Vitamin <scp>D</scp> – a <scp>E</scp>uropean perspective on needs, intake and status

On 20 May 2014, the British Nutrition Foundation (BNF) held a half-day symposium at the Royal College of Surgeons entitled, ‘Vitamin D – a European perspective on needs, intake and status'. The conference was chaired by Dr Mairead Kiely (University College Cork) and introduced by Ayela Spiro (BNF), who welcomed the attendees and gave an overview of the objectives of the conference from a public health perspective. Ms Spiro began by highlighting the increased interest in the media with regard to vitamin D deficiency and the rise in the number of scientific publications, which have resulted in recent revisions to dietary intake recommendations in many European countries, including Germany, Austria, The Netherlands and the Nordic countries. Recommended intakes across Europe vary from 5–20 μg/day and are often higher for older adults (aged 65 years or more). The average amount of dietary vitamin D required depends upon a population's endogenous synthesis of vitamin D from exposure to the sun, with some countries assuming low exposure, while others assume high exposure. Nevertheless, mean dietary intakes of vitamin D in Europe do not currently meet the recommended intakes. The European Prospective Investigation into Cancer and Nutrition (EPIC) study found mean vitamin D intakes to be 4.8 and 3.3 μg/day for men and women, respectively, but with high variation around the mean (Freisling et al. 2010). In addition, European adult national surveys show typical intakes to be 2–4 μg/day, with the lowest intakes being found in Spain, and the highest in Scandinavian countries where there is limited endogenous synthesis of vitamin D from sun exposure (Roman Viñas et al. 2011; Mensink et al. 2013). Dietary sources of vitamin D are limited and the contribution of different sources is dependent upon habitual consumption in each country. For example, meat provides 30% of dietary vitamin D intake in the UK and Ireland, while fish provides 68% and 31% in Spain and France, respectively (AESAN 2011; IUNA 2011; ANSES 2013; Bates et al. 2014). Fortified fats (such as spreads) are the most important source of vitamin D in The Netherlands, providing 36% of dietary intake (van Rossum et al. 2011). Low intake of dietary vitamin D is reflected in measurements of serum 25-hydroxyvitamin D [25(OH)D] (an indicator of vitamin D status) in European adults. For example, there is evidence of low status in the UK (<25 mmol/l), which occurs in 8.4% of UK adults in summer and 39.3% in winter (an average of 23% over the year) (Bates et al. 2014). This indicates that a high proportion of serum 25(OH)D is derived from sun-induced endogenous synthesis, which does not occur in the UK during the winter months, rather than from dietary sources. Similar findings can also be seen in other countries, although direct comparison is difficult due to the use of different cut-off figures for deficiency/insufficiency and the lack of seasonal reporting. Vitamin D supplementation can help to increase serum 25(OH)D levels (Black et al. 2014) and most European countries recommend the use of supplements for infants (<1 year) and young children (1–3 years), those with little sun exposure and older adults (around 65 years and above). However, the compliance and rate of uptake of supplements appears to be poor (Yetley 2008), which may be due to lack of awareness among health professionals, inadequate policy promotion and/or poor population acceptance. Fortification of foods with vitamin D is another option to help increase intake. Fortification of fat spreads and milk is mandatory in some European countries (e.g. in Finland), occurring voluntarily in other European countries and is evident in foods such as breakfast cereals and dairy products. Further discussion can be found in a review by Spiro and Buttriss (2014). Professor Roger Bouillon (University of Leuven, Belgium) highlighted the importance of revisiting our evolutionary history when considering optimal levels of serum 25(OH)D. The vitamin D endocrine system evolved with the start of the vertebrates. Lower calcium supply on land compared to the ocean led to the need for efficient calcium absorption. Bone was required as a reservoir of calcium, with parathyroid hormone (PTH) and vitamin D working together to remodel bone when calcium levels were low. In addition, this system allowed the creation of hollow bones (i.e. solid bones but with less weight), which was important in terms of bone weight on land. During human evolution, there was abundant vitamin D due to very intensive sun exposure, with excess vitamin D being more likely to be a problem than deficiency. This is supported by the fact that we have five processes for dealing with vitamin D excess and none for deficiency. These include skin pigmentation, ultraviolet B (UVB)-induced destruction of pre-vitamin D, kinetic plateau of vitamin conversion into 25(OH)D, tight feedback regulation of renal 1-alpha-hydroxylase [the enzyme that converts 25(OH)D into its active form, 1,25(OH)2D] and 1,25(OH)2D metabolism. For these reasons, Professor Bouillon proposed that ‘historic’ levels of serum 25(OH)D are the maximum levels that avoid toxicity and probably do not reflect optimal biological activity. The importance of using randomised controlled trials (RCTs) when forming guidelines and recommendations on vitamin D is paramount. Looking at such studies, Professor Bouillon suggested that the optimal concentration of 25(OH)D may be around 50 nmol/l. In a severely deficient population of older adults (mean age 78 years), vitamin D supplementation increases serum 25(OH)D up to 40 nmol/l, leading to an increase in renal production of the active form of vitamin D – 1,25(OH)2D (Bouillon et al. 1987). In another study, increasing serum 25(OH)D beyond 50 nmol/l did not significantly decrease PTH and the investigators concluded that the risk of secondary hyperparathyroidism (excess production of PTH) is minimised when serum 25(OH)D is ≥20 nmol/l (Malabanan et al. 1998). In addition, when serum 25(OH)D is at 20 nmol/l, calcium absorption has been shown to be at the maximum level (Need et al. 2008). Increasing serum 25(OH)D beyond 50 nmol/l has been shown to have no significant effect on bone mineral density (Peacock et al. 2000). With regard to hard endpoints, hip fracture risk in older adults has been shown through meta-analysis of RCTs to be reduced by about 20% with a combination of vitamin D (20 μg) and calcium supplementation (Boonen et al. 2007), which would increase serum 25(OH)D to ≥50 nmol/l. Therefore, evidence-based medicine from RCTs suggests that a vitamin D status of ≥50 nmol/l, which can be reached through supplementation with 20 μg vitamin D/day, is both a safe and effective approach for bone health in older adults. The extra skeletal effects of vitamin D supplementation are still unfolding. The vitamin D receptor is present in a large range of cells and 3% of human genes are thought to be regulated by vitamin D, which indicates that it may have an effect on many outcomes. For example, the vitamin D receptor is present in all immune cells and nearly all genes important in the immune system are regulated by 25(OH)D. Pre-clinical data and uncontrolled prospective and retrospective studies suggest that low vitamin D status is associated with increased risk of infections and autoimmune diseases. However, there is a lack of RCTs to confirm these findings. The effect of vitamin D on muscle has been investigated, and meta-analyses of RCTs have shown that supplementation with 20 μg of vitamin D in older adults reduces the number of falls by around 15–20% (Bischoff-Ferrari et al. 2009; Michael et al. 2010; Murad et al. 2011). Interestingly, low vitamin D status has been found to increase risk of mortality in both observational studies (Melamed et al. 2008) and RCTs (Autier & Gandini 2007). Professor Christel Lamberg-Allardt (University of Helsinki) provided an overview of the process that resulted in the increased Nordic Nutrition Recommendations (NNR) for vitamin D. The recommendations were reviewed by an expert group, which conducted a series of systematic literature reviews, based upon a set of agreed criteria by the NNR working group. The objectives of the reviews were to determine vitamin D dietary reference values for different life stages; to assess the requirements for healthy growth, development and maintenance of health; and to consider the health effects of different intakes and exposures. A number of limitations and confounding factors were noted by the working group when performing the systematic literature reviews, including a lack of intervention studies for outcomes other than in relation to bone, lack of account taken for UV exposure and habitual vitamin D intake within the study population groups and heterogeneity of study designs. The expert group concluded that there was evidence of a protective effect of vitamin D for bone health, total mortality and risk of falling, especially when basal serum 25(OH)D concentrations were low. Vitamin D combined with calcium rather than vitamin D alone was reported to lead to these benefits in most of the reviewed intervention studies. The optimal serum 25(OH)D concentration was deemed most likely to be ≥50 nmol/l and dose–response studies indicated that an intake of 10 μg/day vitamin D would probably be required to meet this. To cover 97.5% of the population, two standard deviations were added, resulting in an intake requirement of 15 μg/day. It should be noted that these values are based upon studies conducted in winter, with no sunlight exposure, and that the requirement is probably less in summer. In addition, dose–response is dependent upon basal concentrations, sunshine exposure and habitual dietary intake. The publication of the expert group's conclusions (Lamberg-Allardt et al. 2013) was closely followed by the NNR 2012, which recommended an intake of 10 μg/day for infants (<2 years), children and adults (3–74 years) and 20 μg/day for older adults (≥75 years) (NNR 2014). Professor Susan Lanham-New (University of Surrey) presented recent findings from studies investigating vitamin D status in the UK and the effect of fortification on vitamin D status and bone health. The Vitamin D, Food Intake, Nutrition and Exposure to Sunlight in Southern England Study (D-FINES) was set up to investigate the effect of the interaction between diet and sunlight exposure on vitamin D status and markers of calcium metabolism and bone health in South Asian and Caucasian women in southern England. The study found that Caucasian women had consistently higher serum 25(OH)D status compared to South Asian women. Caucasian women were found to have vitamin D insufficiency in late autumn and winter compared to South Asian women who were deficient all year round. This is despite consistent dietary vitamin D intakes between seasons and between ethnic groups (Darling et al. 2013). Vitamin D can be endogenously synthesised via UVB exposure, but only at wavelengths of 290–315 nm. In the UK, this means we can only synthesise vitamin D from sunlight between April and September. It has been previously assumed that the vitamin D synthesised during the summer months helps maintain an adequate supply of vitamin D for the winter. However, the D-FINES, together with a couple of similar notable studies (Cashman et al. 2013; Mavroeidi et al. 2013), challenges that assumption. As dietary intakes of vitamin D are too low in the UK and there are in any case too few foods providing a valuable contribution, fortification could be one way of helping raise vitamin D intakes in the UK and elsewhere. Dietary vitamin D can be found in two forms: ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3). Vitamin D2 is found in some plants and fungi, while vitamin D3 is found in foods such as fish and eggs. Some studies have suggested vitamin D3 to be more effective than vitamin D2 in raising serum 25(OH)D levels, while others have shown no difference. A meta-analysis of supplementation studies has indicated vitamin D3 to be more effective than vitamin D2 at raising serum 25(OH)D, but most studies used relatively high doses and were insufficiently powered (Tripkovic et al. 2012). The D2 – D3 Study, currently funded by the Biotechnology and Biological Sciences Research Council's Diet and Health Research Industry Club (BBSRC-DRINC), compares the effect of modest vitamin D2 and vitamin D3 fortification (in solid and liquid formats) on serum 25(OH)D concentrations in Caucasian and Asian women. The study, the largest of its kind, will also explore the mechanisms of action and common genetic variants affecting serum 25(OH)D concentrations. Published results are anticipated shortly and will help to inform both the food industry and the scientific community on the effectiveness of fortification and the mechanism of any differences found. Vitamin D intake and fortification was discussed further by Dr Mairead Kiely (University College Cork). She started by highlighting that substantial portions of the world's population rely upon dietary sources of vitamin D to maintain nutritional adequacy all year round, especially in populations residing at latitudes greater than 40° north or south of the Earth's equatorial plane (at latitudes greater than 40°, there is limited exposure to the UVB wavelength needed for endogenous vitamin D synthesis). However, the prevalence of vitamin D deficiency is high and deficiency can impair healthy growth and development and maintenance of health during ageing. Dr Kiely stated that public health strategies to prevent vitamin D deficiency are hindered by fundamental knowledge gaps. Dietary recommendations are established based upon the best available information at the time. Surveillance within a population can help to assess population serum 25(OH)D levels, vitamin D intake and sun exposure, as well as the prevalence of vitamin D deficiency and inadequacy. However, the links between intake and status and status and health outcome are not currently well defined. For example, data on the dose–response of serum 25(OH)D to vitamin D intake are limited, especially in infants, children, adolescents and pregnant women, making recommendations in these population groups more difficult. However, these links will hopefully become more defined as new research emerges. A recent dose–response study in infants found that 55% of infants receiving 10 μg/day of vitamin D had 25(OH)D levels above 75 nmol/l and this increased to 80–100% for infants on higher doses (20, 30 and 40 μg/day). In all groups, 97% of infants achieved 25(OH)D levels of 50 nmol/l or higher at 3 months. In addition, growth and bone mineral content was not found to differ by dosage (Gallo et al. 2013). Interestingly, a study in Montreal (latitude 45° north) found that although 95% of 2–5 year-olds had an intake of vitamin D below the estimated average requirement, vitamin D status was adequate in most of the children [i.e. 89% had 25(OH)D > 50 nmol/l] (El Hayek et al. 2013). Consequently, further research and ongoing surveillance activities are paramount to ascertain vitamin D recommendations within different population groups. Fortification of foods can have a significant impact on vitamin D intakes (Black et al. 2012, 2014; Madsen et al. 2013), especially if the fortification of foods is mandatory, such as in Canada and the Nordic countries (Calvo et al. 2005). Intake of vitamin D is typically around 5–6 μg/day in Canada, compared to ∼2 μg/day in the UK (Whiting et al. 2011), where vitamin D fortification is still voluntary with the exception of full-fat margarine, consumption of which is now relatively low. The VitmaD study in Copenhagen used fortified bread and milk to increase vitamin D intake in a family-based RCT and found deficiency of vitamin D to be prevented with no reported adverse effects. This was achieved through relatively modest intakes of vitamin D within the fortified group of 10 and 8 μg/day in 4–17 year-olds and adults, respectively (Madsen et al. 2013). The risk of individuals reaching the tolerable upper intake level by consuming foods fortified with vitamin D is also very small (Fulgoni et al. 2011). There are currently a number of ongoing research activities aimed at addressing the fundamental knowledge gaps for vitamin D intake and status across Europe. The Vitamin D Standardisation Program aims to improve detection, evaluation and treatment of vitamin D deficiency by improving the accuracy and comparability of serum 25(OH)D measurements over time, location and assessment centre (Sempos et al. 2012). The ODIN Project, a collaboration of 31 partners in 19 European countries, aims to assess the prevalence of vitamin D deficiency, dietary intakes, requirements during pregnancy and childhood, viability of food-based solutions and long-term safety of high serum 25(OH)D levels (ODIN 2014). The supposition is that as the data become richer in these knowledge areas, recommendations for vitamin D will be more easily defined. The topic of early life influences on bone mass and body composition was covered by Dr Nick Harvey (University of Southampton). Osteoporosis-related fractures are a common problem in older adults, especially post-menopausal women, costing Europe around €37 billion (Hernlund et al. 2013). Bone mass increases through pre-natal life and throughout childhood, peaking in early adulthood before slowly decreasing. The loss of bone mass in later years is accelerated in women due to the loss of oestrogen following menopause. The peak bone mass reached in early adulthood predicts the risk of osteoporosis in later life. Factors early in life, such as and body to the peak bone mass reached et al. 2012). factors during pregnancy may also the bone mass and later risk of osteoporosis and fracture of the in later life et al. et al. factors have been in the in which women years were and followed were and the were at and months, with assessment by at 8 and years et al. in of around and such as and during are associated with body composition and bone mass at et al. 2007). bone appears to increase with increasing (i.e. number of to increasing and in late pregnancy et al. 2010). The with vitamin D was in a of the study serum 25(OH)D in late pregnancy was associated with at age years et al. In addition, low serum 25(OH)D was associated with low fat mass at but high fat mass at years of with an fat mass level at years et al. 2012). Interestingly, a recent systematic review also found a significant between vitamin D status and et al. in an low levels of serum 25(OH)D during late pregnancy was found to be associated with reduced body bone mineral content in the at years of age et al. In addition, the of the to be to in who had low levels of serum 25(OH)D compared to those with higher at a more level is typically seen in This suggests that low vitamin D status during pregnancy may the of the the between vitamin D and bone mass may be by calcium concentration and calcium et al. concentration is higher in the compared to the and calcium is via and active It is the active of calcium across the by that has been to be greater of has been associated with greater bone and bone mineral content of the at et al. 2007). although it to be in are thought to be regulated by active form of vitamin in The way in which may of genes could be through is a common if a group is to a it an increase in of of where a occurs to a within the of [i.e. the for the action of with vitamin D has been associated with a decrease in body bone mass of the at an was found between at an and 25(OH)D during late pregnancy et al. or not vitamin D supplementation is for the health of the to be further through studies have shown vitamin D at relatively high to increase serum calcium concentration in the et al. However, these studies are now and further is needed to any health benefits in the which may from vitamin D such study, the Vitamin D Study is currently et al. 2012). women with a serum 25(OH)D within nmol/l were and vitamin D or from the of The outcome being is body bone mass of the at and it is anticipated that these results should be available this can help to factors that can bone mass in early life, for the creation of strategies to help improve the bone mass of children and the risk of osteoporosis in later life. The British Nutrition Foundation is to Europe for this The has no of interest to

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