Journal of Human Nutrition and Dietetics
INVITED REVIEW Recommended dietary intakes for vitamin D: where do they come from, what do they achieve and how can we meet them? K. D. Cashman1,2 & M. Kiely1 1
Vitamin D Research Group, School of Food and Nutritional Sciences, University College Cork, Cork, Ireland Department of Medicine, University College Cork, Cork, Ireland
2
Keywords dietary reference values, food-based strategies, preventing vitamin D deficiency, vitamin D. Correspondence K. D. Cashman, Vitamin D Research Group, School of Food and Nutritional Sciences, University College Cork, Cork, Ireland. Tel.: +353 21 4901317 Fax: +353 21 4270244 E-mail: [email protected] How to cite this article Cashman K.D. & Kiely M. (2014) 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. doi:10.1111/jhn.12226
Abstract There is substantial evidence that the prevalence of vitamin D deficiency is high across Europe, particularly, but not exclusively, among those resident at Northerly latitudes. This has significant implications for human health throughout the lifecycle and impacts upon healthy growth and development and successful ageing for current and possibly future generations. In recent years, there have been several important reports from North America and Europe in relation to dietary reference values (DRVs) for vitamin D. These may be of enormous value from a public health perspective in terms of preventing vitamin D deficiency and promoting adequate vitamin D status in the population. In this concise review, we provide a brief summary of current DRVs for vitamin D, their background and their application to vitamin D deficiency prevention. The review also provides some brief guidance with respect to applying the DRVs in a clinical nutrition setting. In addition, the review illustrates how current dietary intakes of most populations, young and adult, are well short of the newly established DRVs. Accordingly, the review highlights potential food-based or dietary strategies for increasing the distribution of vitamin D intake in the population with the aim of preventing vitamin D deficiency. Finally, despite the explosion in scientific research in vitamin D and health, there are many fundamental gaps in the field of vitamin D from the public health perspective. The impact of these knowledge gaps on current DRVs for vitamin D is highlighted, as are some future developments that may help address these gaps.
Introduction Vitamin D is the nutrient that has most captured the minds and imaginations of the scientific community, authoritative agencies, regulatory bodies, industry, and the public alike in the opening decade of the new millennium (Cashman, 2012a). The major source of vitamin D in humans is cutaneous synthesis of cholecalciferol in the presence of ultraviolet B (UVB) radiation (290–315 nm) [North American Institute of Medicine (IOM), 2011]. However, there are several environmental factors that impede year-round synthesis, such as latitude and prevailing weather conditions, which determine the availability ª 2014 The British Dietetic Association Ltd.
of UVB of sufficient intensity to stimulate the conversion of 7-dehydrocholesterol in the skin to precholecalciferol. Personal characteristics, such as skin pigmentation, age, attire, sunscreen, working environment, physical activity and sun exposure behaviour, can also prevent or impede vitamin D synthesis (IOM, 2011; Health Council of the Netherlands, 2012). Thus, substantial portions of the World’s population, including all who reside at latitudes greater than approximately 40° (for reference, those individuals who reside above Rome in the Northern hemisphere) rely on body stores and dietary sources to maintain adequate vitamin D status all year round. Given that body stores, which have yet to be fully defined, are 1
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dependent on sun exposure, the importance of vitamin D intake on overall vitamin D status is a corollary of UVB sunshine deficit (Holick, 2008; Kiely & Black, 2012). Vitamin D status is currently best defined by circulating concentrations of 25-hydroxyvitamin D [25(OH)D], which reflect exposure from both cutaneous synthesis, dietary intake and mobilisation of tissue stores (Brannon et al., 2008; Seamans & Cashman, 2009), although the relative contributions of each of these sources is unknown and is likely to vary considerably according to environmental factors and personal characteristics. These multiple sources of variation create a uniquely complex set of considerations within which dietary requirements for vitamin D must be framed (Cashman & Kiely, 2013). In addition, fundamental gaps still exist in our understanding of the relationships between circulating 25(OH)D concentrations and health outcomes, with the possible exception of indicators of skeletal health (IOM, 2011; Health Council of the Netherlands, 2012; Cashman & Kiely, 2013). Notwithstanding these complexities and knowledge deficits, amongst others (Cashman & Kiely, 2011a), several authoritative agencies have either recently completed [IOM, German Nutrition Society, Dutch Health Ministry, and Nordic Council of Ministers (NORDEN)] or are undergoing [UK Scientific Advisory Committee on Nutrition (SACN) and European Food Safety Authority (EFSA)] the process of defining dietary reference values (DRVs) for vitamin D. Although these reports are of enormous value from a public health perspective in terms of preventing vitamin D deficiency and promoting adequate vitamin D status in the population, consideration of their application in clinical practice is useful because the application of public health-based recommendations to individual requirements warrants separate consideration. With this in mind, the Dietary Reference Intakes (DRI) Expert Committee who compiled the IOM report on calcium and vitamin D provided a commentary specifically for dietetics practitioners shortly after publication (Ross et al., 2011). In this concise review, we provide a brief summary of current DRVs for vitamin D, their background and their application to vitamin D deficiency prevention. We do not address the issue of dosing regimens for vitamin D deficiency treatment (e.g. in vitamin D-dependent paediatric rickets or osteomalacia), nor do we discuss vitamin D metabolism in renal disease. In light of the fact that current dietary intakes of most populations are well short of the newly established DRVs, the review highlights potential food-based or dietary strategies for increasing the distribution of vitamin D intake in the population aiming to prevent vitamin D deficiency and provides guidance with respect to applying the DRVs in a clinical nutrition setting. 2
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Recent dietary requirement values for vitamin D from North America In response to growing public concern and uncertainty, the US and Canadian governments requested the North American IOM to assess the current data on health outcomes associated with calcium and vitamin D and update the DRIs for both nutrients. Following a 10-year period of review of the process of developing DRIs in general, as documented across several reports (IOM, 2006, 2007, 2008; Taylor, 2008), the IOM committee approached the task of revising DRIs for calcium and vitamin D using the risk assessment framework for the first time. The risk assessment framework as it relates to vitamin D has been summarised in three recent reviews (Cashman & Kiely, 2011a, 2013; Cashman, 2012b) and, without doubt, this approach has led to one of the most transparent and comprehensive re-evaluations of vitamin D requirements, culminating in the published report by the IOM in 2011. Although the process of establishing DRVs varies by country, not surprisingly, the risk assessment framework is becoming widely adopted by competent authorities because it facilitates decision-making and provides increased transparency. For example, NORDEN, SACN and EFSA have all (or will shortly) issue new DRVs for vitamin D, using as much as possible a sequence of independent systematic evidence-based reviews (SEBRs) followed by an appraisal of the evidence to derive population targets for 25(OH)D and associated dietary vitamin D requirements. Given that the process undertaken by the IOM was the major international catalyst to this change in the process of establishing DRVs, a brief overview of that process is provided. During the period between 1997, when the last DRIs for calcium and vitamin D were published (IOM, 1997), and late 2010, when it revised the DRIs for calcium and vitamin D (IOM, 2011), the research output in the field of vitamin D increased exponentially, yielding a considerable body of data to inform the IOM DRI re-evaluation. Two Agency for Healthcare Research and Quality (AHRQ) SEBRs were commissioned as part of the preparation for the IOM vitamin D and calcium DRI exercise from the Ottawa (Cranney et al., 2007) and Tufts (Chung et al., 2009) evidence-based practice centres in 2007 and 2009, respectively. The purpose of AHRQ SEBRs was to use electronic searches of the medical literature to review and synthesise the published literature in relation to a priori questions relating to vitamin D sources, health effects and possible toxicity. In particular, the AHRQTufts SEBR was commissioned to answer key questions on how dietary vitamin D and calcium intake affect health outcomes, both bone and nonskeletal. The IOM committee used these SEBRs to identify, describe and rate ª 2014 The British Dietetic Association Ltd.
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potential indicators (including clinical outcomes, biomarkers of effect, functional outcomes and biomarkers of exposure) (Table 1) to be used in developing the DRIs for vitamin D and calcium. Taking indicators of bone health, including rickets and osteomalacia, bone mineral density and calcium absorption, for which there was sufficient evidence to provide a reasonable and supportable basis for DRI development, the committee proposed a serum 25(OH)D concentration of 40 nM as the median value above which approximately half the population might meet its vitamin D requirement [and below which half might not; which the committee called the estimated average requirement (EAR)-like concentration] and 50 nM as its estimate of the serum 25 (OH)D concentration that would meet the requirement of almost all (i.e. 97.5%) ‘normal healthy persons’ [which
Table 1 List of potential indicators of health outcomes for nutrient adequacy for calcium and vitamin D as considered by the Dietary Reference Intakes committee (Institute of Medicine, 2011), arranged alphabetically and group by general outcome Cancer/neoplasms • All cancers • Breast cancer • Colorectal cancer/colon polyps • Prostate cancer Cardiovascular diseases and hypertension Diabetes (type 2) and metabolic syndrome (obesity) Falls Immune responses • Asthma • Autoimmune disease
○ ○ ○ ○ ○ •
Diabetes (type 1) Inflammatory bowel and Crohn’s disease Multiple sclerosis Rheumatoid arthritis Systemic lupus erythematosus Infectious diseases
○ Tuberculosis ○ Influenza/upper respiratory infections Neuropsychological functioning • Autism • Cognitive function • Depression Physical performance (together with falls) Pre-eclampsia of pregnancy and other nonskeletal reproductive outcomes Skeletal health (commonly bone health) • Serum 25-hydroxyvitamin D, as intermediate • Parathyroid hormone, as intermediate • Calcium absorption • Calcium balance • Bone mineral content/bone mineral density • Fracture risk • Rickets/osteomalacia
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the committee called the Recommended Dietary Allowance (RDA)-like concentration] (IOM, 2011). Of note, the IOM expert committee suggested that health benefits beyond bone were from studies that provided often mixed and inconclusive results and could not be considered reliable at that time to establish trusted dietary recommendations for the population. It is worth noting that dietary recommendations to meet nutrient requirements are iterative, and using the risk assessment framework, based on the best available evidence at that time. Revisions of vitamin D DRVs would be based on an evaluation of a considerably larger body of evidence, including randomised controlled trials designed and implemented with the benefit of experience. Nonetheless, the IOM report generated much controversy among scientists in the vitamin D research field, many of whom considered that the reference indicators were overly conservative. Following the publication of the IOM report, an Endocrine Society task force in the US provided guidelines for clinicians for the evaluation, treatment and prevention of vitamin D deficiency (Holick et al., 2011). The task force appeared to be of the same view as the IOM committee that the evidence for nonskeletal effects of vitamin D is not sufficiently strong at this time and also based their recommendations for patients on bone health indices. However, it is worth emphasising at this point that definitions of vitamin D status vary considerably and the lack of agreed thresholds for vitamin D deficiency/adequacy continues to cause confusion. Although the IOM suggested thresholds for serum 25(OH)D as: 65 years, may be in need of a vitamin D supplement to ensure desired 25(OH)D concentration (German Nutrition Society, 2012). The DRV for the Netherlands (RDA of 20 lg day 1 for those aged ≥70 years [serum 25(OH)D > 50 nM]; an adequate intake of 10 lg day 1 [serum 25(OH)D > 30 nM] was set for other population groups because the EAR and RDA were not considered determinable) apply in the case of insufficient exposure to sunlight (Health Council of the Netherlands, 2012). In relation to at-risk groups, however, there is specific guidance provided in terms of supplementation (10 to 20 lg day 1 of supplemental vitamin D depending on age group, and supplemental to a good and varied diet) for those with insufficient exposure to sunlight or of dark skin (Health Council of the Netherlands, 2012). Patient versus population-focused approach to vitamin D recommendations The DRIs are intended to safeguard against nutrient deficiency in the population and in healthy individuals but are not prescriptions to treat a diagnosed deficiency, nor are they intended to safeguard against deficiency in individuals at high risk as a result of a metabolic disorder or medication antagonistic to the nutrient in question (Cashman & Kiely, 2011b). The Endocrine Society task force proposed that, to maximise the effect of vitamin D on calcium, bone and muscle metabolism, serum 25(OH)D should exceed 75 nM, which may require an intake of 1500–2000 IU vitamin D day–1 in adults (Holick et al., 2011). However, there are a number of points for careful consideration arising from these recommendations and these have been outlined in more detail recently (Cashman & Kiely, 2011b). In brief, although the report aimed to 6
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provide clinical guidance for patients, the supporting evidence-base mainly included studies in healthy individuals across the life spectrum, which may be inappropriate. Patient groups identified in the report included those with clinical disease, as well as pregnant and lactating women, African American and Hispanic adults and children, and people with a BMI over 30 kg m 2, which encompasses a high proportion of the ‘healthy’ population. Thus, the implication of the Endocrine Society report is either that ‘normal healthy persons’ (in addition to patients at risk of deficiency) require serum 25(OH)D > 75 nM, or that the requirements of the various candidate groups highlighted as being at risk of vitamin D deficiency are, as a consequence of their underlying disease/physiological state, 50% higher than the 50 nM estimated in the IOM report to cover the needs of almost all of the healthy population. The report failed to provide an adequate description and evaluation of the evidence-base to support this higher proposed threshold and there was very little emphasis on the data arising from such patient groups and whether they have higher vitamin D requirements for bone health. In addition, the report did not provide a methodological approach or rationale for its recommended vitamin D intake range of 1500–2000 IU day 1 needed to achieve serum 25(OH)D > 75 nM, or guidance as to which patient groups require 1500 versus 2000 IU day 1 or something in between, which introduced a potential dilemma for the clinical practitioner (Cashman & Kiely, 2011b). How do current intake in young and adult populations in Europe compare against new dietary targets ? The dietary intakes of children and adults in European countries, as well as beyond Europe, have been reviewed recently (Kiely & Black, 2012; Cashman & Kiely, 2013). In brief, intakes of vitamin D in national surveys throughout Europe (e.g. UK, Ireland, Denmark, France and Finland) are typically below 5 lg day 1 and vary according to country-specific fortification practices, sex and age. The main source of variation is the contribution from nutritional supplements. For example, the mean daily intake of vitamin D from food sources only in Irish adults from the North/South Ireland Food Consumption Survey was estimated at 3.2 lg (Hill et al., 2004). Despite a low prevalence of consumption of D-containing supplements at 15%, the contribution from supplements increased the overall mean intake to 4.2 lg day 1. Vitamin D-containing supplement users had intakes of 7.1 lg day 1. A similar picture of low vitamin D intakes emerges for children in Europe. For example, The European Nutrition and Health Report (Elmadfa et al., 2009) summarised vitamin D intake in children and teens from ª 2014 The British Dietetic Association Ltd.
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a variety of sources. Data showed an interval of intakes from 1.2–6.5 lg in children and teenagers aged 4–14 years, depending on country, sex and age group. Overall, it is clear that the current dietary supply of vitamin D makes it unfeasible for most children and adults in Europe to meet the IOM EAR of 10 lg day 1, let alone the RDA of 15 lg day 1. Dietary strategies for increasing vitamin D intake and status The estimates referred to above clearly show that the habitual mean vitamin D intakes by European populations are below the estimates of intake requirement, whether they be viewed as being approximately 10 versus 25 lg day 1 for serum 25(OH)D > 30 and >50 nM, respectively. It has been emphasised and re-emphasised 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 (Cashman, 2012a, 2013; Kiely & Black, 2012), and so only a brief overview is provided here: Improving intake of naturally occurring vitamin D-rich foods. This is the least likely strategy to counteract low dietary vitamin D intake because there are very few food sources that are rich in vitamin D. Furthermore, most of these are not frequently consumed by many in the population (Henderson et al., 2004). Vitamin D supplementation. Supplementation with vitamin D has been shown to significantly improve vitamin D intake across a variety of age, race, ethnic and gender groups, as well as improving vitamin D status per se (whose efficacy is dependent on dose) (Calvo & Whiting, 2006; Seamans & Cashman, 2009). However, evidence appears to suggest that the population intake of vitamin D from supplements is quite low (Flynn et al., 2009). This is a function mainly of the relatively low vitamin D content of most supplements in some countries relative to the requirement as discussed earlier. Some are of the view that, although not highly effective at a population level, vitamin D supplementation may be appropriate in high-risk groups such as the elderly (Viljakainen et al., 2006; Standing Committee of European Doctors, 2009). Vitamin D fortification (mandatory or voluntarily) of food. Although supplements are an effective method for individuals to increase their intake, food fortification represents the best opportunity to increase the vitamin D supply to the population and this has been reviewed in detail elsewhere (Kiely & Black, 2012; Cashman & Kiely, 2013), including the forms of vitamin D that might be used and their pros and cons (Cashman, 2012a). Fortification of foods with vitamin D in the USA and Canada ª 2014 The British Dietetic Association Ltd.
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has an important effect on the mean daily intake of vitamin D by the average adult; however, Calvo & Whiting (2006) suggest that the current level of fortification in the USA and Canada is not effective in reaching the required levels of vitamin D intake. This may relate to the level of fortification, types and choice of food vehicles and the issue of mandatory or optional/voluntary fortification (Cashman, 2012a; Kiely & Black, 2012). Flynn et al. (2009) have recently shown that the 95th percentile of intake of vitamin D from voluntary fortified foods in Europe is low. Well-designed sustainable fortification strategies, which use a range of foods to accommodate diversity, have potential to increase vitamin D intakes across the population distribution and minimise the prevalence of low serum 25 (OH)D (Black et al., 2012). To ensure that such strategies are evidence-based and informed from a European perspective, we need to model European food and vitamin D intake data to determine which food vehicles and what level of vitamin D addition will ensure an effective but safe rise in serum 25(OH)D concentration in European populations. This research together, with an evaluation of the benefits and limitations of biofortification of various foods (plant and animal-based), will be undertaken in a recently funded EU Framework 7 collaborative project called ‘ODIN; Food-based solutions for Optimal vitamin D Nutrition and health through the life cycle’ (http://www. ODIN-vitD.eu), which commenced in November, 2013. Concluding remarks and future considerations An awareness is required of a number of activities that may further add to our understanding of vitamin D from a public health nutrition perspective. Although the IOM DRIs are based in bone health outcomes, and not nonskeletal health outcomes, largely based on the available evidence as presented for consideration in the AHRQ SEBRs, research output in the field of vitamin D is still increasing exponentially and, in recognition of this, an update on the 2009 Tufts AHRQ SEBR on vitamin D/ calcium and health outcomes is currently being finalised following a public consultation phase. This may change the storyline and, if so, potentially open the debate again on the serum 25(OH)D threshold and associated vitamin D DRI. This is entirely appropriate because the establishment of DRI and DRVs, respectively, is intended (and needs) to be an iterative process. In this context, the vitamin D DRV from SACN and EFSA due out in the next year or so will be also interesting as the next set of authoritative reports on vitamin D. Finally, the ODIN project, as mentioned above, will add further much needed data in relation to identified knowledge gaps not only on vitamin D dietary requirement in early life and 7
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pregnancy (which have mostly been extrapolations as a result of an absence of firm data), but also on nonskeletal health outcomes in early life and the elderly.
Conflict of interests, source of funding and authorship The authors declare that they have no conflicts of interest. No funding declared. All authors critically reviewed the manuscript and approved the final version submitted for publication.
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INVITED REVIEW Recommended dietary intakes for vitamin D: where do they come from, what do they achieve and how can we meet them? K. D. Cashman1,2 & M. Kiely1 1
Vitamin D Research Group, School of Food and Nutritional Sciences, University College Cork, Cork, Ireland Department of Medicine, University College Cork, Cork, Ireland
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Keywords dietary reference values, food-based strategies, preventing vitamin D deficiency, vitamin D. Correspondence K. D. Cashman, Vitamin D Research Group, School of Food and Nutritional Sciences, University College Cork, Cork, Ireland. Tel.: +353 21 4901317 Fax: +353 21 4270244 E-mail: [email protected] How to cite this article Cashman K.D. & Kiely M. (2014) 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. doi:10.1111/jhn.12226
Abstract There is substantial evidence that the prevalence of vitamin D deficiency is high across Europe, particularly, but not exclusively, among those resident at Northerly latitudes. This has significant implications for human health throughout the lifecycle and impacts upon healthy growth and development and successful ageing for current and possibly future generations. In recent years, there have been several important reports from North America and Europe in relation to dietary reference values (DRVs) for vitamin D. These may be of enormous value from a public health perspective in terms of preventing vitamin D deficiency and promoting adequate vitamin D status in the population. In this concise review, we provide a brief summary of current DRVs for vitamin D, their background and their application to vitamin D deficiency prevention. The review also provides some brief guidance with respect to applying the DRVs in a clinical nutrition setting. In addition, the review illustrates how current dietary intakes of most populations, young and adult, are well short of the newly established DRVs. Accordingly, the review highlights potential food-based or dietary strategies for increasing the distribution of vitamin D intake in the population with the aim of preventing vitamin D deficiency. Finally, despite the explosion in scientific research in vitamin D and health, there are many fundamental gaps in the field of vitamin D from the public health perspective. The impact of these knowledge gaps on current DRVs for vitamin D is highlighted, as are some future developments that may help address these gaps.
Introduction Vitamin D is the nutrient that has most captured the minds and imaginations of the scientific community, authoritative agencies, regulatory bodies, industry, and the public alike in the opening decade of the new millennium (Cashman, 2012a). The major source of vitamin D in humans is cutaneous synthesis of cholecalciferol in the presence of ultraviolet B (UVB) radiation (290–315 nm) [North American Institute of Medicine (IOM), 2011]. However, there are several environmental factors that impede year-round synthesis, such as latitude and prevailing weather conditions, which determine the availability ª 2014 The British Dietetic Association Ltd.
of UVB of sufficient intensity to stimulate the conversion of 7-dehydrocholesterol in the skin to precholecalciferol. Personal characteristics, such as skin pigmentation, age, attire, sunscreen, working environment, physical activity and sun exposure behaviour, can also prevent or impede vitamin D synthesis (IOM, 2011; Health Council of the Netherlands, 2012). Thus, substantial portions of the World’s population, including all who reside at latitudes greater than approximately 40° (for reference, those individuals who reside above Rome in the Northern hemisphere) rely on body stores and dietary sources to maintain adequate vitamin D status all year round. Given that body stores, which have yet to be fully defined, are 1
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dependent on sun exposure, the importance of vitamin D intake on overall vitamin D status is a corollary of UVB sunshine deficit (Holick, 2008; Kiely & Black, 2012). Vitamin D status is currently best defined by circulating concentrations of 25-hydroxyvitamin D [25(OH)D], which reflect exposure from both cutaneous synthesis, dietary intake and mobilisation of tissue stores (Brannon et al., 2008; Seamans & Cashman, 2009), although the relative contributions of each of these sources is unknown and is likely to vary considerably according to environmental factors and personal characteristics. These multiple sources of variation create a uniquely complex set of considerations within which dietary requirements for vitamin D must be framed (Cashman & Kiely, 2013). In addition, fundamental gaps still exist in our understanding of the relationships between circulating 25(OH)D concentrations and health outcomes, with the possible exception of indicators of skeletal health (IOM, 2011; Health Council of the Netherlands, 2012; Cashman & Kiely, 2013). Notwithstanding these complexities and knowledge deficits, amongst others (Cashman & Kiely, 2011a), several authoritative agencies have either recently completed [IOM, German Nutrition Society, Dutch Health Ministry, and Nordic Council of Ministers (NORDEN)] or are undergoing [UK Scientific Advisory Committee on Nutrition (SACN) and European Food Safety Authority (EFSA)] the process of defining dietary reference values (DRVs) for vitamin D. Although these reports are of enormous value from a public health perspective in terms of preventing vitamin D deficiency and promoting adequate vitamin D status in the population, consideration of their application in clinical practice is useful because the application of public health-based recommendations to individual requirements warrants separate consideration. With this in mind, the Dietary Reference Intakes (DRI) Expert Committee who compiled the IOM report on calcium and vitamin D provided a commentary specifically for dietetics practitioners shortly after publication (Ross et al., 2011). In this concise review, we provide a brief summary of current DRVs for vitamin D, their background and their application to vitamin D deficiency prevention. We do not address the issue of dosing regimens for vitamin D deficiency treatment (e.g. in vitamin D-dependent paediatric rickets or osteomalacia), nor do we discuss vitamin D metabolism in renal disease. In light of the fact that current dietary intakes of most populations are well short of the newly established DRVs, the review highlights potential food-based or dietary strategies for increasing the distribution of vitamin D intake in the population aiming to prevent vitamin D deficiency and provides guidance with respect to applying the DRVs in a clinical nutrition setting. 2
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Recent dietary requirement values for vitamin D from North America In response to growing public concern and uncertainty, the US and Canadian governments requested the North American IOM to assess the current data on health outcomes associated with calcium and vitamin D and update the DRIs for both nutrients. Following a 10-year period of review of the process of developing DRIs in general, as documented across several reports (IOM, 2006, 2007, 2008; Taylor, 2008), the IOM committee approached the task of revising DRIs for calcium and vitamin D using the risk assessment framework for the first time. The risk assessment framework as it relates to vitamin D has been summarised in three recent reviews (Cashman & Kiely, 2011a, 2013; Cashman, 2012b) and, without doubt, this approach has led to one of the most transparent and comprehensive re-evaluations of vitamin D requirements, culminating in the published report by the IOM in 2011. Although the process of establishing DRVs varies by country, not surprisingly, the risk assessment framework is becoming widely adopted by competent authorities because it facilitates decision-making and provides increased transparency. For example, NORDEN, SACN and EFSA have all (or will shortly) issue new DRVs for vitamin D, using as much as possible a sequence of independent systematic evidence-based reviews (SEBRs) followed by an appraisal of the evidence to derive population targets for 25(OH)D and associated dietary vitamin D requirements. Given that the process undertaken by the IOM was the major international catalyst to this change in the process of establishing DRVs, a brief overview of that process is provided. During the period between 1997, when the last DRIs for calcium and vitamin D were published (IOM, 1997), and late 2010, when it revised the DRIs for calcium and vitamin D (IOM, 2011), the research output in the field of vitamin D increased exponentially, yielding a considerable body of data to inform the IOM DRI re-evaluation. Two Agency for Healthcare Research and Quality (AHRQ) SEBRs were commissioned as part of the preparation for the IOM vitamin D and calcium DRI exercise from the Ottawa (Cranney et al., 2007) and Tufts (Chung et al., 2009) evidence-based practice centres in 2007 and 2009, respectively. The purpose of AHRQ SEBRs was to use electronic searches of the medical literature to review and synthesise the published literature in relation to a priori questions relating to vitamin D sources, health effects and possible toxicity. In particular, the AHRQTufts SEBR was commissioned to answer key questions on how dietary vitamin D and calcium intake affect health outcomes, both bone and nonskeletal. The IOM committee used these SEBRs to identify, describe and rate ª 2014 The British Dietetic Association Ltd.
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potential indicators (including clinical outcomes, biomarkers of effect, functional outcomes and biomarkers of exposure) (Table 1) to be used in developing the DRIs for vitamin D and calcium. Taking indicators of bone health, including rickets and osteomalacia, bone mineral density and calcium absorption, for which there was sufficient evidence to provide a reasonable and supportable basis for DRI development, the committee proposed a serum 25(OH)D concentration of 40 nM as the median value above which approximately half the population might meet its vitamin D requirement [and below which half might not; which the committee called the estimated average requirement (EAR)-like concentration] and 50 nM as its estimate of the serum 25 (OH)D concentration that would meet the requirement of almost all (i.e. 97.5%) ‘normal healthy persons’ [which
Table 1 List of potential indicators of health outcomes for nutrient adequacy for calcium and vitamin D as considered by the Dietary Reference Intakes committee (Institute of Medicine, 2011), arranged alphabetically and group by general outcome Cancer/neoplasms • All cancers • Breast cancer • Colorectal cancer/colon polyps • Prostate cancer Cardiovascular diseases and hypertension Diabetes (type 2) and metabolic syndrome (obesity) Falls Immune responses • Asthma • Autoimmune disease
○ ○ ○ ○ ○ •
Diabetes (type 1) Inflammatory bowel and Crohn’s disease Multiple sclerosis Rheumatoid arthritis Systemic lupus erythematosus Infectious diseases
○ Tuberculosis ○ Influenza/upper respiratory infections Neuropsychological functioning • Autism • Cognitive function • Depression Physical performance (together with falls) Pre-eclampsia of pregnancy and other nonskeletal reproductive outcomes Skeletal health (commonly bone health) • Serum 25-hydroxyvitamin D, as intermediate • Parathyroid hormone, as intermediate • Calcium absorption • Calcium balance • Bone mineral content/bone mineral density • Fracture risk • Rickets/osteomalacia
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the committee called the Recommended Dietary Allowance (RDA)-like concentration] (IOM, 2011). Of note, the IOM expert committee suggested that health benefits beyond bone were from studies that provided often mixed and inconclusive results and could not be considered reliable at that time to establish trusted dietary recommendations for the population. It is worth noting that dietary recommendations to meet nutrient requirements are iterative, and using the risk assessment framework, based on the best available evidence at that time. Revisions of vitamin D DRVs would be based on an evaluation of a considerably larger body of evidence, including randomised controlled trials designed and implemented with the benefit of experience. Nonetheless, the IOM report generated much controversy among scientists in the vitamin D research field, many of whom considered that the reference indicators were overly conservative. Following the publication of the IOM report, an Endocrine Society task force in the US provided guidelines for clinicians for the evaluation, treatment and prevention of vitamin D deficiency (Holick et al., 2011). The task force appeared to be of the same view as the IOM committee that the evidence for nonskeletal effects of vitamin D is not sufficiently strong at this time and also based their recommendations for patients on bone health indices. However, it is worth emphasising at this point that definitions of vitamin D status vary considerably and the lack of agreed thresholds for vitamin D deficiency/adequacy continues to cause confusion. Although the IOM suggested thresholds for serum 25(OH)D as: 65 years, may be in need of a vitamin D supplement to ensure desired 25(OH)D concentration (German Nutrition Society, 2012). The DRV for the Netherlands (RDA of 20 lg day 1 for those aged ≥70 years [serum 25(OH)D > 50 nM]; an adequate intake of 10 lg day 1 [serum 25(OH)D > 30 nM] was set for other population groups because the EAR and RDA were not considered determinable) apply in the case of insufficient exposure to sunlight (Health Council of the Netherlands, 2012). In relation to at-risk groups, however, there is specific guidance provided in terms of supplementation (10 to 20 lg day 1 of supplemental vitamin D depending on age group, and supplemental to a good and varied diet) for those with insufficient exposure to sunlight or of dark skin (Health Council of the Netherlands, 2012). Patient versus population-focused approach to vitamin D recommendations The DRIs are intended to safeguard against nutrient deficiency in the population and in healthy individuals but are not prescriptions to treat a diagnosed deficiency, nor are they intended to safeguard against deficiency in individuals at high risk as a result of a metabolic disorder or medication antagonistic to the nutrient in question (Cashman & Kiely, 2011b). The Endocrine Society task force proposed that, to maximise the effect of vitamin D on calcium, bone and muscle metabolism, serum 25(OH)D should exceed 75 nM, which may require an intake of 1500–2000 IU vitamin D day–1 in adults (Holick et al., 2011). However, there are a number of points for careful consideration arising from these recommendations and these have been outlined in more detail recently (Cashman & Kiely, 2011b). In brief, although the report aimed to 6
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provide clinical guidance for patients, the supporting evidence-base mainly included studies in healthy individuals across the life spectrum, which may be inappropriate. Patient groups identified in the report included those with clinical disease, as well as pregnant and lactating women, African American and Hispanic adults and children, and people with a BMI over 30 kg m 2, which encompasses a high proportion of the ‘healthy’ population. Thus, the implication of the Endocrine Society report is either that ‘normal healthy persons’ (in addition to patients at risk of deficiency) require serum 25(OH)D > 75 nM, or that the requirements of the various candidate groups highlighted as being at risk of vitamin D deficiency are, as a consequence of their underlying disease/physiological state, 50% higher than the 50 nM estimated in the IOM report to cover the needs of almost all of the healthy population. The report failed to provide an adequate description and evaluation of the evidence-base to support this higher proposed threshold and there was very little emphasis on the data arising from such patient groups and whether they have higher vitamin D requirements for bone health. In addition, the report did not provide a methodological approach or rationale for its recommended vitamin D intake range of 1500–2000 IU day 1 needed to achieve serum 25(OH)D > 75 nM, or guidance as to which patient groups require 1500 versus 2000 IU day 1 or something in between, which introduced a potential dilemma for the clinical practitioner (Cashman & Kiely, 2011b). How do current intake in young and adult populations in Europe compare against new dietary targets ? The dietary intakes of children and adults in European countries, as well as beyond Europe, have been reviewed recently (Kiely & Black, 2012; Cashman & Kiely, 2013). In brief, intakes of vitamin D in national surveys throughout Europe (e.g. UK, Ireland, Denmark, France and Finland) are typically below 5 lg day 1 and vary according to country-specific fortification practices, sex and age. The main source of variation is the contribution from nutritional supplements. For example, the mean daily intake of vitamin D from food sources only in Irish adults from the North/South Ireland Food Consumption Survey was estimated at 3.2 lg (Hill et al., 2004). Despite a low prevalence of consumption of D-containing supplements at 15%, the contribution from supplements increased the overall mean intake to 4.2 lg day 1. Vitamin D-containing supplement users had intakes of 7.1 lg day 1. A similar picture of low vitamin D intakes emerges for children in Europe. For example, The European Nutrition and Health Report (Elmadfa et al., 2009) summarised vitamin D intake in children and teens from ª 2014 The British Dietetic Association Ltd.
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a variety of sources. Data showed an interval of intakes from 1.2–6.5 lg in children and teenagers aged 4–14 years, depending on country, sex and age group. Overall, it is clear that the current dietary supply of vitamin D makes it unfeasible for most children and adults in Europe to meet the IOM EAR of 10 lg day 1, let alone the RDA of 15 lg day 1. Dietary strategies for increasing vitamin D intake and status The estimates referred to above clearly show that the habitual mean vitamin D intakes by European populations are below the estimates of intake requirement, whether they be viewed as being approximately 10 versus 25 lg day 1 for serum 25(OH)D > 30 and >50 nM, respectively. It has been emphasised and re-emphasised 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 (Cashman, 2012a, 2013; Kiely & Black, 2012), and so only a brief overview is provided here: Improving intake of naturally occurring vitamin D-rich foods. This is the least likely strategy to counteract low dietary vitamin D intake because there are very few food sources that are rich in vitamin D. Furthermore, most of these are not frequently consumed by many in the population (Henderson et al., 2004). Vitamin D supplementation. Supplementation with vitamin D has been shown to significantly improve vitamin D intake across a variety of age, race, ethnic and gender groups, as well as improving vitamin D status per se (whose efficacy is dependent on dose) (Calvo & Whiting, 2006; Seamans & Cashman, 2009). However, evidence appears to suggest that the population intake of vitamin D from supplements is quite low (Flynn et al., 2009). This is a function mainly of the relatively low vitamin D content of most supplements in some countries relative to the requirement as discussed earlier. Some are of the view that, although not highly effective at a population level, vitamin D supplementation may be appropriate in high-risk groups such as the elderly (Viljakainen et al., 2006; Standing Committee of European Doctors, 2009). Vitamin D fortification (mandatory or voluntarily) of food. Although supplements are an effective method for individuals to increase their intake, food fortification represents the best opportunity to increase the vitamin D supply to the population and this has been reviewed in detail elsewhere (Kiely & Black, 2012; Cashman & Kiely, 2013), including the forms of vitamin D that might be used and their pros and cons (Cashman, 2012a). Fortification of foods with vitamin D in the USA and Canada ª 2014 The British Dietetic Association Ltd.
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has an important effect on the mean daily intake of vitamin D by the average adult; however, Calvo & Whiting (2006) suggest that the current level of fortification in the USA and Canada is not effective in reaching the required levels of vitamin D intake. This may relate to the level of fortification, types and choice of food vehicles and the issue of mandatory or optional/voluntary fortification (Cashman, 2012a; Kiely & Black, 2012). Flynn et al. (2009) have recently shown that the 95th percentile of intake of vitamin D from voluntary fortified foods in Europe is low. Well-designed sustainable fortification strategies, which use a range of foods to accommodate diversity, have potential to increase vitamin D intakes across the population distribution and minimise the prevalence of low serum 25 (OH)D (Black et al., 2012). To ensure that such strategies are evidence-based and informed from a European perspective, we need to model European food and vitamin D intake data to determine which food vehicles and what level of vitamin D addition will ensure an effective but safe rise in serum 25(OH)D concentration in European populations. This research together, with an evaluation of the benefits and limitations of biofortification of various foods (plant and animal-based), will be undertaken in a recently funded EU Framework 7 collaborative project called ‘ODIN; Food-based solutions for Optimal vitamin D Nutrition and health through the life cycle’ (http://www. ODIN-vitD.eu), which commenced in November, 2013. Concluding remarks and future considerations An awareness is required of a number of activities that may further add to our understanding of vitamin D from a public health nutrition perspective. Although the IOM DRIs are based in bone health outcomes, and not nonskeletal health outcomes, largely based on the available evidence as presented for consideration in the AHRQ SEBRs, research output in the field of vitamin D is still increasing exponentially and, in recognition of this, an update on the 2009 Tufts AHRQ SEBR on vitamin D/ calcium and health outcomes is currently being finalised following a public consultation phase. This may change the storyline and, if so, potentially open the debate again on the serum 25(OH)D threshold and associated vitamin D DRI. This is entirely appropriate because the establishment of DRI and DRVs, respectively, is intended (and needs) to be an iterative process. In this context, the vitamin D DRV from SACN and EFSA due out in the next year or so will be also interesting as the next set of authoritative reports on vitamin D. Finally, the ODIN project, as mentioned above, will add further much needed data in relation to identified knowledge gaps not only on vitamin D dietary requirement in early life and 7
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pregnancy (which have mostly been extrapolations as a result of an absence of firm data), but also on nonskeletal health outcomes in early life and the elderly.
Conflict of interests, source of funding and authorship The authors declare that they have no conflicts of interest. No funding declared. All authors critically reviewed the manuscript and approved the final version submitted for publication.
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