Ergocalciferol (D2) vs. Cholecalciferol (D3) Food Fortification: Comparative Efficiency in Raising 25OHD Status & Mechanisms of Action (D2-D3 Study)

Lead Research Organisation: University of Surrey
Department Name: Nutrition & Metabolism

Abstract

Vitamin D is the term used to describe two molecules, ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3). The first of these is derived by ultra-violet irradiation of the ergosterol that is widely distributed in plants and other fungi whereas cholecalciferol is formed from the action of ultra-violet irradiation on the skin. Poor vitamin D status is a very common problem in the UK. This has important health consequences (such as muscle/bone function, increasing the risk of diabetes). We urgently need to find ways of improving vitamin D intake that are acceptable as a public health strategy. Research that has just been completed by our group at the University of Surrey (Food Standards Agency funding; Project No. NO5064; £0.5M) has shown that (1) dietary intake of vitamin D is too low to have any effect on vitamin D status as there are too few foods providing a valuable natural source; (2) South Asian women are extremely vitamin D deficient; (3) Caucasians have extensive vitamin D insufficiency. There is evidence in the literature of differences in key polymorphisms of important genes that are critical to vitamin D metabolism in Asian Indian vs. Caucasians aswell as differences in key vitamin D metabolism enzymes. This requires a fuller investigation since there are differences in the availability of vitamin D2 and vitamin D3 and hence public health advice on increasing vitamin D intake (particularly with respect to the development of vitamin D rich food products) needs to confirm that either form of vitamin D is effective. Furthermore, the South Asian community are vegan/strict vegetarians (~26%) and hence the source of vitamin D3 is a problem in this group due to being derived from animals (vitamin D3 supplements come from Lanolin, which is extracted from sheep's wool.) There is currently controversy as to the effectiveness of vitamin D2 vs. D3 in raising 25HOD levels in humans. It has been assumed, largely on the strength of evidence from studies inthe 1930s, that D2 and D3 were equally effective in humans but some studies show that D3 is superior to D2 in raising 25OHD levels whereas the most recently published data suggests that D2 and D3 are equally effective. This requires urgent attention. The proposed study will enable a better understanding of how comparable the two forms of vitamin D (ergocalciferol [D2] vs. cholecalciferol [D3]) are at raising vitamin D status in Caucasians and Asians and investigate the mechanisms of action with respect to any differences observed between the two vitamin D forms or between ethic groups. Mechanisms of action will focus on genetic differences aswell as differences in vitamin D metabolizing enzymes. Using a team of scientists with different expertise, our principal objectives are to: (i) compare the efficiency of 10mcg/d [400IU/d] of ergocalciferol (Vitamin D2) vs. cholecalciferol (Vitamin D3) fortification of food products in raising 25OHD levels in Asian/Caucasian women; (ii) determine which vehicle for fortification (i.e. a SOLID vs. FLUID food) with ergocalciferol (Vitamin D2) vs. cholecalciferol (Vitamin D3) is more effective in raising 25OHD levels, independent of ethnicity; (iii) investigate if 10mcg/d [400IU/d] is effective in raising wintertime 25OHD levels above 'deficiency/insufficiency' thresholds (25nmol/l and 40nmol/l respectively) in Caucasian and Asian women and whether there are any differences in ergocalciferol v. cholecalciferol fortification, independent of ethnicity; iv) investigate the mechanisms (genetic/enzymatic) for the differences observed in (i), (ii) & (iii).

Technical Summary

Growing evidence for the positive effects of vitamin D in reducing risk from disease has increased our awareness of the need for evidence-based strategies to redress the high prevalence of low vitamin D status in the UK. This requirement has special relevance to a multi-cultural Society in which large numbers of important Minority Groups are at significantly increased risk of hypovitaminosis D. While food fortification is a sustainable solution for the prevention of vitamin D deficiency, the Food Industry needs to determine the most effective means of carriage, optimal concentration and chemical form of vitamin D if it is to maximize the effectiveness of fortification. This RCT proposal will provide much needed evidence that will; (a) directly compare the biological effects of vitamin D2 vs. vitamin D3 in fortified foods of different matrices (i.e. a solid vs. liquid food); (b) use a dose of vitamin D that is realistic and relevant to the Food Industry and the RNI (400IU); (c) examine responses in Caucasians and South Asians; (d) explore 'systems' level (genetic/enzymatic) differences in potential responses to vitamin D fortification. We hypothesise that at least some differences in the responses of participants to vitamin D fortification will be attributable to differences in gene expression. The VDR is a nuclear transcription factor which controls expression of a wide range of genes, including several that encode cytochrome P450 enzymes and cytokines. Human leukocytes are known to express the VDR-encoding gene and it is therefore envisaged that differences in vitamin D responses of individuals could be reflected by differences in leukocyte gene expression. We will determine what foods would be the best vehicles for fortification and whether there is a significant difference between the efficiency of fortification with vitamin D2 vs. vitamin D3 in their ability to raise 25OHD levels given that vitamin D intakes are insufficient in the UK throughout the year.

Planned Impact

We have a real nutrition problem in UK Caucasians of reduced vitamin D levels and a current nutrition crisis in UK South Asians of widespread severe hypovitaminosis D. Safeguarding vitamin D levels seriously matters since it is now recognized that almost every tissue and cell in the body has a vitamin D receptor (VDR) and that for those systems to function properly, they require an adequate amount of vitamin D. The growing evidence for the positive effects of vitamin D in reducing risk from disease and all cause mortality has heightened our awareness of the need for evidence-based strategies to redress the high prevalence of low vitamin D status in the UK. From a public-health perspective, increasing dietary intake through vitamin D fortification is ideal as it is likely to reach larger proportion of the population (compared to universal recommendation for vitamin D supplementation). This proposal will significantly benefit the Food Industry by providing them with key information on the most effective means of fortification of products with vitamin D, including data on carriage, optimal concentration and chemical form of vitamin D. This will allow maximization of the effectiveness of food fortification in the future. This proposal will also significantly benefit Caucasian and Asian communities since it will provide them with examples of 'real' foods that can be consumed and which are able to increase their vitamin D levels. This study will be particularly of benefit to our multi-cultural Society in which large numbers of important Minority Groups are so at risk of low vitamin D status.. By exploring both SOLID and LIQUID food vehicles, we can determine potential vehicles for fortification and plan further for future products. For example, if vitamin D could be added to Chapati Flour, this would be likely to have a very significant impact on raising vitamin D levels in Asian communities. This study will also be of great benefit to vegans/vegetarians who find the vitamin D3 form unacceptable for consumption (as supplements or in food fortification) due to it animal origins. This proposal will ofcourse also be of great benefit to the scientific community by exploring the vitamin D2 vs. vitamin D3 food fortification comparisons for the first time in the same study design aswell as the 'systems' level differences (genetic/enzymatic) in potential responses to vitamin D fortification, independent of ethnicity. We will ensure that the results of our study are widely disseminated - at the scientific level through peer-reviewed publications, at the food industry level through published literature in technical documents but also at the population level through our established Caucasian and Asian networks, community talks and community publications (such as health magazines, newspapers and ethnic group newsletters).

Publications

10 25 50

publication icon
Lanham-New S (2016) Vitamin D - has the new dawn for dietary recommendations arrived? in Nutrition Bulletin

publication icon
Lanham-New SA (2016) Vitamin D - has the new dawn for dietary recommendations arrived? in Journal of human nutrition and dietetics : the official journal of the British Dietetic Association

publication icon
Tripkovic L (2012) Reply to HM Macdonald et al in The American Journal of Clinical Nutrition

 
Description We have shown, conclusively, that vitamin D3 is much better than vitamin D2 at raising vitamin D status in the UK white Caucasian and South Asian population groups with a properly conducted randomised controlled trial (RCT) which had adequate statistical power. For over 30 years, the field of vitamin D has thought that it does not matter which form of vitamin D that you give (vitamin D2 being a plant based source and vitamin D3 being an animal derived source).

Choosing which form of vitamin D to use really matters; vitamin D2 is the only form available on prescription in both the UK and the US. Many fortified products in the US are with vitamin D2.

It has been considered in the past that it doesn't matter - indeed the US Institute of Medicine (IOM) panel, in their document for the new US vitamin D requirements published in 2010 and still remaining in place, state that both forms are equally bioavailable as do the National Institutes of Health (NIH). We show, in this largest RCT ever conducted on comparising vitamin D2 with vitamin D3, that vitamin D3 is 50% more efficient than vitamin D2 in raising vitamin D status. This is a key finding for the medical field.

The UK's Scientific Advisory Committee on Nutrition (SACN) has used our results in the new UK Vitamin D Requirements report which was published in July. As noted above, the USA's Institute of Medicine (IOM) - the US equivalent to SACN reported in their documentation that D2 and D3 are the same.

We have shown that if you have a low level of vitamin D, being supplemented with 600IU (the current IOM recommendation for vitamin D) of vitamin D2 per day will not ensure that you are over 50nmol/l for vitamin D status which is the IOM recommendation. However. supplementation with 600IU of vitamin D3 does ensure you being over this 50nmol/l threshold. This is a key finding and has never been shown before.

What is also a most important finding is that vitamin D2 does raise vitamin D levels. From a food fortification point of view, this form of vitamin D, which is from a vegetarian source, is likely to be much more popular.

From our key work, we are able to provide to the food industry how much additional vitamin D2 is required to achieve the same results as for vitamin D3. This is extremely important and relevant work for the food and drink industry in the UK and worldwide.

We have also shown that it does not matter which food or drink vehicle is used for vitamin D fortification. We have proved that vitamin D is heat stable and that it can be contained safely and effectively in a juice matrix and a solid matrix.

Our key work in Ethnic Minorities is critical to ensuring that this population group does not continue to suffer from low vitamin D status. We completed one of the only available food fortification RCT's in South Asian populations. Our results will help drive further public health policies for these ethnic groups.

Our study is one of the largest vitamin D RCTs ever conducted in an incredibly vulnerable group for vitamin D deficiency, namely British South Asians. We show extensive and severe vitamin D longitudinally in the placebo group, showing conclusively that there must be a much greater public health awareness of the problem of vitamin D deficiency in this ethnic group.

We have identified a number of different genetic and metabolic pathways mechanisms for the observed differences in vitamin D2 and vitamin D3. This work is absolutely key as it will help us to start identifying why some individuals are good responders and some individuals are poor responders to increased vitamin D intake.

Finally, our work has been published in the American Journal of Clinical Nutrition (Tripkovic et al. (2017) Am J Clin Nutr. 106(2):481-490. doi: 10.3945/ajcn.116.138693). We have also published a large number of abstracts (n>50) at national and international conferences and picked several key awards as detailed below.
Exploitation Route Our results are key for the Food Industry in helping them provide important information on what is the best form of vitamin D to use in their products, and will provide essential support for future grant application.
Sectors Agriculture, Food and Drink,Education,Environment,Healthcare,Leisure Activities, including Sports, Recreation and Tourism,Government, Democracy and Justice,Pharmaceuticals and Medical Biotechnology

URL http://www.ncbi.nlm.nih.gov/pubmed/28679555
 
Description Our findings have benefited the Food Industry, the Scientific Field and the Public at Large for the following reasons. It has given: (1) a better understanding of how comparable the two forms of vitamin D (ergocalciferol [D2] vs. cholecalciferol [D3]) are in raising 25-hydroxyvitamin D (25OHD) status. It has shown that both forms of vitamin D are effective in raising vitamin D levels but that vitamin D3 (the source derived from animals) is far more effective that vitamin D2 (the source derived from plants) is helping us increase our vitamin D levels in the body. (2) confirmation that it doesn't matter which vehicle for fortification is used (i.e. a SOLID vs. FLUID food) with ergocalciferol (Vitamin D2) vs. cholecalciferol (Vitamin D3). Both a solid food (biscuit) and liquid food (juice) is equally effective for both vitamin D2 and vitamin D3 and this finding is the same in groups of different ethnicity. (3) some new insights into the potential genetic mechanisms of different metabolic pathways to help us answer why some individuals are 'good' responders to increase vitamin D intake and others are 'bad' responders. Our proposed has provided: (i) the UK Food Industry with information on the comparative effectiveness of the two different forms of vitamin D as food fortificants in raising 25HOD levels in UK populations with known 'insufficiency' (Caucasian) and 'deficiency' (Asian); (ii) the Scientific Community with exciting data on the potential mechanisms of action of any such differences in D2 vs. D3 in Caucasian vs. South Asians; (iii) the General Population with examples of how to improve vitamin D intakes through food fortification, particularly Asian groups who are so prone to D deficiency.
First Year Of Impact 2012
Sector Agriculture, Food and Drink,Education,Healthcare,Government, Democracy and Justice
Impact Types Cultural,Societal,Policy & public services

 
Description Final Publication of the new SACN Vitamin D Requirements
Geographic Reach National 
Policy Influence Type Gave evidence to a government review
Impact Public Health England's new Vitamin D Recommendations for Vitamin D were published on the 21st July 2016. This was a publication written by the Scientific Advisory Committee on Nutrition (SACN) and the data from our D2-D3 study was included in the Report as showing conclusively that vitamin D3 is far more effective than vitamin D2. .
 
Description Scientific Advisory Committee on Nutrition (SACN) Vitamin D Requirements
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
 
Description EU FP7
Amount € 6,000,200 (EUR)
Funding ID FP7613977 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 11/2013 
End 10/2017
 
Description Ministry of Defence
Amount £625,000 (GBP)
Funding ID D-SAF 
Organisation Ministry of Defence (MOD) 
Sector Public
Country United Kingdom
Start 12/2014 
End 11/2019
 
Description Ministry of Defence
Amount £500,000 (GBP)
Organisation Ministry of Defence (MOD) 
Sector Public
Country United Kingdom
Start 01/2014 
End 12/2016
 
Description Science Without Borders PhD Studentship
Amount £150,000 (GBP)
Organisation Government of Brazil 
Department Science without Borders
Sector Public
Country Brazil
Start 07/2015 
End 06/2019
 
Description British Nutrition Foundation: Half Day Symposium on Vitamin D 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact On 20 May 2014, BNF held a half day symposium to discuss Vitamin D: Needs, Intake and Status - A European Perspective, where experts reviewed the current evidence base on Vitamin D, provided an update on European wide intake, status and recommendations, and looked at the role and type of fortification and the importance of maternal intake.

Professor Susan Lanham-New was invited to present on the topic of 'Vitamin D2 and Vitamin D3: Are they one and the same?'. This event, and Professor Lanham-New's presentation, generated excellent discussions and subsequent requests for further information after the event.

After the event I got requests for several PhD students to come and visit the labs and I was asked to present further talks to industry
Year(s) Of Engagement Activity 2014
URL https://www.nutrition.org.uk/bnfevents/pastevents/vitamind.html
 
Description International Women's Day 2012 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact The Surrey Team (Prof Sue Lanham-New, Dr Laura Tripkovic, Dr Kath Hart and Louise Wilson) hosted a 'Surrey Vitamin D Research Team' stall at the International Women's Day event in Woking. At this event we were able to raise awareness about vitamin D and associated health risks, as well as recruit participants for the D2-D3 Study.
Year(s) Of Engagement Activity 2012
 
Description Maybury Centre Recruitment Presentation, Dec 2012 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact The Surrey Team (Prof Sue Lanham-New, Dr Laura Tripkovic, Dr Kath Hart and Louise Wilson) gave a presentation to local South Asian women at the Maybury Centre in Woking in Dec 2012. This presentation was aimed at advising these women about the importance of vitamin D and the association health risks within their population, as well as recruiting participants onto the D2-D3 Study.
Year(s) Of Engagement Activity 2012
 
Description Maybury Centre Recruitment Presentation, Jan 2012 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact The Surrey Team (Prof Sue Lanham-New, Dr Laura Tripkovic, Dr Kath Hart and Louise Wilson) gave a presentation to local South Asian women at the Maybury Centre in Woking in Jan 2012. This presentation was aimed at advising these women about the importance of vitamin D and the association health risks within their population, as well as recruiting participants onto the D2-D3 Study.
Year(s) Of Engagement Activity 2012
 
Description Maybury Centre Recruitment Presentation, Oct 2011 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact The Surrey Team (Prof Sue Lanham-New, Dr Laura Tripkovic, Dr Kath Hart and Louise Wilson) gave a presentation to local South Asian women at the Maybury Centre in Woking in October 2011. This presentation was aimed at advising these women about the importance of vitamin D and the association health risks within their population, as well as recruiting participants onto the D2-D3 Study.
Year(s) Of Engagement Activity 2011
 
Description Maybury Centre Results Presentation, 2014 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact We organised an event at the Maybury Centre in Woking, for the local South Asian communities, to present the overall D2-D3 Study results. We had great discussions with the local communities about the importance of achieving optimal vitamin D levels.
Year(s) Of Engagement Activity 2014
 
Description Nutrition Society Summer Meeting 2013: BBSRC Satellite Symposium 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Prof Susan Lanham-New was invited to present a summary of our BBSRC DRINC funded project: Ergocalciferol (D2) vs. Cholecalciferol (D3) Food Fortification: Comparative Efficiency in Raising 25OHD Status & Mechanisms of Action (D2-D3 Study), alongside a few other selected projects.
Year(s) Of Engagement Activity 2013
URL http://www.nutritionsociety.org/sites/www.nutritionsociety.org/files/BBSRC%20satellite%20session%201...
 
Description Participant Results Dissemintation Event 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Study participants or study members
Results and Impact We hosted a study results dissemination event, to share the D2-D3 study results with the participants.
Year(s) Of Engagement Activity 2017
 
Description Queen Elizabeth Park Summer Fayre 2012 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact The Surrey Team (Prof Sue Lanham-New, Dr Laura Tripkovic, Dr Kath Hart and Louise Wilson) hosted a 'Surrey Vitamin D Research Team' stall at the Queen Elizabeth Park Summer Fayre. At this event we were able to raise awareness about vitamin D and associated health risks, as well as recruit participants for the D2-D3 Study.
Year(s) Of Engagement Activity 2012
 
Description Shah Jahan Mosque, Eid Fayre 2012 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact The D2-D3 Study Team (Prof Sue Lanham-New, Dr Laura Tripkovic, Dr Kath Hart and Louise Wilson) were invited to host a 'University of Surrey Vitamin D Research Team' stall at the Eid Fayre at the Shah Jahan Mosque in Woking, in August 2012. At this event we were not only able to recruit local participants on to the D2-D3 Study, but we were also able to promote the important of vitamin D, particularly among the local South Asian communities.
Year(s) Of Engagement Activity 2012
 
Description Surrey County Council's Public Health Reflections Session 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact The team were invited to present the D2-D3 Study main results at one of Surrey County Council's Public Health reflections Sessions in Sept 2015. This was attended by public health staff from the Surrey area.
Year(s) Of Engagement Activity 2015
 
Description Surrey Heath Muslim Association, Eid Event 2012 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact The D2-D3 Study Team (Prof Sue Lanham-New, Dr Laura Tripkovic, Dr Kath Hart and Louise Wilson) were invited to host a 'University of Surrey Vitamin D Research Team' stall at the Eid Fayre at the Surrey Health Muslim Association's Eid Event in Camberley, in September 2012. At this event we were not only able to recruit local participants on to the D2-D3 Study, but we were also able to promote the important of vitamin D, particularly among the local South Asian communities.
Year(s) Of Engagement Activity 2012
 
Description Surrey Minority Ethnic Forum/Surrey Community Action 'Eat Well: Live Well' Event, 2012 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact The Surrey Team (Prof Sue Lanham-New, Dr Laura Tripkovic, Dr Kath Hart and Louise Wilson) hosted a 'Surrey Vitamin D Research Team' stall at the Surrey Minority Ethnic Forum/Surrey Community Action 'Eat Well: Live Well' Event in Redhill in April 2012. At this event we were able to raise awareness about vitamin D and associated health risks, as well as recruit participants for the D2-D3 Study.
Year(s) Of Engagement Activity 2012
 
Description Vitamin D Research Team Twitter Page 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact We created a Twitter page for the 'Vitamin D Research Team' at the University of Surrey. This unable us to promote the D2-D3 Study during the recruitment phase, but to also discuss ongoing research our promote the D2-D3 Study results.
Year(s) Of Engagement Activity 2012,2013,2014,2015,2016
 
Description Vitamin D and Bone Health Talk to South London Muslim Women 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Key talk to South London South Asian women on the importance of vitamin D and the dietary factors affecting bone health
Year(s) Of Engagement Activity 2017,2018
 
Description Woking Summer Festival 2012 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact The Surrey Team (Prof Sue Lanham-New, Dr Laura Tripkovic, Dr Kath Hart and Louise Wilson) hosted a 'Surrey Vitamin D Research Team' stall at the Woking Summer Festival. At this event we were able to raise awareness about vitamin D and associated health risks, as well as recruit participants for the D2-D3 Study.
Year(s) Of Engagement Activity 2012