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Sakhaei R, Talenezhad N, Mohammadi M, Ramezani-Jolfaie N. Vitamin D Food Fortification is an Effective Approach for Improving Vitamin D Status; A Systematic Review . JNFS. 2019; 4 (2) :126-141
URL: http://jnfs.ssu.ac.ir/article-1-256-en.html
Nutrition and Food Security Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
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Vitamin D Food Fortification is an Effective Approach for Improving Vitamin D Status; A Systematic Review
 
Roya Sakhaei; MSc1,2, Nasir Talenezhad; BSc1,2, Mohammad Mohammadi; MSc1,2 & Nahid Ramezani-Jolfaie; MSc*1,2
 
1 Nutrition and Food Security Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
2 Department of Nutrition, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
 
ARTICLE INFO   ABSTRACT
SYSTEMATIC REVIEW Background: Low vitamin D (vit D) serum levels have been linked to various diseases such as multiple sclerosis, cardiovascular diseases, and diabetes. Maintenance of optimal vit D level should be supported by foods and supplements. Limited food sources of vit D made researchers focus on food fortification in recent years. Methods: A systematic review of randomized controlled trials reporting the impact of vit D food fortification on 25-hydroxy vitamin D [25(OH)D] level was conducted on PubMed, Scopus, ISI Web of Science and Google Scholar from inception up to August 2017. Results: Sixteen studies met the inclusion criteria and most of them (n =14) have represented the significant effect of food fortification on the improvement of vit D status of the participants. However, two studies failed to find any reasonable associations. Furthermore, it was observed that vit D food fortification has a greater impact on the people with lower 25(OH)D serum levels. Conclusions: Fortification of foods with vit D has a significant impact on serum 25(OH)D concentrations. Therefore, food enrichment is an economical and effective approach for different populations to prevent vit D deficiency.
Keywords: Vitamin D; 25-hydroxy vitamin D; 1, 25 dihydroxy vitamin D; Food fortification.
Article history:
Received: 10 Apr 2018
Revised: 18 Jun 2018
Accepted: 14 Aug 2018
*Corresponding author
Ramezani.n.j@gmail.com
Department of Nutrition, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
 
Postal code: 8915173160
Tel: +(98) 3531492136
 
Introduction
V
itamin D (vit D) belongs to the class of fat-soluble steroids that is categorized as two forms; cholecalciferol (vit D3) and ergocalciferol (vit D2) which are derived from animal and plant sources, respectively (Holick, 2007, Jolfaie et al., 2016). Although sunlight exposure is the main source of vit D (Baeke et al., 2007, Singh et al., 2011), access to other sources of vit D through diet is also possible (Holick, 2007, Spiro and Buttriss, 2014).
Natural Sunlight exposure (UV light of wavelength 290-315 nm) can penetrate the epidermis and photolysis 7-dehydrocholesterol to previtamin D3, which is metabolized in the liver after its entrance. Vit D3 is then converted to 25-hydroxy vitamin D [25(OH)D] by 25-hydroxylases in the liver. Subsequently, 1, 25-dihydroxy vitamin D [1,25(OH)2D] is made in the kidneys by 1-hydroxylation of 25(OH)D (Bauer et al., 2013, Spiro and Buttriss, 2014). Although 1,25(OH)2D is the active metabolite of vit D, the plasma concentration of 25(OH)D is the best clinical indicator of vit D status (Runia et al., 2012).
Vit D deficiency is a worldwide concern and presents when serum 25(OH)D levels are below 50 nmol/L (20 ng/ml) (Christodoulou et al.). Dark pigmentation, lack of sufficient sun exposure, wearing clothes covering most of the body, sunscreen use, air pollution, and aging are known as common causes of vit D deficiency (Holick, 2002, Nicolaidou et al., 2006, O’Riordan et al., 2008, Sloka et al., 2009, van der Meer et al., 2006). Additionally, vegetarians and lactose intolerant people are highly at the risk of vit D deficiency (Alharbi and El-Sohemy, 2017, Outila, 2001).
Vit D deficiency adversely affects the health, leading to increased risk for several diseases including rickets in children or osteoporosis in adults, cardiovascular diseases, diabetes, cancer, and autoimmune diseases such as multiple sclerosis (Garland et al., 2006, Garland et al., 2009, Kriegel et al., 2011, Norman et al., 1974, Papandreou and Hamid, 2015, Pierrot-Deseilligny and Souberbielle, 2013, Wagner and Greer, 2008). Therefore, sufficient vit D status plays a major role in the prevention and treatment of various diseases (Holick, 2004, Holick et al., 2011, Jolfaie et al., 2016).
Several studies have suggested that vit D supplementation can increase circulating serum 25(OH)D levels (Björkman et al., 2009, Havens et al., 2012, Todd et al., 2015). In addition to vit D supplementation, food fortification would be advisable to compensate vit D deficiency. Today, food fortification is considered to be a common strategy to improve and combat vit D deficiency. Vit D food fortification is an important and inexpensive strategy to certify the adequacy of vit D intake among populations (Biancuzzo et al., 2010a, Calvo et al., 2004, Upreti et al., 2002).
Vit D3 is typically added to foods such as cheese and yogurt (Al-Khalidi et al., 2015, Green et al., 2010, Johnson et al., 2005, Levinson et al., 2016, Madsen et al., 2013, Neyestani et al., 2012, Rich-Edwards et al., 2011, Wagner et al., 2008), orange juice (Biancuzzo et al., 2010b, Tangpricha et al., 2003, Tripkovic et al., 2017), bread (Itkonen et al., 2016, Natri et al., 2006, Nikooyeh et al., 2016) and mushrooms (Mehrotra et al., 2014, Urbain et al., 2011). The efficiency of vit D2 as a fortificant in raising and maintaining blood concentrations of 25(OH)D is not yet definitively proven (Itkonen et al., 2016, Mehrotra et al., 2014, Urbain et al., 2011). Due to the concern about the changes in cooking and preparation of foods, studies have used several fortification methods including the use of ultraviolet radiation and water-soluble vit D (Biancuzzo et al., 2010b, Mehrotra et al., 2014, Natri et al., 2006, Urbain et al., 2011).
The main purpose of the present systematic review was to evaluate the findings from available studies regarding the effect of food fortification with vit D on serum 25(OH)D levels.
Materials and Methods
Search strategy: A systematic search was performed among the published studies in the following electronic databases: PubMed (www.pubmed.com), Scopus (www.scopus.com), ISI Web of Science (www.isiknowledge.com) and Google Scholar (www.scholar.google.com) from inception up to August 2017. The search was done without restriction on language or publication year,
using the combined MeSH and non-MesSH terms
as follows: (vitamin D, vitamin D2, vitamin D3, vitamin-D2, vitamin-D3, 25-hydroxy vitamin D, 25-hydroxyvitamin D2, 25-hydroxyvitamin D3, 1,25-dihydroxy vitamin D, 1,25-dihydroxy vitamin D2, 1,25-dihydroxy vitamin D3, 25(OH)D, 25(OH)D2, 25(OH)D3, 1,25(OH)2D, 1,25(OH) 2D2, 1,25(OH) 2D3, hydroxycalcidol, 7-dehydrocholesterol, ergosterol, calcitriol, 25-hydroxy cholecalciferol, calcidiol, cholecalciferol, ergocalciferol) AND (“fortified food”, “fortified foods”, “Enriched Food”, “Enriched Foods”, “enriched food”, “enriching food”, “enhanced foods”, “complementary food”).
Broad screening of titles and abstracts were carried out by Talenezhad N and Mohammadi M to exclude irrelevant studies. Discrepancies between reviewers were resolved by the third author (Ramezani-Jolfaie N). In order to look for potential eligible articles and to increase the sensitivity of the search; the references of the retrieved studies were also checked.
Eligibility criteria: The literature that met the following criteria were considered for inclusion in the present systematic review: 1) original articles; 2) randomized controlled clinical trials (RCTs); 3) studies evaluating the effect of fortified foods with vit D on serum 25(OH)D. The studies that did not measure vit D levels, were non-human (in vitro and animal), used fortified food with vit D and another nutrient were excluded from the research. Moreover, the studies that besides vit D food enrichment, had used vit D supplementation were also excluded from the present research since the effect of enrichment could not be controlled separately.
Data extraction: Two reviewers (Talenezhad N, Ramezani-Jolfaie N) independently extracted the data in each study and participant characteristics including the author's last name, publication date, the country in which study was conducted, study design, study duration, number of participants, gender (female/male/both), age (mean or range), type of fortified food, dose, type of vit D, baseline, endpoint and changes in 25(OH)D levels. Data were then tabulated for further evaluations.
Quality assessment: The Cochrane Collaboration's tool for assessing the risk of bias was employed to describe the methodological quality of eligible trials. This tool consists of six domains including random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, and selective reporting. The included studies were classified into three categories: “yes” (low risk of bias), “no” (high risk of bias) or “unclear” (uncertain risk of bias) (Higgins and Green, 2011). The quality of each study was evaluated as good (low risk for more than two domains), fair (low risk for two domains), and weak (low risk for less than two domains).
Results
Study selection and characteristics: A total of 791 articles were retrieved based on electronic data search. After further reading of title and abstract, deduplication and exclusion of irrelevant articles, 44 studies were totally remained for the full-text screening, and 30 articles that met exclusion criteria were dropped out. Eventually, after including two papers through hand search, 16 studies were selected for the present systematic review. The description of the study selection is illustrated in Figure 1.
Table 1 presents the characteristics of the sixteen chosen articles which were published between 2003 and 2017 (Al-Khalidi et al., 2015, Biancuzzo et al., 2010b, Green et al., 2010, Itkonen et al., 2016, Johnson et al., 2005, Levinson et al., 2016, Madsen et al., 2013, Mehrotra et al., 2014, Natri et al., 2006, Neyestani et al., 2012, Nikooyeh et al., 2016, Rich-Edwards et al., 2011, Tangpricha et al., 2003, Tripkovic et al., 2017, Urbain et al., 2011, Wagner et al., 2008). From these articles, eight studies had examined the effect of dairy products fortifications on 25(OH)D (Al-Khalidi et al., 2015, Green et al., 2010, Johnson et al., 2005, Levinson et al., 2016, Madsen et al., 2013, Neyestani et al., 2012, Rich-Edwards et al., 2011, Wagner et al., 2008), three on bread (Itkonen et al., 2016, Natri et al., 2006, Nikooyeh et al., 2016), two on mushrooms (Mehrotra et al., 2014, Urbain et al., 2011) and three on orange juice (Biancuzzo et al., 2010b, Tangpricha et al., 2003, Tripkovic et al., 2017). Four studies were carried out in the United States (Biancuzzo et al., 2010b, Johnson et al., 2005, Mehrotra et al., 2014, Tangpricha et al., 2003), two studies in Canada (Al-Khalidi et al., 2015, Wagner et al., 2008), two in Iran (Neyestani et al., 2012, Nikooyeh et al., 2016), two in Finland (Itkonen et al., 2016, Natri et al., 2006) and one study was conducted in Germany (Urbain et al., 2011), one in Israel (Levinson et al., 2016), one in United Kingdom (Tripkovic et al., 2017), one in Denmark (Madsen et al., 2013), one in Mongolia (Rich-Edwards et al., 2011), and one in New Zealand (Green et al., 2010). All trials were designed as parallel-group studies, and duration of their intervention ranged from two weeks to sixteen weeks.
Risk of bias assessment: The quality assessment of the included articles for all domains of Cochrane risk of bias tool is summarized in Table 2. Most of the studies (n=12) had good quality (low risk for more than 2 items) (Biancuzzo et al., 2010b, Green et al., 2010, Johnson et al., 2005, Madsen et al., 2013, Mehrotra et al., 2014, Neyestani et al., 2012, Nikooyeh et al., 2016, Rich-Edwards et al., 2011, Tangpricha et al., 2003, Tripkovic et al., 2017, Urbain et al., 2011, Wagner et al., 2008), two of them were fair (low risk for 2 items) (Itkonen et al., 2016, Levinson et al., 2016) and others (n=2) were classified as poor quality (low risk for less than 2 items) (Al-Khalidi et al., 2015, Natri et al., 2006). The articles having weak quality score did not report blinding of outcome assessment, allocation concealment, and random sequence generation.
The effect of bread fortification with vit D on 25(OH) D levels: Three studies investigated the effect of fortified bread with vit D on serum 25(OH)D concentrations (Itkonen et al., 2016, Natri et al., 2006, Nikooyeh et al., 2016). Natri et al. (Natri et al., 2006) observed that bioavailability of vit D from both wheat and rye bread is equal, although rye bread contains more fiber. Their three-week investigation emphasized that the consumption of either fortified wheat or rye bread with vit D (12µg/100g) can significantly improve serum 25(OH)D levels in 41 healthy women. In line with their study, Nikooyeh et al. (Nikooyeh et al., 2016) revealed that over longer intervention among 90 healthy men and women who consumed 50 g bread fortified with 25µg vit D for eight weeks, there was a significant raising in the circulation of 25(OH)D concentrations.
Another study assessed the bioavailability of vit D2 from UV-irradiated yeast present in bread during eight-week intervention among 33 young adult females (Itkonen et al., 2016). Participants were divided into four groups with different interventions: placebo pill and regular bread; D2 supplement and regular bread; D3 supplement and regular bread and placebo pill and D2-biofortified bread. The results represented that vit D2 fortified bread (25µg D2/d) modestly increased serum 25(OH)D2, but not as much as vit D supplement (6.4 vs. 31.3 nmol/l, respectively).
The effect of mushroom fortification with vit D on 25(OH)D levels: Two studies assessed the effect of consuming fortified mushrooms with vit D on 25(OH)D changes in the body (Mehrotra et al., 2014, Urbain et al., 2011). Twenty-six young adults with low serum 25)OH(D (≤ 50 nmol/l) and normal serum calcium concentration (2.2-2.7 nmol/l) were enrolled in a randomized, placebo-controlled study to determine the bioavailability of vit D2 from vit D2-enhanced mushrooms by ultraviolet irradiation (Urbain et al., 2011). An experimental soup was made by fresh mushrooms irradiated with a UV-B dose of 1.5 J/cm2, increasing vit D2 content from <1 to 491µg/100g. It was observed that serum 25(OH)D concentrations rose significantly after ingesting 28000 IU of D2/week for four weeks via experimental soup (3.9 nmol/l) vs. supplement (4.7 nmol/l).
Another research was conducted among pre-diabetic individuals, included 43 nonsmoking participants, with at least two features of metabolic syndrome (Mehrotra et al., 2014). Two groups of participants who consumed entrees made by 100 g of UVB-treated mushrooms containing 600 IU D2 or 4000 IU D2 for sixteen weeks had modest or no increase in 25(OH)D2 or total 25(OH)D.
The effect of orange juice fortification with vit D on 25(OH)D levels: Tangpricha et al. (Tangpricha et al., 2003) carried out a study to determine the bioavailability of vit D3 in orange juice and vit D2 in whole milk, skim milk, and corn oil on toast. Eighteen healthy adults were asked to drink 240 ml of whole milk or skim milk that contained 25000 IU ergocalciferol or 25000 IU vit D2 that had been dissolved in 0.1 ml corn oil and applied to toast. After ingestion of fortified whole milk, skim milk and corn oil on toast, there were not any significant changes in blood vit D2 concentrations. However, remarkable differences appeared in blood vit D3 among the participants who consumed fortified orange juice.
In addition, another study was conducted on fortified orange juice with vit D2 and vit D3 (Biancuzzo et al., 2010b). Eighty-six healthy participants were randomly assigned into one of the five groups: 1) placebo capsule + orange juice without vit D, 2) placebo capsule + orange juice containing 1000 IU vit D3, 3) placebo capsule + orange juice containing 1000 IU vit D2, 4)1000 IU vit D3 capsule + placebo orange juice, and 5) 1000 IU vit D2 capsule + placebo orange juice. After eleven weeks of intervention, analysis of the area under the curved demonstrated that the bioavailability of vit D2 and vit D3 in orange juice and capsules were similar and raised 25(OH)D effectively. Also, there were no considerable changes in serum 25(OH)D2 and 25(OH)D3 in the placebo groups, which means that sunlight exposure and diet could not significantly affect the vit D status.
Another research was carried out in 2017 by Tripkovic et al. (Tripkovic et al., 2017) indicating that whether vit D2 or vit D3 added to juice or biscuit is effective in increasing serum total 25(OH)D. The results showed that 335 women who received 15 µg vit D2 or vit D3 added to juice and biscuit for twelve weeks had improvement in their vit D status.
The effect of dairy products fortification with vit D on 25(OH)D levels: Neyestani et al. (Neyestani et al., 2012) carried out a study to determine the effect of vit D fortification either with or without calcium on certain inflammatory markers among 90 Iranian individuals with type 2 diabetes. All subjects were randomly divided into three groups of 1) receiving two 250-ml bottles of Doogh (Persian yogurt drink) per day (PD, containing 150 mg calcium and no detectable vit D3/250ml); 2) vit D-fortified Doogh (DD, containing 500 IU vit D3 and 150 mg calcium/250ml); and 3) calcium + vit D3-fortified Doogh (CDD, containing 500 IU vit D3 and 250 mg calcium/250ml). There was a detectable improvement in vit D status of DD and CDD groups following twelve weeks of intervention. Moreover, inflammatory markers and retinol binding protein-4 concentrations significantly decreased in those groups.
Green et al. also demonstrated that 73 women who consumed fortified milk (5µg vit D3) for twelve weeks had 10 nmol/L higher serum 25(OH)D concentrations compared those consumed the placebo (Green et al., 2010).
In the two researches conducted by Johnson, the bioavailability of vit D from fortified process cheese and its effects on 25(OH)D status in the elderly subjects was assessed (Johnson et al., 2005). One hundred older men and women randomly received 85 g of 600 IU vit D fortified cheese, non-fortified cheese or no cheese during two months of intervention. Unexpectedly, a greater decrease in serum 25(OH)D was observed among the vit D fortified cheese group. The researchers speculate that this decrement may be related to higher baseline serum 25(OH)D concentrations. An additional randomized cross over the trial was also conducted to determine the bioavailability of vit D2 and its absorption from process cheese and fortified water dilution (Johnson et al., 2005). A total sample of eight people, divided into two groups of young and old, randomly received either vit D-fortified cheese or water. Consistent with the results obtained from serial blood sampling collected during 24-hours after the intervention, there was a similar peak in the serum vit D of younger (23 to 50 yr) and older (72 to 84 yr) adults, and vit D2 absorbed more significantly from cheese than from water.
Another study was done by Wanger et al. (Wagner et al., 2008) also investigated the bioavailability of vit D from fortified cheese. Eighty adults were randomly assigned to one of six weekly interventions of: 1) fortified cheddar cheese (DC) (34g, n=20); 2) fortified low-fat cheese (DLF) (41g, n=10); liquid vit D supplement (1ml), taken with food (DS+) (n=20) or without food (DS-) (n=10); placebo cheddar cheese (n=10); or placebo supplement (n=10). Over eight weeks of intervention, in the placebo groups, baseline 25(OH) D levels of 55.0±25.3 nmol/l declined to 50.7±24.2 nmol/l. In the vit D-treated groups, the mean increases in 25(OH)D values were as follows: 65.3±24.1 (DC), 69.4±21.7 (DLF), 59.3±23.3 (DS+) and 59.3 ±19.6 nmol/l (DS-) which presents that fortified cheese boost vit D status as adequately as a supplement, making it a proper choice for vit D fortification.
The other research was performed to assess the bioavailability and safety of vit D3 from fortified mozzarella cheese baked on pizza (Al-Khalidi et al., 2015). The research demonstrated that ingesting 200 IU or 28000 IU vit D3-fortified mozzarella cheese for eight weeks could increase 25(OH)D levels by 5.1± 11 nmol/l in the low-dose group (n=47; P-value=0.003) and by 73±22nmol/l in the high-dose group (n=49; P-value<0.0001).
Levinson et al. (Levinson et al., 2016) also assessed the bioavailability of vit D3 from fat-free yogurt, in re-assembled casein micelles (rCMs) compared to polysorbate-80 (PS80/Tween80) which is commonly used a synthetic emulsifier. Serum 25(OH)D status of participants consuming fat-free yogurt with 50000 IU of either VD3-rCM, VD3-PS8 showed increases of ~ 8 ng/ml after two weeks, and no significant differences were found between mean changes of 25(OH)D among the individuals who consumed rCM yogurt versus PS80.
On the other hand, Madsen et al. (Madsen et al., 2013) investigated the association of fortified milk and bread with vit D status of 782 children and adults. Participants were recruited from 201 families and were randomly assigned to vit D-fortified or non-fortified milk and bread for six months. When comparing from baseline to completion of the intervention, a greater serum 25(OH)D level was seen in the fortification group (67.6 nmol/L) than in the control group (41.7 nmol/L). Similar finding was also reported by Rich-Edwards et al. (Rich-Edwards et al., 2011). There were improvements in 25(OH)D concentrations among 579 children in Mongolia who received 300 IU vit D via fortified milk.














Discussion
The current systematic review was undertaken to evaluate the effect of food fortification with vit D on serum 25(OH)D levels. According to the findings of reviewed studies, vit D food fortification can be an effective and cost-effective approach to provide sufficient 25(OH)D concentrations and reduce the number of people suffering vit D deficiency. It was also observed that vit D3 fortified foods had better efficacy than vit D2 fortified foods. Overally, fourteen studies supported the benefits of food enrichment (Al-Khalidi et al., 2015, Biancuzzo et al., 2010b, Green et al., 2010, Johnson et al., 2005, Levinson et al., 2016, Madsen et al., 2013, Natri et al., 2006, Neyestani et al., 2012, Nikooyeh et al., 2016, Rich-Edwards et al., 2011, Tangpricha et al., 2003, Tripkovic et al., 2017, Urbain et al., 2011, Wagner et al., 2008) and only two studies failed to find reasonable changes as a result of food fortification on serum 25(OH)D levels (Itkonen et al., 2016, Mehrotra et al., 2014). Food fortification with vit D significantly increases serum 25(OH)D levels, helping perpetuation of vit D status among the populations.
Different foods have been suggested to be fortified with vit D, such as milk, mushrooms, bread, and orange juice. Dairy products fortification is very common in the United States, but many people avoid consuming milk due to lactose intolerance and vegetation cause (Gibson, 1994, Pawłowska et al., 2016). On the other hand, there was a concern that low PH of orange juice (~4) would limit stability of added vit D. However HPLC analysis indicated that vit D3 remained unchangeable after storage for 30 days at 4ºC (Tangpricha et al., 2003). Therefore, some researchers have suggested that since bread is the primary food and also available in many countries, it is a good choice for fortification (Mocanu and Vieth, 2013, Natri et al., 2006, Nikooyeh et al., 2016).
Vit D is bioavailable from cheddar, low-fat cheese, whole milk and skim milk and also fat content of milk and its products cannot change the bioavailability (Tangpricha et al., 2003, Wagner et al., 2008). In addition, some studies showed that vit D fortified bread, orange juice and mushrooms improved 25(OH)D status in different population groups (Biancuzzo et al., 2010b, Natri et al., 2006, Nikooyeh et al., 2016, Tangpricha et al., 2003, Urbain et al., 2011). Whereas UVB-activated D2 yeast added to bread did not increase total 25(OH)D concentrations which may be results of low bioavailability of vit D from UVB irradiated yeast in bread (Itkonen et al., 2016). On the other hand, in another RCT, vit D2-UVB-mushrooms did not increase total 25(OH)D which may be attributed to cooking loss and probable low absorption of vit D (Mehrotra et al., 2014).
In addition, the efficacy of vit D fortification varied among the included studies, which might be related to differences in doses, type of vit D, type of food, fortification method, age and baseline vit D status of participants. According to the results of eligible studies, the higher 25(OH)D concentrations were achieved among participants with lower baseline 25(OH)D levels and no differences were reported between men and women (Natri et al., 2006, Tangpricha et al., 2003).
Despite beneficial effects of vit D fortification in the prevention of many diseases, it may cause some serious side effects on human health; consequently, it has limitation of consumption for some individuals. Just as some researchers reported the withdrawal of participants from their studies because of gastrointestinal discomfort, especially those who consumed fortified dairy products (Daly et al., 2006, Johnson et al., 2005, Lau et al., 2001).
The limitations of this systematic review are the lack of information on dietary intake of vit D of the participants,the baseline vit D status of participants that varied in the included studies which may impact on the 25(OH)D responses to fortified foods, thethe power of detecting small changes in 25(OH)D is different between laboratories, and the results varied by countries depending on their lifestyle, dietary habits and genetic background which are all being involved in responses to vit D fortification.
The current study comprehensively investigated the effect of food fortification with vit D on 25(OH)D levels based on all available RCTs to date, which have high levels of credibility. Cochrane's risk of bias tool was also used to investigate the methodological quality of the trials which is considered as the strength of the present review.
Conclusion
The present systematic review of RCTs demonstrated that fortification of foods with vit D has significantly improved 25(OH)D serum status and has similar efficacy with vit D supplements. Moreover, it was observed that food fortification has a greater impact on the people with lower 25(OH)D serum levels. Therefore, food enrichment is an economical and effective approach for different populations to prevent vit D deficiency. Further studies are still needed to determine the best food and optimal dosage of vit D for fortification.
Conflict of Interest
The authors declare that there is no conflict of interest.      
Author Contributions
Mohammadi M designed the search strategy; Mohammadi M and Talenezhad N performed electronic search and study selection; Talenezhad N and Ramezani-Jolfaie N extracted the data; Sakhaei R and Ramezani-Jolfaie N wrote the manuscript, and all authors read and approved the final manuscript.
Funding source
The study was funded by the Nutrition and Food Security Research Center at Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
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Kriegel MA, Manson JE & Costenbader KH 2011. Does vitamin D affect risk of developing autoimmune disease?: a systematic review. In Seminars in arthritis and rheumatism, pp. 512-531. e518. Elsevier.
Lau E, Woo J, Lam V & Hong A 2001. Milk supplementation of the diet of postmenopausal Chinese women on a low calcium intake retards bone loss. Journal of bone and mineral research. 16 (9): 1704-1709.
Levinson Y, Ish-Shalom S, Segal E & Livney YD 2016. Bioavailability, rheology and sensory evaluation of fat-free yogurt enriched with VD3 encapsulated in re-assembled casein micelles. Food & function. 7 (3): 1477-1482.
Madsen KH, et al. 2013. Randomized controlled trial of the effects of vitamin D–fortified milk and bread on serum 25-hydroxyvitamin D concentrations in families in Denmark during winter: the VitmaD study–. American journal of clinical nutrition. 98 (2): 374-382.
Mehrotra A, et al. 2014. Bioavailability of vitamin D-2 from enriched mushrooms in prediabetic adults: a randomized controlled trial. European journal of clinical nutrition. 68 (10): 1154-1160.
Mocanu V & Vieth R 2013. Three-year follow-up of serum 25-hydroxyvitamin D, parathyroid hormone, and bone mineral density in nursing home residents who had received 12 months of daily bread fortification with 125 μg of vitamin D 3. Nutrition journal. 12 (1): 137.
Natri AM, et al. 2006. Bread fortified with cholecalciferol increases the serum 25-hydroxyvitamin D concentration in women as effectively as a cholecalciferol supplement. Journal of nutrition. 136 (1): 123-127.
Neyestani TR, et al. 2012. Improvement of vitamin D status via daily intake of fortified yogurt drink either with or without extra calcium ameliorates systemic inflammatory biomarkers, including adipokines, in the subjects with type 2 diabetes. Journal of clinical endocrinology and metabolism. 97 (6): 2005-2011.
Nicolaidou P, et al. 2006. Low vitamin D status in mother-newborn pairs in Greece. Calcified tissue international. 78 (6): 337-342.
Nikooyeh B, et al. 2016. Vitamin D-fortified bread is as effective as supplement in improving Vitamin D Status: A randomized clinical trial. Journal of clinical endocrinology and metabolism. 101 (6): 2511-2519.
Norman AW, Coburn JW & Hartenbower D 1974. Vitamin D and calcium homeostasis. Western journal of medicine. 121 (6): 508.
O’Riordan M, Kiely M, Higgins J & Cashman K 2008. Prevalence of suboptimal vitamin D status during pregnancy. Irish medical journal. 101 (8): 240-242.
Outila T 2001. The effect of vitamin D status on calcium and bone metabolism. In Department of Applied Chemistry and Microbiology Division of Nutrition. University of Helsinki: Finland.
Papandreou D & Hamid Z-T-N 2015. The role of vitamin D in diabetes and cardiovascular disease: an updated review of the literature. Disease markers. 2015.
Pawłowska K, Umławska W & Iwańczak B 2016. The impact of lactose malabsorption and lactose intolerance on dairy consumption in children and adolescents with selected gastrointestinal diseases. Pediatria Polska. 91 (3): 192-198.
Pierrot-Deseilligny C & Souberbielle J-C 2013. Contribution of vitamin D insufficiency to the pathogenesis of multiple sclerosis. Therapeutic advances in neurological disorders. 6 (2): 81-116.
Rich-Edwards JW, et al. 2011. Randomized trial of fortified milk and supplements to raise 25-hydroxyvitamin D concentrations in schoolchildren in Mongolia–. American journal of clinical nutrition. 94 (2): 578-584.
Runia TF, Hop WC, de Rijke YB, Buljevac D & Hintzen RQ 2012. Lower serum vitamin D levels are associated with a higher relapse risk in multiple sclerosis. Neurology. 79 (3): 261-266.
Singh SK, et al. 2011. Summer and winter prevalence of vitamin D deficiency of young resident doctors in North India. Nutrition & Dietetics. 68 (4): 280-284.
Sloka S, Stokes J, Randell E & Newhook LA 2009. Seasonal variation of maternal serum vitamin D in Newfoundland and Labrador. Journal of obstetrics and gynaecology canada. 31 (4): 313-321.
Spiro A & Buttriss J 2014. Vitamin D: An overview of vitamin D status and intake in Europe. Nutrition bulletin. 39 (4): 322-350.
Tangpricha V, et al. 2003. Fortification of orange juice with vitamin D: a novel approach for enhancing vitamin D nutritional health. American journal of clinical nutrition. 77 (6): 1478-1483.
Todd JJ, Pourshahidi LK, McSorley EM, Madigan SM & Magee PJ 2015. Vitamin D: Recent advances and implications for athletes. Sports medicine. 45 (2): 213-229.
Tripkovic L, et al. 2017. Daily supplementation with 15 μg vitamin D2 compared with vitamin D3 to increase wintertime 25-hydroxyvitamin D status in healthy South Asian and white European women: a 12-wk randomized, placebo-controlled food-fortification trial. American journal of clinical nutrition. 106 (2): 481-490.
Upreti P, Mistry V & Warthesen J 2002. Estimation and fortification of vitamin D 3 in pasteurized process cheese. Journal of dairy science. 85 (12): 3173-3181.
Urbain P, Singler F, Ihorst G, Biesalski HK & Bertz H 2011. Bioavailability of vitamin D 2 from UV-B-irradiated button mushrooms in healthy adults deficient in serum 25-hydroxyvitamin D: A randomized controlled trial. European journal of clinical nutrition. 65 (8): 965-971.
van der Meer IM, et al. 2006. High prevalence of vitamin D deficiency in pregnant non-Western women in The Hague, Netherlands. American journal of clinical nutrition. 84 (2): 350-353.
Wagner CL & Greer FR 2008. Prevention of rickets and vitamin D deficiency in infants, children, and adolescents. Pediatrics. 122 (5): 1142-1152.
Wagner D, Sidhom G, Whiting SJ, Rousseau D & Vieth R 2008. The bioavailability of vitamin D from fortified cheeses and supplements is equivalent in adults. Journal of nutrition. 138 (7): 1365-1371.
 

 
Type of article: review article | Subject: public specific
Received: 2018/04/10 | Accepted: 2018/08/14 | Published: 2019/05/1

References
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21. Itkonen ST, et al. 2016. Effects of vitamin D-2-fortified bread v. supplementation with vitamin D-2 or D-3 on serum 25-hydroxyvitamin D metabolites: an 8-week randomised-controlled trial in young adult Finnish women. British journal of nutrition. 115 (7): 1232-1239.
22. Johnson JL, et al. 2005. Bioavailability of vitamin D from fortified process cheese and effects on vitamin D status in the elderly. Journal of dairy science. 88 (7): 2295-2301.
23. Jolfaie NR, Rouhani MH, Onvani S & Azadbakht L 2016. The association between Vitamin D and health outcomes in women: A review on the related evidence. Journal of research in medical sciences. 21.
24. Kriegel MA, Manson JE & Costenbader KH 2011. Does vitamin D affect risk of developing autoimmune disease?: a systematic review. In Seminars in arthritis and rheumatism, pp. 512-531. e518. Elsevier.
25. Lau E, Woo J, Lam V & Hong A 2001. Milk supplementation of the diet of postmenopausal Chinese women on a low calcium intake retards bone loss. Journal of bone and mineral research. 16 (9): 1704-1709.
26. Levinson Y, Ish-Shalom S, Segal E & Livney YD 2016. Bioavailability, rheology and sensory evaluation of fat-free yogurt enriched with VD3 encapsulated in re-assembled casein micelles. Food & function. 7 (3): 1477-1482.
27. Madsen KH, et al. 2013. Randomized controlled trial of the effects of vitamin D–fortified milk and bread on serum 25-hydroxyvitamin D concentrations in families in Denmark during winter: the VitmaD study–. American journal of clinical nutrition. 98 (2): 374-382.
28. Mehrotra A, et al. 2014. Bioavailability of vitamin D-2 from enriched mushrooms in prediabetic adults: a randomized controlled trial. European journal of clinical nutrition. 68 (10): 1154-1160.
29. Mocanu V & Vieth R 2013. Three-year follow-up of serum 25-hydroxyvitamin D, parathyroid hormone, and bone mineral density in nursing home residents who had received 12 months of daily bread fortification with 125 μg of vitamin D 3. Nutrition journal. 12 (1): 137.
30. Natri AM, et al. 2006. Bread fortified with cholecalciferol increases the serum 25-hydroxyvitamin D concentration in women as effectively as a cholecalciferol supplement. Journal of nutrition. 136 (1): 123-127.
31. Neyestani TR, et al. 2012. Improvement of vitamin D status via daily intake of fortified yogurt drink either with or without extra calcium ameliorates systemic inflammatory biomarkers, including adipokines, in the subjects with type 2 diabetes. Journal of clinical endocrinology and metabolism. 97 (6): 2005-2011.
32. Nicolaidou P, et al. 2006. Low vitamin D status in mother-newborn pairs in Greece. Calcified tissue international. 78 (6): 337-342.
33. Nikooyeh B, et al. 2016. Vitamin D-fortified bread is as effective as supplement in improving Vitamin D Status: A randomized clinical trial. Journal of clinical endocrinology and metabolism. 101 (6): 2511-2519.
34. Norman AW, Coburn JW & Hartenbower D 1974. Vitamin D and calcium homeostasis. Western journal of medicine. 121 (6): 508.
35. O’Riordan M, Kiely M, Higgins J & Cashman K 2008. Prevalence of suboptimal vitamin D status during pregnancy. Irish medical journal. 101 (8): 240-242.
36. Outila T 2001. The effect of vitamin D status on calcium and bone metabolism. In Department of Applied Chemistry and Microbiology Division of Nutrition. University of Helsinki: Finland.
37. Papandreou D & Hamid Z-T-N 2015. The role of vitamin D in diabetes and cardiovascular disease: an updated review of the literature. Disease markers. 2015.
38. Pawłowska K, Umławska W & Iwańczak B 2016. The impact of lactose malabsorption and lactose intolerance on dairy consumption in children and adolescents with selected gastrointestinal diseases. Pediatria Polska. 91 (3): 192-198.
39. Pierrot-Deseilligny C & Souberbielle J-C 2013. Contribution of vitamin D insufficiency to the pathogenesis of multiple sclerosis. Therapeutic advances in neurological disorders. 6 (2): 81-116.
40. Rich-Edwards JW, et al. 2011. Randomized trial of fortified milk and supplements to raise 25-hydroxyvitamin D concentrations in schoolchildren in Mongolia–. American journal of clinical nutrition. 94 (2): 578-584.
41. Runia TF, Hop WC, de Rijke YB, Buljevac D & Hintzen RQ 2012. Lower serum vitamin D levels are associated with a higher relapse risk in multiple sclerosis. Neurology. 79 (3): 261-266.
42. Singh SK, et al. 2011. Summer and winter prevalence of vitamin D deficiency of young resident doctors in North India. Nutrition & Dietetics. 68 (4): 280-284.
43. Sloka S, Stokes J, Randell E & Newhook LA 2009. Seasonal variation of maternal serum vitamin D in Newfoundland and Labrador. Journal of obstetrics and gynaecology canada. 31 (4): 313-321.
44. Spiro A & Buttriss J 2014. Vitamin D: An overview of vitamin D status and intake in Europe. Nutrition bulletin. 39 (4): 322-350.
45. Tangpricha V, et al. 2003. Fortification of orange juice with vitamin D: a novel approach for enhancing vitamin D nutritional health. American journal of clinical nutrition. 77 (6): 1478-1483.
46. Todd JJ, Pourshahidi LK, McSorley EM, Madigan SM & Magee PJ 2015. Vitamin D: Recent advances and implications for athletes. Sports medicine. 45 (2): 213-229.
47. Tripkovic L, et al. 2017. Daily supplementation with 15 μg vitamin D2 compared with vitamin D3 to increase wintertime 25-hydroxyvitamin D status in healthy South Asian and white European women: a 12-wk randomized, placebo-controlled food-fortification trial. American journal of clinical nutrition. 106 (2): 481-490.
48. Upreti P, Mistry V & Warthesen J 2002. Estimation and fortification of vitamin D 3 in pasteurized process cheese. Journal of dairy science. 85 (12): 3173-3181.
49. Urbain P, Singler F, Ihorst G, Biesalski HK & Bertz H 2011. Bioavailability of vitamin D 2 from UV-B-irradiated button mushrooms in healthy adults deficient in serum 25-hydroxyvitamin D: A randomized controlled trial. European journal of clinical nutrition. 65 (8): 965-971.
50. van der Meer IM, et al. 2006. High prevalence of vitamin D deficiency in pregnant non-Western women in The Hague, Netherlands. American journal of clinical nutrition. 84 (2): 350-353.
51. Wagner CL & Greer FR 2008. Prevention of rickets and vitamin D deficiency in infants, children, and adolescents. Pediatrics. 122 (5): 1142-1152.
52. Wagner D, Sidhom G, Whiting SJ, Rousseau D & Vieth R 2008. The bioavailability of vitamin D from fortified cheeses and supplements is equivalent in adults. Journal of nutrition. 138 (7): 1365-1371.

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