Individual participant data (IPD)-level meta-analysis of randomised controlled trials with vitamin D-fortified foods to estimate Dietary Reference Values for vitamin D

Abstract

Context and purpose

Individual participant data-level meta-regression (IPD) analysis is superior to meta-regression based on aggregate data in determining Dietary Reference Values (DRV) for vitamin D. Using data from randomized controlled trials (RCTs) with vitamin D3-fortified foods, we undertook an IPD analysis of the response of winter serum 25-hydroxyvitamin (25(OH)D) to total vitamin D intake among children and adults and derived DRV for vitamin D.

Methods

IPD analysis using data from 1429 participants (ages 2–89 years) in 11 RCTs with vitamin D-fortified foods identified via a systematic review and predefined eligibility criteria. Outcome measures were vitamin D DRV estimates across a range of serum 25(OH)D thresholds using unadjusted and adjusted models.

Results

Our IPD-derived estimates of vitamin D intakes required to maintain 97.5% of winter 25(OH)D concentrations ≥ 25 and ≥ 30 nmol/L are 6 and 12 µg/day, respectively (unadjusted model). The intake estimates to maintain 90%, 95% and 97.5% of concentrations ≥ 50 nmol/L are 33.4, 57.5 and 92.3 µg/day, respectively (unadjusted) and 17.0, 28.1 and 43.6 µg/day, respectively (adjusted for mean values for baseline serum 25(OH)D, age and BMI).

Conclusions

IPD-derived vitamin D intakes required to maintain 90%, 95% and 97.5% of winter 25(OH)D concentrations ≥ 50 nmol/L are much higher than those derived from standard meta-regression based on aggregate data, due to the inability of the latter to capture between person-variability. Our IPD provides further evidence that using food-based approaches to achieve an intake of 12 µg/day could prevent vitamin D deficiency (i.e., serum 25(OH)D < 30 nmol/L) in the general population.

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Fig. 1
Fig. 2

Code availability

The R code for fitting linear and nonlinear models is presented in Cashman KD, Ritz C (2019). Individual participant data (IPD)-level meta-analysis of randomised controlled trials among dark-skinned populations to estimate the dietary requirement for vitamin D [34].

Abbreviations

25(OH)D:

25-Hydroxyvitamin D

AI:

Adequate intake

DRI:

Dietary reference intake

DRV:

Dietary reference values

EAR:

Estimated average requirement

EFSA:

The European Food Safety Authority

FFQ:

Food frequency questionnaire

IOM:

Institute of Medicine

IPD:

Individual participant data

NNR:

The Nordic Council of Ministers’ Nordic Nutrition Recommendations

RCT:

Randomized controlled trial

RDA:

Recommended dietary allowance

RI:

Recommended intake

RNI:

Reference nutrient intake

SACN:

The Scientific Advisory Committee on Nutrition

UVB:

Ultraviolet B

WHO-FAO:

World Health Organisation–Food and Agriculture Organization

SR-MA:

Systematic reviews and meta-analyses

References

  1. 1.

    Cashman KD, Kiely M (2011) Towards prevention of vitamin D deficiency and beyond: knowledge gaps and research needs in vitamin D nutrition and public health. Br J Nutr 106:1617–1627

    CAS  PubMed  Google Scholar 

  2. 2.

    Cashman KD, Dowling KG, Škrabáková Z, Gonzalez-Gross M, Valtueña J, De Henauw S, Moreno L, Damsgaard CT, Michaelsen KF, Mølgaard C et al (2016) Vitamin D deficiency in Europe: pandemic? Am J Clin Nutr 103:1033–1044

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Pilz S, März W, Cashman KD, Kiely ME, Whiting SJ, Holick MF, Grant WB, Pludowski P, Hiligsmann M, Trummer C et al (2018) Rationale and plan for vitamin D food fortification: a review and guidance paper. Front Endocrinol (Lausanne) 9:373

    Google Scholar 

  4. 4.

    Institute of Medicine (2011) Dietary reference intakes for calcium and vitamin D. The National Academies Press, Washington, DC

    Google Scholar 

  5. 5.

    Brooks SPJ, Greene-Finestone L, Whiting S, Fioletov VE, Laffey P, Petronella N (2017) An analysis of factors associated with 25-Hydroxyvitamin D levels in white and non-white Canadians. J AOAC Int 100:1345–1354

    CAS  PubMed  Google Scholar 

  6. 6.

    Herrick KA, Storandt RJ, Afful J, Pfeiffer CM, Schleicher RL, Gahche JJ, Potischman N (2019) Vitamin D status in the United States, 2011-2014. Am J Clin Nutr 110:150–157

    PubMed  PubMed Central  Google Scholar 

  7. 7.

    EFSA Nda Panel (EFSA Panel on Dietetic Products, Nutrition and Allergies) (2016) Scientific opinion on dietary reference values for vitamin D. EFSA Journal 14:4547. https://doi.org/10.2903/j.efsa.2016.4547

    CAS  Article  Google Scholar 

  8. 8.

    Nordic Council of Ministers (2014) Nordic Nutrition Recommendations 2012, 5th edn (NNR5). Vitamin D. https://doi.org/10.6027/Nord2014-002. Accessed April 2020.

  9. 9.

    Scientific Advisory Committee on Nutrition. Report on Vitamin D and Health (2016) https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/537616/SACN_Vitamin_D_and_Health_report.pdf. Accessed 21 July 2016

  10. 10.

    Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM, Endocrine Society (2011) Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 96:1911–1930

    CAS  PubMed  Google Scholar 

  11. 11.

    Rejnmark L, Bislev LS, Cashman KD, Eiríksdottir G, Gaksch M, Grübler M, Grimnes G, Gudnason V, Lips P, Pilz S, van Schoor NM, Kiely M, Jorde R (2017) Non-skeletal health effects of vitamin D supplementation: a systematic review on findings from meta-analyses summarizing trial data. PLoS ONE 12:e0180512

    PubMed  PubMed Central  Google Scholar 

  12. 12.

    Autier P, Mullie P, Macacu A, Dragomir M, Boniol M, Coppens K, Pizot C, Boniol M (2017) Effect of vitamin D supplementation on non-skeletal disorders: a systematic review of meta-analyses and randomised trials. Lancet Diabetes Endocrinol 5:986–1004

    CAS  PubMed  Google Scholar 

  13. 13.

    Maretzke F, Bechthold A, Egert S, Ernst JB, Melo van Lent D, Pilz S, Reichrath J, Stangl GI, Stehle P, Volkert D et al (2020) Role of vitamin D in preventing and treating selected extraskeletal diseases—an umbrella review. Nutrients 12:pii:E969

    Google Scholar 

  14. 14.

    Cashman KD (2020) Vitamin D deficiency: defining, prevalence, causes, and strategies of addressing. Calcif Tissue Int 106:14–29

    CAS  PubMed  Google Scholar 

  15. 15.

    Roman Viñas B, Ribas Barba L, Ngo J, Gurinovic M, Novakovic R, Cavelaars A, de Groot LC, van't Veer P, Matthys C, Serra Majem L (2011) Projected prevalence of inadequate nutrient intakes in Europe. Ann Nutr Metab 59:84–95

    PubMed  Google Scholar 

  16. 16.

    Elmadfa I, Meyer A, Nowak V, Hasenegger V, Putz P, Verstraeten R, Remaut-DeWinter AM, Kolsteren P, Dostálová J, Dlouhý P et al (2009) European nutrition and health report 2009. Ann Nutr Metab 55:1–40

    PubMed  Google Scholar 

  17. 17.

    Shakur YA, Lou W, L'Abbe MR (2014) Examining the effects of increased vitamin D fortification on dietary inadequacy in Canada. Can J Public Health 105:e127–e132

    PubMed  PubMed Central  Google Scholar 

  18. 18.

    Newman JC, Malek AM, Hunt KJ, Marriott BP (2019) Nutrients in the US Diet: Naturally occurring or enriched/fortified food and beverage sources, plus dietary supplements: NHANES 2009–2012. J Nutr 149:1404–1412

    PubMed  PubMed Central  Google Scholar 

  19. 19.

    Kiely M, Black LJ (2012) Dietary strategies to maintain adequacy of circulating 25-hydroxyvitamin D concentrations. Scand J Clin Lab Invest Suppl 243:14–23

    PubMed  Google Scholar 

  20. 20.

    Allen L, de Benoist B, Dary O, Hurrell R (2006). Guidelines on food fortification with micronutrients. World Health Organization and Food and Agriculture Organization of the United Nations. Geneva, 2006. https://apps.who.int/iris/bitstream/10665/43412/1/9241594012_eng.pdf. Accessed 28 June 2016

  21. 21.

    Black LJ, Seamans KM, Cashman KD, Kiely M (2012) An updated systematic review and meta-analysis of the efficacy of vitamin D food fortification. J Nutr 142:1102–1108

    CAS  PubMed  Google Scholar 

  22. 22.

    O’Donnell S, Cranney A, Horsley T, Weiler HA, Atkinson SA, Hanley DA, Ooi DS, Ward L, Barrowman N, Fang M, Sampson M, Tsertsvadze A, Yazdi F (2008) Efficacy of food fortification on serum 25-hydroxyvitamin D concentrations: systematic review. Am J Clin Nutr 88:1528–1534

    PubMed  Google Scholar 

  23. 23.

    Cashman KD, Kiely M (2016) Tackling inadequate vitamin D intakes within the population: fortification of dairy products with vitamin D may not be enough. Endocrine 51:38–46

    CAS  PubMed  Google Scholar 

  24. 24.

    Itkonen ST, Erkkola M, Lamberg-Allardt CJE (2018) Vitamin D fortification of fluid milk products and their contribution to vitamin D intake and vitamin D status in observational studies—a review. Nutrients 10:pii:E1054

    Google Scholar 

  25. 25.

    Hayes A, Cashman KD (2017) Food-based solutions for vitamin D deficiency: putting policy into practice and the key role for research. Proc Nutr Soc 76:54–63

    PubMed  Google Scholar 

  26. 26.

    Brett NR, Gharibeh N, Weiler HA (2018) Effect of vitamin D supplementation, food fortification, or bolus injection on vitamin D status in children aged 2–18 Years: a meta-analysis. Adv Nutr 9:454–464

    PubMed  PubMed Central  Google Scholar 

  27. 27.

    Vale CL, Rydzewska LH, Rovers MM, Emberson JR, Gueyffier F, Stewart LA, Cochrane IPD Meta-Analysis Methods Group (2015) Uptake of systematic reviews and meta-analyses based on individual participant data in clinical practice guidelines: descriptive study. BMJ 350:h1088

    PubMed  PubMed Central  Google Scholar 

  28. 28.

    Cashman KD, Ritz C, Kiely M, Odin Collaborators (2017) Improved dietary guidelines for vitamin D: application of individual participant data (IPD)-level meta-regression analyses. Nutrients 9:pii:E469

    Google Scholar 

  29. 29.

    Cashman KD (2018) Vitamin D requirements for the future—lessons learned and charting a path forward. Nutrients 10:pii:E533

    Google Scholar 

  30. 30.

    Seamans KM, Cashman KD (2008S) Existing and potentially novel functional markers of vitamin D status: a systematic review. Am J Clin Nutr 89:1997S–2008S

    CAS  PubMed  Google Scholar 

  31. 31.

    Cashman KD, Fitzgerald AP, Kiely M, Seamans KM (2011) A systematic review and meta-regression analysis of the vitamin D intake-serum 25-hydroxyvitamin D relationship to inform European recommendations. Br J Nutr 106:1638–1648

    CAS  PubMed  Google Scholar 

  32. 32.

    Cashman KD, Kiely M, Seamans KM, Urbain P (2016) Effect of ultraviolet light-exposed mushrooms on vitamin D status: liquid chromatography-tandem mass spectrometry reanalysis of biobanked sera from a randomized controlled trial and a systematic review plus meta-analysis. J Nutr 146:565–575

    CAS  PubMed  Google Scholar 

  33. 33.

    Stewart LA, Clarke M, Rovers M, Riley RD, Simmonds M, Stewart G, Tierney JF, PRISMA-IPD Development Group (2015) Preferred eporting Items for Systematic Review and Meta-Analyses of individual participant data: the PRISMA-IPD Statement. JAMA 313:1657–1665

    PubMed  Google Scholar 

  34. 34.

    Cashman KD, Ritz C (2019) Individual participant data (IPD)-level meta-analysis of randomised controlled trials among dark-skinned populations to estimate the dietary requirement for vitamin D. Syst Rev 8:128. https://doi.org/10.1186/s13643-019-1032-6

    Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Brouwer-Brolsma EM, Berendsen AAM, Vaes AMM, Dullemeijer C, de Groot LCPGM, Feskens EJM (2016) Collection and analysis of published scientific information as preparatory work for the setting of Dietary Reference Values for Vitamin D. EFSA supporting publication, EN-766, 171 pp

  36. 36.

    EFSA (European Food Safety Authority) (2012) Scientific opinion on the tolerable upper intake level of vitamin D. EFSA J 10:2813

    Google Scholar 

  37. 37.

    Rooney MR, Harnack L, Michos ED, Ogilvie RP, Sempos CT, Lutsey PL (2017) Trends in use of high-dose vitamin D supplements exceeding 1000 or 4000 International Units daily, 1999–2014. JAMA 317(23):2448–2450

    PubMed  PubMed Central  Google Scholar 

  38. 38.

    Tripkovic L, Lambert H, Hart K, Smith CP, Bucca G, Penson S, Chope G, Hyppönen E, Berry J, Vieth R et al (2012) Comparison of vitamin D2 and vitamin D3 supplementation in raising serum 25-hydroxyvitamin D status: a systematic review and meta-analysis. Am J Clin Nutr 95:1357–1364

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Autier P, Gandini S, Mullie P (2012) A systematic review: influence of vitamin D supplementation on serum 25-hydroxyvitamin D concentration. J Clin Endocrinol Metabol 97:2606–2613

    CAS  Google Scholar 

  40. 40.

    Cashman KD, Hayes A, O'Donovan SM, Zhang JY, Kinsella M, Galvin K, Kiely M, Seamans KM (2014) Dietary calcium does not interact with vitamin D3 in terms of determining the response and catabolism of serum 25-hydroxyvitamin D during winter in older adults. Am J Clin Nutr 99:1414–1423

    CAS  PubMed  Google Scholar 

  41. 41.

    Cashman KD (2015) Vitamin D: dietary requirements and food fortification as a means of helping achieve adequate vitamin D status. J Steroid Biochem Mol Biol 148:19–26

    CAS  PubMed  Google Scholar 

  42. 42.

    Harris SS, Dawson-Hughes B (2002) Plasma vitamin D and 25(OH)D responses of young and old men to supplementation with vitamin D3. J Am Coll Nutr 21:357–362

    CAS  PubMed  Google Scholar 

  43. 43.

    Cashman KD, Hill TR, Lucey AJ, Taylor N, Seamans KM, Muldowney S, Fitzgerald AP, Flynn A, Barnes MS, Horigan G et al (2008) Estimation of the dietary requirement for vitamin D in healthy adults. Am J Clin Nutr 88:1535–1542

    CAS  PubMed  Google Scholar 

  44. 44.

    Cashman KD, Wallace JM, Horigan G, Hill TR, Barnes MS, Lucey AJ, Bonham MP, Taylor N, Duffy EM, Seamans K et al (2009) Estimation of the dietary requirement for vitamin D in free-living adults >=64 y of age. Am J Clin Nutr 89:1366–1374

    CAS  PubMed  Google Scholar 

  45. 45.

    Moher D, Liberati A, Tetzlaff J, Altman DG, Group P (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 339:2535

    Google Scholar 

  46. 46.

    Stewart LA, Tierney JF, Clarke M, on behalf of the Cochrane Individual Patient Data Meta-analysis Methods Group (2011) Chapter 18: Reviews of individual patient data. In: Higgins JPT, Green S, (eds) Part 3: Special topics. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. https://handbook-5-1.cochrane.org/chapter_18/18_2_the_collaborative_nature_of_ipd_meta_analyses.htm

  47. 47.

    Ohmann C, Banzi R, Canham S, Battaglia S, Matei M, Ariyo C, Becnel L, Bierer B, Bowers S, Clivio L et al (2017) Sharing and reuse of individual participant data from clinical trials: principles and recommendations. BMJ Open 7:e018647. https://doi.org/10.1136/bmjopen-2017-018647

    Article  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJM, Gavaghan DJ, McQuay HJ (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 17:1–12

    CAS  PubMed  Google Scholar 

  49. 49.

    Higgins JPT, Altman DG, Sterne JAC, on behalf of the Cochrane Statistical Methods Group and the Cochrane Bias Methods Group (2011) Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Green S (eds) Part 2: general methods for Cochrane reviews. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 The Cochrane Collaboration [Internet]. 2011 [updated 2011 Mar; cited 2015 Dec 18]. https://handbook.cochrane.org/ chapter_8/8_assessing_risk_of_-bias_in_included_studies.htm.

  50. 50.

    Stewart GB, Altman DG, Askie LM, Duley L, Simmonds MC, Stewart LA (2012) Statistical analysis of individual participant data meta-analyses: a comparison of methods and recommendations for practice. PLoS ONE 7:e46042

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Morris TP, Fisher DJ, Kenward MG, Carpenter JR (2018) Meta-analysis of Gaussian individual patient data: two-stage or not two-stage? Stat Med 37(9):1419–1438

    PubMed  PubMed Central  Google Scholar 

  52. 52.

    Pan H, Cole TJ. LMS growth, a Microsoft Excel add‐in to access growth references based on the LMS method. Version 2.2. [Online]. https://www.healthforallchildren.co.uk/. Accessed Mar 2014

  53. 53.

    EFSA Nda Panel (EFSA Panel on Dietetic Products, Nutrition and Allergies) (2018) Scientific opinion on the update of the tolerable upper intake level for vitamin D for infants. EFSA J 16:5365. https://doi.org/10.2903/j.efsa.2018.5365

    CAS  Article  Google Scholar 

  54. 54.

    Maurya VK, Aggarwal M (2017) Factors influencing the absorption of vitamin D in GIT: an overview. J Food Sci Technol 54:3753–3765

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    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. J Nutr 138:1365–1371

    CAS  PubMed  Google Scholar 

  56. 56.

    Biancuzzo RM, Young A, Bibuld D, Cai MH, Winter MR, Klein EK, Ameri A, Reitz R, Salameh W, Chen TC et al (2010) Fortification of orange juice with vitamin D(2) or vitamin D(3) is as effective as an oral supplement in maintaining vitamin D status in adults. Am J Clin Nutr 91:1621–1626

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Natri AM, Salo P, Vikstedt T, Palssa A, Huttunen M, Kärkkäinen MU, Salovaara H, Piironen V, Jakobsen J, Lamberg-Allardt CJ (2006) Bread fortified with cholecalciferol increases the serum 25-hydroxyvitamin D concentration in women as effectively as a cholecalciferol supplement. J Nutr 136:123–127

    CAS  PubMed  Google Scholar 

  58. 58.

    Nikooyeh B, Neyestani TR, Zahedirad M, Mohammadi M, Hosseini SH, Abdollahi Z, Salehi F, Mirzay Razaz J, Shariatzadeh N, Kalayi A et al (2016) Vitamin D-fortified bread is as effective as supplement in improving vitamin D status: a randomized clinical trial. J Clin Endocrinol Metab 101:2511–2519

    CAS  PubMed  Google Scholar 

  59. 59.

    Whiting SJ, Bonjour JP, Payen FD, Rousseau B (2015) Moderate amounts of vitamin D3 in supplements are effective in raising serum 25-hydroxyvitamin D from low baseline levels in adults: a systematic review. Nutrients 7:2311–2323

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Bates D, Maechler M, Bolker B, Walker S (2015) Fitting linear mixed-effects models using lme4. J Stat Soft 67:1–48

    Google Scholar 

  61. 61.

    Pinheiro J, Bates D, DebRoy S, Sarkar D, R Core T (2018) nlme: linear and nonlinear mixed effects models. R package version 3:1–137

    Google Scholar 

  62. 62.

    Johnson JL, Mistry VV, Vukovich MD, Hogie-Lorenzen T, Hollis BW, Specker BL (2005) Bioavailability of vitamin D from fortified process cheese and effects on vitamin D status in the elderly. J Dairy Sci 88:2295–2301

    CAS  PubMed  Google Scholar 

  63. 63.

    Hower J, Knoll A, Ritzenthaler KL, Steiner C, Berwind R (2013) Vitamin D fortification of growing up milk prevents decrease of serum 25-hydroxyvitamin D concentrations during winter: a clinical intervention study in Germany. Eur J Pediatr 172:1597–1605

    CAS  PubMed  Google Scholar 

  64. 64.

    Madsen KH, Rasmussen LB, Andersen R, Mølgaard C, Jakobsen J, Bjerrum PJ, Andersen EW, Mejborn H, Tetens I (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. Am J Clin Nutr 98:374–382

    CAS  PubMed  Google Scholar 

  65. 65.

    Toxqui L, Pérez-Granados AM, Blanco-Rojo R, Wright I, de la Piedra C, Vaquero MP (2014) Low iron status as a factor of increased bone resorption and effects of an iron and vitamin D-fortified skimmed milk on bone remodelling in young Spanish women. Eur J Nutr 53:441–448

    CAS  PubMed  Google Scholar 

  66. 66.

    Trautvetter U, Neef N, Leiterer M, Kiehntopf M, Kratzsch J, Jahreis G (2014) Effect of calcium phosphate and vitamin D3 supplementation on bone remodelling and metabolism of calcium, phosphorus, magnesium and iron. Nutr J 13:6. https://doi.org/10.1186/1475-2891-13-6

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Brett NR, Lavery P, Agellon S, Vanstone CA, Maguire JL, Rauch F, Weiler HA (2016) Dietary vitamin D dose-response in healthy children 2 to 8 y of age: a 12-wk randomized controlled trial using fortified foods. Am J Clin Nutr 103:144–152

    CAS  PubMed  Google Scholar 

  68. 68.

    Hayes A, Duffy S, O'Grady M, Jakobsen J, Galvin K, Teahan-Dillon J, Kerry J, Kelly A, O'Doherty J, Higgins S et al (2016) Vitamin D-enhanced eggs are protective of wintertime serum 25-hydroxyvitamin D in a randomized controlled trial of adults. Am J Clin Nutr 104:629–637

    CAS  PubMed  Google Scholar 

  69. 69.

    Öhlund I, Lind T, Hernell O, Silfverdal SA, Karlsland Åkeson P (2017) Increased vitamin D intake differentiated according to skin color is needed to meet requirements in young Swedish children during winter: a double-blind randomized clinical trial. Am J Clin Nutr 106:105–112

    PubMed  Google Scholar 

  70. 70.

    Tripkovic L, Wilson LR, Hart K, Johnsen S, de Lusignan S, Smith CP, Bucca G, Penson S, Chope G, Elliott R et al (2017) Daily supplementation with 15 μg vitamin D(2) compared with vitamin D(3) to increase wintertime 25-hydroxyvitamin D status in healthy South Asian and white European women: a 12-wk randomized, placebo-controlled food-fortification trial. Am J Clin Nutr 106:481–490

    CAS  PubMed  Google Scholar 

  71. 71.

    Grønborg IM, Tetens I, Christensen T, Andersen EW, Jakobsen J, Kiely M, Cashman KD, Andersen R (2020) Vitamin D-fortified foods improve wintertime vitamin D status in women of Danish and Pakistani origin living in Denmark: a randomized controlled trial. Eur J Nutr 59:741–753

    PubMed  Google Scholar 

  72. 72.

    Mortensen C, Damsgaard CT, Hauger H, Ritz C, Lanham-New SA, Smith TJ, Hennessy Á, Dowling K, Cashman KD, Kiely M et al (2016) Estimation of the dietary requirement for vitamin D in white children aged 4–8 y: a randomized, controlled, dose-response trial. Am J Clin Nutr 104:1310–1317

    CAS  PubMed  Google Scholar 

  73. 73.

    Smith TJ, Tripkovic L, Damsgaard CT, Mølgaard C, Ritz C, Wilson-Barnes SL, Dowling KG, Hennessy Á, Cashman KD, Kiely M et al (2016) Estimation of the dietary requirement for vitamin D in adolescents aged 14–18 y: a dose-response, double-blind, randomized placebo-controlled trial. Am J Clin Nutr 104:1301–1309

    CAS  PubMed  Google Scholar 

  74. 74.

    Cashman KD, Seamans KM, Lucey AJ, Stöcklin E, Weber P, Kiely M, Hill TR (2012) Relative effectiveness of oral 25-hydroxyvitamin D3 and vitamin D3 in raising wintertime serum 25-hydroxyvitamin D in older adults. Am J Clin Nutr 95:1350–1356

    CAS  PubMed  Google Scholar 

  75. 75.

    Ní Chaoimh C, McCarthy EK, Hourihane JO, Kenny LC, Irvine AD, Murray DM, Kiely ME (2018) Low vitamin D deficiency in Irish toddlers despite northerly latitude and a high prevalence of inadequate intakes. Eur J Nutr 57:783–794

    PubMed  Google Scholar 

  76. 76.

    Drincic AT, Armas LA, Van Diest EE, Heaney RP (2012) Volumetric dilution, rather than sequestration best explains the low vitamin D status of obesity. Obesity (Silver Spring) 20:1444–1448

    CAS  Google Scholar 

  77. 77.

    Cashman KD, Kiely M (2017) Vitamin D and food fortification. In: David Feldman J, Pike W, Bouillon R, Giovannucci E, Goltzman D, Hewison M (eds) Vitamin D, 4th edn. Elsevier, Amsterdam

    Google Scholar 

  78. 78.

    Raulio S, Erlund I, Männistö S, Sarlio-Lähteenkorva S, Sundvall J, Tapanainen H, Vartiainen E, Virtanen SM (2017) Successful nutrition policy: improvement of vitamin D intake and status in Finnish adults over the last decade. Eur J Public Health 27:268–273

    PubMed  Google Scholar 

  79. 79.

    Jääskeläinen T, Itkonen ST, Lundqvist A, Erkkola M, Koskela T, Lakkala K, Dowling KG, Hull GL, Kröger H, Karppinen J et al (2017) The positive impact of general vitamin D food fortification policy on vitamin D status in a representative adult Finnish population: evidence from an 11-y follow-up based on standardized 25-hydroxyvitamin D data. Am J Clin Nutr 105:1512–1520

    PubMed  Google Scholar 

  80. 80.

    Carter GD (2011) Accuracy of 25-hydroxyvitamin D assays: confronting the issues. Curr Drug Targets 12:19–28

    CAS  PubMed  Google Scholar 

  81. 81.

    Brooks SPJ, Sempos CT (2017) The importance of 25-Hydroxyvitamin D assay standardization and the vitamin D standardization program. J AOAC Int 100:1223–1224

    CAS  PubMed  Google Scholar 

  82. 82.

    Willet W (2013) Nutritional epidemiology, 3rd edn. Oxford University Press, New York

    Google Scholar 

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Authors

Contributions

KDC, MEK and CR designed the research; KDC and MEK defined the eligibility criteria for the food-based vitamin D randomized controlled trials (RCTs) for inclusion in the individual participant data (IPD)-level meta-regression analysis; KDC conducted the electronic searches; Study selection and decision on which met the eligibility criteria and we included was conducted by KDC and MEK; KDC, LT and MEK performed the quality assessment of eligible studies; KDC, RA, IMG, KHM, JN, IT, LT, SAL-N, LT, MPV, UT, GJ, VVM, BLS, JH, AK, DW, RV, IO, PKA, NRB, HAW accessed, formatted and supplied the IPD from their 11 included RCTs which formed the core pooled dataset upon which this work was based; An assessment of the risk of bias in the included RCTs was performed by KDC and LT; CR performed the statistical analyses and derivation of vitamin D dietary reference value estimates; KDC and CR wrote the first draft of the paper, with all authors providing input and comment on subsequent versions; All authors read and approved the final manuscript.

Corresponding author

Correspondence to Kevin D. Cashman.

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Conflicts of interest

The following authors had no conflicts of interest: Kevin D. Cashman, Mairead E. Kiely, Rikke Andersen, Ida M. Grønborg, Katja H. Madsen, Janna Nissen, Inge Tetens, Laura Tripkovic, Laura Toxqui, M. Pilar Vaquero, Ulrike Trautvetter, Gerhard Jahreis, Vikram V. Mistry, Bonny L. Specker, Jürgen Hower, Anette Knoll, Dennis Wagner, Reinhold Vieth, Inger Öhlund, Pia Karlsland Åkeson, Neil R. Brett, Christian Ritz. Hope A. Weiler at the time of the trial received a small speaker’s honoraria for presenting at the annual conferences organized by Dairy Farmers of Canada [Weiler H. Role of dairy in body composition and health. Dairy Research Symposium, Dairy Farmers of Canada and Agriculture Canada, Ottawa, Feb 5, 2016]. Susan A. Lanham-New is Research Director of D3Tex Ltd which holds the UK and Gulf Corporation Council (GCC) Patents for the use of UVB material in preventing vitamin D deficiency in women who dress for cultural style. SLN also received a small speaker’s honoraria for presentations at two conferences on Vitamin D organised by Solaris.

Ethics standards

Approval by a research ethics committee to conduct this meta-analysis was not required because the aim of this secondary analysis was consistent with the ethical approval received for the individual studies. The current analysis was conducted on anonymized data.

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Cashman, K.D., Kiely, M.E., Andersen, R. et al. Individual participant data (IPD)-level meta-analysis of randomised controlled trials with vitamin D-fortified foods to estimate Dietary Reference Values for vitamin D. Eur J Nutr 60, 939–959 (2021). https://doi.org/10.1007/s00394-020-02298-x

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Keywords

  • Vitamin D recommendations
  • Dietary reference values
  • Recommended dietary allowance
  • Individual participant data-level meta-regression analyses
  • Vitamin D-fortified foods