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Contents lists available at ScienceDirect

Journal of Steroid Biochemistry & Molecular Biology journal homepage: www.elsevier.com/locate/jsbmb

Review

Vitamin D: Dietary requirements and food fortification as a means of helping achieve Kevin D. Cashman a,b, * a b

Vitamin D Research Group, School of Food and Nutritional Sciences, University College Cork, Ireland Department of Medicine, University College Cork, Ireland

A R T I C L E I N F O

A B S T R A C T

Article history: Received 14 August 2014 Received in revised form 23 January 2015 Accepted 25 January 2015 Available online xxx

Vitamin D deficiency is evident in many parts of the globe, even in the sunnier regions, for a variety of reasons. Such deficiency contributes to risk of metabolic bone disease as well as potentially other nonskeletal chronic diseases in both early-life and later-life, and thus strategies for its prevention are of major public health importance. Dietary Reference Intervals (called Dietary Reference Intakes (DRI) and Dietary Reference Values (DRVs) in North America and Europe, respectively) for vitamin D have a key role in protecting against vitamin D deficiency in the population, and these have been re-evaluated in recent years on both sides of the Atlantic. The current DRI and DRVs for vitamin D and their basis will be overviewed in this review as well as some limitations that existed within the evidence-base and which contribute some degree of uncertainty to these new requirement estimates for vitamin D. The review will also compare current population intake estimates for children and adults in North America and Europe against the estimated average requirement (EAR) for vitamin D, as a benchmark of nutritional adequacy. While vitamin D supplementation has been suggested as a method of bridging the gap between current vitamin D intakes and new recommendations, the level of usage of vitamin D supplements in many countries as well as the vitamin D content of available supplements in these countries, appears to be low. The fortification of food with vitamin D has been suggested as a strategy for increasing intake with potentially the widest reach and impact in the population. The present review will highlight the need to re-evaluate current food fortification practices as well as consider new additional food-based approaches, such as biofortification of food with vitamin D, as a means of collectively tackling the low intakes of vitamin D within populations and the consequent high prevalence of low vitamin D status that are observed. This article is part of a Special Issue entitled ‘17th Vitamin D Workshop’. ã 2015 Published by Elsevier Ltd.

Keywords: Vitamin D Dietary reference values Preventing vitamin D deficiency Food-based strategies Food fortification Biofortification

Contents 1.

2.

Introduction 1.1. Recent 1.1.1. 1.1.2.

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 dietary requirement values for vitamin D: IOM and post-IOM era . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 A few considerations in relation to current DRI and DRV for vitamin D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 The role of UVB sun exposure in establishing the dietary requirement values for vitamin D – how did the various expert groups00 deal with? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . How do current intakes of vitamin D in young and adult populations in North America and Europe compare against these new dietary00 1.2. targets? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bridging the gap; dietary strategies for increasing vitamin D intake . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 1.3. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

* Correspondence to: School of Food and Nutritional Sciences, University College Cork, Ireland. Tel.: +353 214901317. http://dx.doi.org/10.1016/j.jsbmb.2015.01.023 0960-0760/ ã 2015 Published by Elsevier Ltd.

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1. Introduction An enormous body of research in relation to various aspects of vitamin D and health over the last decade and a half has been instrumental in informing the recent estimates of dietary requirements for vitamin D. While in North America the term used to describe the distribution of dietary requirements is Dietary Reference Intakes (DRI), its equivalent in Europe is Dietary Reference Values (DRV) (1). The North American Institute of Medicine (IOM) has recently established DRI for vitamin D (and calcium), and likewise a number of European agencies (German Nutrition Society, Dutch Health Ministry, and Nordic Council of Ministers (NORDEN)) have recently established DRV for vitamin D. The UK Scientific Advisory Committee on Nutrition (SACN) and European Food Safety Authority (EFSA) will produce their new DRV for vitamin D over the next year or so. The DRI/DRV are crucial from public health perspective in providing a framework for prevention of vitamin D deficiency and optimizing vitamin D status of individuals. The present review will first of all concisely overview these current DRI/DRV for vitamin D as key dietary targets, but also highlight some issues and the persisting knowledge gaps that need to be addressed by key research, and which will inform and further refine subsequent DRI/DRV. It will then also briefly benchmark current intakes of vitamin D in selected representative samples in North America and Europe against these dietary targets, and, finally, it will consider means of addressing the gap between current intakes and these dietary targets. In particular, focus will be placed on the area of fortification of food with vitamin D, and especially ‘biofortification’ with vitamin D, as a means of increasing the distribution of vitamin D intake in the population to prevent vitamin D deficiency. These three aspects of dietary vitamin D in the present review were the central thrust of the author’s accompanying presentation at the 17th Vitamin D Workshop in Chicago, IL, USA. 1.1. Recent dietary requirement values for vitamin D: IOM and postIOM era The risk assessment framework and process by which the North American IOM established their current DRI for vitamin D (and calcium) has been well characterized and overviewed [1–5], so only the most salient points will be very briefly re-iterated in the present review and, in particular, those relative to its scope. Following a review of the evidence-base in relation to vitamin D (and calcium) and health (skeletal and non-skeletal) effects, the DRI committee selected calcium absorption, bone mineral density (BMD) and either rickets in children or osteomalacia in adults, for which the evidence was sufficiently strong, for DRI development for vitamin D. The committee was of the view that data from studies on non-skeletal health outcomes were at times of a mixed and inconclusive nature, prohibiting these health outcomes as being a reliable base for setting vitamin D DRI at that juncture [5]. The DRI committee established a serum 25(OH)D concentration of 40 and 50 nmol/L as Estimated Average Requirement (EAR)-like and Recommended Dietary Allowance (RDA)-like concentrations, respectively, on the basis that these would meet the requirement of half and 97.5% of healthy individuals, respectively [5]. Using these serum 25(OH)D target concentrations, the DRI committee was able, using a meta-regression approach on data from winter-based vitamin D RCTs which reported serum 25(OH)D response, to derive dietary requirement estimates which form the DRI values, namely the EAR (10 mg/d for those aged 1 and above) and RDA (15 mg/d from 1 to 70, and 20 mg/d for those over 70) [5]. These DRI assume minimal ultraviolet B (UVB) sunlight contribution to serum 25(OH) D concentration and thus are over-estimates for many in the population, particularly during summer (see 1.1.2).

There has been much comment and debate in relation to these DRI in the time following their publication, with some suggesting they, and indeed the underpinning target serum 25(OH)D concentrations, were overly conservative, and that they should have included outcomes other than just bone-related. The process of defining DRI (or DRV) is by necessity an iterative one and while the current DRI was based on the committee’s interpretation of the best available evidence at the time, this may change in the next iteration when new evidence becomes available. In this regard, further revisions of vitamin D DRI/DRV would be based on an evaluation of a considerably larger body of evidence, including randomized placebo-controlled trials (RCTs) designed and implemented with the benefit of experience. That there are many new vitamin D and health outcome-focused RCTs underway, including several very large RCT (now being referred to as ‘mega-trials’) with n ranging from 2000 to 28,000 and which will report findings roughly between 2016 and 2020 (see Table 1), will all add to the evidence-base for such future DRV/DRI evaluations in one way or another. While the ‘mega-trials’ may provide important data on causality, due to the fact that they are mostly single dose trials, they will not contribute data on distributions of serum 25(OH)D as linked to health outcome(s). It is noteworthy that even though established two years later in Europe, the recent Nordic Nutrition Recommendations (NNR) for vitamin D [6], and which also followed the widely-adopted risk assessment framework approach, used bone health outcomes, and placed emphasis on serum 25(OH)D concentrations of 30 and 50 nmol/L. The NNR vitamin D report also highlighting emerging evidence linking vitamin D to cardiovascular disease risk. However, it should be noted that the NNR’s ‘Recommended Intakes’ (RDA equivalents) for vitamin D (which also used 50 nmol as the serum 25(OH)D target in terms of bone, and also employed metaregression analysis) was set at 10 mg/d for all individuals aged 2–70 years [6], lower than the IOM’s 15 mg/d for equivalent age range [5]. The difference might relate, at least in part, to small differences in the constituent RCTs selected and included in the meta-regression analyses used by both expert groups. It is worth noting that while the serum 25(OH)D concentration of 50 nmol/L, as it relates to the North American RDA and NNR Recommended Intake (RI) for vitamin D [5,6], and is also the threshold concentration of choice for the German Nutrition Society and the Dutch Health Ministry, it is not universally used. For example, the new recommendations from the UK SACN due out later this year are likely to stick with 25 nmol/L and EFSA’s decision on what serum 25(OH)D threshold to support their Population Reference Intake for vitamin D will be known later in the year. Furthermore, the Endocrine Society in the US has suggested that a serum concentration of 75 nmol/L is optimal for skeletal and possibly some non-skeletal health outcomes [7]. 1.1.1. A few considerations in relation to current DRI and DRV for vitamin D The IOM DRI committee in their report acknowledged that the meta-regression approach used for derivation of the EAR and RDA had potential limitations, and these have been the topic of much discussion in terms of their impact on DRI/DRV estimates [2,3,5,6]. To further illustrate the variability within the meta-regression approach and its impact on DRI/DRV estimates, we have recently shown that when the original immuno-assay based serum 25(OH) D values (which in general were positively biased relative to that from liquid chromatography tandem mass spectroscopy (LCtandem MS); [8]) for just two RCTs (representing 8 individual group mean data-points in the total of 22) in our original metaregression [9] were substituted with LC-tandem MS-derived values on the same bio-banked sera, the RDA estimate (at serum 25(OH)D = 50 nmol/L) of 510 IU/day increased to 727 IU/day,

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Table 1 Brief overview of selected vitamin D ‘Mega-trials’ currently underway. Short name (location)

Subjects

Dose of vitamin D3

1 Outcomes

Year results expected

VITALa (USA)

n 20,000 Men: 50+ years Women: 55+ years

2000 IU/d

Cancer CVD

2017

VIDAb (New Zealand)

n 5100 all: 50+ years

100,000 IU/month (after 200,000 IU loading dose)

Fracture CVD Respiratory disease

2017

FINDc (Finland)

n 18,000 Men: 60+ years Women: 65+ years

1600 or 3200 IU/d

Cancer CVD

2019

DO-HEALTHd (Europe)

n 2150 all: 70+ years

2000 IU/d

Fracture Blood pressure Cognitive decline Infections Functional decline

2017

TIPS-3e (Canada and India)

n 5500 Men: 55+ years Women: 60+ years

60,000 IU/month

Fracture CVD Cancer

2019

a b c d e

https://clinicaltrials.gov/ct2/show/NCT01169259. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=336777. https://clinicaltrials.gov/ct2/show/NCT01463813. https://clinicaltrials.gov/ct2/show/NCT01745263. https://clinicaltrials.gov/ct2/show/NCT01646437.

respectively (unpublished data). Also, we have queried the completeness of IOM’s and NORDEN’s RDA/Recommended Intakes of 10–15 mg/d, respectively, in terms of their ability to maintain nearly all (i.e., 97.5%) of individuals with serum 25(OH)D concentrations above 50 nmol/L in winter, especially in latitudes above 50 N [4,9]. This contention is based on data from a vitamin D RCTs in teenage girls in Denmark and Finland [10] and two doserelated vitamin D RCTs in adults and older adults in Ireland (50–55 N) ([11,12] and see Table 2). For example, between 26 and 10% of adults (aged 20–40 years) and older adults (aged 64+ years) in the RCT arms who received a total intake of vitamin D (supplemental and diet-derived) of 15 mg/d (the IOM RDA) had winter-time serum 25(OH)D concentrations less than 50 nmol/L [11,12]. Even in the RCT arms who were receiving a total vitamin D intake close to 20 mg/d, about 8–10% had winter serum 25(OH)D concentrations less than 50 nmol/L (Table 2). On the other hand, only 0–3% of older subjects (>50 years) in our vitamin D RCT arms who were receiving a total intake of around 25 mg/d had winter serum 25(OH)D concentrations less than 50 nmol/L [13,14] (Table 2). Our RCT data does show, however, that vitamin D

intakes in the range of 10–15 mg/d will maintain winter-time serum 25(OH)D concentrations in nearly all of the white population in Northern European countries as well as in North America above 25/30 nmol/L (serum thresholds defining vitamin D deficiency on the basis of metabolic bone disease [5,15,16]), and thus protective against vitamin D-dependent rickets and osteomalacia in these populations. When these RCT data are mathematically modeled to predict the RDA required to maintain serum 25(OH)D concentrations of 50 nmol/L, the estimates range from 19 to 28 mg/d [9,17]. This seemingly conundrum in the RDA estimates can be solved when one considers that meta-regression analyses generate average responses and as such its RDA estimates of 10 or 15 mg/d [5,6] might only be expected to offer protection for 50% of the population and not the intended 97.5%. The use of a 95% confidence interval in the regression models allow some confidence that the mean response lies somewhere when this relatively tight band of variance is around the mean (see Fig. 1). On the other hand, use of a 95% prediction interval in the regression analysis allow for estimation of requirement of 97.5% of the population (Fig. 1, and reviewed elsewhere [9]). Thus, it is this author’s

Table 2 The percentage of participants in various vitamin D RCTs with winter-time serum 25(OH)D concentrations below 50 nmol/L, stratified by vitamin D dose. RCT (age group) [Ref no.]

Vitamin D3 study arm (n)

Dietary vitamin D3 intake mg/d/d) (total intake)a

Percentage with serum 25(OH)D 64 year olds) [12]

5 mg/d (48) 10 mg/d (53) 15 mg/d (48)

4.1 (91) 4.2 (142) 4.8 (198)

41.3% (64.2%, Placebo) 9.8% 10.0%

20 mg/d (13) Cashman et al. 2012 (>50 year olds) [13] Cashman et al. 2014 (>50 year olds; low Ca) [14] 20 mg/d (28) Cashman et al. 2014 (>50 year olds; high Ca) 20 mg/d (35) [14]

7.6 (276) 4.0 (240) 6.1 (261)

0% (81.3%, Placebo) 0% (67.9%, Placebo) 2.9% (69.7%, Placebo)

a

Habitual diet plus supplemental dose of vitamin D.

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Fig. 1. Relationship between total vitamin D intake and achieved serum 25(OH)D in winter time using data from randomized controlled trails used in our previous metaregression [9]. The thick solid line is the regression line and thus represents the average response, the two curved lines represent the 95% confidence intervals around that mean, whereas the two dark dashed lines represent the 95% prediction intervals. The dashed horizontal line at 50 nmol/L is for illustrate purposes as this represents the serum 25(OH)D concentration associated with the RDA.

contention that 10 or 15 mg/d, as established by NORDEN [6] and the IOM [5] respectively, reflect EAR estimates rather than RDA/Recommended Intakes. The datasets used in the meta-regression approaches have been, in general, derived from RCT in white adults and elderly [5,6,9], with relatively limited data from younger age groups, and did not include other life-stage groups, such as pregnancy and lactation. Furthermore, while the EAR and RDA were established for the entire population and, as such, cover dark-skinned population groups; they were based at the time on an assumption that the requirements between white and other ethnic groups do not differ, largely due to the absence of data [5]. In the United States, non-Hispanic blacks and Mexican Americans (representing 13% and 17% of the adult population, respectively, based on 2012 US Census data) have been shown to have a higher risk of vitamin D inadequacy [serum 25(OH)D 50 nmol/L in 97.5% of

African–American adults was 42 mg/d. This is considerably higher than the age-specific 15 and 20 mg/d established by the IOM [5], albeit using data from multiple RCT with predominantly white subjects in their meta-regression, as mentioned above. Unfortunately, the RCT by Ng et al. [20] did not include a white group so it is not possible to be sure whether requirements between their African–American adults and a corresponding Caucasian group would actually differ or not. Gallagher et al. [21] also recently reported RCT data on the dose-response effects of vitamin D3 supplementation on serum 25(OH)D over 12 months in older African–American women (n 110) residing in Indiana (40 N) and Omaha, Nebraska (41 N), which was in parallel to their similarlydesigned RCT in older Caucasian women [22]. Using combined data from both of their RCTs, Gallagher et al. evaluated the potential interaction of race in their regression analysis and found no significant interaction, which led the authors to conclude the vitamin D RDA estimate (20 mg/d) was similar for white and African–American postmenopausal women of a similar age (average, 67 years) [21], and approximately half the estimate by Ng et al. [20]. There were several differences between the two RCTs in African–American adults, which might, at least in part, explain the disparate results, and these have been discussed elsewhere [23]. Furthermore, these findings have stimulated some recent debate [24,25]. Interestingly, a separate dose-related vitamin D RCT in young African–American (n 79) and white (n 119) women, aged 25–45 years, which was also conducted by Gallagher et al. [26], suggests the vitamin D RDA of 30 mg/d for young African–American women and 10 mg/d for white women (a three-fold difference). It is unclear whether this possibly higher requirement for African–Americans, would also be the case for other dark-skinned ethnic subgroups within the population. The issue of possibly different dietary requirements for vitamin D in darker-skin subgroups of the population is also of key relevance to Europe, and indeed beyond. Clearly, the above points highlight that while the current DRI/DRV, which are of key public health significance in terms of preventing vitamin D deficiency in the population, perhaps they should not be considered as absolute or definitive targets. These current recommendations are the best

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estimates based on available evidence at the time of their establishment, but will benefit further from new data in future iterations of their re-evaluation. 1.1.2. The role of UVB sun exposure in establishing the dietary requirement values for vitamin D – how did the various expert groups deal with? The IOM DRI committee indicated that as vitamin D is also synthesized in the skin following exposure to UVB sunlight, their examination of the vitamin D dose–repose relationship data, was complicated by the confounding factors this introduces, and furthermore they stressed that public health concerns about skin cancer preclude the possibility of using UVB sunlight in relation to vitamin D requirements. On this basis, the DRI committee concluded that the best approach was to estimate vitamin D requirements under conditions of minimal UVB sun exposure even though it is a ‘markedly cautious approach’ given that the vast majority of North Americans obtain at least some vitamin D from inadvertent or intentional sun exposure [5]. In Europe, the NNR’s RI value for vitamin D of 10 mg/d for children and adults (up to 75 years) is based on intervention study data which showed that this intake maintains serum 25(OH)D concentrations around 50 nmol/L among the majority of the population during winter-time at latitudes within the Nordic sphere [6]. However, this RI considers some contribution of vitamin D from outdoor activities during the summer-season (late Spring – early Autumn), which is compatible with normal, everyday life and also in line with recommendations on physical activity. For people with little or no sun-exposure (including those aged >75 years, where dermal synthesis potential is reduced), an intake of 20 mg/d is recommended [6]. The German Nutrition Society vitamin D recommendations for the DACH region (Germany, Austria and Switzerland) region (20 mg/d for children adolescents and adults, based on serum 25(OH)D 50 nmol/L) were established in the context of endogenous synthesis being lacking [27]. They suggest however that UVB exposure of uncovered skin areas may have a role in attaining required levels of vitamin D, but that individuals who spend little time outside in the sun or fully cover their skin when outside as well as those of darker skin types and individuals >65 years, may be in need of a vitamin D supplement [27]. The DRV for the Netherlands (RDA of 20 mg/d for those aged 70 years (25(OH)D >50 nmol/L); and an Adequate Intake of 10 mg/d for other population groups (25(OH)D >30 nmol/L) was set for other population groups) apply in the case of insufficient exposure to sunlight [28]. There is specific guidance provided in terms of supplementation (10–20 mg/d of supplemental vitamin D depending on age group, and supplemental to a good and varied diet) typically for those with insufficient exposure to sunlight or of dark skin [28]. It should be noted, however, there are an increasing number of studies which report the amount of UVB exposure which might be required to meet specified serum 25(OH)D concentrations [29–31], and more are underway including one in an EU Framework 7 (FP7) collaborative project called ‘ODIN; Food-based solutions for optimal vitamin D nutrition and health through the life cycle’ (www.ODIN-vitD.eu). 1.2. How do current intakes of vitamin D in young and adult populations in North America and Europe compare against these new dietary targets? The IOM and the European equivalent agency, the EFSA [32], use the EAR (i.e., the average daily nutrient intake level that is estimated to meet the requirements of half of all healthy individuals in a particular life-stage and gender-specific group [5]), as an indicator of adequacy of nutrient intake within the

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population. By convention, the percentage of the population (or population subgroup) that are consuming less than the EAR value is a reflection of the degree of inadequate intake for that particular nutrient. As mentioned in Section 1.1, the North American EAR value for vitamin D is currently 10 mg daily [5]. The dietary intakes of children and adults in North America and some European countries have been reviewed recently [3,33]. Data from national surveys in North European member states show that vitamin D intakes are, in general, less than 5 mg/d [33]. The data also show that while intakes differ by age and gender as well as vitamin D fortification practices in these countries, the most important determinant of variation in intakes between countries is the contribution of vitamin D from supplements [33,34]. For example, data from the National Adult Nutrition Survey in Ireland show that mean vitamin D intake derived from dietary sources was 4.0 mg/d, whereas in those individuals who consumed vitamin Dcontaining supplements, the mean daily intake from all sources (foods and supplements) was 13.0 mg/d [34]. The European Nutrition and Health Report [35] summarized vitamin D intake in children and teenagers (aged 4–14 years) and showed that intakes were in the range 1.2–6.5 mg/d. Again, intakes were variable between countries, gender and age group of the participants. In North America, data from analysis of the National Health and Nutrition Examination Survey (NHANES) (covering period, 2003–2006) showed that the median vitamin D intake (from all sources) was 6.3 mg/d for children (aged 2–18 years) and 5.8 mg/d for adults (aged >19 years) [36]. In Canada, median vitamin D intakes from food sources were calculated from data reported in the 2004 Canadian Community Health Survey Cycle 2.2 [37]. Median daily intakes ranged from 3.5 to 4.5 mg in adult women and 5.3–5.7 mg in adult men, while 5.0–6.9 mg for children, aged 1–18 years [37]. These North American and European population vitamin D intake estimates, highlight the degree of inadequacy relative to the EAR and furthermore underscore the need for strategies to increase vitamin D intakes within the population. 1.3. Bridging the gap; dietary strategies for increasing vitamin D intake As outlined above, there is considerable importance placed on dietary supply of vitamin D in terms of protecting against vitamin D deficiency, especially when UVB availability is low or impeded due to environmental or individual characteristics. However of public health concern, the findings, as outlined in Section 1.2, highlight the gap between current dietary intakes of vitamin D by North American and European populations and the EAR. It has been emphasized and re-emphasized that there are only a limited number of public health strategies available to correct low dietary vitamin D intake, and these have been reviewed in detail elsewhere [4,17,33,38]. Recommending increased intake of naturally occurring vitamin D-rich foods is the least likely strategy to counteract low dietary vitamin D intake due to the fact that there are very few food sources that are rich in vitamin D and most are not frequently consumed by many in the population [34]. There is little doubt that vitamin D supplement use will increase serum 25 (OH)D concentrations across population subgroups [39,40]; the degree of enhancement of vitamin D status is dependent on the dose of vitamin D in the supplements. In the USA, Fulgoni et al. [36] showed using data from NHANES 2003–2006 that the percentage of individuals aged 2 and older below the EAR was reduced modestly (by 7%) when the contribution of vitamin D supplements was accounted for, but still 93.3% did not reach the EAR. Likewise, data for European populations confirms that vitamin D intakes from supplements are relatively modest [41]. That use of supplemental vitamin D does not offer population protection in terms of achieving the EAR may relate to the relatively low

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amounts of vitamin D used in many supplements in such countries. The percentage of the population that take vitamin D-containing supplements in many countries is also relatively low [4]. The fortification of food with vitamin D has been suggested as a strategy with potentially widest reach and impact in the population in terms of enhancing vitamin D intakes [4,33,34]. Fortification of foods with vitamin D in the USA and Canada has an important effect on the mean daily intake of vitamin D by the average adult [39], and the fortification practices in these countries has been recently reviewed [42]; however, Fulgoni et al. also showed that the percentage of individuals aged 2 and older below the EAR was reduced further again (from 93.3%) when the contribution of vitamin D fortified foods was accounted for, but of note, 69.5% still did not reach the EAR [36]. Despite mandatory fortification of milk, the majority of Canadians consumed less than the EAR for vitamin D [37]. Likewise in Europe, the intake of vitamin D from voluntary fortified foods has been reported as low [41]. The relatively low level of protection against inadequate intakes at a population level apparently offered by current food fortification with vitamin D has been suggested to relate to several fortification practices (e.g., voluntary versus mandatory, level of addition, food vehicles used for fortification), all of which might need to be evaluated further [33,38]. On the basis of intake estimates in the Canadian survey and the impact of food fortification on same, Vatanparast et al. suggested increasing the range of foods to which vitamin D can be lawfully added and wider practice of voluntary fortification [37]. This and similar type data from elsewhere has prompted suggestions of an over-reliance of fortification of dairy-based foods and consideration of the types of foods that might be used for vitamin D fortification and the levels of addition suitable for each so as to ensure adequacy while minimizing risk of high intakes [43]. Interestingly, Madsen et al. [44] recently provided experimental evidence, in the form of a RCT data, of the effects of vitamin D-fortified milk and bread on serum 25(OH)D in 201 families (n 782 children and adults, aged 4–60 years) in Denmark during winter. Bread was included as an additional vehicle for fortification in recognition of the skewness of milk intake across some population groups. The groups randomized to vitamin D unfortified and fortified foods had median intakes of vitamin D of 2.2 and 9.6 mg/d, respectively over the 6 months of the study. By the end of the study period, none and 16% in the fortified food group had serum 25(OH)D levels below 25 and 50 nmol/L, respectively, with the corresponding prevalence estimates for the group receiving unfortified foods at 12 and 65%, respectively [44]. From a European perspective, voluntary fortification of foods with vitamin D (as D2 or D3) is permitted under EC Regulation 1925/2006. No addition is permitted to unprocessed foods or alcoholic beverages. The legislation provides for the setting of safe maximum levels of micronutrients in fortified foods; however, these levels have not yet been established. Fortification with vitamin D is mandatory for some foods, e.g. margarine, skim milk and infant foods. Some countries (e.g., Finland) have a policy to promote voluntary fortification of fluid milk and milk products with vitamin D. Clearly, fortification of food with vitamin D holds much promise as a means of increasing intakes of vitamin D and minimizing risk of vitamin D deficiency in the population. While traditional fortification practices in which exogenous vitamin D is added to the foodstuffs will continue to be an important approach for increasing the content of vitamin D but possibly in a wider variety of foods, the use of biofortified foods with vitamin D also merits serious attention not only as it may hold more consumer appeal in some cases, but also as it may increase other metabolites of vitamin D which would boost the overall relative effectiveness of these foods in raising vitamin D status. The term ‘biofortification’ has more

routinely been used in the context of improving the nutritional value, such as zinc, iron, beta-carotene, of plant foods, either by conventional selective breeding, or through genetic engineering, and which differs from traditional fortification in which the nutrients are added to the foods when they are being processed. In relation to biofortification with vitamin D, the animal produce (such as, e.g., cultured fish, beef, pork, lamb, chicken, eggs, and milk) could have increased vitamin D and/or 25-hydroxyvitamin D contents by virtue of addition of vitamin D or 25-hydroxyvitamin D (where permissible) to the livestock feeds. The vitamin D compounds in the resulting foodstuffs from the animals will be incorporated in a manner similar to native vitamin D and unlike in traditional fortification will be under some degree of biological regulatory control mechanisms in the animal. As one example, Mattila et al. [45] has shown that adding vitamin D3 or 25-hydroxyvitamin D3, or indeed both, to the diet of hens can produce eggs with a significantly increased total vitamin D activity (i.e., vitamin D3 content plus the 25-hydroxyvitamin D3 content multiplied by 5 on the basis of its relative effectiveness [13]). Considering that meat and fish and their associated dishes have been shown to contribute 41% to the mean daily intake of vitamin D in adult Irish population [34], and meat alone contributing 31% in Canada [36], the possibility of enhancing the content further by biofortification and its potential impact on population intake estimates is of significant public health nutrition relevance. Finally, biofortification with vitamin D could also embrace the practice of UVB-irradiation of mushrooms and baker’s yeast which have been shown to stimulate their endogenous vitamin D2 content. While only small amounts of vitamin D can be found in selected species of plants, intriguingly, Jäpelt and Jakobsen [46] recently suggested that increased knowledge of vitamin D and of its metabolites in plants, as well as improvements in analytical methods for detection of vitamin D and of its derivatives, can offer new tools for increasing vitamin D content in edible parts of plants. However, this would seem to be contingent on confirmation of the biosynthetic pathway(s) for vitamin D3 in plants. The potential of bio-fortification of animal-derived foods (such as beef, pork, cultured fish, eggs) as well as the mushrooms and baker’s yeast with vitamin D compounds are under investigation in both the EU FP7 collaborative ‘ODIN’ project and an Irish nationally funded project (‘EnhanceD Meats’; http://www.ucc.ie/en/vitamind/ history/ongoing/enhancedmeats). The animal feeding trials within the project which lead to the production of these biofortified animal-derived foods also have animal welfare and safety considerations built into their design, and the levels of addition of the various vitamin D compounds do not exceed the European Commission allowable upper level of addition to animal feeds. Some of these vitamin D bio-fortified foods will be tested in these projects using winter-based RCTs in terms of evaluating their potential at raising serum 25(OH)D and thus contributing to vitamin D deficiency prevention. In addition, as the dietary patterns of some of Europe’s immigrant populations differ to those of the indigenous population, ‘ODIN’ is also conducting a foodbased RCT in which the impact of biofortification and/or fortification of more tailored foods on vitamin D status of young adult immigrant women in Denmark will be studied. 2. Conclusions Current DRI/DRV for vitamin D are essential public health policy instruments in terms of promoting adequate vitamin D status in the population and prevention of vitamin D deficiency. As discussed in earlier sections of this review, while they are excellent dietary targets developed with the evidence-base and data available at the time, there are some issues which need to be considered in future iterations and ideally with new data to help

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address some fundamental knowledge gaps. Thus, by design and necessity further iterations of DRI/DRV will be more fine-tuned estimates of the dietary requirements for vitamin D which will even provide for more population protection. It is clear that for most populations there are a majority of individuals failing to meet the EAR for vitamin D and thus strategies for bridging the gap between current population intakes and this dietary target are needed. While increasing the intake of vitamin D from naturally rich foods and/or supplements can undoubtedly improve nutritional status of individuals consuming them, their limited impact at population level requires other dietary strategies, such as fortification and biofortification, to be explored. To enable such strategies be evidence-based and informed, data from national surveys in which changes in the intake distribution of vitamin D within the population arising from the different fortification approaches (i.e., foods and levels of addition) will be of value. This research from a European perspective is also being undertaken in the EU ODIN project. Finally, any public health policy or practice which is designed to increase vitamin D intakes across the distribution need to be cognizant of not compromising safety. In this regard, the UL acts as a dietary intake ceiling and one fortification policies must aim to prevent individuals from breaching. Carefully designed and evidence-based fortification (including potentially biofortification) initiatives can be an important bow in the quiver of public health authorities mandated with a risk management function and thus implementing the DRI/ DRV. References [1] K.D. Cashman, Dietary reference intervals for vitamin D, Scand. J. Clin. Lab. Invest. Suppl. 243 (2012) 136–143. [2] K.D. Cashman, M. Kiely, Towards prevention of vitamin D deficiency and beyond: knowledge gaps and research needs in vitamin D nutrition and public health, Br. J. Nutr. 106 (2011) 1617–1627. [3] K.D. Cashman, M. Kiely, EURRECA-estimating vitamin D requirements for deriving dietary reference values, Crit. Rev. Food Sci. Nutr. 53 (2013) 1097–1099. [4] K.D. Cashman, M. Kiely, Recommended dietary intakes for vitamin D: where do they come from, what do they achieve and how can we meet them? J. Hum. Nutr. Diet. 27 (2014) 434–442. [5] IOM Institute of Medicine, Dietary Reference Intakes for Calcium and Vitamin D, The National Academies Press, Washington, D.C, 2011. [6] NORDEN Nordic Nutrition Recommendations, 5th Edition (NNR5) – Vitamin D. http://www.slv.se/en-gb/Startpage-NNR/Public-consultation11/, 2013 (accessed 08.13). [7] M.F. Holick, N.C. Binkley, H.A. Bischoff-Ferrari, C.M. Gordon, D.A. Hanley, R.P. Heaney, M.H. Murad, C.M. Weaver, Endocrine society. Evaluation, treatment, and prevention of vitamin D deficiency: an endocrine society clinical practice guideline, J. Clin. Endocrinol. Metab. 96 (July (7)) (2011) 1911–1930. [8] K.D. Cashman, M. Kiely, M. Kinsella, R.A. Durazo-Arvizu, L. Tian, Y. Zhang, A. Lucey, A. Flynn, M.J. Gibney, H.W. Vesper, K.W. Phinney, P.M. Coates, M.F. Picciano, C.T. Sempos, Evaluation of vitamin D standardization program protocols for standardizing serum 25-hydroxyvitamin D data: a case study of the program’s potential for national nutrition and health surveys, Am. J. Clin. Nutr. 97 (2013) 1235–1242. [9] K.D. Cashman, A.P. Fitzgerald, M. Kiely, K.M. Seamans, A systematic review and meta-regression analysis of the vitamin D intake-serum 25-hydroxyvitamin D relationship to inform European recommendations, Br. J. Nutr. 106 (2011) 1638–1648. [10] K.D. Cashman, A.P. FitzGerald, H.T. Viljakainen, J. Jakobsen, K.F. Michaelsen, C. Lamberg-Allardt, C. Mølgaard, Estimation of the dietary requirement for vitamin D in healthy adolescent white girls, Am. J. Clin. Nutr. 93 (2011) 549–555. [11] K.D. Cashman, T.R. Hill, A.J. Lucey, N. Taylor, K.M. Seamans, S. Muldowney, A.P. Fitzgerald, A. Flynn, M.S. Barnes, G. Horigan, M.P. Bonham, E.M. Duffy, J.J. Strain, J.M. Wallace, M. Kiely, Estimation of the dietary requirement for vitamin D in healthy adults, Am. J. Clin. Nutr. 88 (2008) 1535–1542. [12] K.D. Cashman, J.M. Wallace, G. Horigan, T.R. Hill, M.S. Barnes, A.J. Lucey, M.P. Bonham, N. Taylor, E.M. Duffy, K. Seamans, S. Muldowney, A.P. Fitzgerald, A. Flynn, J.J. Strain, M. Kiely, Estimation of the dietary requirement for vitamin D in free-living adults 64 y of age, Am. J. Clin. Nutr. 89 (2009) 1366–1374. [13] K.D. Cashman, K.M. Seamans, A.J. Lucey, E. Stöcklin, P. Weber, M. Kiely, T.R. Hill, Relative effectiveness of oral 25-hydroxyvitamin D3 and vitamin D3 in raising

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Vitamin D: dietary requirements and food fortification as a means of helping achieve adequate vitamin D status.

Vitamin D deficiency is evident in many parts of the globe, even in the sunnier regions, for a variety of reasons. Such deficiency contributes to risk...
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