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FP7

ODIN Report Summary

Project ID: 613977
Funded under: FP7-KBBE
Country: Ireland

Periodic Report Summary 2 - ODIN (Food-based solutions for Optimal vitamin D Nutrition and health through the life cycle)

Project Context and Objectives:
ODIN (Food-based solutions for optimal vitamin D nutrition and health through the life cycle www.odin-vitd.eu) is a 4-year integrated project, which commenced in November 2013. The Cork Centre for Vitamin D and Nutrition Research at University College Cork, Ireland is leading the ODIN consortium of 31 partners from 19 countries.

Vitamin D has simultaneously captured the attention of the public, the scientific and medical communities, regulatory agencies and the food industry. While there are many controversies in relation to vitamin D requirements and its impact on human health, it is generally agreed that prevention of vitamin D deficiency is a public health priority, for prevention of nutritional rickets and osteomalacia, which have severe and lasting consequences for bone growth and skeletal integrity throughout life. While data showing associations between vitamin D and non-skeletal disorders are abundant, the evidence base to support its role in prevention of non-bone related disorders is currently less robust. Nonetheless, public health authorities are now aware of the importance of preventing vitamin D deficiency, which was until recently an unacknowledged health problem.

The major source of vitamin D in humans is sunshine; ultraviolet B (UVB) radiation stimulates skin synthesis of cholecalciferol (vitamin D3), which is stored in adipose tissue or metabolised in the liver to 25-hydroxyvitamin D [25(OH)D], the biomarker of vitamin D status, and further metabolised in the kidney to calcitriol, the biologically active metabolite. The most extensively documented function of vitamin D is regulation of serum calcium and phosphate homeostasis, a critical component of normal skeletal mineralisation throughout the growing years and during the ageing process.

Several environmental factors, such as latitude and prevailing weather conditions, determine the availability of sunshine of sufficient strength to stimulate skin synthesis of vitamin D. Personal attributes, such as skin pigmentation, age, attire, sunscreen, working environment, physical activity and sun exposure behaviour can also prevent or impede vitamin D synthesis. Substantial portions of the European population, including all who reside at latitudes greater than around 40oN rely on body stores and vitamin D in the diet to maintain healthy vitamin D status all year round. As much of Europe experiences 4-6 winter months during which UVB availability is too low to permit cutaneous synthesis of vitamin D3, dietary supply is critical to meeting population requirements. Thus, a sizeable proportion of the school-aged and working population, as well as the more widely acknowledged older adult demographic is at risk of low vitamin D status.

Vitamin D does occur in the diet, both naturally, as an added nutrient for fortification and in nutritional supplements. However, vitamin D intakes are typically low, as it occurs naturally in few foods and in low concentrations and the dietary supply is currently unable to offset the seasonal sunshine deficit. Nutritional supplements contribute a high proportion of vitamin D intake among users, however supplement uptake is too low to make it viable for deficiency prevention across the population. Despite much scientific research in vitamin D, there are still many fundamental gaps in the field from the public health perspective and these impede the development of strategies for prevention of vitamin D deficiency. ODIN aims to address some of these gaps.

The overall objective of ODIN is to develop effective, safe and sustainable solutions to prevent vitamin D deficiency and improve vitamin D related health outcomes using a food-first approach. We have adopted a triage approach to selecting the most critical issues for attention.

Prioritised Questions

Exposure
• What is the actual prevalence of vitamin D deficiency in Europe and how do countries compare with each other and the rest of the world?
• What is the distribution of vitamin D intake in Europe?
• How will increasing vitamin D in the food supply affect this distribution and reduce the prevalence of inadequate intakes?
• What is the potential contribution from UVB to circulating 25(OH)D across the European latitude gradient (~35-70oN).
• What is the dose-response of 25(OH)D to UVB at habitual or everyday skin exposure levels?

Food-based strategies to meet dietary requirements for deficiency prevention
• What changes in the food supply will increase population intakes of vitamin D sufficiently to modify the distribution of 25(OH)D and prevent deficiency?
• How can we harness technological advances in food production and animal nutrition to increase vitamin D in the food supply with consideration for dietary diversity and local preferences?

Nutritional requirements for vitamin D?
• What are the dietary requirements during pregnancy, childhood and adolescence to prevent vitamin D deficiency?
• What is the impact of ethnicity on dietary requirements for vitamin D in adults?

Health and safety
• Are associations between 25(OH)D and non-skeletal health in adults independent of pre-existing risk, body composition, co-morbidities and compromised nutritional status and possible modulation by genetic variation ?
• Are associations between vitamin D and perinatal outcomes robust in well-powered, prospective, clinically validated, disease-specific pregnancy and birth cohorts?
• Does vitamin D status modulate physical growth and development in early life?
• Are high vitamin D intakes and serum 25(OH)D concentrations safe in the long-term?

Project Results:
Work package 1 on ‘Vitamin D status: distribution of standardized serum 25(OH)D concentrations in European populations’ was completed on schedule (month 18) and successfully applied the international Vitamin D Standardization Program (VDSP) protocols to existing serum 25(OH)D data from 14 representative childhood/teenage (8) and adult/older adult (6) European populations, representing a sizeable geographical footprint and a total sample size of 55,844, to quantify the prevalence of vitamin D deficiency in Europe.

The first internationally comparable dataset of vitamin D status was published in the American Journal of Clinical Nutrition in 2016 (open access at http://www.ncbi.nlm.nih.gov/pubmed/26864360 and described “An overall pooled estimate, irrespective of age group, ethnic mix, and latitude of study populations, of 13.0% of the 55,844 European individuals had serum 25(OH)D concentrations <30 nmol/L on average in the year, with 17.7% and 8.3% in those sampled during the extended winter (October-March) and summer (April-November) periods, respectively. According to an alternate suggested definition of vitamin D deficiency (<50 nmol/L), the prevalence was 40.4%. Dark-skinned ethnic subgroups had much higher (3- to 71-fold) prevalence of serum 25(OH)D <30 nmol/L than did white populations”. The concerning magnitude of the deficiency estimates, from a public health perspective, attracted an accompanying editorial in the AJCN which highlighted the importance of the data. In addition, and of key relevance to ODIN, the authors of the editorial suggest that ‘because food fortification is deeply lacking within the EU, we suggest that future work, which may lead to realistic and actionable public health policies, should focus on determining the most effective fortification strategies to meet requirements for vitamin D among community-dwelling Europeans’.

Conscious of the quality and importance of these data and taking the point from the expert reviewer for the First ODINPeriodic Report (i.e., ‘..the public in Europe should hear about their own situation in relation to vitamin D status and the ODIN website could be used to provide them with some key information’), we decided we would establish an online European Vitamin D Deficiency Map. This map, generated by the Cork Centre for Vitamin D and Nutrition Research presents data on standardized serum 25(OH)D from ODIN as well as a number of other projects in which UCC and the Office of Dietary Supplements at NIH, who lead the Vitamin D Standardization Program (VDSP), together with several collaborating European partners, have applied protocols for standardizing 25(OH)D data in a number of important European population studies. These new data are presented in summary and very user-friendly format in this new interactive map available at: http://www.odin-vitd.eu/public/7-european-vitamin-d-deficiency-map/. The map has been disseminated widely.

Other outcomes from WP1 were:
• Younger children (age ranges, 1-6 and 7-14 years) were at much lower risk of vitamin D deficiency, with a prevalence of ~4 to 7% with serum 25(OH)D <30 nmol/L compared to 12-40% among teenage study populations (age range, 15-18 years).
• Older adults (>61/70 years) had a relatively lower annualized prevalence of vitamin D deficiency (4.6 to 8.4%) than younger adult samples (age range 18-64 years) with 9 to 24%. The exception was Tromsø, Norway where the adult sample had a very low prevalence (0.9%).
• While the seasonal amplitude was variable among study populations, the prevalence of serum 25(OH)D <30 nmol/L was generally higher in the extended winter (Nov-March) period than extended summer (April-Oct).
• The Maamu Finnish ethnic adults had a high annualized prevalence of serum 25(OH)D <30 nmol/L at 28.5% collectively, and 4.5, 28.0 and 50.4% for Russian-speaking, Somali and Kurdish immigrant subgroups resident in Finland, respectively. While the sample size was limited relative to the analysis among white-skinned samples, this much higher prevalence of vitamin D deficiency in dark-skinned ethnic subgroups was evidenced in other WP1 EU populations. Quality biobanks with well-characterised data in ethnic population groups in the EU are urgently required.
• The average annualized prevalence of vitamin D deficiency in studies of populations, irrespective of age-grouping, residing at ≤47oN, 48-60oN and >60oN was 8.1, 11.0 and 12.3%, respectively.
• Collectively, gender differences in prevalence of vitamin D deficiency within the collection of ODIN WP1 population studies were minor compared to ethnic and age-grouping differences
• Based on the systematic literature review on vitamin D status in the CEEC, no nationally representative datasets were identified that could be used to conduct analysis of appropriately phenotyped and curated biobanks using the ODIN-‘VDSP Europe’ analytical platform.
• From the literature, it could be concluded that 25(OH)D levels are on average below 75 nmol/L and <50 nmol/L in adults in winter in most studies in CEEC (based on data from Bulgaria, Estonia, Hungary, Lithuania, Poland, Serbia, Ukraine). No studies on vitamin D status were found for Albania, Bosnia and Herzegovina, and Macedonia.
• Data are very limited for children, adolescents, pregnant women and the elderly in CEEC.
• The results from the systematic literature review of studies from Southern European countries were indicative of a considerably high heterogeneity of published evidence regarding 25(OH)D levels and vitamin D status among southern European countries. More than one-third of studies identified by the systematic literature review reported mean 25(OH)D levels <50 nmol/L (i.e. threshold of vitamin D deficiency) and approximately 10% of studies reported mean 25(OH)D levels <25 nmol/L (i.e. threshold of severe vitamin D deficiency).
• Regarding the audit of available quality bio-banks in southern European countries, serum and/or plasma samples were identified for a total number of 22,346 subjects aged 10 years and older from four countries in southern Europe (France, Greece, Italy and Spain) as well as from Israel and Turkey.
Work package 2 on Dietary exposure and modelling for food fortification was completed during the 2nd reporting period (month 30). Development of the ODIN-EUROFIR vitamin D food composition database had been finalised in the first reporting period and these data have been widely disseminated. In the 1st period we also described the first harmonised, validated vitamin D intake data in 10 nationally representative surveys from 4 EU countries and reported intakes of 3-5 μg/d in the UK, Denmark, the Netherlands and Ireland with 77-100% of people at risk of inadequate vitamin D intakes. Some traditional sources of vitamin D, such as eggs, were still important, while others such as oily fish, made a limited contribution due to low consumption levels in most countries, particularly among children.

In WP2, we developed and validated of a novel ODIN system for progressing step-wise dietary modelling of food fortification scenarios, based on data from WP5, and completed these analyses in the 2nd period (month 19-30). Data from incremental and combined dietary modelling experiments in 10 nationally representative surveys in 4 EU countries showed that proposed combined ODIN fortification and enhancement strategies, including milk, eggs, cheese and meat achieve desired population intakes and distributions of vitamin D, relative to the EAR of 10 μg/day/d, without increasing the risk of excessive intakes. Supplemental doses exceeding 25 μg/day in children and 50 μg/day in adults were associated with risk of exceeding the age-specific ULs.

In general, we confirmed that current levels of vitamin D fortification are low and to date, no EU country other than Finland has taken a strategic approach to fortification, which limits its benefit. There is currently no evidence of excessive intakes of vitamin D across the 10 surveys in the four countries we studied.

Variable estimates of vitamin D intakes from a systematic review of CEEC showed very low intakes of vitamin D, which is probably a function of the dietary assessment method and food composition data available, but no survey was identified to contribute to the ODIN databank. There is an urgent need for quality dietary survey data in CEEC countries.

The analysis of ethnic and traditional foods in ODIN confirmed that targeted approaches to designing food fortification strategies were required for ethnic subgroups. Potentially useful foods are baked goods and vegetable oils. However, contemporary intake data are urgently required among ethnic subgroups to perform dietary modelling experiments as these are currently not available or insufficiently small datasets.

Work package 3 (Sunlight exposure: risk-benefit analysis) has successfully developed and validated the two planned European case-study integrated models of sun-diet-25(OH)D and has demonstrated their utility in predicting population serum 25(OH)D distributions arising from changes in vitamin D intake, accounting for solar UVB-derived sources. The first model was developed for Ireland and this has recently been published in the Journal of Nutrition. The second model, which was for the UK, was a more complex model as it had to take account of the fact that unlike the Irish population, the UK population is an ethnically mixed one (consisting of ~90% white and ~10% black and Asian minority ethnic individuals, based on recent census data). Our modelling used key data from UVB observational and interventional studies in Manchester, UK to inform the design of the dark-skinned model component, which was then successfully integrated with that for the white populatoon to generate an overall model. This was validated against standardized serum 25(OH)D in the nationally representative National Diet and Nutrition Survey – 4 year rolling programme in the UK (generated in WP1). Data from WP2 (above) will be used in the two models in terms of predicting population serum 25(OH)D distributions arising from changes in vitamin D intake arising from food-based solutions for prevention of vitamin D deficiency, while accounting for solar UVB-derived sources.

The sun exposure trial (at 12-14% skin area exposure) within WP3, which explored the response of serum 25(OH)D to UVB exposure in a controlled human study with artificial UV light to provide data to test whether simulated summer UVB exposure level of public health relevance, was also successfully completed in 55 volunteers. The results show that exposure of hands, forearms and face only to simulated Manchester summer sunlight in white Caucasian adults produces a small but significant increase in circulating serum 25(OH)D. This resulted in over three-quarters with serum 25(OH)D concentrations above a deficiency cut-off (30 nmol/L) but only about one quarter of the volunteers achieving circulating 25(OH)D ≥50 nmol/L, reflective of vitamin D adequacy. These findings are important in terms of informing the impact of summer sunlight exposure on vitamin D status.

WPs (4 and 6) Dietary requirements for Vitamin D in under-researched population subgroups are ongoing. The 3 dose-response RCTs to establish the dietary requirement for vitamin D in children, adolescents and ethnic adults have been completed and of these studies, two primary publications are under review. The 4th study in pregnant women is ongoing and will report in early 2017. The food-based RCT among white Danish and South Asian women in Copenhagen is completed and sample and data analysis are under way.
The three major outcomes of WP4 to date from the RCTs in children, adolescents and women of East African descent are:
• Intakes of 8 and 20 µg/day, respectively, are needed to ensure that nearly all white 4-8 year-old children avoid vitamin D deficiency (serum 25(OH)D < 30 nmol/L) and ensure adequacy (serum 25(OH)D ≥ 50 nmol/L) during winter at Northern latitudes.
▪ Intakes of 10 and 23 µg/day, respectively, are needed to ensure that nearly all white 14-18 year-old adolescents avoid vitamin D deficiency (serum 25(OH)D < 30 nmol/L) and ensure adequacy (serum 25(OH)D ≥ 50 nmol/L) during winter at Northern latitudes.

▪ Dietary requirements for vitamin D are significantly higher in women of East African descent than in women of Finnish descent. Intakes of 6.4 µg/day and 21.5 µg/day were required to ensure prevention of vitamin D deficiency (serum 25(OH)D < 30 nmol/L) among women of Finnish and East African descent, respectively.

The animal and human studies in WP5 focussed on food and food-technology-based solutions for prevention of vitamin D deficiency have all been completed in line with the DOW, with the exception of one delayed subtask. The new data from these WP5 studies on UVB-exposed mushrooms and bakers’ yeast as well as vitamin D-fortified, low-fat, cheese have been published, and the work on meats, fish and eggs is in preparation for publication. The investigation of the potential advantages and limitations of use of UVB-exposed mushrooms and bakers’ yeast food-based solutions for prevention of vitamin D deficiency has clearly shown that from a technological perspective dramatic increases in the content of vitamin D2 in the food produce is feasible, but evidence of their efficacy in terms of raising serum 25(OH)D is more mixed. The vitamin D2 in the UVB-exposed yeast survived baking and was confirmed analytically in the resulting bread, but it did not induce an increase in serum 25(OH)D in subjects who consumed the bread over 8 weeks of winter in Finland as part of one of our ODIN WP5 RCTs (paper published in British Journal of Nutrition). It is likely the vitamin D2 was not bioavailable to transit the intestine into the circulation. Likewise, despite an increase in vitamin D2 content of UV exposed mushrooms, their effect on serum 25(OH)D in available RCTs is very variable. The meta-analysis performed in WP5 suggested that individuals with lower vitamin D status may get the benefit, but potentially not this with higher vitamin D status (paper published in Journal of Nutrition), although this should be confirmed experimentally. The feeding studies in pigs, cattle, and farmed fish within WP5 exploring the potential of biofortification (enhancement via inclusion of additional vitamin D and/or 25-hydroxyvitamin D [in the case of fish] in feedstuffs) demonstrated that small to moderate increases in the total vitamin D activity of the resulting meats/fish flesh are achievable. Finally, the second dedicated food-based RCT in WP5, which aimed to provide proof of effectiveness of a novel, vitamin D-fortified food, showed that consumption of 60 g of vitamin D3 enriched, reduced-fat Gouda type cheese (providing a daily dose of 5.7 μg of additional vitamin D3) was effective in increasing mean serum 25(OH)D concentration and in counteracting of vitamin D deficiency during winter months in postmenopausal women in Greece. This paper will soon appear in the European Journal of Nutrition. These data informed the modelling experiments WP2 and 3.

The WPs on Health outcomes in pregnancy and early life (WP7) and older adults (WP8) have made significant progress and will be the focus of the 3rd periodic report. The first paper from Task 7.1, based on analysis of the SCOPE Ireland pregnancy cohort, has been published and will form the blueprint for the integrated WP7 analysis in pregnancy cohorts. This was the first report of CDC-accredited 25(OH)D data and pregnancy outcomes from a large, clinically validated prospective cohort study. In 1786 women who participated in the SCOPE Ireland pregnancy study, we reported a prevalence of vitamin D deficiency (serum 25(OH)D < 30 nmol/L) of 17%. We observed a protective association of having a 25(OH)D concentration >75 nmol/L with a reduced risk of uteroplacental dysfunction, indicated by a composite outcome of small for gestational age and pre-eclampsia.

WP8 has submitted the first IPD meta-analysis using standardized measurement of 25(OH)D for publication. In almost 27,000 participants (median age 61•6 years, 58% females) with a median 25(OH)D concentration of 53•8 nmol/L, we reported adjusted hazard ratios (with 95% confidence interval) for mortality in the 25(OH)D groups with 40 to 49•99, 30 to 39•99, and <30 nmol/L of 1•15 (1•00–1•29), 1•33 (1•16–1•51), and 1•67 (1•44–1•89), respectively, compared to participants with 25(OH)D concentrations of 75 to 99•99 nmol/L, over a median follow-up time of 10•5 years. We observed similar results for cardiovascular mortality, but there was no significant association between 25(OH)D and cancer mortality. On the basis of this association between low 25(OH)D and increased risk of all-cause mortality, it is of public health interest to evaluate whether treatment of vitamin D deficiency prevents premature deaths.

The ongoing safety monitoring as part of ODIN’s WP9 safety dossier shows that the occurrence of high serum 25(OH)D or hypercalcaemia in either the population based studies or in the intervention studies is extremely low.

Potential Impact:
To date, ODIN has delivered:
• The first internationally comparable estimates of vitamin D status and prevalence of deficiency in European populations across the life span.
• Population distributions of vitamin D intake following modifications to the dietary supply of vitamin D by mathematical modelling of food consumption and food composition data.
• Novel technologies and food products to increase the vitamin D supply in food using bio-fortification of meat, fish, eggs, mushrooms and yeast with data on efficacy of these food-based solutions from human intervention studies in diverse population groups.
• Data from 3 new RCTs to estimate dietary requirements for vitamin D during childhood and adolescence and in dark-skinned immigrants, resident at Northerly latitude

In the 3rd and final reporting period, ODIN will
• Integrate sun exposure and dietary modelling data to predict changes in serum 25(OH)D following implementation of food-based strategies to increase vitamin D in the food supply.
• Conduct trial and patient-level meta-analyses to clarify conflicted associations between vitamin D and health outcomes in pregnancy, childhood [allergic disease, bone development and body composition] and ageing adults [premature mortality, cardiovascular disease and mental health]
• Maintain a watching safety brief over all activities with respect to exposure, status and health outcomes (WP9)
• Translate knowledge for industry and regulatory stake-holders, the medical and scientific communities and citizens using interactive technology transfer in WP10

These outcomes will have major societal impact by preventing vitamin D deficiency, which is a global problem with far-reaching consequences for human health, and will promote normal childhood development and healthy aging. The socio-economic impact is considerable, as evidenced by the involvement at no cost to the project and considerable benefit-in-kind for the ODIN budget, of 5 large food and nutrition companies, who have already identified opportunities for product innovation.

The ODIN concept is based on the hypothesis that increasing vitamin D intake moderately across the population intake distribution, using a combination of bio-fortification and nutrient addition, will generate increases in serum 25(OH)D concentrations that are sufficient to effectively prevent vitamin D deficiency. We have now demonstrated that this commodity-based strategy, including both fresh and processed foods in several food groups, ensures widespread coverage of the population and minimizes the risk of excessive exposure at the top end of the intake distribution, thereby ensuring safety and safeguarding human health.

We consider it a core obligation of ODIN to provide reliable evidence on which the EFSA and other regulatory authorities can base decisions that have direct impacts for European citizens. We are continuously generating data and making these data available to the authorities to enable safe progression of development and implementation of public health strategies for vitamin D deficiency prevention.

List of Websites:
www.odin-vitd.eu

Reported by

UNIVERSITY COLLEGE CORK, NATIONAL UNIVERSITY OF IRELAND, CORK
Ireland
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