomized trial. Clin J Am Soc Nephrol. 2015;10(4):611–19.View ArticleGoogle Scholar
  55. Jorde R, Sneve M, Figenschau Y, Svartberg J, Waterloo K. Effects of vitamin D supplementation on symptoms of depression in overweight and obese subjects: randomized double blind trial. J Intern Med. 2008;264(6):599–609.View ArticleGoogle Scholar
  56. Wejse C, Gomes VF, Rabna P, et al. Vitamin D as supplementary treatment for tuberculosis: a double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med. 2009;179(9):843–50.View ArticleGoogle Scholar
  57. Rastelli AL, Taylor ME, Gao F, et al. Vitamin D and aromatase inhibitor-induced musculoskeletal symptoms (AIMSS): a phase II, double-blind, placebo-controlled, randomized trial. Breast Cancer Res Treat. 2011;129(1):107–16.View ArticleGoogle Scholar
  58. Kjaergaard M, Waterloo K, Wang CE, et al. Effect of vitamin D supplement on depression scores in people with low levels of serum 25-hydroxyvitamin D: nested case-control study and randomised clinical trial. Br J Psychiatry. 2012;201(5):360–68.View ArticleGoogle Scholar
  59. Lehouck A, Mathieu C, Carremans C, et al. High doses of vitamin D to reduce exacerbations in chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med. 2012;156(2):105–14.View ArticleGoogle Scholar
  60. Murdoch DR, Slow S, Chambers ST, et al. Effect of vitamin D3 supplementation on upper respiratory tract infections in healthy adults: the VIDARIS randomized controlled trial. JAMA. 2012;308(13):1333–39.View ArticleGoogle Scholar
  61. Abou-Raya A, Abou-Raya S, Helmii M. The effect of vitamin D supplementation on inflammatory and hemostatic markers and disease activity in patients with systemic lupus erythematosus: a randomized placebo-controlled trial. J Rheumatol. 2013;40(3):265–72.View ArticleGoogle Scholar
  62. McAlindon T, LaValley M, Schneider E, et al. Effect of vitamin D supplementation on progression of knee pain and cartilage volume loss in patients with symptomatic osteoarthritis: a randomized controlled trial. JAMA. 2013;309(2):155–62.View ArticleGoogle Scholar
  63. Amrein K, Schnedl C, Holl A, et al. Effect of high-dose vitamin D3 on hospital length of stay in critically ill patients with vitamin D deficiency: the VITdAL-ICU randomized clinical trial. JAMA. 2014;312(15):1520–30.View ArticleGoogle Scholar
  64. Lopez-Torres Hidalgo J, Grupo A. [Effect of calcium and vitamin D in the reduction of falls in the elderly: a randomized trial versus placebo]. Med Clin (Barc). 2014;142(3):95–102.Google Scholar
  65. Tran B, Armstrong BK, Ebeling PR, et al. Effect of vitamin D supplementation on antibiotic use: a randomized controlled trial. Am J Clin Nutr. 2014;99(1):156–61.View ArticleGoogle Scholar
  66. Turner AN, Carr Reese P, Fields KS, et al. A blinded, randomized controlled trial of high-dose vitamin D supplementation to reduce recurrence of bacterial vaginosis. Am J Obstet Gynecol. 2014;211(5):479 e471–479 e413.View ArticleGoogle Scholar
  67. Martineau AR, MacLaughlin BD, Hooper RL, et al. Double-blind randomised placebo-controlled trial of bolus-dose vitamin D3 supplementation in adults with asthma (ViDiAs). Thorax. 2015;70(5):451–57.Google Scholar
  68. Miskulin DC, Majchrzak K, Tighiouart H, et al. Ergocalciferol Supplementation in Hemodialysis Patients With Vitamin D Deficiency: A Randomized Clinical Trial. J Am Soc Nephrol. 2015.Google Scholar
  69. Sandoughi M, Zakeri Z, Mirhosainee Z, Mohammadi M, Shahbakhsh S. The effect of vitamin D on nonspecific low back pain. Int J Rheum Dis. 2015;18(8):854–58.View ArticleGoogle Scholar
  70. Tukvadze N, Sanikidze E, Kipiani M, et al. High-dose vitamin D3 in adults with pulmonary tuberculosis: a double-blind randomized controlled trial. Am J Clin Nutr. 2015;102(5):1059–69.View ArticleGoogle Scholar
  71. Chapuy MC, Chapuy P, Meunier PJ. Calcium and vitamin D supplements: effects on calcium metabolism in elderly people. Am J Clin Nutr 1987;46:324–8.View ArticleGoogle Scholar
  72. Lips P, van Ginkel FC, Jongen MJ, Rubertus F, van der Vijgh WJ, Netelenbos JC. Determinants of vitamin D status in patients with hip fracture and in elderly control subjects. Am J Clin Nutr 1987;46:1005.View ArticleGoogle Scholar
  73. Lowik MR, Schrijver J, Odink J, van den Berg H, Wedel M, Hermus RJ. Nutrition and aging: nutritional status of “apparently healthy” elderly (Dutch nutrition surveillance system). J Am Coll Nutr 1990;9:18–27.View ArticleGoogle Scholar
  74. Lips P, Wiersinga A, van Ginkel FC, Jongen MJ, Netelenbos JC, Hackeng WH, Delmas PD, van der Vijgh WJ. The effect of vitamin D supplementation on vitamin D status and parathyroid function in elderly subjects. J Clin Endocrinol Metab 1988;67:644–50.View ArticleGoogle Scholar
  75. Mowe M, Bohmer T, Haug E. Vitamin D-mangel hos eldre sykehusinnlagte og hjemmeboende i Oslo. Tidsskr Nor Laegeforen 1998;118:3929–31.Google Scholar
  76. Nes M, Lund-Larsen K, Trygg K, Hoivik HO, Pedersen JI. Nutrition and the elderly in Europe: low prevalence of obesity and biochemical deficiencies in Norwegian subjects. Age Nutr 1993;4:72–81.Google Scholar
  77. Finch S, Doyle W, Lowe C, Bates CJ, Prentice A, Smithers G, Clarke PC. National diet and nutrition survey: people aged 65 years and over. London: The Stationery Office; 1998.Google Scholar
  78. Lund B, Sorensen OH. Measurement of 25-hydroxyvitamin D in serum and its relation to sunshine, age and vitamin D intake in the Danish population. Scand J Clin Lab Invest 1979;39:23–30.View ArticleGoogle Scholar
  79. Schleicher RL, Sternberg MR, Lacher DA, Sempos CT, Looker AC, Durazo-Arvizu RA, Yetley EA, Chaudhary-Webb M, Maw KL, Pfeiffer CM, Johnson CL. The vitamin D status of the US population from 1988 to 2010 using standardized serum concentrations of 25-hydroxyvitamin D shows recent modest increases. Am J Clin Nutr 2016;104:454–61.View ArticleGoogle Scholar
  80. Gordon CM, DePeter KC, Feldman HA, Grace E, Emans SJ. Prevalence of vitamin D deficiency among healthy adolescents. Arch Pediatr Adolesc Med 2004;158:531–7.View ArticleGoogle Scholar
  81. Kauppi M, Impivaara O, Maki J, Heliovaara M, Marniemi J, Montonen J, Jula A. Vitamin D status and common risk factors for bone fragility as determinants of quantitative ultrasound variables in a nationally representative population sample. Bone 2009;45:119–24.View ArticleGoogle Scholar
  82. Pasco JA, Henry MJ, Nicholson GC, Sanders KM, Kotowicz MA. Vitamin D status of women in the Geelong Osteoporosis Study: association with diet and casual exposure to sunlight. Med J Aust 2001;175:401–5.Google Scholar
  83. Javaid MK, Crozier SR, Harvey NC, Gale CR, Dennison EM, Boucher BJ, Arden NK, Godfrey KM, Cooper C, and the Princess Anne Hospital Study Group. Maternal vitamin D status during pregnancy and childhood bone mass at age 9 years: longitudinal study. Lancet 2006;367:36–43.Google Scholar
  84. National Diet and Nutrition Survey. Results from years 1, 2, 3 and 4 (combined) of the Rolling Programme (2008/2009 – 2011/2012). London: Public Health London; 2014. Available from: https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/310995/NDNS_Y1_to_4_UK_report.pdf.
  85. Rockell JE, Skeaff CM, Williams SM, Green TJ. Serum 25-hydroxyvitamin D concentrations of New Zealanders aged 15 years and older. Osteoporosis Int 2006;17:1382–9.View ArticleGoogle Scholar
  86. Ministry of Health. 2012. Vitamin D status of New Zealand adults: Findings from the 2008/09 New Zealand adult nutrition survey. Wellington: Ministry of Health.Google Scholar
  87. Tran B, Armstrong BK, Carlin JB, Ebeling PR, English DR, Kimlin MG, Rahman B, van der Pols JC, Venn A, Gebski V, Whiteman DC, Webb PM,Neale RE. Recruitment and results of a pilot trial of vitamin D supplementation in the general population of Australia. J Clin Endocrinol Metab 2012;97:4473–80.View ArticleGoogle Scholar
  88. Waterhouse M, Tran B, Ebeling PR, English DR, Lucas RM, Venn AJ, Webb PM, Whiteman DC, Neale RE. Effect of vitamin D supplementation on selected inflammatory biomarkers in older adults: a secondary analysis of data from a randomised, placebo-controlled trial. Br J Nutr 2015;114:693–9.View ArticleGoogle Scholar
  89. Australian Health Survey 2011 – 2012 http://www.abs.gov.au/AUSSTATS/abs@.nsf/DetailsPage/4364.0.55.0062011-12?OpenDocument.
  90. Hurskainen AR, Virtanen JK, Tuomainen TP, Nurmi T, Voutilianen S. Association of serum 25-hydroxyvitamin D with type 2 diabetes and markers of insulin resistance in a general older population in Finland. Diabetes/Metab Research Reviews 2012;28:418–23View ArticleGoogle Scholar
  91. Salminen M, Saaristo P, Salonoja M, Vaapio S, Vahlberg T, Lamberg-Allardt C, Aarnio P, Kivela S-L. Arch Gerontol Geriatric 2015;61:419–24.Google Scholar
  92. Carlberg C, Seuter S, de Mello VD, Schwab U, Voutilainen S, Pulkki K, Nurmi T, Virtanen J, Tuomainen TP, Uusitupa M. Primary Vitamin D Target Genes Allow a Categorization of Possible Benefits of Vitamin D3 Supplementation. PLOS ONE. 2013;8(7): e71042.View ArticleGoogle Scholar
  93. Hirani V, Primatesta P. Vitamin D concentrations among people aged 65 years and over living in private households and institutions in England: population survey. Age Ageing. 2005;34:485–91.View ArticleGoogle Scholar
  94. Looker AC, Dawson-Hughes B, Calvo MS, Gunter EW, Sahyoun NR. Serum 25-hydroxyvitamin D status of adolescents and adults in two seasonal subpopulations from NHANES III. Bone 2002;30:771–77.View ArticleGoogle Scholar

Copyright

© The Author(s). 2018

Advertisement