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Journal of Endocrinological Investigation

, Volume 42, Issue 12, pp 1391–1399 | Cite as

Overview of results from the Vitamin D Assessment (ViDA) study

  • R. K. R. ScraggEmail author
Short Review

Abstract

Background

The Vitamin D Assessment (ViDA) study is a randomised, double-blind, placebo-controlled trial to evaluate the efficacy of monthly vitamin D supplementation in reducing the incidence of a range of acute and chronic diseases and intermediate outcomes.

Methods

The study was carried out in Auckland, New Zealand, among 5110 adults, aged 50–84 years, who were followed for a median 3.3 years. The intervention was vitamin D3 (2.5 mg or 100,000 IU) or placebo softgel oral capsules, mailed monthly to participants’ homes, with two capsules sent in the first mail-out post-randomisation (i.e. 200,000 IU bolus, or placebo), followed 1 month later (and thereafter monthly) with 100,000 IU vitamin D3 or placebo capsules. Outcomes were monitored through routinely collected health data and self-completed questionnaires.

Results

The results showed no beneficial effect of vitamin D supplementation on incidence of cardiovascular disease, falls, non-vertebral fractures and all cancer. However, beneficial effects from vitamin D supplementation were seen: for persistence with taking statins in participants on long-term statin therapy; and also in bone mineral density and arterial function in participants with low 25-hydroxyvitamin D levels, and in lung function among ever smokers (especially if vitamin D deficient). The latter findings are consistent with several previous studies,

Conclusion

Monthly high-dose vitamin D supplementation does not prevent a range of diseases, but may be beneficial for some intermediate outcomes in people who are vitamin D deficient.

Trial registration

Australian New Zealand Clinical Trials Registry identifier: ACTRN12611000402943.

Keywords

Cancer Cardiovascular disease Clinical trial Falls Fractures Vitamin D supplementation 

Introduction

The origin of the Vitamin D Assessment (ViDA) study goes back to 2008. Around that time there was emerging evidence from observational epidemiological studies of significant inverse associations between vitamin D status, as measured by circulating 25-hydroxyvitamin D (25(OH)D) concentrations, and a range of non-skeletal diseases or medical conditions such as cardiovascular disease (CVD) [1, 2], diabetes [3], high blood pressure [4], poor lung function [5] and respiratory infection [6].

In addition, a meta-analysis of randomised controlled trials of vitamin D supplementation reported a small 7%, although significant, reduction in all-cause mortality [7]. The latter result contrasted with null findings from the Women’s Health Initiative (WHI) which found that a low dose of vitamin D (400 IU/day), in combination with a calcium supplement, did not prevent colorectal cancer [8] or fractures [9]. The lack of effect observed in the WHI was attributed to its low dose of vitamin D, low compliance, and the continued consumption of vitamin D supplements being taken at enrolment by both arms of the study, including those in the placebo arm [10]. The latter would have attenuated any difference in vitamin D status between study arms, particularly among those with low vitamin D status [11].

A key driver for further RCTs of vitamin D supplementation was the low vitamin D dose given by most RCTs up to that time (400 or 800 IU/day), as the increase in 25(OH)D from a given daily vitamin D dose had been better quantified and found to be too small, it being estimated that 25(OH)D would increase by about 1 ng/mL (2.5 nmol/L) for each 100 IU/day [12]. In addition, the Autier meta-analysis had found that all-cause mortality had fallen by 7% from a weighted vitamin D dose of 528 IU/day [7] and it was thought possible that even greater reductions in mortality might result from a higher dose of vitamin D. It was in this context that several large-scale clinical trials were planned to determine if high doses of vitamin D supplementation (≥ 2000 IU/day or monthly equivalent) prevented a variety of diseases including CVD, cancer and mortality [13].

The ViDA study was developed in 2008 by the author, in collaboration with Prof Carlos A. Camargo Jr, from Massachusetts General Hospital and Harvard Medical School. An RO1 application was submitted to the National Institutes of Health (NIH) in 2008 for a large randomised controlled trial to investigate in New Zealand whether high monthly doses of vitamin D3 would protect against cardiovascular disease (CVD) and all-cause mortality. The application coincided with another to the NIH for the vitamin D and Omega-3 (VITAL) study with US participants, which was chosen for funding [14]. The ViDA application was revised (with a smaller sample size) to look at CVD and respiratory infection outcomes, and submitted to the Health Research Council of New Zealand which funded the study in 2010. Supplementary funding was provided several months later by the Accident Compensation Corporation, the main government insurer of costs arising from injury, to examine outcomes of falls and fractures. Thus, fortunately both VITAL and ViDA were funded, and both reassuringly have reported similar results for major outcomes (discussed below), despite giving vitamin D in different dosing schedules: daily for VITAL and monthly for ViDA. ViDA was the first of the vitamin D mega-trials to be published, and the aims of this report are to describe the design and methods of the ViDA study, the main published findings to date, and their implications for ongoing research and clinical practice.

Methods

The ViDA study is a randomised, double-blind, placebo-controlled trial to evaluate the efficacy of monthly vitamin D supplementation in reducing the incidence of CVD, acute respiratory infection, falls and non-vertebral fractures, plus several other secondary outcomes [15]. Briefly, the study was carried out in 5110 adults, aged 50–84 years, recruited mainly from family practices in Auckland during 2011–2012 and followed up to 31 July 2015.

Baseline assessments during 05 April 2011 to 06 November 2012 included collecting written informed consent, followed by questions on: socio-demographic status; lifestyle (tobacco smoking, alcohol drinking, leisure-time physical activity and sun exposure); intake of vitamin D or calcium supplements; and past medical history told by a doctor (for a wide range of diseases). Physical measurements included height, weight, brachial blood pressure, arterial waveform pressure and lung function by spirometry. A non-fasting blood sample was collected to screen for hypercalcaemia, with the remaining serum aliquoted and stored at − 80 °C for later 25(OH)D measurement.

Two sub-samples were formed to assess secondary outcomes. A random sub-sample of 438 participants agreed to return annually to provide a blood sample to measure serum calcium levels (to monitor safety), and all physical measurements were repeated in these people at 12 months follow-up (called the annual sample). In the final months of recruitment, a further sub-study was formed of participants who agreed to have total body bone density at baseline and at 2 years follow-up (called the bone density sample).

Participants were allocated randomly, within ethnic group (Maori, Pacific Islander, South Asian, European/Other) and 5-year age strata, to receive either vitamin D3 (2.5 mg or 100,000 IU) or placebo softgel oral capsules. These were mailed monthly to participants’ homes, with a one-page duplex questionnaire (and reply-paid envelope) to record self-reported adherence; the return of which was used to monitor retention. Two capsules were sent in the first mail-out post-randomisation (i.e. 200,000 IU bolus, or placebo), followed 1 month later (and thereafter monthly) with 100,000 IU vitamin D3 or placebo capsules. Two participants withdrew after being randomised, leaving 2558 in the vitamin D arm and 2550 in the placebo arm.

Outcomes were monitored by the following: (1) Ministry of Health routinely collected data: all New Zealand residents are given a unique number by the Ministry of Health, called the National Health Index (NHI) number, which was used to track deaths, hospital discharges, cancer registrations and dispensed prescriptions; (2) Accident Compensation Corporation, the government insurer for injury, which provided details of all non-vertebral fractures; (3) the monthly home questionnaire which provided self-reported information on falls, kidney stones and respiratory infections. This also provided information on adherence, and its return confirmed retention.

Results

Baseline characteristics of the study sample

Table 1 summarises the characteristics of participants at their baseline assessment. Mean age (SD) was 65.9 (8.3) years, and 58% were male. About 80% were of European ancestry, with 5–7% of participants each of Maori, Pacific Islander or South Asian ethnicity. The sample was well educated with 56% having attended tertiary education, and 51% were currently employed with a further 40% being retired. The overall lifestyle patterns of participants were healthier than those of the general population, with only 6% being current tobacco smokers and 43% being ex-smokers, and 55% engaged in vigorous physical activity each week, although 86% reported drinking alcohol in the last 12 months. Sun exposure was common with 23% having more than 2 h per day, 8% were taking vitamin D supplements within the eligibility dose criteria (≤ 600 IU per day if aged 50–70 years, ≤ 800 IU per day if aged 71–84 years), and only 5% were taking calcium supplements (the low proportion being due to recent concerns about their safety by New Zealand researchers [16]). Overall, the study sample was a little overweight, having a mean body mass index (BMI) of 28.4, and mean 25(OH)D was 64 nmol/L with 25% of participants < 50 nmol/L. The distributions and means of these variables were similar in both study arms.
Table 1

Selected baseline characteristics of all study participants

Category

Variable

Level

% of total (= 5108)

Socio-demographic

Sex

Male

58%

  

Female

42%

 

Age (years)

50–59

22%

  

60–69

43%

  

70–79

28%

  

88–84

6%

 

Ethnicity

European/other

83%

  

Maori

5%

  

Pacific Islander

7%

  

South Asian

5%

 

Education

Tertiary

56%

 

Employment

Employed

51%

  

Retired

40%

Lifestyle

Tobacco smoking

Current

6%

  

Past

43%

 

Alcohol drinking

Yes, last 12 months

86%

 

Vigorous activity

> 0 h/week

55%

 

Sun exposure

> 2 h/day

23%

 

Take supplements

Vitamin Da

8%

  

Calcium

5%

Medical history

Hypertension

Yes

37%

 

Myocardial infarction

Yes

6%

 

Diabetes

Yes

10%

Serum

25(OH)D (nmol/L)b

< 25

2%

  

25–49

23%

  

50–74

42%

  

≥ 75

33%

Category

Variable

Level

Mean (SD)

 

25(OH)D (nmol/L)c

 

64 (24)

Physical measures

Weight (kg)

 

81.3 (18.3)

 

BMI (kg/m2)

 

28.4 (5.1)

 

Blood pressure (mmHg)

Systolic

139 (19)

  

Diastolic

78 (10)

a≤ 600 IU per day if aged 50–70 years, ≤ 800 IU per day if aged 71–84 years

bBased on average concentration over four seasons

cObserved 25(OH)D 25(OH)D = 25-hydroxyvitamin D

Retention and adherence

Median follow-up was 3.3 years (range 2.5–4.2 years). Retention was high, with 87% of participants returning the final or penultimate home questionnaire. Reported adherence was also high, being 85% in the vitamin D group and 83% in the placebo (84% overall, 168,667 capsules reported taken during 200,936 person-months) up to 31 July 2015. This high adherence was confirmed by the mean observed 25(OH)D concentrations of participants in the randomly selected annual sample, who returned to give blood samples at 6 months, and up to 36 months post-randomisation. These ranged from 119 to 135 nmol/L in the vitamin D group, being consistently > 50 nmol/L higher than the mean in the placebo group [17]. Mean serum calcium levels throughout the follow-up period in this sub-sample were similar for the vitamin D and placebo groups [17].

Cardiovascular disease

Incident CVD events were identified mainly from deaths and hospitalisations for CVD. There was no effect of vitamin D on the cumulative incidence of CVD which occurred in 11.8% of the vitamin D group and 11.5% of placebo, yielding a hazard ratio of 1.02 (95% CI 0.87–1.20), adjusted for age, sex and ethnicity. Similar results were seen for participants with baseline 25(OH)D < 50 nmol/L [17]. These findings were replicated in the recent publication of the main findings from the VITAL study, which gave vitamin D3 2000 IU/day and reported a hazard ratio for major CVD events (myocardial infarction, stroke or death from CVD) of 0.97 (95% CI 0.85–1.12) [18].

Falls

This outcome was based on self-reports of falls in the home questionnaire, which was mailed to participants monthly from June 2011 to November 2013, and then 4-monthly (because of cost reasons) up to July 2015. The recommended wording for measuring falls was used [19]. There was no effect of vitamin D on the incidence of falls, with 51.7% in the vitamin D group and 52.7% in the placebo group reporting at least one fall, giving an adjusted hazard ratio for falls of 0.98 (95% CI 0.92–1.06). Similar results were seen for participants with baseline 25(OH)D < 50 nmol/L and ≥ 50 nmol/L [20].

Fractures

Incident fractures after randomisation were identified from hospitalisations and claims made to the Accident Compensation Corporation, the government insurer of injury events, which funds all costs (medical and social) arising from injury including fractures not resulting in hospitalisation. Fractures were identified in 292 participants. However, there was no effect of vitamin D on the incidence of fractures, which were observed in 6% of participants in the vitamin D arm and 5% in the placebo arm. The adjusted hazard ratio of fracture was 1.15 (95% CI 0.92–1.45) for vitamin D compared to placebo. Results were similar in participants with baseline 25(OH)D concentrations < 50 and ≥ 50 nmol/L [20]. A limitation of the fracture data in the ViDA study is the lower than expected number of people having a fracture (n = 430), which was the basis of the initial power calculation.

Cancer

It was always the intention of the ViDA study investigators to analyse cancer as an outcome. These plans were accelerated by the publication in JAMA of a study reporting a 30% reduction in cancer incidence from vitamin D3 2000 IU/day (given in combination with a calcium supplement), which just failed to reach statistical significance [21]. In the ViDA study, 328 incident cancer cases were identified from the national cancer registry, with the cumulative incidence being 6.5% in the vitamin D group and 6.4% in the placebo group. The adjusted hazard ratio was 1.01 (95% CI 0.81–1.25). Similar results were seen for all secondary outcomes, including cancer mortality and in participants with baseline 25(OH)D < 50 nmol/L [22]. The VITAL study reported a similar hazard ratio for all incident cancer to that observed in the ViDA study—hazard ratio = 0.96 (95% CI 0.88–1.06) [18]—indicating that daily dosing is no more beneficial than monthly for preventing cancer.

Bone mineral density

About three-quarters of the way through recruitment in the main ViDA study, a bone density sub-study was started to determine the effect of monthly vitamin D supplementation on bone mineral density (BMD), which was measured at baseline and after 2 years follow-up in the 418 participants by dual-energy X-ray absorptiometry. Among all participants in the sub-study, no significant treatment effect from vitamin D was seen in the lumbar spine or total body, but BMD loss at both hip sites was significantly attenuated by ~  ½% over 2 years in the vitamin D group compared to placebo. There was a significant interaction between baseline 25(OH)D and treatment effect (P = 0.04). In participants with baseline 25(OH)D ≤ 30 nmol/L, there were between-group BMD changes at the spine and femoral sites of ~ 2%, significant in the spine and femoral neck, but no effect on total body BMD. When baseline 25(OH)D was > 30 nmol/L, differences were ~ ½% and significant only at the total hip [23]. These results have been replicated in a re-analysis of an earlier trial from Scotland which found significant beneficial treatment effects over 12 months in both the spine and hip, separately for vitamin D doses of 400 IU/day and 1000 IU/day compared with placebo, in participants with baseline 25(OH)D ≤ 30 nmol/L, but not in participants with 25(OH)D above this [24]. As with the similar null cancer and CVD results from the ViDA and VITAL studies, the bone density results indicate that the beneficial effects on spine and hip BMD occur in vitamin D-deficient people, regardless of whether a daily or monthly dose of vitamin D is given.

Lung function

A positive association between vitamin D status and lung function was first reported in 2005 from analyses of the NHANES III study, a representative cross-sectional sample of the US population surveyed during 1988–1994 [5]. In the ViDA study, among 442 participants in the annual sample who had spirometry at baseline and 12 months after randomisation, there were no significant lung function improvements (vitamin D versus placebo) in the total sample, vitamin D-deficient participants or asthma/COPD participants. However, mean (95% CI) forced expiratory volume in 1 s (FEV1) increased among ever-smokers (82% of whom were ex-smokers) by 57 (4–109) mL (P = 0.03) in the vitamin D group versus placebo. This increase was larger among vitamin D-deficient ever-smokers: 122 (8–236) mL (P = 0.04); and largest among ever-smokers with asthma/COPD: 160 (53–268) mL (P = 0.004) [25]. A change in FEV1 > 100 mL is clinically significant [26]. These findings are consistent with data from NHANES III showing greater variations in FEV1 across 25(OH)D quintiles in smokers compared with non-smokers [5]. However, they are preliminary and require replication before firm conclusions can be made about them.

Arterial function

Arterial waveforms were measured using a validated oscillometric device at baseline and 12 months after randomisation in 380 participants in the annual sample [27]. In the total sub-sample, no beneficial effects on arterial function were seen for any of the parameters of arterial function. However, there were significant reductions in several arterial waveform parameters, such as augmentation index and pulse wave velocity, in participants with baseline 25(OH)D < 50 nmol/L compared with those above this cut-point (P < 0.05). This finding of a beneficial effect on arterial function from vitamin D supplementation in people with 25(OH)D < 50 nmol/L has been reported by clinical trials of overweight African-Americans [28] and patients with chronic kidney disease [29]. Both latter studies gave bolus doses of vitamin D.

Statins

Myalgia is a common side effect in patients on statins taken primarily to reduce their risk of CVD [30]. Observational studies have shown lower 25(OH)D levels in patients with statin myalgia than those without [31], while vitamin D supplementation in patients with 25(OH)D < 32 ng/mL (80 nmol/L) and previous statin myalgia has been reported to allow most of these patients restart their statin therapy without recurrence of symptoms [32]. Given this, we decided to investigate the effect of vitamin D supplementation on adherence (proportion of days) and persistence (continuation) with taking statins. Complete data on dispensed prescriptions of statins during follow-up for all ViDA study participants were provided by the Ministry of Health. From these, 2494 participants on long-term statins (vitamin D = 1243, placebo = 1251) were identified. Compared with placebo, monthly vitamin D supplementation did not improve adherence (risk ratio 1.01, 95% CI 0.97–1.05), but did improve the persistence probability of taking statins after 24 months (hazard ratio 1.15, 95% CI 1.02–1.30; P = 0.02) [33]. Similar findings were seen in participants with 25(OH)D < 50 nmol/L. The increased hazard ratio for the whole study statin sample has clinical significance as it converts to a number needed to treat over 2 years of 23. However, this finding needs to be confirmed in further clinical trials.

Pain

A recent meta-analysis of clinical trials reported that vitamin D supplementation lowers mean pain score, particularly in patients with pre-existing pain [34]. Given this, the effect of vitamin D supplementation on self-reported pain and prescribed analgesics was examined in ViDA study participants [35]. A short six-item self-completed pain impact questionnaire (PIQ-6) was administered at baseline, 1 year and final follow-up. Mean PIQ-6 score did not vary between the two treatment arms at any time point, including among participants with 25(OH)D < 50 nmol/L, or with moderate or severe body pain. It is possible that the short pain questionnaire used in the study was not sufficiently sensitive to detect changes in pain, neither was there a beneficial effect from vitamin D during follow-up on the number of participants dispensed prescribed opioids or non-steroidal anti-inflammatory drugs. However, among participants with 25(OH)D < 50 nmol/L, a lower proportion of participants in the vitamin D arm were dispensed non-steroidal anti-inflammatory drugs compared to those in the placebo arm: relative risk 0.87 (95% CI 0.78–0.96), which could be a chance finding.

Adverse events

A major concern over the last two decades has been the possible increased risk of kidney stones caused by vitamin D supplements. This arose primarily from the WHI study which reported a 17% increased risk of kidney stones in the vitamin D and calcium arm compared to placebo [9]. The increase was most likely due to the calcium supplement and not vitamin D, since a recent meta-analysis of supplementation trials, which compared vitamin D with placebo, and only included trials with calcium supplements if it was included in neither or both arms (so that calcium was balanced between the comparison groups), found no increase in the risk of kidney stones (risk ratio 0.66, 95% CI 0.41, 1.09) [36]. However, given that most previous studies gave vitamin D at low doses for short periods of time, there was still a need to determine whether high-dose vitamin D, given for a long period, increased kidney stone risk. Data collected from self-reports in the questionnaire mailed to participants’ homes showed that 3.0% of participants in the vitamin D arm reported a kidney stone event, compared with 3.3% in the placebo arm, giving a hazard ratio of 0.90 (95% CI 0.66–1.23). This finding was consistent with hospitalisation data for kidney stones, which occurred in 0.3% of the vitamin D arm and 0.4% of the placebo arm (hazard ratio 0.62, 95% CI 0.24–1.26). Thus, the 100,000 IU monthly vitamin D dose given in the ViDA study did not increase the risk of kidney stones, nor increase serum calcium levels [37]. Also, it did not increase the reporting of other adverse events attributed by participants to the study capsule, with a hazard ratio of 1.03 (95% CI 0.90–1.18) for the vitamin D arm compared to placebo [38]. Thus, the above evidence indicates that the monthly bolus dose used in the ViDA study is safe, particularly when considered along with the falls and fracture outcomes (above) which were not increased in the vitamin D arm. These latter findings contrast with those from an earlier study in Geelong, Australia, which found that a vitamin D mega-dose of 500,000 IU per year increased the rate ratio of both falls and fractures, showing that very high amounts of vitamin D, given annually in pharmacological doses, are not safe [39].

Discussion

The results from the ViDA study (summarised in Table 2) show that high-dose monthly vitamin D supplementation does not reduce the incidence of the main study outcomes: CVD, falls, fractures and cancer, neither does it improve intermediate outcomes, such as bone mineral density, lung function and arterial function, except in those who are vitamin D deficient. The beneficial effect seen on statin persistence is preliminary and needs to be confirmed by other studies. These findings, when combined with the recent results from the VITAL study and meta-analyses, provide important insights regarding the use of vitamin D supplementation for preventing disease.
Table 2

Summary of results from the ViDA study for the vitamin D group compared to placebo

Outcome

Measure of effect

Effect estimate (95% CI)

Total sample

Vitamin D deficient 25(OH)D < 50 nmol/L

Cardiovascular disease

Hazard ratio

1.02 (0.87–1.20)

1.00 (0.74–1.35)

Falls

Hazard ratio

0.99 (0.92–1.07)

1.07 (0.91–1.25)

Fractures

Hazard ratio

1.19 (0.94–1.50)

0.94 (0.58–1.52)

Cancer

Hazard ratio

1.01 (0.81–1.25)

1.01 (0.65–1.58)

Bone mineral density

Spine, %, mean change (2 years)

0.6% (p = 0.093)

2.6% (p = 0.035)a

Lung function

FEV1, mL, in ever smokers, mean change (1 year)

57 (4–109)

122 (8–236)

Arterial function

Augmentation index, %, mean change (1 year)

0.0 (− 2.4 to 2.5)

− 5.7 (− 10.8 to − 0.6)

Statin persistence

Hazard ratio

1.15 (1.02–1.30)

1.12 (0.89–1.41)

NSAID prescriptions

Rate ratio

0.97 (0.92–1.02)

0.87 (0.78–0.96)

CI confidence interval, 25(OH)D 25-hydroxyvitamin D, FEV1 forced expiratory volume in 1 s, NSAID non-steroidal anti-inflammatory drug

a25(OH)D ≤ 30 nmol/L

Daily versus monthly bolus dosing

A case has been made recently that daily or weekly vitamin D supplementation may be more beneficial than bolus monthly dosing, as frequent doses at short intervals make parent vitamin D more continuously available for internalisation into cells than does bolus dosing, since parent vitamin D is only available for a period of several days after each dose because of its short half-life [40, 41]. However, this explanation for the null results from the ViDA study is not supported by the results from the VITAL study which gave a daily vitamin D dose and reported the same findings as the ViDA study for cancer and CVD [18]. There is evidence from a recent meta-analysis that daily dosing, but not bolus dosing, protects against acute respiratory infections [42]. Further results from the VITAL ancillary studies [14], which are expected to be published in the near future, should help to clarify the issue of dosing frequency.

Beneficial effects in vitamin D deficiency

The evidence of beneficial effects for some outcomes in ViDA participants with vitamin D deficiency further argues against the dosing frequency hypothesis for null outcomes seen in this and other recent trials that used a bolus dose. The stronger beneficial effect on arterial function from monthly dosing observed among vitamin D-deficient participants in the ViDA study has been reported among the same type of participants in two other studies which gave bolus doses [28, 29], while daily dosing has also been shown to be beneficial for bone mineral density in vitamin D-deficient participants [24]. Strong beneficial effects from vitamin D supplementation against acute respiratory infection and exacerbations of asthma and chronic obstructive pulmonary disease have been reported for people with very low vitamin D levels (25(OH)D < 25 nmol/L) in three recent meta-analyses [42, 43, 44].

The accumulating evidence from clinical trials that vitamin D is mainly beneficial in people with vitamin D deficiency provides a possible explanation for the apparent incongruent results in the ViDA study of beneficial effects for some intermediate outcomes, such as bone mineral density and arterial function, but not for disease end points such as CVD and fractures. The ViDA study had only 91 participants with 25(OH)D < 25 nmol/L and 1270 in total < 50 nmol/L. These numbers are too small to detect the beneficial effects for disease end points such as CVD, fracture and cancer, which are relatively rare over a period of only 3–4 years follow-up.

However, other explanations for the null results for disease end points in ViDA cannot be ruled out at the moment. These include lack of co-supplementary calcium or too short a follow-up period for chronic disease outcomes such as CVD, cancer and fractures. In contrast, these explanations are unlikely to be the reason for the null effect against falls, which is a short-term outcome that would not be expected to require calcium, and for which the ViDA study had adequate power.

Conclusions and implications

The overall null findings for participants in the ViDA study for CVD, falls, fractures and cancer do not support widespread vitamin D supplementation in patients to prevent these outcomes. However, the beneficial effects seen for some outcomes (bone mineral density, lung function and arterial function) in participants with 25(OH)D concentrations < 50 nmol/L are consistent with several previous studies, which collectively suggest that vitamin D supplementation may only be beneficial in people who are deficient [45].

Two broad strategies are available for boosting vitamin D levels in the general population to prevent disease: the so-called population and high-risk strategies [46]. The high-risk strategy involves screening for vitamin D deficiency and supplementing those with very low 25(OH)D levels. The issue of screening for vitamin D deficiency has been debated in a recent publication [47]. Such a strategy is not cost-effective in populations where only a small proportion of the population is vitamin D deficient and likely to benefit from vitamin D supplements, although it could be considered for some populations, such as those from South Asia, where deficiency is common. The alternate population approach to prevention would aim to increase vitamin D levels in the general population through vitamin D fortification of foods and increased safe sun exposure. Results from further studies are required to decide which prevention strategy, if any, should be pursued in the future.

Notes

Funding

The ViDA study was funded by the Health Research Council of New Zealand (Grant 10/400) and the Accident Compensation Corporation of New Zealand.

Compliance with ethical standards

Conflict of interest

The author declares no conflict of interest.

Ethical approval

This was granted for the ViDA study by the Multiregion Ethics Committee, Wellington (MEC/09/08/082). All procedurers in this study on human participants were in accordance with the ethical standards of the aforementioned committee, and with the 1964 Helsinki declaration and its later ammendments.

Informed consent

All participants in the ViDA study gave written informed consent.

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Copyright information

© Italian Society of Endocrinology (SIE) 2019

Authors and Affiliations

  1. 1.School of Population HealthUniversity of AucklandAucklandNew Zealand

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