Current vitamin D status in European and Middle East countries and strategies to prevent vitamin D deficiency: a position statement of the European Calcified Tissue Society

in European Journal of Endocrinology
Correspondence should be addressed to P Lips; Email: p.lips@vumc.nl

(Dedicated to the memory of Prof. Steven Boonen and Prof. Silvano Adami)

Vitamin D deficiency (serum 25-hydroxyvitamin D (25(OH)D) <50 nmol/L or 20 ng/mL) is common in Europe and the Middle East. It occurs in <20% of the population in Northern Europe, in 30–60% in Western, Southern and Eastern Europe and up to 80% in Middle East countries. Severe deficiency (serum 25(OH)D <30 nmol/L or 12 ng/mL) is found in >10% of Europeans. The European Calcified Tissue Society (ECTS) advises that the measurement of serum 25(OH)D be standardized, for example, by the Vitamin D Standardization Program. Risk groups include young children, adolescents, pregnant women, older people (especially the institutionalized) and non-Western immigrants. Consequences of vitamin D deficiency include mineralization defects and lower bone mineral density causing fractures. Extra-skeletal consequences may be muscle weakness, falls and acute respiratory infection, and are the subject of large ongoing clinical trials. The ECTS advises to improve vitamin D status by food fortification and the use of vitamin D supplements in risk groups. Fortification of foods by adding vitamin D to dairy products, bread and cereals can improve the vitamin D status of the whole population, but quality assurance monitoring is needed to prevent intoxication. Specific risk groups such as infants and children up to 3 years, pregnant women, older persons and non-Western immigrants should routinely receive vitamin D supplements. Future research should include genetic studies to better define individual vulnerability for vitamin D deficiency, and Mendelian randomization studies to address the effect of vitamin D deficiency on long-term non-skeletal outcomes such as cancer.

Abstract

Vitamin D deficiency (serum 25-hydroxyvitamin D (25(OH)D) <50 nmol/L or 20 ng/mL) is common in Europe and the Middle East. It occurs in <20% of the population in Northern Europe, in 30–60% in Western, Southern and Eastern Europe and up to 80% in Middle East countries. Severe deficiency (serum 25(OH)D <30 nmol/L or 12 ng/mL) is found in >10% of Europeans. The European Calcified Tissue Society (ECTS) advises that the measurement of serum 25(OH)D be standardized, for example, by the Vitamin D Standardization Program. Risk groups include young children, adolescents, pregnant women, older people (especially the institutionalized) and non-Western immigrants. Consequences of vitamin D deficiency include mineralization defects and lower bone mineral density causing fractures. Extra-skeletal consequences may be muscle weakness, falls and acute respiratory infection, and are the subject of large ongoing clinical trials. The ECTS advises to improve vitamin D status by food fortification and the use of vitamin D supplements in risk groups. Fortification of foods by adding vitamin D to dairy products, bread and cereals can improve the vitamin D status of the whole population, but quality assurance monitoring is needed to prevent intoxication. Specific risk groups such as infants and children up to 3 years, pregnant women, older persons and non-Western immigrants should routinely receive vitamin D supplements. Future research should include genetic studies to better define individual vulnerability for vitamin D deficiency, and Mendelian randomization studies to address the effect of vitamin D deficiency on long-term non-skeletal outcomes such as cancer.

Introduction

The clinical practice committee of the European Calcified Tissue Society (ECTS) met during the European Calcified Tissue Symposium at Stockholm in May 2012. The different guidelines of the Institute of Medicine (IOM) and the Endocrine Society (1, 2) were discussed, including their different scopes, the many uncertainties surrounding the required circulating 25-hydroxyvitamin D (25(OH)D) concentrations, supplementation doses and extra-skeletal effects of vitamin D (3). While the IOM’s recommendations were directed at population health, the Endocrine Society guidelines aimed at a clinical care perspective. The members agreed that a European statement outlined in a position paper would be appropriate. A working group was established to prepare a position statement regarding various aspects of vitamin D deficiency and prevention for Europe and the Middle East. Such a document should be appropriate following the recent reports of the IOM, the guidelines of the Endocrine Society, the statement of the Standing Committee of European Doctors and reports from the Scientific Advisory Committee on Nutrition (SACN) (https://www.gov.uk/government/publications/sacn-vitamin-d-and-health-report) in the UK, the European Food Safety Authority (EFSA) (https://www.efsa.europa.eu/en/efsajournal/pub/4547)     for Europe as well as the ongoing discussions in the American, European and international journals.

The present position paper discusses assessment of vitamin D status and standardization of measurement of 25(OH)D concentration. It includes an overview of the vitamin D status and vitamin D intake in different European and Middle East countries, the prevalence of vitamin D deficiency according to different thresholds, the required circulating 25(OH)D concentrations and required vitamin D intake (from food and/or supplements) to prevent vitamin D deficiency and possible impact on skeletal and non-skeletal outcomes. The perspective of the ECTS Working Group was the whole population, including risk groups such as children, older persons and immigrants. Data on food fortification policy and the use of supplements in risk groups are included. The ECTS Working Group discussed strategic options and proposes possible implementation strategies for adults and elderly subjects in Europe and the Middle East. Finally recommendations and a research agenda are presented.

Assessment of serum 25-hydroxyvitamin D

There is a general consensus, also adopted by the ECTS, that the serum/plasma 25(OH)D concentration is the best indicator of vitamin D nutritional status, as it reflects the contributions from diet and dermal production in response to ultraviolet B (UVB) sunlight exposure (4). It is not surprising therefore that serum/plasma 25(OH)D was used as an indicator of vitamin D status recently by several authorities in North America and Europe who were commissioned to establish dietary reference intake values for vitamin D.

The circulating concentration of total 25(OH)D (i.e. comprising the sum of 25(OH)D2 and 25(OH)D3) is used diagnostically and clinically as well as in the derivation of dietary reference values for vitamin D. While vitamin D3 comes from skin synthesis or animal sources, vitamin D2 is derived from supplements or irradiated foods. As the biological activity of the C3 epimer of serum 25(OH)D is low and its concentration in adults represents only a small fraction of the total 25(OH)D concentration, its separate measurement is not a priority, certainly not in adults. Ideally, measurement of serum 25(OH)D should have a minimal interference from 24,25(OH)2D – the vitamin D metabolite with the highest concentration apart from 25(OH)D3 (5, 6, 7). Separate measurement of 24,25(OH)2D may be important in case of suspected genetic CYP24A1 deficiency (8, 9). Measurement of serum 1α,25(OH)2D can be important for establishing the etiology of hyper- or hypocalcemia and some metabolic bone diseases but not for the general assessment of the vitamin D status in a population or individual. Serum 1α,25(OH)2D may be high in patients with inflammatory and granulomatous diseases and lymphoproliferative disorders (10, 11).

The impact of pre-analytical factors (e.g. serum versus plasma, fasting versus non-fasting state, or time of day) on circulating 25(OH)D is not fully defined. Several assay types are currently in use for measurement of circulating 25(OH)D, each with strengths and weaknesses (12). The two most common types of assays are (1) antibody-based methods, which use a kit or an automated clinical chemistry platform; and (2) liquid chromatography (LC)-based methods with either UV or mass spectrometric (MS) detection. While they will both provide a measure of total serum 25(OH)D, mass spectrometry can allow for the separate estimation of 25(OH)D2 and 25(OH)D3 (and in some cases the C-3 epimers and 24,25(OH)2D) from serum samples. The antibody-based methods lack the features that allow them to distinguish between 25(OH)D2 and 25(OH)D3 (4, 7, 10, 13). Various commercial assays differ because of the nature of the antibody used, some claiming an advantage that they do not discriminate between 25(OH)D2 and 25(OH)D3 (13), whereas others in fact do underestimate the 25(OH)D2 component and therefore provide correction factors to compensate for high 25(OH)D2 content (2, 14). It is important to note that the majority of the data collected over the past 20–30 years have been analyzed using antibody-based assays. LC-based assays using a tandem mass spectrometer (LC–MS/MS) allow the analyst to discriminate between 25(OH)D2 and 25(OH)D3 and other compounds by their unique molecular masses and mass fragments (12). The potential advantages of LC-based assays include high specificity, high sensitivity and better reproducibility (<10%). The consensus among analysts is that LC–MS/MS assays will become the ‘gold standard’ for assay performance in the future (15). However, LC–MS/MS will not be available everywhere, and antibody-based assays are still being improved and cross-calibrated against LC–MS/MS, so that smaller labs will be able to perform adequate measurements provided they participate in a quality control program. In the circulation, 25(OH)D is bound to serum proteins, and unbound or free 25(OH)D constitutes <1% of the total concentration. As only free 25(OH)D can enter the cell for further intra/paracrine production of the active metabolite 1,25(OH)2D, it is plausible that free 25(OH)D is more important for local actions than total 25(OH)D. The free 25(OH)D concentration can either be calculated (based on vitamin D-binding protein (DBP), albumin and total 25(OH)D concentrations and the affinity between both components) or can be directly measured. Whether free 25(OH)D is a better predictor for clinical outcomes than total 25(OH)D is presently unclear (16).

Standardization of the measurement of serum 25(OH)D

Standard reference materials, inter-laboratory collaboration and quality assurance schemes are important aspects of overcoming the challenges that the assay methodologies present. An external quality assurance scheme, the Vitamin D External Quality Assurance Scheme (or DEQAS) (www.deqas.org, Charing Cross Hospital in London, UK), exists since the early 1990s and it has grown steadily, such that it now serves as a quarterly monitor of performance of analysts and 25(OH)D analytical methods for more than 1000 laboratories worldwide (5, 17, 18, 19, 20). The introduction of the National Institute of Standards and Technology (NIST) reference standards, calibrated using a reference LC–MS/MS procedure, offers hope that the variability of all methods will be diminished in the future. Recent data suggest that an improvement is already occurring (18) but there is still a long way to go for general implementation of well-validated and accurate measurements of vitamin D metabolites (20, 21, 22).

For reasons of pre-analytical as well as analytical factors, as outlined above, inter-laboratory variation in serum 25(OH)D may be high (17, 18, 19, 23, 24, 25). The international standardization of serum 25(OH)D measurement is also promoted by the Vitamin D Standardization Program (VDSP) – a collaborative initiative between the Office of Dietary Supplements of the National Institutes of Health and the Centers for Disease Control and Prevention (CDC), NIST and a number of the national health surveys around the world (21, 26). The international quality assurance/collaboration schemes, such as DEQAS and VDSP, as well as existing and next generation standard reference materials for 25(OH)D, can further limit inter-laboratory differences. The impact of standardization to NIST standards has been amply demonstrated by recalibration of the (US) NHANES data (27), whereby the J-shaped increased mortality in subjects with high serum 25(OH)D concentration disappeared simply because very few subjects had ‘corrected’ 25(OH)D levels above 100 nmol/L. Similarly, a recalibration of European studies in the framework of the EU Framework 7-funded ODIN project (food-based solutions for optimal vitamin D nutrition and health through the life cycle; http://www.odin-vitd.eu/) markedly changed the number of vitamin D deficient subjects (28).

Definitions

An international consensus on the definition of vitamin D deficiency and sufficiency is lacking. The IOM has defined a serum 25(OH)D concentration of 30 nmol/L (divide by the conversion factor 2.496 to obtain 12 ng/mL) as the threshold below which clinical vitamin D deficiency may occur (2, 14, 19). It has defined a 25(OH)D concentration of 50 nmol/L (20 ng/mL) as the threshold of sufficiency, that is sufficient for 97.5% of the population in terms of bone health, a definition also recently adopted by the EFSA (29). The serum concentration of 40 nmol/L fits with the estimated average requirement (EAR), that is sufficient for 50% of the population. Serum 25(OH)D levels between 30 and 50 nmol/L (12 and 20 ng/mL), referred to by the IOM as ‘inadequacy’, represent an uncertain range and can be sufficient or not for a certain individual (Table 1).

Table 1

Definitions of vitamin D deficiency and sufficiency according to different advisory bodies.

Serum 25(OH)D concentration (nmol/L)Institute of Medicine (2)Endocrine Society (1)EFSA (29)SACN (27)ECTS (this paper)
<25/30DeficientDeficientDeficientDeficientSeverely deficient
25–50Uncertain*DeficientDeficientDeficient
50–75SufficientInsufficientSufficientSufficient
>75Sufficient

*According to the IOM serum 25(OH)D 30–50 nmol/L can be adequate or inadequate.

The Endocrine Society has defined serum 25(OH)D of 50 nmol/L (20 ng/mL) as the threshold for deficiency and 75 nmol/L (30 ng/mL) as the threshold for sufficiency, that is sufficient for 97.5% of the population (1). The 2016 UK SACN guidelines defined serum 25(OH)D concentrations below 25 nmol/L as being deficient for all age groups but concluded that there was insufficient evidence to define a higher 25(OH)D being optimal for bone or global health (30).

The ECTS Working Group defines vitamin D deficiency as a serum 25(OH)D concentration below 50 nmol/L. A serum 25(OH)D level below 30 nmol/L is considered severe vitamin D deficiency. A serum 25(OH)D concentration of 50 nmol/L and above is considered sufficient.

A problem with these definitions is that they heavily rely on the accuracy of serum 25(OH)D measurement. The latter depends on standardization and the discussions on this subject have not been finalized (28).

In this review, results for serum 25(OH)D are reported in nmol/L (1 nmol/L = 0.4 ng/mL). Vitamin D intake can be presented in IU/day or in µg/day (1 µg = 40 IU). While clinicians often use IU/day, nutritionists usually prefer µg/day. We have chosen the use of µg/day, with frequent reference to the conversion factor for ease of the reader.

Vitamin D status and prevalence of vitamin D deficiency in Europe

Vitamin D status has been studied in many European countries in various age groups. Since different studies use different laboratories and different assays, the data should be compared with caution because, as mentioned above, the inter-laboratory variation may be high (19, 23). Another point is the study population which may be either a population sample (31) or a convenience sample (32). Data from various studies in different European countries are summarized in Table 2. Recent reviews on vitamin D status in Europe or worldwide were published by Spiro and Buttriss, Wahl et al. and Hilger et al. (33, 34, 35).

Table 2

Vitamin D status in adults and children in different European countries.

CountryCommentsStudy populationnAge (years)25(OH)DReferences
Mean ± s.d. (nmol/L)<25 nmol/L (%)<50 nmol/L (%)
Iceland (Reykjavik)Latitude 64°Regionally representativeAdult men and women551966–9657.0 ± 17.84.233.6Cashman et al. 2016 (28)
Norway (Tromso)Latitude 69°Regionally representativeAdult men and women12 81730–8765.0 ± 17.60.318.6Cashman et al. 2016 (28)
Norway (Oslo)Latitude 60°Adult men and women86630–7671.0 ± 19.5 (white)0.1 (white)14.9 (white)Cashman et al. 2015 (36)
SwedenLatitude 58°Older men11947168.7 ± 19.10.817Melhus et al. 2010 (38)
SwedenLatitude 56°OPRA women99580 (80–81)78 ± 300 ???16Buchebner et al. 2014 (37)
FinlandLatitude 60–70°Nationally representativeAdult men and women410229–7767.7 ± 13.20.26.6Cashman et al. 2015 (36)Jaaskelainen et al. 2017 (47)
Denmark (Copenhagen)Latitude 56°Regionally representativeAdult men and women340919–7265.0 ± 19.2023.6Cashman et al. 2015 (36)
UKLatitude 50–59°Nationally representativeChildren, teens and adults14881.5–9147.4 ± 19.815.456.4Cashman et al. 2016 (28)
Northern IrelandLatitude 55°Girls and boys101512 and 1566.216.766.2Carson et al. 2015 (48)
IrelandLatitude 51–54°Adults (national representative sample)111818–8456.4 ± 22.26 (year round)45 (year round)Cashman et al. 2013 (56)
NetherlandsLatitude 52°Nationally representativeLASA 200991561–9964.7 ± 22.62.428.5Cashman et al. 2016 (28)
NetherlandsLatitude 52°Regionally representativeAdults262540–6659.5 ± 21.74.933.6Cashman et al. 2016 (28)
BelgiumLatitude 51°Adults69742.7 (32–53)49.3 (35–65)7.351.1Hoge et al. 2015 (51)
GermanyLatitude 47–55°Nationally representativeAdults699518–7950.1 ± 18.14.254.5Cashman et al. 2016 (28)
GermanyLatitude 48–52°Nationally representativeChildren and adolescents10 0151–1754.0 ± 19.26.044.5Cashman et al. 2016 (28)
FranceVarieté studyLatitude 43–49°Men and women89218–8960 ± 206.334.6Souberbielle et al. 2016 (54)
SwitzerlandLatitude 47°MONICA327625–7446 (median)6 (<20)>50Burnand et al. 1992 (55)
Latitude 47°Nursing homeWomen 246Men 10385 ± 781 ± 823 ± 1826 ± 216548Krieg et al. 1998 (58)
Latitude 47°Non-institut.Elderly19380 ± 918 ± 1890Theiler et al. 1999 (57)
Spain
ItalyLatitude 38–45°Postmenop. women57059 ± 845 ± 2028Bettica et al. 1999 (69)
ItalyLatitude 38–45°Multicenter70060–8076Isaia et al. 2003 (70)
GreeceLatitude 35–40°Regionally representativeAdolescents8069–1447.3 ± 12.52.262.4Cashman et al. 2016 (28)
GreeceLatitude 37°Regionally representativeChildren2223–654.3 ± 15.71.440.5Cashman et al. 2016 (28)
PolandWarsawPostmenop. women656172 ± 112.6 ± 0.532.530.625339287Andersen et al. 2005 (41)
Regionally representativeGirls
Estonia59° winterWomenMen20016749 ± 1249 ± 1244.6 ± 15.842.7 ± 14.0873Pludowski et al. 2014 (72)Kull et al. 2009 (74)
SummerWomenMen20016749 ± 1249 ± 1258.4 ± 17.760.5 ± 18.5129
Czech Republic50°WomenMen32123953 ± 1462.5 ± 10Mayer et al. 2012 (75)
Slovakia49°Women16232.7 ± 4.481.5 ± 31.515Pludowski et al. 2014 (72)
SloveniaLatitude 46°44817–8930.566.4Kocjan et al. 2006 (76)
Hungary47°Women31965 (41–91)48.4 (12.5–135)56.7 (w + m)Bhattoa et al. 2004 (78)
Men20660 (51–81)72.8 (11–185)Bhattoa et al. 2013 (79)
CroatiaLatitude 45°Postmenop. women12061.1 ± 8.846.9 ± 16.814.2 (<30)63.3Laktasic et al. 2010 (80)
Belarus53°WomenMenWomenWomen16817617810145–5555–6565–75>7572 ± 3767 ± 3565 ± 3546 ± 22Pludowski et al. 2014 (72)
Ukraine44–52°WomenMenWomenMen6491297118647 (20–59)44 (20–59)69 (60–95)71 (60–91)29 ± 1527 ± 1426 ± 1419 ± 9Pludowski et al. 2014 (72)
RussiaOlder personsHip fracture patients976370.268.828 ± 1022 ± 114765Bakhtiyarova et al. 2006 (81)
Russia57–67°Northern indigenous17817–5939.7–47.72–538–84Kozlov et al. 2014 (82)
Vitamin D status in adults and children in different Middle East countries
 TurkeyManisa119 M272 F45 ± 1745 ± 1751.8 ± 38.738.1 ± 28.76679Hekimsoy et al. 2010 (93)
 TurkeyIstanbulstudents100 F21 ± 265.7 ± 25Covered: 52 ± 20Uncovered: 74 ± 834Buyukuslu et al. 2014 (94)
 TurkeyKahramanmarasPregnant women newborns, 97 pairs97 women97 neonates27 ± 5012.5 ± 810.7 ± 6859398100Parlak et al. 2015 (95)
 TurkeyTrabzonSchoolchildren397 M349 F14.6 ± 1.914.6 ± 1.837.3 ± 20.831.3 ± 17.328427887Karaguzel 2014 (96)
 IranShiraz (latitude 30°N)Selected by postal code number520 M20–7435 ± 1733.729.9 (<35 nmol/L)Masoompour et al. 2008 (97)
 IranTehran (latitude 35°N)Controls from lipid and glucose Study251 M + F56.7 ± 11.745 (26–77)19.154 (<37.5 nmol/L)Hosseinpanah et al. 2011 (99)
 IranZahedan (latitude 30°N)NA431 M562 F20–8834.4 ± 29.4NA85.2Kaykhaei et al. 2011 (100)
 IranTehranPregnant women14927.9 ± 4.338.9 ± 16.638% <30Naseh et al. 2018 (102)
 IranTehranPediatric clinic2864.5 ± 2.850 ± 38<2 year: 8>2 year: 43Torkaman et al. 2016 (103)
 SyriaDamascus (33°N)Healthy volunteers37234.1 ± 10.024.7 ± 16.961Sayed-Hassan et al. 2014 (104)
 IsraelPopulation based (31°N)Clalit Health Services198 834 M F0 to >80 median 6051.9 ± 24.514.449.8Saliba et al. 2012 (105)
 IsraelRetrospectivePopulation based (31°N)Maccabi healthcare services8175 M26 699 FF 55 ± 15M 55 ± 17M 60 ± 25F 56.6 ± 24.7NANASteinvil et al. 2011 (106)
 Israel(31°N)Volunteers95 M100 FAll ages57.15 ± 25.227.278Oren et al. 2010 (107)
 IsraelJerusalemHealthy children primary care2471.5–664.2 ± 25.028.3Korchia et al. 2013 (108)
 JordanPopulation basedNational sample459041.9 ± 13.4M 183.3 ± 73.3F 99.5 ± 51.71.514.2Batieha et al. 2011 (109)
 JordanNational Micronutrient SurveyAl Basheer Hospital2032 F15–49Median 27.560% <30 nmol/L95Nichols et al. 2012 (110)
 JordanNational Micronutrient SurveyAl Basheer Hospital10771–5Median 45 nmol/L20% <30 nmol/L56.5Nichols et al. 2015 (111)
 JordanHealthy volunteersM 99F 2012932M 44 ± 10F western 40 ± 8F hijab 31 ± 6F niqab 28 ± 40049769098100Mallah et al. 2011 (112)
 JordanNeonates Al Bashir Government Hospital Amman37310Median 21.5±9094%Khuri-Bulos et al. 2013 (113)
 LebanonBeirutHospital database20082002 2008Hoteit et al. 2014 (114)
2000–2004 and 2007–20083493024176212.2 ± 4.549.5 ± 11.672.7 ± 5.7F 42.7 M 48.2F 57.0 M 54.0F 59.0 M 54.563 5860 4462 40
 Lebanon Population basedBeirut (34°N)Home-dwelling ambulatory subjects157 M286 F65–85Mean 73 years25.7 (10–96.7)M 30.2F 27.337569495Arabi et al. 2010 (115)
 KuwaitSchoolchildren1997–9.5Median 30M 34; F 27Alyahya 2017 (116)
 KuwaitMothers and neonatesAl Adan and maternity hospitals128 pairs27Mothers 36.5Neonates 20.540657696Molla et al. 2005 (117)
 Saudi ArabiaRiyadhPregnant women16020–4949.9 (IQR 28)1850Al-Faris 2016 (120)
 Saudi ArabiaPopulation basedJeddah (22°N)40 (PHCCs)M < 50: 550M > 50: 28420–7431.3 ± 17.526.8 ± 15.052.641.989.983.8Ardawi et al. 2012 (118)
 Saudi ArabiaSchools all over countrySchool children 1013 M1097 F6–1528 ± 11M 25F 64M 93F 98Al Shaikh et al. 2016 (119)
 United Arab EmAbu DhabiUniversity students70 M208 F21 ± 4M 27.3 ± 15.7F 24.2 ± 14.994Al Anouti et al. 2011 (122)
 United Arab EmAbu DhabiPediatric outpatients1835.3 ± 3.753.6 ± 33.417±57Rajah et al. 2012 (121)
 BahreinManamaBlood donors50033.7 ± 10.127.9 ± 19.349.486.4Golbahar et al. 2014 (123)
 QatarDohaRetrospective study in 547 hospital patients54749 ± 1336.0 ± 27.546El-Menyar et al. 2012 (124)
 Egypt Cairo and Port SaidWomen Lactating 51Pregnant 50Non pregnant 208Elderly 38Geriatric 5726 ± 526 ± 531 ± 858 ± 476 ± 730372766377354724077Botros et al. 2015 (125)
 TunisiaTunisMothers and newborns87 mothers87 neonates31 ± 5017 ± 1315 ± 487 (<30)78 (<30)9798Ayadi et al. 2016 (126)
 AlgeriaTizi-OuzouHealthy children4355–15Sept: 71.4March: 52.98.1 (<30)17.4 (<30)29.941.4Djennane et al. 2014 (127)
 MoroccoRabatPostmenopaual women17858.8 ± 8.239.5 ± 29.051.6El Maghraoui et al. 2012 (128)
Vitamin D status in different European countries: immigrants. Included studies which use standardized serum 25(OH)D data have the references highlighted in bold
 Norway (Oslo)latitude 60°NorwegianPakistani86617630–7671.0 ± 19.527.6 ± 12.30.152.314.992.0Cashman et al. 2015 (36)
 FinlandLatitude 60–63°Representative of immigrant populationsEthnic (all):White Russian KurdishSomalian131046650036418–6445.5 ± 21.962.8 ± 21.033.7 ± 15.640.5 ± 16.618.22.534.215.763.728.785.676.4Cashman et al. 2016 (28)
 FinlandLatitude 60BangladeshiSomaliFinnish 34486120–4842.9 ± 16.136.8 ± 11.854.1 ± 19.108.33.370.681.344.3Islam et al. 2012 (84)
 DenmarkLatitude 55PakistaniChildren 37Premenopausal women 115Men 9512.236.238.310.912.020.7818465959795Andersen et al. 2008 (43)
 NetherlandsAdult women and men613:18–65Van der Meer et al. 2008 (64)
DutchTurkishMoroccanSurinam AsianSurinam CreoleAfrican67273024273364137514519

Included studies are from the last 10 years, nationally or regionally representative and use standardized serum 25(OH)D data, when possible. The references highlighted in bold refer to studies in which the serum 25(OH)D data was standardized. Results for serum 25(OH)D are reported in nmol/L, to convert to ng/mL the value should be divided by 2.496.

The ODIN project (28) as well as a small project funded by the Nordic Council of Ministers (36) have recently allowed for the generation of standardized serum 25(OH)D data which facilitates estimating and comparing the prevalence of vitamin D deficiency in various European countries. These projects utilized available biobanks from national nutrition and health surveys and cohorts in Europe and used a centralized laboratory LC–MS/MS analytical platform for 25(OH)D, which is traceable to the two higher order reference measurement procedures (NIST, VDSP) and certified by the Centres for Disease Control and Prevention (CDC). The data from these projects together with data from other studies in different countries in Europe and the Middle East is summarized in Table 2. We have selected studies from the last 10 years, and, where available, prioritized population-based studies having standardized serum 25(OH)D values according to the VDSP program.

Northern Europe

The prevalence of serum 25(OH)D <30 nmol/L ranged from 0.4 to 8.4%, and <50 nmol/L from 6.6 to 33.6% in adults, according to standardized data from the ODIN study, and some Nordic studies (28, 36, 37, 38, 39). However, vitamin D status was poor in teenagers in Norway and Denmark with serum 25(OH)D <30 nmol/L at 39% and 51% respectively (40, 41). Vitamin D status was also poor in immigrants (42, 43), and in older persons, especially residents of nursing homes (44, 45). The generally adequate vitamin D status in the Nordic countries is due to the use of cod liver oil and supplements (46) and vitamin D fortification, leading to a great improvement in Finland during the last decade (47).

Western Europe

The prevalence of serum 25(OH)D <30 nmol/L ranged from 4.6 to 30.7% and <50 nmol/L from 27.2 to 61.4% according to standardized data from ODIN (28). Vitamin D status generally was worse in the UK (30.7% < 30 nmol/L and 61.4% < 50 nmol/L) than in other countries (25, 28, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62), and recently a rise in the incidence of rickets was observed (63). A poor vitamin D status was observed in black and Asian people in the UK, in teenagers and adolescents in the UK (25, 48), in (pregnant) non-Western immigrants (64, 65) and in general in older persons (66).

Southern Europe

Standardized data from adults are not available. An older European population-based study in older persons, the Seneca study, showed a mean serum 25(OH)D of 26 nmol/L in Spain, 39 nmol/L in Portugal, 28 nmol/L in Italy and 25 nmol/L in Greece while it was around 45 nmol/L in the Nordic countries (31). Other studies in these countries usually show mean serum 25(OH)D concentrations below 50 nmol/L and higher percentages of serum 25(OH)D <30 nmol/L than in Northern and Western Europe (67, 68, 69, 70, 71). Standardized data from infants and children in Greece (ODIN) showed serum 25(OH)D <30 nmol/L in 4.2–6.9%, and <50 nmol/L in 40.5–62.4% (28).

Eastern Europe

Standardized data from adults are not available. In general, a review and individual studies showed a mean serum 25(OH)D usually lower than 50 nmol/L, and a poorer vitamin D status than in Northern and Western Europe (72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82).

Immigrants in Europe

Studies from Norway, Finland, Denmark and the Netherlands confirm a very poor vitamin D status in non-Western immigrants in European countries, in comparison with the locally born and with people in their country of origin (43, 64, 65, 83, 84, 85). A study in Dutch general practices showed a mean serum 25(OH)D of 30 nmol/L or lower in Turkish, Moroccan and Surinamese people in comparison with a mean serum 25(OH)D of 67 nmol/L in locally born people (64).

European population studies

As mentioned early, the Seneca study was performed in eight countries but serum 25(OH)D was measured in one central laboratory to avoid variation between different laboratories (31). Some studies reporting baseline data from randomized clinical trials in patients with osteoporosis also used a central laboratory facility, making comparisons between countries more reliable (raloxifene and bazedoxifene studies) (86, 87). A general trend in these data is that vitamin D status usually is much better in Nordic countries than around the Mediterranean. The European ODIN study used standardized data from epidemiological studies in Europe. Severe vitamin D deficiency (serum 25(OH)D <30 nmol/L) was observed in 12.5% of the participants and 40% was deficient (serum 25(OH)D <50 nmol/L) (28).

Vitamin D status and prevalence of vitamin D deficiency in the Middle East

Population-based studies are rare. The prevalence of vitamin D deficiency and rickets is high in the Middle East despite abundant sunshine (25, 88, 89, 90, 91, 92) (Table 2). The median or mean serum 25(OH)D in almost all surveys was between 25 and 50 nmol/L, with lower values in women than in men, that also depend on clothing style (93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131). In a recent systematic review, the prevalence of vitamin D deficiency in the Middle East varied between 30 and 90% depending on the type of study, country, age group and assay used (92). Vitamin D status was poor in several surveys in Saudi Arabia (118, 119), probably due to a very traditional lifestyle. Vitamin D status is better in Israel.

In general, vitamin D deficiency is much more prevalent in the Middle East than in Northern and Western Europe. Risk groups for severe deficiency include children, adolescents and pregnant women.

Determinants of vitamin D status and risk groups for vitamin D deficiency

Demographic, anthropometric and lifestyle factors are robust predictors of rickets and poor vitamin D status worldwide in general, and in the Middle East in particular (Fig. 1). Sunshine exposure and vitamin D intake are the main determinants, but these are modified by other factors. Vitamin D status deteriorates with aging above 70 years due to decreased sun exposure and cutaneous synthesis (132), and is poor in the institutionalized, 75% of them being severely vitamin D deficient (serum 25(OH)D <25 nmol/L), and in patients with hip fracture (66, 133). The good vitamin D status in the Nordic countries is explained by the frequent consumption of cod liver oil and vitamin D supplements (134, 135). Furthermore, fortification of milk and milk products over the last 10 years has considerably improved vitamin D status in Finland (47). On the other side, strong sunshine in Southern Europe and the Middle East may lead to decreased exposure (136), and skin pigmentation decreases vitamin D synthesis (137). Vitamin D status in the Middle East is strongly dependent on clothing style, with decreasing vitamin D status going from Western-style clothing to hijab and niqab (129, 130, 131). A low calcium intake is common in the Middle East (92). It increases the risk of rickets, and it leads to secondary hyperparathyroidism and bone loss. Pollution and urban living are other factors.

Figure 1
Figure 1

Causes, consequences and prevention of vitamin D deficiency. The red arrows lead to vitamin D deficiency, the green arrows can prevent it. Vitamin D-related gene polymorphisms indicate gene polymorphisms in the vitamin D metabolic pathway that decrease vitamin D bioavailability. Low sun exposure may also be due to clothing style, skin pigmentation and sunscreen use. Poor diet means no fish, no dairy products, no vitamin D-fortified foods. A full color version of this figure is available at https://doi.org/10.1530/EJE-18-0736.

Citation: European Journal of Endocrinology 180, 4; 10.1530/EJE-18-0736

Risk groups for vitamin D deficiency are children, adolescents, pregnant women and older persons. Vitamin D status usually is very poor in immigrants from non-Western countries, compared with native people (28, 64, 83, 84, 85), fatty fish and supplements being the most important determinants (64). This is even worse in pregnant non-Western immigrants, who displayed mean serum 25(OH)D concentrations around 25 nmol/L (65).

Vitamin D intake in Europe and the Middle East

Measurements of vitamin D content of food requires special expertise due to its low concentration, the possible presence of vitamin D esters with uncertain bioavailability, and the presence of 25(OH)D in some food items. Most of the data presented below is based on methodology which estimated vitamin D only. Studies on vitamin D intake in Europe have been nicely summarized by Spiro and Buttriss (33), and Kiely and Black (138). An overview of the data is presented in Table 3.

Table 3

Vitamin D intake in European and Middle East countries.

CountryStudy populationnAge (years)Vitamin D intake (µg/day)References
Iceland3.9 µg13.5 µg (with cod liver oil)Thorgeirsdottir et al. 2012 (139)
NorwayVolunteersNorkost329.6 µgM: 15 µgF: 12.9 µgBrustad et al. 2004 (134)Norkost (144)
SwedenRiksmaten7.1 µgRiksmaten (145)
FinlandNational Diet SurveyFindiet170825–74M: 11 µgF: 9 µgOM: 14 µgOW: 19 µgHelldán et al. 2013 (147)
DenmarkDan Nat Survey3.93.1
United KingdomNDNS rolling survey (2008/2009 to 2009/2010)M: 210 M: 238 M: 346M: 96F: 213F: 215F: 461F: 1284–1011–1819–64>654–1011–1819–64>652.2 (median)2.12.83.921.72.63.1 (median)Department of Health 2011 (153)
IrelandNational Adult Nutrition Survey127418–643.5 (median)6.4 (mean)Black et al. 2015 (151)
IrelandIrish Preschool Children Survey5001–42–2.5 µg (median)Hennessy et al. 2016 (152)
IrelandIrish Children’s and Teens’ National Nutrition Surveys5944415–89–1213–171.9 (median)2.1 (median)2.4 (median)Black et al. 2014 (150)
NetherlandsHip fract pat controls1257475.975.62.82.9Lips et al. 1987 (156)
Food cons surveyM: 4.8F: 3.6
GermanyNat Nutr SurveyM: 4.4F: 3.4
PortugalEpiportoM: 3.4F: 3.3Spiro & Buttriss 2014 (33)
SpainENCAT 2002–2003M: 0.7F: 0.7Spiro & Buttriss 2014 (33)
ItalyINN-CA 1996M: 2.5F: 2.4Spiro & Buttriss 2014 (33)
10 European countries (EPIC)European Prospective Investigation into Cancer and Nutrition (EPIC) studyM: 13 025 F: 23 009 35–7435–745.53.6Jenab et al. 2009 (163)
 SouthernM: 4530 F: 737235–7435–744.25.1
 CentralM: 3807 F: 8561 35–7435–744.73.4
 NorthernM: 4688 F: 7076 35–7435–747.45.0
Middle East
 TurkeyMining facility135 coal miners32.6 ± 7.42.1 ± 1.3Bilici et al. 2016 (164)
 IranTehran Lipid and Glucose Study552418–70M: 2.5 ± 4.3F: 3.8 ± 3.1Ejtahed et al. 2016 (165)
 IranIranian Multicentric Osteoporosis StudyF: 58142.4 ± 12.21.5 ± 1.2Khashayar et al. 2017 (166)
 IranPregnant women2.3±1.9Sabour et al. 2006 (167)
 IranChildren1.4Feizabad et al. 2017 (168)
 Iran100 children4–1011.7Kelishadi et al. 2014 (169)
 KuwaitRepres. national sample10491–2.9Zaghloul et al. 2013 (170)
 LebanonBeirut FM39.4 ± 5.641.3 ± 5.52.2 ± 1.53.2 ± 2.0Gannage-Yared et al. 2000 (171)
 Lebanon128 pregnant women10.6 ± 10.9 (FFQ)8.9 ± 2.5 (24 h recall)Papazian et al. 2016 (172)
 Qatar60 young women293.0Salameh et al. 2016 (173)
 United Arab Emirates350 adolescent females15.3 ± 28.5Narchi et al. 2015 (174)
 Saudi ArabiaUniversity students Tabuk19–2553% < 15 µg/dayAlzaheb & Al-Amer 2017 (175)
 Tunisia225 boys8Bezrati et al. 2016 (176)
 Tunisia87 pregnant women2.2Ayadi et al. 2016 (126)

M, male; F, female; OM, older male; OF, older female.

Northern Europe

The mean intake of vitamin D in Northern Europe varies between 4 and 14 µg/day (41, 43, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149), with high values found in Norway, due to the consumption of oily fish and cod liver oil. In Iceland, the difference between users and non-users of cod liver oil was more than 9 µg/day. In Sweden, fish and fortified milk products were important sources. In Finland, the fortification of fluid milk products was recently increased to 10 µg/L. Vitamin D supplement of 10 µg/day was recommended for children younger than 3 years, and 7.5 µg/day for children and adolescents aged 3–18 years. The recent Finrisk–Findiet survey has shown that the dietary vitamin D intake has increased to above 10 µg/day in men and nearly as much in women (47, 147). The mean dietary vitamin D intake was around 3 µg/day in Denmark.

Western Europe

The mean vitamin D intake in Western Europe varies between 1.5 and 5 µg/day, far below the EAR of 10 µg/day (150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161).

Southern Europe

Food consumption surveys presented in Table 3 showed vitamin D intakes from below 1 µg/day to about 3 µg/day in Italy, Spain and Portugal.

Eastern Europe

The mean vitamin D intake varied between 2 and 5 µg/day, according to a recent review (162).

European studies

National dietary and food consumption surveys as well as smaller studies use various methods of data collection, analysis and reporting, making meaningful comparison of vitamin D intakes problematic (155). Some studies compared different countries with the same methods. A European study done in Denmark, Finland, Ireland and Poland found a mean vitamin D intake of 2.4–5.0 µg/day in girls and 3.4–9.5 µg/day in older women (41)

The European Prospective Investigation into Cancer and Nutrition (EPIC) compared vitamin D intakes in ten European countries. The mean vitamin D intake was 5.5 and 3.6 µg/day in men and women respectively with the highest intake in the Northern countries (163).

In conclusion, mean vitamin D intake in most European countries is rather low, in most countries less than 5 μg/day (200 IU/day). Vitamin D intake is highest in the Nordic countries and poor in Southern Europe.

Vitamin D intake in the Middle East

Population-based studies on vitamin D intake are scarce. The used food frequency and 24 h recall questionnaires varied and these tools were mostly validated in Western populations, with little or no adaptation to the Mediterranean/Middle Eastern diet. Vitamin D fortification varies widely between countries, as detailed in the section on Food fortification with vitamin D. These drawbacks may explain the wide variability between countries and the lack of a consistent pattern by age. The mean vitamin D intake ranged between 1 and 4 µg/day, with some exceptions in selected groups of children, adolescents and pregnant women, probably due to vitamin D supplements (126, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176). These intakes are well below the RDA of 10–20 µg/day, depending on age and reproductive stage (2, 177).

Genetic factors

Genetic factors may contribute to up to 28% of inter-individual variability in serum 25(OH)D concentrations, while clinical correlates such as season, vitamin D intake and waist circumference explain another 24% of variability (178). Studies have applied the candidate gene approach to relatively common single nucleotide polymorphisms which play an important biological role in vitamin D metabolism, transport, degradation and downstream pathways, to evaluate their impact on circulating 25(OH)D concentrations (Fig. 1). These include genes involved in cholesterol synthesis (DHCR7), 1-α-hydroxylase (CYP27B1), 25-hydroxylase (CYP2R1), vitamin D transport (GC (group specific component), identical to DBP) and to a lesser extent also 24-hydroxylase (CYP24A1) (179, 180, 181, 182). Similar effects of polymorphisms of these genes (especially DBP/GC) were confirmed in several studies (183). The combined effects of these genes do not explain more than about 5% of the variability and considerably less than the seasonal variation in serum 25(OH)D (179, 184).

25(OH)D and all other metabolites of vitamin D are bound to a high capacity, high affinity serum DBP or GC. A smaller proportion is loosely bound to albumin. Therefore the free concentration of 25(OH)D represents less than 0.1% of the total concentration. Genetic polymorphisms of DBP are associated with different DBP concentrations but this depends on the antibody used for measuring DBP. When polyclonal anti-DBP antibodies are used, subjects with GC2 genotype have a slightly lower DBP concentration compared to others (185), associated with lower 25(OH)D concentrations. A monoclonal antibody method found much (about 50%) lower DBP concentrations in GC 1f–1f homozygotes (mainly African-Americans) than in subjects with other genotypes (186). Subsequent studies using mass spectrometry to measure serum DBP, however, did not find a significant difference in DBP according to race (187, 188), creating serious doubt (189) on the conclusions based on the monoclonal antibody (186). As the free concentration of 25(OH)D is dependent on both DBP concentration and affinity it is yet not possible to conclude whether clinical correlates and thresholds for vitamin D deficiency depend on genetic polymorphisms of DBP. An assay to measure the free 25(OH)D concentration is available, but currently it is uncertain whether the measurement of this metabolite in its free state has clinical implications (189, 190).

Impact of vitamin D on bone

A beneficial effect of vitamin D on musculoskeletal health is well established, as severe vitamin D deficiency causes rickets in children and osteomalacia in adults. While rickets is rare in almost all European countries, it is still reported in the Middle East, in some Asian countries and in immigrants of those countries in Europe (88). In general, rickets in Europe is mostly reported in non-Western immigrants, mainly coming from Africa and Asia and in persons consuming macrobiotic or vegan diets (191, 192). This can be explained by the fact that oily fish and dairy products are the major dietary source of vitamin D and calcium, both being absent in these diets. Milder vitamin D deficiency results in secondary hyperparathyroidism, increased bone turnover and accelerated bone loss, osteoporosis and fractures (66). The vitamin D endocrine system primarily tries to maintain a normal serum calcium homeostasis whereby its role on bone can be either beneficial or deleterious depending on calcium intake and availability (193, 194). Many cross-sectional studies and especially randomized controlled trials have demonstrated a beneficial role of vitamin D supplementation, in a sufficient dose of daily 20 µg (800 IU) vitamin D (195, 196, 197) and in combination with calcium supplements (198, 199), among seniors (institutionalized and community-dwelling) at risk for vitamin D deficiency and with a lower than recommended calcium intake, showing a reduction of falls as well as hip and other fractures (3, 195, 196, 197, 200). This conclusion has been reached in most (195, 201) but not all meta-analyses (202, 203, 204). Whether such supplements would be beneficial for bone health in adolescents and non-elderly adults requires additional controlled intervention studies. The 2018 meta-analysis on the musculoskeletal benefits of vitamin D monotherapy on BMD, fractures and falls by Bolland and colleagues suggests no benefit on these outcomes, but they did not analyze clinical trials with vitamin D and calcium vs double placebo (205).

Extra-skeletal health

The presence of the vitamin D receptor (VDR) in most cells and tissues, as well as the expression of the 1α-hydroxylation enzyme CYP27B1 in many cells and the large number of genes under the control of 1α,25(OH)2D suggest a broader role of the vitamin D endocrine system beyond bone and calcium homeostasis (206, 207, 208). Moreover, such potential effects on non-classical or non-skeletal outcomes are in line with data from association studies between low vitamin D status and cardiovascular diseases, diabetes and the metabolic syndrome, inflammatory, infectious and immune disorders, as well as a variety of cancers. A low vitamin D status was also associated with increased mortality risks as extensively reviewed (3, 27, 206, 209). Whether skeletal or cardiac muscles are target tissues for the vitamin D endocrine system has been debated. The presence of the VDR in skeletal muscle tissue has been questioned recently by Wang and DeLuca suggesting that the VDR is undetectable in muscle tissue (210), in contrast with many earlier studies (211, 212, 213, 214, 215), including the most recent one using a new multi-step immunofluorescent technique to detect the VDR in muscle biopsy tissue from older female subjects (216). Recently, others found VDR to be expressed albeit at low (mRNA and protein) levels (217). VDR null mice (systemic or cardiac muscle-specific deletion), however, show a clear muscle phenotype and many in vitro studies also show clear coherent positive effects of 1α,25(OH)2D on muscle cell precursors. Severe vitamin D deficiency is frequently associated with muscle weakness/hypotonia and an increased risk of falling (218). Several double-blind intervention studies also show a significant average reduction of 19% in fall frequency when elderly vitamin D deficient subjects receive a vitamin D supplement, but meta-analyses of these studies came to divergent conclusions depending on the quality of fall assessment, and the inclusion of trials with or without blinding (2, 219, 220). The overall interpretation of the presently available data suggest that correction of severe vitamin D deficiency improves muscle function and reduces the risk of falls (3, 220). High intermittent dosing of vitamin D or doses resulting in high serum 25(OH)D levels (above 125 nmol/L, 50 ng/mL) may, however, result in increased risk of falls (221, 222) so that the therapeutic range for serum 25(OH)D and fall prevention may be between 50 and 75 nmol/L (20 and 30 ng/mL) for optimal fall prevention (222). Based on current evidence, this range is safely reached with a vitamin D intake of 20 µg (800 IU) per day (223) or 600 µg (24 000 IU) per month (222, 224). Among somewhat younger postmenopausal women (mean age 66 year), a most desirable range of serum 25(OH)D for optimal fall prevention was suggested to be 80–95 nmol/L (32–38 ng/mL) based on a multidose vitamin D trial (225). Notably, both trials suggested that a serum 25(OH)D higher than 113 nmol/L (45 ng/mL) was associated with a significantly increased risk of falling compared to a 25(OH)D range of 80–95 nmol/L (221).

An additional aspect with potential impact on muscles and falls as well as bone density is the relationship between vitamin D status and sex steroid levels in men with a parallel seasonal variation of both hormones (226, 227, 228, 229). While it has been demonstrated that vitamin D increases testosterone production in human primary testicular cells (230), clinical trials were controversial (231, 232) and a pooled analysis did not show an increase (233). Meta-analyses of RCTs on cardiovascular outcomes, and glycaemic control and type 2 diabetes have shown disappointing effects (208, 234, 235, 236). This was confirmed by a Mendelian randomization study (237). However, a recent meta-analysis of RCTs of vitamin D on acute respiratory infection showed that vitamin D in a daily or weekly dose reduced the risk of acute respiratory infection by 12%, the results being larger in those with baseline serum 25(OH)D <25 nmol/L (238). A large 4 year RCT of vitamin D 2000 IU/day and calcium 1500 mg/day in postmenopausal women showed a borderline (P = 0.06) decrease in cancer incidence (239). A recent Mendelian randomization study showed an association between genetically lowered serum 25(OH)D concentrations and higher ovarian cancer susceptibility (240).

In Mendelian randomization studies, the use of 25(OH)D measurements in relation to GC, CYP2R1, DHCR7 genotypes and a binary study outcome variable such as mortality has revealed associations of genotypes with 25(OH)D concentrations, and of 25(OH)D concentrations and mortality, but the statistical association of genotypes and binary outcome mortality was ambiguous (241). Thus, a direct influence of genotypes on clinical outcomes was not always visible (208). Further studies on mortality causes and low vitamin D status showed an association with cancer and all-cause mortality but not with cardiovascular mortality (241).

Recently, the results of two megatrials have become available. The VIDA trial in 5110 subjects compared vitamin D 100 000 IU/month with placebo and found no effect of vitamin D on cardiovascular disease (242). The VITAL trial comparing vitamin D 2000 IU/day with placebo in more than 25 000 subjects, concluded that vitamin D did not result in a lower incidence of invasive cancer or cardiovascular events than placebo (243). The baseline mean serum 25(OH)D was rather high in these trials, 63 and 75 nmol/L, respectively. From all this data, it can be concluded that the prevention of chronic diseases is not a reason to start vitamin D supplementation in a vitamin D replete population (244).

Optimal levels of 25-hydroxyvitamin D

Although a great degree of consensus exists concerning the essential role of vitamin D on bone health, and some controversy on its effect on muscle strength and falls, there is less consensus about the optimal or required concentration of 25(OH)D to achieve these effects. As there is no proven causality for the frequent association between vitamin D status and many other extra-skeletal effects, no threshold concentration can be defined for these putative protective effects.

The ECTS Working Group has defined severe vitamin D deficiency as a serum 25(OH)D lower than 30 nmol/L (12 ng/mL) as such concentrations and even more so concentrations below 15 nmol/L are associated with rickets or osteomalacia (245). The ECTS has defined vitamin D deficiency as a serum 25(OH)D concentration below 50 nmol/L, a concentration that according to the IOM covers the needs of nearly all healthy individuals in the population in relation to bone health (2) (see ‘Definitions’ section), similar to the EFSA (29). In contrast, an extensive analysis in the UK (30) concluded that serum 25(OH)D concentrations should be above 25 nmol/L at all ages as to avoid rickets or osteomalacia, and that these concentrations can be achieved in all otherwise healthy subjects, even when deprived from sunlight, by a daily vitamin D intake of 10 µg (30). These experts did not find sufficient hard data to define higher serum 25(OH)D or recommend higher vitamin D intake as to improve bone quality or provide extra-skeletal health benefits.

At the other end of the spectrum, a 25(OH)D concentration of 75 nmol/L (30 ng/mL) or higher is recommended by the Endocrine Society (1). Regarding general health endpoints, the Endocrine Society states that while evidence from RCTs is lacking, numerous epidemiological studies have suggested that a serum 25(OH)D concentration of 75 nmol/L (30 ng/mL) and above may have additional health benefits in reducing the risk of common cancers, autoimmune diseases, type 2 diabetes, cardiovascular disease and infectious diseases (246, 247, 248). In contrast, the IOM concludes that there is no evidence that a 25(OH)D threshold greater than 50 nmol/L (20 ng/mL) has any additional benefit to health (2), based on the results of RCTs. More recently several other organizations (249), including the European Standing Committee of Medical Doctors (250) and several scientists (3) supported the conclusions of IOM on optimal 25(OH)D concentrations being ≥50 nmol/L. This conclusion is based on RCTs looking at surrogate endpoints such as the level of 25(OH)D needed to normalize serum 1,25(OH)2D or PTH concentrations, intestinal calcium absorption or bone mineral density. The required intake of vitamin D to achieve such serum 25(OH)D concentrations has been evaluated in numerous studies and an intake in the range of 600–1000 IU of vitamin D3 per day (15–25 µg/day) is adequate for achieving concentration levels of ≥50 nmol/L in more than 97% of postmenopausal Caucasian or Afro-American women (223). Similar results were found in some European RCTs of young children, children, teenagers, young adults and older adults (251, 252, 253, 254, 255, 256). Whether a higher dosage is needed for populations with lower baseline 25(OH)D concentrations has not yet been established but evidence from two randomized clinical trials from Lebanon, one in children and another in elderly, suggest that this is the case for countries in the Middle East (257, 258). However, calculations of the required vitamin D to replace the daily metabolic clearance of 25(OH)D suggest that 600–1000 IU/day should be sufficient to maintain serum 25(OH)D concentrations above 50 nmol/L (3). An intake of 800 IU/day (20 µg/day) has also been proven to be efficient in reducing the risks of fractures and falls in elderly Caucasian women (3, 196, 200, 218). The recent individual participant data meta-analysis in the ODIN study concluded that higher doses are required in order to reach a serum 25(OH)D concentration of 50 nmol/L in 97.5% of the population (259).

Whether higher concentrations of 25(OH)D would translate into additional skeletal and extra-skeletal effects as suggested by some cross-sectional or observational studies needs to be investigated in additional RCTs. The presently available usually small RCTs using doses of vitamin D above 2000 IU/day, however, have not proven additional benefits so far (3). Fortunately, several large scale, long-term RCTs are ongoing (Table 5) and are expected to better define efficacy and optimal dosages of vitamin D for a variety of other major non-skeletal outcomes (3, 260). The negative results of the VIDA and VITAL trials suggest that vitamin D is not effective with regard to cardiovascular disease and cancer when baseline 25(OH)D is high (242, 243). Very high dosages of vitamin D or very high serum 25(OH)D concentrations may be detrimental. First, vitamin D toxicity can occur (261, 262, 263), characterized by increased urinary calcium excretion, hypercalcemia and ectopic soft tissue calcification, but only exists as a iatrogenic disease when serum 25(OH)D exceeds 250 nmol/L. However, large, intermittent pulse doses of vitamin D (300 000 IU or more) have been found to be associated with increased risks of fractures and falls (221, 264). In cross-sectional studies a U-shaped relationship has been found between serum 25(OH)D concentrations and cancer or mortality whereby not only low but also the highest concentrations were found to pose risks (209). Therefore as has been observed for other fat-soluble vitamins too much as well as too little has to be avoided. Also, vitamin D hypersensitivity due to mutation in the gene encoding for the vitamin D catabolizing enzyme 24-hydroxylase (CYP24A1) should not be neglected (265, 266).

Table 5

Megatrials with multiple outcomes with expected results in the coming 5 years.

ConsortiumNumber of subjectsStudy designDoseOutcomeResultsReferences
VIDA5110DB, two groups100 000 IU/monthFract, CVD, ARINo effect on falls and fractures, CVDKhaw et al. 2017 (298)Scragg et al. 2017 (242)
VITAL28 875Factorial design 2/22000 IU/day/fish oil/placeboCancer, CVDNo effect on CVD and cancerBassuk et al. 2016 (299)Manson et al. 2018 (243)
TIPS-35500Factorial design 2/2/260 000 IU/month/polycaps/aspirinCVD, fract, cancerJan 2019Nbib1646437*
FIND18 0003200 vs 1600 IU/day vs placeboCVD, cancerDec 2019Nbib1463813*
DO-HEALTH2152Factorial design 2/2/22000 IU/omega-3/physical exerciseFract, functional decline, blood pressure, cognitive decline, infectionNbib1745263*
D-HEALTH25 00060 000 IU/monthCVD, DM, cancerNeale et al. 2016 (300)
VIDIKids5400 childrenDB, two groups10 000 IU/weekTuberculosis, astma, acute resp infection2022Nbib2880982*

Results are expected between 2015 and 2020. Investigators: R Scragg, JE Manson, S Yusuf, TP Tuomainen, H Bischoff-Ferrari, R Neale, A Martineau.

*Clinical Trials Registry at clinicaltrials.gov. DB, double blind; ARi, acute respiratory infection.

A recent review (267) proposes a desirable concentration range of 50–100 nmol/L (20–40 ng/mL), provided precise and accurate assays are used. This range allows practitioners to tailor treatment, taking into account season, lifestyle factors and individual vitamin D intake. Most children reach the desirable target concentrations by a daily intake of 400–600 IU (10–15 µg/day), and adults by an intake of 800 IU/day (20 µg/day). This is in line with results from randomized dose-ranging clinical trials (223, 251). Additional data is needed to validate the above proposed concentration range and vitamin D doses, especially in children, pregnant women and non-Caucasian populations.

Recommendations on vitamin D intake in Europe and the Middle East

As stated in the Introduction, the focus of guidelines may be different, varying from public health, as in the IOM guidelines, to individual patients, as in the Endocrine Society guideline. Most national guidelines are made from a public health perspective. A summary of guidelines and recommendations is presented in Table 4. Recently, a more detailed overview of present guidelines for more than 40 countries was published (268).

Table 4

Dietary reference intakes for vitamin D in µg/day according to different European countries, the Institute of Medicine and the Endocrine Society.

<1 year1–3 years4–10 years11–18 yearsAdultsOlderPregnantReferences*
Nordic NR10101010102020NORDEN 2014 (144)
UK8.5–10101010101010SACN 2015 (30)
Ireland7.0–8.5100–100–150–101010FSAI 1999***
Netherlands10100–100–100–102010Weggemans et al. 2013 (249)
Belgium10101010–1510–151520Spiro and Buttriss 2014 (33)
France20–2510555510Spiro and Buttriss 2014 (33)
DACH10202020202020Spiro and Buttriss 2014 (33)
Spain10151515152015Spiro and Buttriss 2014 (33)
Central Europe1015–2515–2515–2520–5020–5020–50Pludowski et al. 2013 (269)
EFSA 201610151515151515EFSA 2016 (29)
Institute of Medicine10151515152015IOM 2011 (2)
Endocrine Society10–2515–2515–2515–2537.5–5037.5–5015–25**37.5–50Holick et al. 2011 (1)

Partly adapted from Spiro and Buttriss (33).

*The required serum 25(OH)D concentration should be higher than 50 nmol/L in most guidelines. The Endocrine Society recommends a serum 25(OH)D >75 nmol/L and the Central European guideline recommends 75–125 nmol/L; **pregnant 14–18 year 15–25 µg/day. ***Food Safety Authority of ireland

Most guidelines resemble those of the IOM. The guideline of Central Europe was made by professional societies and resembles the Endocrine Society guideline (269). When recommended intakes are compared with the actual intake, the values only approach each other in the Nordic countries, Norway, Sweden and Finland (144, 147).

Recommendations for supplement use have explicitly been made for small children in the Nordic countries, the DACH countries, the UK, Ireland, the Netherlands and Turkey. Specific recommendations for supplement use in other age groups have been made in Finland and the Netherlands. Two guidelines, from Saudi Arabia and United Arabic Emirates, recommended 800–2000 IU/day, depending on age category and reproductive status (270, 271). The former was developed with the ESCEO group, and both were exclusively based on expert opinion and review of the evidence from studies conducted in Western populations. The actual use of supplements is high in the Nordic countries and very low in Southern Europe (33) and the Middle East (177).

Strategic options

The principal goal of a strategy aiming to improve vitamin D status is to prevent vitamin D deficient bone disease, for example rickets in children and fractures in adults and older persons. Strategic options may vary between nihilism and interventions to achieve a serum 25(OH)D level above a threshold. The null option to prevent fractures in adults was advocated by the US Preventive Services Task Force (272). This was based on the opinion of the task force that the evidence for an effect of vitamin D on fracture prevention in older persons was insufficient (273). The IOM has set the required serum 25(OH)D level at 50 nmol/L (20 ng/mL) (2). The corresponding required intake (required daily allowance RDA) of vitamin D to achieve 50 nmol/L was therefore defined at 15 µg (600 IU) for 1–70 year olds and 20 µg (800 IU) for older subjects per day, when sun exposure is minimal. The mean vitamin D intake in most European countries with the exception of the Nordic countries is well below the minimal requirement to achieve the 25(OH)D threshold of 50 nmol/L unless there is regular access to sunlight or to vitamin D supplements including cod liver oil (Table 3). Depending on the lifestyle and nutritional habits, the required vitamin D supplementation may vary for different segments of the population and for different countries. For example, in Norway, vitamin D status is adequate in a large part of the population, due to sun exposure on a skin with little pigment, high consumption of fish and cod liver oil and adequate dietary calcium intake. In contrast, vitamin D status in Southern Italy may be poor due to low sun exposure on a more pigmented skin, little access to vitamin D-rich food (oily fish or cod liver oil), and a low dietary calcium intake. This means that implementation strategies have to be tailored to the local situation in different countries.

The Endocrine Society has set the required serum 25(OH)D level at 75 nmol/L (30 ng/mL), leading to higher recommendations for vitamin D intake (1) up to 37.5–50 µg/day (1500–2000 IU/day) in adults (Table 4). The ECTS Working Group does not support this option for the general European population.

Implementation strategies

Several concepts on implementation exist based either on individual responsibility or on public responsibility. In the first situation this may lead to vitamin D supplementation on an individual basis, based on requirements as stated by national regulatory bodies or professional societies. In the second situation, a more active public health approach, supported by the ECTS, is required involving recommendations for lifestyle including sunshine exposure, healthy nutrition, food fortification and vitamin D supplementation. Implementation can occur through guidelines, professional organizations, special clinics for young children or other risk groups, and publications in the lay press. Providing vitamin D supplements for free is a very effective implementation strategy, as has been shown in Turkey, where children received a free supplement leading to near eradication of rickets within a few years (274).

Vitamin D can be supplemented as vitamin D3, vitamin D2 and 25-hydroxyvitamin D (calcifediol). In three clinical trials, using assays that well differentiated D2 and D3 metabolites, vitamin D3 appeared to be somewhat more effective than vitamin D2 in increasing serum 25(OH)D (275, 276, 277). Most RCTs have used vitamin D3 and currently this is more readily available. Regarding calcifediol, this metabolite appears 2–3 times more effective in increasing serum 25(OH)D than vitamin D3 (224). Calcifediol might be of value in patients with gastro-intestinal disorders, such as celiac disease, serious liver disease or after gastric bypass surgery, but it is not widely available.

Vitamin D supplements have been dosed daily, weekly, monthly and with larger intervals up to one year. Daily, weekly and monthly doses have been compared in two studies. In one of these, in 48 women serum 25(OH)D was similar after 2 months in all dosing groups (278). The other study in 338 nursing home residents showed a similar increase of serum 25(OH) D with daily or weekly doses, while monthly doses were less effective (279). A yearly dose of 500 000 IU was given in an Australian clinical trial to prevent hip fractures, but the fall and fracture incidence in the vitamin D group were higher than in the placebo group (221). A yearly intramuscular dose of vitamin D (300 000 IU) given in a UK study also was not effective (264).

Absorption with a meal containing some fat appears to improve vitamin D absorption (280). While loading doses have been recommended in case of deficiency by some experts, there is no evidence of the clinical value of such loading doses.

Public health options

The use of cod liver oil was very common in Western Europe to prevent rickets, and still is very widespread in the Nordic countries. A recent meta-analysis demonstrated that at a dose as low as 400 IU/day (10 μg/day) vitamin D prevents the occurrence of rickets (281). The advice to use vitamin D drops 10 µg/day (400 IU/day) in infants and children below 4 years was and still is common practice in the Netherlands and several other Western European countries in special children consultation clinics visited by a great majority of young children. Rickets was an important public health problem in Turkey, leading to the institution of a population-based preventive program in 2005 (274). The free distribution of vitamin D drops to all newborn infants visiting primary care facilities in Turkey has decreased the prevalence of rickets from 6% in 1998 to 0.1% in 2008 in children under 3 years of age (274, 282). A similar experience has been reported from Finland, Canada and New Zealand (47, 283, 284).

The IOM increased its RDAs for vitamin D 7 years ago, ranging from 10 to 20 µg/day, considerably lower than those of the Endocrine Society (1, 14). There were also recent global consensus recommendations on prevention and management of nutritional rickets (285): supplementation with 10 µg/day (400 IU/day) is adequate to prevent rickets and is recommended for all infants from birth to 12 months of age, independent of their mode of feeding. Beyond 12 months of age, all children and adults need to meet their nutritional requirement for vitamin D through diet and/or supplementation, which is at least 15 µg/day (600 IU/day), similar to the recommendation of the IOM. The global consensus of rickets also recommends an intake of 15 µg/day for pregnant women (285). Based on a Cochrane meta-analysis, the WHO recommends against routine vitamin D supplementation in pregnancy (286). A more recent update of the Cochrane analysis was more positive about potential benefits of vitamin D supplementation in pregnancy, but the authors concluded that evidence is not sufficient yet for a general supplementation advice in pregnancy (287). Recommendations from a WHO-sponsored symposium during the 2015 Vitamin D Workshop (288) endorsed a correction of widespread vitamin D deficiency of pregnant women in line with the recommendations for all adult females (10–15 µg/day), as part of antenatal care in general. Special risk groups such as pregnant women in the Middle East and pregnant non-Western immigrant women in Europe probably require a vitamin D supplement (65, 85). Some randomized vitamin D trials revealed that the majority of mothers failed to achieve the required serum 25(OH)D level even with doses by far exceeding current recommendations (92). However, it is questionable whether vitamin D doses of 15–20 µg/day (600–800 IU/day) actually are too low, or rather that compliance to these doses may not have been adequate. In a recent dose-finding trial, doses of 600–800 IU/day were sufficient to achieve a 25(OH)D concentration of more than 50 nmol/L in 97% of postmenopausal women (223) similar to findings in an earlier study in Dutch institutionalized elderly (251).

Food fortification with vitamin D

As mentioned above, the dietary intakes of children and adults in European countries, as well as beyond Europe, have been comprehensively reviewed recently (33, 138, 289). In brief, intakes of vitamin D in national surveys throughout Europe (e.g. UK, Ireland, Denmark and France) are typically below 5 μg/day, except for the Nordic countries, and vary according to contribution from nutritional supplements, country-specific fortification practices, sex and age; with the nutritional supplements being the main source of variation. Overall, it is clear that the current dietary supply of vitamin D makes it unfeasible for most children and adults in Europe to meet the IOM’s EAR of 10 µg/day (400 IU/day), let alone the RDA of 15 µg/day (600 IU/day), which were established on the assumption of minimal or absent UVB-induced dermal supply. It has been emphasized that there is only a limited number of public health strategies available to correct low dietary vitamin D intake (289, 290). A brief overview will be provided here:

  • Improving intake of naturally occurring vitamin D-rich foods. This is the least likely strategy to increase dietary vitamin D intake because there are very few food sources that are rich in vitamin D, such as oily fish, with limited availability. Furthermore, most of these are not frequently consumed by many in the population (290).

  • Vitamin D supplementation. Supplementation with vitamin D has been shown to significantly improve vitamin D intake across a variety of age, race, ethnic and gender groups as well as improving vitamin D status per se. However, the population intake of vitamin D from supplements is quite low (291). This is mainly due to the relatively low vitamin D content of most supplements compared to the requirement as discussed earlier. While not highly effective at a population level due to the low percentage of compliance in the general population for most European countries, vitamin D supplementation may be appropriate in high-risk groups such as infants and young children, pregnant women and older persons (250). Actually, vitamin D supplements are systematically recommended for young children from 0 to 3 years in several countries and also for all institutionalized elderly subjects (249).

  • Vitamin D fortification (mandatory or voluntarily) of food. While supplements are an effective method for individuals to increase their intake, food fortification represents the best opportunity to increase the vitamin D supply to the population (138, 289, 292). Fortification of foods with vitamin D in the United States and Canada has an important effect on the mean daily intake of vitamin D by the average adult, but it does not yet reach the required levels of vitamin D intake (293). This may relate to the level of fortification, types and choice of food vehicles and the issue of mandatory or optional/voluntary fortification. It was recently demonstrated that the 95th percentile of intake of vitamin D from voluntary fortified foods in Europe is low (291). Finland has focused on improving vitamin D status in the whole population by extensive fortification. In April 2010, The National Nutrition Council launched a new recommendation that the earlier fortification levels should be doubled to 1.0 µg/100 g (40 IU/100 g) for all fluid milk products and that 20 µg/100 g (800 IU/100 g) should be used for spreadable fats. These recommendations were based on simulations of the effect of fortification. Especially the dairy industry responded immediately and almost all fluid milk products were fortified, with the exception of ecological products. This fortification has had a positive impact on the vitamin D intake and status in adults, whose mean vitamin D intake now is about 10 µg, where close to 40–50% comes from fortified milk products (147). The vitamin D status has also improved as demonstrated recently when a comparison of standardized serum 25(OH)D data from two nationally representative surveys of Finnish adults 11 years apart showed that less than 6% had a 25(OH)D concentration lower than 50 nmol/L in the autumn/early winter months in 2011 compared to the situation in 2000 when about 50% had concentrations lower than 50 nmol/L (47). Also of note, the prevalence of severe vitamin D deficiency (<30 nmol/L) decreased from 13% to 0.6% over the 11 year period (47).

The ECTS Working Group acknowledges the valuable contribution of fortified milk to vitamin D intakes, particularly in children, and the continued need for fortification of milk and other dairy products. However, fortification, including bio-fortification, of a wider range of foods offers more possibilities. Well-designed sustainable fortification strategies, which use a range of foods to accommodate diversity, have the potential to increase vitamin D intakes across the population distribution and minimize the prevalence of a low serum 25(OH)D concentration (294, 295). To provide evidence, we need to model European food and vitamin D intake data to ascertain which food vehicles and what level of vitamin D addition will ensure an effective but safe rise in serum 25(OH)D concentration in all segments of the European population. The benefits and limitations of bio-fortification of various foods are investigated in the EU Framework 7 ODIN project. This includes plant and animal-based food via UVB irradiation of yeast and mushrooms (296), and addition of the most effective forms of vitamin D (vitamin D3 or calcifediol in some cases) to the feeds of the animals with ultimate inclusion in the tissue for use as foods. Data from the project suggests that a combination of traditional fortification of dairy foods together with the newer approach of bio-fortification of foods with vitamin D can allow for an mean intake within the population of 10 µg/day conforming to the EAR (2) as published by the IOM.

In Middle East countries food fortification is sporadic and the use of supplements is low (177). Furthermore, dairy products are only consumed by a minority of the population. Fortification of wheat flour may have potential to alleviate vitamin D deficiency in countries such as India and Jordan, where pasteurized milk is not widely consumed (297). The Gulf Countries Council mandates a wheat flour standard (GS194) that includes vitamin D fortification of flour, and several countries have initiated it. These include Jordan, Palestine and Saudi Arabia that initiated flour fortification with vitamin D at 13.8 µg (550 IU) per kg of flour, a very cost-effective public health intervention to prevent rickets, estimated to incur a cost of 0.04–0.05 US$ per metric ton of flour (Personal communication Quentin Johnson, Food Fortification Initiative, www.ffinetwork.org and Ayoub Al Jawaldeh WHO Eastern Mediterranean Region). The United States Agency for International Development adds 13.8 µg (550 IU) of vitamin D/kg of vegetable oil standard, 0.4–0.6 µg (16–23 IU) per g of oil for their food aid programs. Such initiatives will help countries like Yemen, Iraq and now Syrian refugees in Lebanon, Jordan, Iraq and Turkey. World Food Program standards include vitamin D in both cereal flours and vegetable oil for their emergency programs, an important point in the Middle East refugee context. While these initiatives will undoubtedly help boost serum 25(OH)D concentrations in these regions, their impact on attaining serum 25(OH)D target concentrations, if higher than very conservative ones, is less clear. In addition, vegetable oil and milk standards may include vitamin A and D, but these are mostly voluntary or by covenant at the moment. More on micronutrient fortification of foods in developing countries can be found on http://www.gainhealth.org/programs/initiatives/#global-tracking.

Recommendations

The ECTS Working Group recommends the following:

  • A reliable estimation of vitamin D status, such as performed in the ODIN project, should be performed in all European countries and the Middle East (28). This requires utilization of protocol to conduct retrospective standardization of the available serum 25(OH)D data as well as a greater effort to standardize assays for accurate measurement of 25(OH)D into the future. All publications and reports on vitamin D status should include such standardized data.

  • Fortification of foods is the preferred strategy to increase vitamin D intake and status over all segments of the population, provided that adequate quality assurance monitoring is performed. Milk, yogurt and other milk products are to be fortified with around 10 µg/L (400 IU/L). Other options such as fortification of flour and oil with vitamin D as well as bio-fortification of animal-derived food products, such as eggs, red meats and cultured fish, should be considered carefully as additional means of increasing vitamin D intake in the population.

  • Vitamin D supplements are recommended for special risk groups in order to increase the serum 25(OH)D concentration above 50 nmol/L in all countries of Europe and the Middle East.

  • A vitamin D supplement of 10 µg/day (400 IU/day) is advised for all children of 0–1 year and preferably 0–3 year to eradicate rickets.

  • A vitamin D supplement of 10–15 µg/day (400–600 IU/day) is advised for all pregnant women.

  • A vitamin D supplement of 10–20 µg/day (400–800 IU/day) is advised- to all older institutionalized subjects and should be considered for all older persons above 70 year.

  • A vitamin D supplement of 10 µg/day (400 IU/day) should be considered for non-Western immigrants and refugees.

Research agenda

  • Effects of food fortification (milk, oil, flour/bread, juice, bio-fortified foods) have to be studied per fortified food item in different countries with regard to different risk groups in the population such as young children, pregnant women, older persons and non-Western immigrants and compared with the effects of vitamin D supplementation.

  • Further study is needed on vitamin D requirement in the Middle East (257, 258) and on measures to prevent vitamin D deficiency.

  • The impact of individual participant data (IPD) meta-regression analysis on the required vitamin D intake compared to standard meta-regression has to be studied, as the latter suggests that the requirement may be higher (259). The IPD approach could be applied to other population subgroups, such as pregnant women and ethnic groups.

  • Regular monitoring of vitamin D intake (using comprehensive vitamin D food composition data) and vitamin D status by standardized 25(OH)D assays should be organized in all European and Middle East countries and should guide future intervention strategies.

  • The occurrence of rickets should be monitored in all European and Middle East countries.

  • When the results of ongoing large randomized vitamin D trials (Table 5) become available, the optimal serum 25(OH)D concentration and the corresponding vitamin D intake should be adjusted.

  • Genetic studies are recommended to investigate the individual vulnerability for vitamin D deficiency. Mendelian randomization studies can elucidate the long-term impact of vitamin D deficiency on cancer and autoimmune disease outcomes, as to guide clinical decision-making in case RCTs are not available and cannot be performed for whatever reason.

Conclusion

In order to compare vitamin D status between different countries and to get a reliable estimate of the prevalence of vitamin D deficiency, standardized 25(OH)D assays should be used in population-based surveys. This should include all ongoing studies and whenever possible, also representative samples of older major published surveys and trials. The prevalence of a low serum 25(OH)D concentration (<50 nmol/L) is high, that is more than 50% during winter, in many European and Middle East countries. Even more worrying is the presence of severe vitamin D deficiency (below 25/30 nmol/L) in specific risk groups. The spectrum ranges from adequate vitamin D status in the Nordic countries to severe deficiency in the Middle East. Vitamin D status usually is poor in non-Western immigrants. According to current evidence, the desirable serum 25(OH)D concentration is set at 50 nmol/L or higher. While most experts agree on this concentration, it is uncertain whether higher concentrations provide additional benefit. When the results of ongoing randomized clinical trials are available, the required serum 25(OH)D concentration may have to be modified, depending on the outcome. It will require a tremendous effort to improve vitamin D status in Europe and the Middle East and reduce the percentage of the population with a serum 25(OH)D concentration below 50 nmol/L. This may translate into targeted approaches such as prudent sun exposure, adequate nutrition, food fortification policy and vitamin D supplementation for high-risk groups. Elimination of nutritional rickets should receive the highest priority. As there is near universal agreement that serum 25(OH)D concentrations should exceed 25/30 nmol/L; at whatever age, strategies to eliminate this deficiency, particularly in children, pregnant women, older persons and immigrants, should receive the highest priority by public health authorities and health care providers.

Declaration of interest

Paul Lips: He received lecture fee from Abiogen. He chaired the vitamin D Workshop in 2015. Kevin D Cashman: He was a member of the UK SACN vitamin D working group. Heike Annette Bischoff-Ferrari: During the last 3 years HABF received investigator-initiated grant support from DSM Nutritional Products and WILD, received speaker fees from Pfizer, Roche Diagnostics, Meda, Sandoz and Sanofi. Maria Luisa Bianchi: She received consultancy honoraria from Alexion Pharmaceuticals and Kyowa Kirin. Roger Bouillon: He received lecture fees (over the last 2 years) from Abiogen, l’Oreal and FAES (Spain) and Fresenius, and is co-owner of an university patent on vitamin D analogs, licensed to Hybrigenix (France); he is member of the organizing committee of the Vitamin D Workshop. The other authors have nothing to disclose.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

References

  • 1

    HolickMFBinkleyNCBischoff-FerrariHAGordonCMHanleyDAHeaneyRPMuradMHWeaverCM & Endocrine Society. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism 2011 96 19111930. (https://doi.org/10.1210/jc.2011-0385)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2

    Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. Washington DC: The National Academies Press2011.

  • 3

    BouillonRvan SchoorNMGielenEBoonenSMathieuCVanderschuerenDLipsP. Optimal vitamin D status: a critical analysis on the basis of evidence-based medicine. Journal of Clinical Endocrinology and Metabolism 2013 98 E1283E1304. (https://doi.org/10.1210/jc.2013-1195)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4

    SeamansKMCashmanKD. Existing and potentially novel functional markers of vitamin D status: a systematic review. American Journal of Clinical Nutrition 2009 89 1997S2008S. (https://doi.org/10.3945/ajcn.2009.27230D)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5

    CarterGDJonesJCShannonJWilliamsELJonesGKaufmannMSemposC. 25-Hydroxyvitamin D assays: potential interference from other circulating vitamin D metabolites. Journal of Steroid Biochemistry and Molecular Biology 2016 164 134138. (https://doi.org/10.1016/j.jsbmb.2015.12.018)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6

    JongenMJvan der VijghWJWillemsHJNetelenbosJCLipsP. Simultaneous determination of 25-hydroxyvitamin D, 24,25-dihydroxyvitamin D, and 1,25-dihydroxyvitamin D in plasma or serum. Clinical Chemistry 1981 27 17571760.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    CashmanKDHayesAGalvinKMerkelJJonesGKaufmannMHoofnagleANCarterGDDurazo-ArvizuRASemposCT. Significance of serum 24,25-dihydroxyvitamin D in the assessment of vitamin D status: a double-edged sword? Clinical Chemistry 2015 61 636645. (https://doi.org/10.1373/clinchem.2014.234955)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    KaufmannMGallagherJCPeacockMSchlingmannKPKonradMDeLucaHFSigueiroRLopezBMourinoAMaestroM et al. Clinical utility of simultaneous quantitation of 25-hydroxyvitamin D and 24,25-dihydroxyvitamin D by LC-MS/MS involving derivatization with DMEQ-TAD. Journal of Clinical Endocrinology and Metabolism 2014 99 25672574. (https://doi.org/10.1210/jc.2013-4388)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9

    MolinABaudoinRKaufmannMSouberbielleJCRyckewaertAVantyghemMCEckartPBacchettaJDeschenesGKesler-RousseyG et al. CYP24A1 mutations in a cohort of hypercalcemic patients: evidence for a recessive trait. Journal of Clinical Endocrinology and Metabolism 2015 100 E1343E1352. (https://doi.org/10.1210/jc.2014-4387)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10

    LipsP. Relative value of 25(OH)D and 1,25(OH)2D measurements. Journal of Bone and Mineral Research 2007 22 16681671. (https://doi.org/10.1359/jbmr.070716)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11

    AbreuMTKantorovichVVasiliauskasEAGruntmanisUMatukRDaigleKChenSZehnderDLinYCYangH et al. Measurement of vitamin D levels in inflammatory bowel disease patients reveals a subset of Crohn’s disease patients with elevated 1,25-dihydroxyvitamin D and low bone mineral density. Gut 2004 53 11291136. (https://doi.org/10.1136/gut.2003.036657)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    MakinHLJJonesGKaufmannMCalverleyMJ. Analysis of vitamin D, their metabolites and analogs. In Steroid Analysis2nd ed. Chapter 11 pp 9671096. Eds MakinHLJ & GowerDB. Springer Science and Business MediaBerlin 2010.

    • Search Google Scholar
    • Export Citation
  • 13

    HollisBWNapoliJL. Improved radioimmunoassay for vitamin D and its use in assessing vitamin D status. Clinical Chemistry 1985 31 18151819.

  • 14

    RossACMansonJEAbramsSAAloiaJFBrannonPMClintonSKDurazo-ArvizuRAGallagherJCGalloRLJonesG et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. Journal of Clinical Endocrinology and Metabolism 2011 96 5358. (https://doi.org/10.1210/jc.2010-2704)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15

    De la HuntyAWallaceAMGibsonSViljakainenHLamberg-AllardtCAshwellM. UK Food Standards Agency Workshop Consensus Report: the choice of method for measuring 25-hydroxyvitamin D to estimate vitamin D status for the UK National Diet and Nutrition Survey. British Journal of Nutrition 2010 104 612619. (https://doi.org/10.1017/S000711451000214X)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16

    BikleDBouillonRThadhaniRSchoenmakersI. Vitamin D metabolites in captivity? Should we measure free or total 25(OH)D to assess vitamin D status? Journal of Steroid Biochemistry and Molecular Biology 2017 173 105116. (https://doi.org/10.1016/j.jsbmb2017.01.007)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17

    CarterGDBerryJLGunterEJonesGJonesJCMakinHLJSufiSWheelerMJ. Proficiency testing of 25-hydroxyvitamin D (25-OHD) assays. Journal of Steroid Biochemistry and Molecular Biology 2010 121 176179. (https://doi.org/10.1016/j.jsbmb.2010.03.033)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18

    CarterGDJonesJC. Use of a common standard improves the performance of liquid chromatography-tandem mass spectrometry methods for serum 25-hydroxyvitamin-D. Annals of Clinical Biochemistry 2009 46 7981. (https://doi.org/10.1258/acb.2008.008135)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    BarakeMDaherRTSaltiICortasNKAl-ShaarLHabibRHFuleihanGel-H. 25-Hydroxyvitamin D assay variations and impact on clinical decision making. Journal of Clinical Endocrinology and Metabolism 2012 97 835843. (https://doi.org/10.1210/jc.2011-2584)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20

    CarterGDBerryJDurazo-ArvizuRGunterEJonesGJonesJMakinHLJPattniPSemposCTTwomeyP et al. Hydroxyvitamin D assays: an historical perspective from DEQAS. Journal of Steroid Biochemistry and Molecular Biology 2018 177 3035. (https://doi.org/10.1016/j.jsbmb.2017.07.018)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21

    BinkleyNSemposCT & Vitamin D Standardization Program (VDSP). Standardizing vitamin D assays: the way forward. Journal of Bone and Mineral Research 2014 29 17091714. (https://doi.org/10.1002/jbmr.2252)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22

    BinkleyNKruegerDCowgillCSPlumLLakeEHansenKEDeLucaHFDreznerMK. Assay variation confounds the diagnosis of hypovitaminosis D: a call for standardization. Journal of Clinical Endocrinology and Metabolism 2004 89 31523157. (https://doi.org/10.1210/jc.2003-031979)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23

    LipsPChapuyMCDawson-HughesBPolsHAHolickMF. An international comparison of serum 25-hydroxyvitamin D measurements. Osteoporosis International 1999 9 394397. (https://doi.org/10.1007/s001980050162)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24

    SemposCTVesperHWPhinneyKWThienpontLMCoatesPM & Vitamin D Standardization Program (VDSP). Vitamin D status as an international issue: national surveys and the problem of standardization. Scandinavian Journal of Clinical and Laboratory Investigation. Supplementum 2012 243 3240. (https://doi.org/10.3109/00365513.2012.681935)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    PrenticeA. Vitamin D deficiency: a global perspective. Nutrition Reviews 2008 66 S153S164. (https://doi.org/10.1111/j.1753-4887.2008.00100.x)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26

    BinkleyNCarterGD. Toward clarity in clinical vitamin D status assessment: 25(OH)D assay standardization. Endocrinology and Metabolism Clinics of North America 2017 46 885899. (https://doi.org/10.1016/j.ecl.2017.07.012)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27

    SemposCTDurazo-ArvizuRADawson-HughesBYetleyEALookerACSchleicherRLCaoGBurtVKramerHBaileyRL et al. Is there a reverse J-shaped association between 25-hydroxyvitamin D and all-cause mortality? Results from the U.S. nationally representative NHANES. Journal of Clinical Endocrinology and Metabolism 2013 98 30013009. (https://doi.org/10.1210/jc.2013-1333)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28

    CashmanKDDowlingKGSkrabakovaZGonzalez-GrossMValtuenaJDe HenauwSMorenoLDamsgaardCTMichaelsenKFMolgaardC et al. Vitamin D deficiency in Europe: pandemic? American Journal of Clinical Nutrition 2016 103 10331044. (https://doi.org/10.3945/ajcn.115.120873)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29

    European Food Safety Authority EEFS. Scientific opinion on dietary reference values for vitamin D. EFSA Journal 2016 14 4547.

  • 30

    Scientific Advisory Committee on Nutrition. Draft SACN vitamin D and health report (Internet). Report Pdf2015.

  • 31

    van der WielenRPLowikMRvan den BergHde GrootLCHallerJMoreirasOvan StaverenWA. Serum vitamin D concentrations among elderly people in Europe. Lancet 1995 346 207210. (https://doi.org/10.1016/S0140-6736(95)91266-5)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    McKennaMJ. Differences in vitamin D status between countries in young adults and the elderly. American Journal of Medicine 1992 93 6977. (https://doi.org/10.1016/0002-9343(92)90682-2)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 33

    SpiroAButtrissJL. Vitamin D: an overview of vitamin D status and intake in Europe. Nutrition Bulletin 2014 39 322350. (https://doi.org/10.1111/nbu.12108)

  • 34

    WahlDACooperCEbelingPREggersdorferMHilgerJHoffmanKJosseRKanisJAMithalAPierrozDD et al. A global representation of vitamin D status in healthy populations. Archives of Osteoporosis 2012 7 155172. (https://doi.org/10.1007/s11657-012-0093-0)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35

    HilgerJFriedelAHerrRRauschTRoosFWahlDAPierrozDDWeberPHoffmannK. A systematic review of vitamin D status in populations worldwide. British Journal of Nutrition 2014 111 2345. (https://doi.org/10.1017/S0007114513001840)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36

    CashmanKDDowlingKGSkrabakovaZKielyMLamberg-AllardtCDurazo-ArvizuRASemposCTKoskinenSLundqvistASundvallJ et al. Standardizing serum 25-hydroxyvitamin D data from four Nordic population samples using the Vitamin D Standardization Program protocols: shedding new light on vitamin D status in Nordic individuals. Scandinavian Journal of Clinical and Laboratory Investigation 2015 75 549561. (https://doi.org/10.3109/00365513.2015.1057898)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37

    BuchebnerDMcGuiganFGerdhemPMalmJRidderstraleMAkessonK. Vitamin D insufficiency over 5 years is associated with increased fracture risk-an observational cohort study of elderly women. Osteoporosis International 2014 25 27672775. (https://doi.org/10.1007/s00198-014-2823-1)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 38

    MelhusHSnellmanGGedeborgRBybergLBerglundLMallminHHellmanPBlomhoffRHagstromEArnlovJ et al. Plasma 25-hydroxyvitamin D levels and fracture risk in a community-based cohort of elderly men in Sweden. Journal of Clinical Endocrinology and Metabolism 2010 95 26372645. (https://doi.org/10.1210/jc.2009-2699)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 39

    BrembeckPWinkvistAOlaussonH. Determinants of vitamin D status in pregnant fair-skinned women in Sweden. British Journal of Nutrition 2013 110 856864. (https://doi.org/10.1017/S0007114512005855)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 40

    ErikssonSStrandvikB. Vitamin D status in healthy children in Sweden still satisfactory. Changed supplementation and new knowledge motivation for further studies. Läkartidningen 2016 107 24742477.

    • Search Google Scholar
    • Export Citation
  • 41

    AndersenRMolgaardCSkovgaardLTBrotCCashmanKDChabrosECharzewskaJFlynnAJakobsenJKarkkainenM et al. Teenage girls and elderly women living in northern Europe have low winter vitamin D status. European Journal of Clinical Nutrition 2005 59 533541. (https://doi.org/10.1038/sj.ejcn.1602108)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42

    HolvikKMeyerHEHaugEBrunvandL. Prevalence and predictors of vitamin D deficiency in five immigrant groups living in Oslo, Norway: the Oslo Immigrant Health Study. European Journal of Clinical Nutrition 2005 59 5763. (https://doi.org/10.1038/sj.ejcn.1602033)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43

    AndersenRMolgaardCSkovgaardLTBrotCCashmanKDJakobsenJLamberg-AllardtCOvesenL. Pakistani immigrant children and adults in Denmark have severely low vitamin D status. European Journal of Clinical Nutrition 2008 62 625634. (https://doi.org/10.1038/sj.ejcn.1602753)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44

    HolvikKAhmedLAForsmoSGjesdalCGGrimnesGSamuelsenSOScheiBBlomhoffRTellGSMeyerHE. Low serum levels of 25-hydroxyvitamin D predict hip fracture in the elderly: a NOREPOS study. Journal of Clinical Endocrinology and Metabolism 2013 98 33413350. (https://doi.org/10.1210/jc.2013-1468)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 45

    HolvikKBrunvandLBrustadMMeyerHE. Vitamin D Status in the Norwegian Population. Oslo: The Norwegian Academy of Science and Letters2008.

    • Search Google Scholar
    • Export Citation
  • 46

    SteingrimsdottirLGunnarssonOIndridasonOSFranzsonLSigurdssonG. Relationship between serum parathyroid hormone levels, vitamin D sufficiency, and calcium intake. JAMA 2005 294 23362341. (https://doi.org/10.1001/jama.294.18.2336)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 47

    JaaskelainenTItkonenSTLundqvistAErkkolaMKoskelaTLakkalaKDowlingKGHullGLKrogerHKarppinenJ et al. 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. American Journal of Clinical Nutrition 2017 105 15121520. (https://doi.org/10.3945/ajcn.116.151415)

    • Search Google Scholar
    • Export Citation
  • 48

    CarsonELPourshahidiLKHillTRCashmanKDStrainJJBorehamCAMulhernMS. Vitamin D, muscle function, and cardiorespiratory fitness in adolescents from the Young Hearts Study. Journal of Clinical Endocrinology and Metabolism 2015 100 46214628. (https://doi.org/10.1210/jc.2015-2956)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 49

    van SchoorNMKnolDLDeegDJPetersFPHeijboerACLipsP. Longitudinal changes and seasonal variations in serum 25-hydroxyvitamin D levels in different age groups: results of the Longitudinal Aging Study Amsterdam. Osteoporosis International 2014 25 14831491. (https://doi.org/10.1007/s00198-014-2651-3)

    • Search Google Scholar
    • Export Citation
  • 50

    BouillonRAAuwerxJHLissensWDPelemansWK. Vitamin D status in the elderly: seasonal substrate deficiency causes 1,25-dihydroxycholecalciferol deficiency. American Journal of Clinical Nutrition 1987 45 755763. (https://doi.org/10.1093/ajcn/45.4.755)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 51

    HogeADonneauAFStreelSKolhPChapelleJPAlbertACavalierEGuillaumeM. Vitamin D deficiency is common among adults in Wallonia (Belgium, 51 degrees 30′ North): findings from the Nutrition, Environment and Cardio-Vascular Health study. Nutrition Research 2015 35 716725. (https://doi.org/10.1016/j.nutres.2015.06.005)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 52

    ChapuyMCPreziosiPMaamerMArnaudSGalanPHercbergSMeunierPJ. Prevalence of vitamin D insufficiency in an adult normal population. Osteoporosis International 1997 7 439443. (https://doi.org/10.1007/s001980050030)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 53

    ChapuyMCSchottAMGarneroPHansDDelmasPDMeunierPJ. Healthy elderly French women living at home have secondary hyperparathyroidism and high bone turnover in winter. EPIDOS Study Group. Journal of Clinical Endocrinology and Metabolism 1996 81 11291133. (https://doi.org/10.1210/jcem.81.3.8772587)

    • Search Google Scholar
    • Export Citation
  • 54

    SouberbielleJCMassartCBrailly-TabardSCavalierEChansonP. Prevalence and determinants of vitamin D deficiency in healthy French adults: the VARIETE study. Endocrine 2016 53 543550. (https://doi.org/10.1007/s12020-016-0960-3)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 55

    BurnandBSloutskisDGianoliFCornuzJRickenbachMPaccaudFBurckhardtP. Serum 25-hydroxyvitamin D: distribution and determinants in the Swiss population. American Journal of Clinical Nutrition 1992 56 537542. (https://doi.org/10.1093/ajcn/56.3.537)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 56

    CashmanKDMuldowneySMcNultyBNugentAFitzGeraldAPKielyMWaltonJGibneyMJFlynnA. Vitamin D status of Irish adults: findings from the National Adult Nutrition Survey. British Journal of Nutrition 2013 109 12481256. (https://doi.org/10.1017/S0007114512003212)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 57

    TheilerRStahelinHBTyndallABinderKSomorjaiGBischoffHA. Calcidiol, calcitriol and parathyroid hormone serum concentrations in institutionalized and ambulatory elderly in Switzerland. International Journal for Vitamin and Nutrition Research 1999 69 96105. (https://doi.org/10.1024/0300-9831.69.2.96)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 58

    KriegMACornuzJJacquetAFThiebaudDBurckhardtP. Influence of anthropometric parameters and biochemical markers of bone metabolism on quantitative ultrasound of bone in the institutionalized elderly. Osteoporosis International 1998 8 115120. (https://doi.org/10.1007/BF02672506)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 59

    Bischoff-FerrariHACanUStaehelinHBPlatzAHenschkowskiJMichelBADawson-HughesBTheilerR. Severe vitamin D deficiency in Swiss hip fracture patients. Bone 2008 42 597602. (https://doi.org/10.1016/j.bone.2007.10.026)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 60

    BischofMGHeinzeGVierhapperH. Vitamin D status and its relation to age and body mass index. Hormone Research 2006 66 211215. (https://doi.org/10.1159/000094932)

  • 61

    AmreinKZajicPSchnedlCWaltensdorferAFruhwaldSHollAPurkartTWunschGValentinTGrisoldA et al. Vitamin D status and its association with season, hospital and sepsis mortality in critical illness. Critical Care 2014 18 R47. (https://doi.org/10.1186/cc13790)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 62

    KudlacekSSchneiderBPeterlikMLebGKlaushoferKWeberKWoloszczukWWillvonsederR & Austrian Study Group on Normative Values of Bone. Assessment of vitamin D and calcium status in healthy adult Austrians. European Journal of Clinical Investigation 2003 33 323331. (https://doi.org/10.1046/j.1365-2362.2003.01127.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 63

    GoldraceMHallNYeatesDG. Hospitalisation for children with rickets in England: a historical perspective. Lancet 2014 383 597598. (https://doi.org/10.1016/S0140-6736(14)60211-7)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 64

    van der MeerIMBoekeAJPLipsPGrootjans-GeertsIWuisterJDDevilleWLJMWieldersJPMBouterLMMiddelkoopBJC. Fatty fish and supplements are the greatest modifiable contributors to the serum 25-hydroxyvitamin D concentration in a multiethnic population. Clinical Endocrinology 2008 68 466472. (https://doi.org/10.1111/j.1365-2265.2007.03066.x)

    • Search Google Scholar
    • Export Citation
  • 65

    van der MeerIMKaramaliNSBoekeAJLipsPMiddelkoopBJVerhoevenIWuisterJD. High prevalence of vitamin D deficiency in pregnant non-western women in the Hague, Netherlands. American Journal of Clinical Nutrition 2006 84 350353; quiz 468. (https://doi.org/10.1093/ajcn/84.1.350)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 66

    LipsP. Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications. Endocrine Reviews 2001 22 477501. (https://doi.org/10.1210/edrv.22.4.0437)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 67

    QuesadaJMJansIBenitoPJimenezJABouillonR. Vitamin D status of elderly people in Spain. Age and Ageing 1989 18 392397. (https://doi.org/10.1093/ageing/18.6.392)

  • 68

    Navarro-ValverdeCQuesada-GomezJM. Vitamin D deficiency in Spain. Reality or myth? Revista de Osteoporosis y Metabolismo Mineral 2014 6 (Supplement 1) S5S10. (https://doi.org/10.4321/S1889-836X2014000500002)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 69

    BetticaPBevilacquaMVagoTNorbiatoG. High prevalence of hypovitaminosis D among free-living postmenopausal women referred to an osteoporosis outpatient clinic in northern Italy for initial screening. Osteoporosis International 1999 9 226229. (https://doi.org/10.1007/s001980050141)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 70

    IsaiaGGiorginoRRiniGBBevilacquaMMaugeriDAdamiS. Prevalence of hypovitaminosis D in elderly women in Italy: clinical consequences and risk factors. Osteoporosis International 2003 14 577582. (https://doi.org/10.1007/s00198-003-1390-7)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 71

    ChallaANtourntoufiACholevasVBitsoriMGalanakisEAndronikouS. Breastfeeding and vitamin D status in Greece during the first 6 months of life. European Journal of Pediatrics 2005 164 724729. (https://doi.org/10.1007/s00431-005-1757-1)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 72

    PludowskiPGrantWBBhattoaHPBayerMPovoroznyukVRudenkaERamanauHVarbiroSRudenkaAKarczmarewiczE et al. Vitamin D status in central Europe. International Journal of Endocrinology 2014 2014 589587. (https://doi.org/10.1155/2014/589587)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 73

    HoleckiMZahorska-MarkiewiczBChudekJWiecekA. Changes in bone mineral density and bone turnover markers in obese women after short-term weight loss therapy during a 5-year follow-up. Polskie Archiwum Medycyny Wewnetrznej 2010 120 248254.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 74

    KullMJKallikormRTammALemberM. Seasonal variance of 25-(OH) vitamin D in the general population of Estonia, a northern European country. BMC Public Health 2009 9 22. (https://doi.org/10.1186/1471-2458-9-22)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 75

    MayerOJFilipovskyJSeidlerovaJVanekJDolejsovaMVrzalovaJCifkovaR. The association between low 25-hydroxyvitamin D and increased aortic stiffness. Journal of Human Hypertension 2012 26 650655. (https://doi.org/10.1038/jhh.2011.94)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 76

    KocjanTTanTM-MConwayGSPrelevicG. Vitamin D status in patients with osteopenia or osteoporosis – an audit of an endocrine clinic. International Journal for Vitamin and Nutrition Research 2006 76 307313. (https://doi.org/10.1024/0300-9831.76.5.307)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 77

    ViraghEHorvathDLocseiZKovacsLJagerRVargaBKovacsLGSalamonneTE. Vitamin D supply among healthy blood donors in Vas County, Hungary. Orvosi Hetilap 2012 153 16291637. (https://doi.org/10.1556/OH.2012.29459)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 78

    BhattoaHPBettembukPGanacharyaSBaloghA. Prevalence and seasonal variation of hypovitaminosis D and its relationship to bone metabolism in community dwelling postmenopausal Hungarian women. Osteoporosis International 2004 15 447451. (https://doi.org/10.1007/s00198-003-1566-1)

    • Search Google Scholar
    • Export Citation
  • 79

    BhattoaHPNagyEMoreCKappelmayerJBaloghAKalinaEAntal-SzalmasP. Prevalence and seasonal variation of hypovitaminosis D and its relationship to bone metabolism in healthy Hungarian men over 50 years of age: the HunMen Study. Osteoporosis International 2013 24 179186. (https://doi.org/10.1007/s00198-012-1920-2)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 80

    Laktasic-ZerjavicNKorsicMCrncevic-OrlicZKovacZPolasekOSoldo-JuresaD. Vitamin D status, dependence on age, and seasonal variations in the concentration of vitamin D in Croatian postmenopausal women initially screened for osteoporosis. Clinical Rheumatology 2010 29 861867. (https://doi.org/10.1007/s10067-010-1409-3)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 81

    BakhtiyarovaSLesnyakOKyznesovaNBlankensteinMALipsP. Vitamin D status among patients with hip fracture and elderly control subjects in Yekaterinburg, Russia. Osteoporosis International 2006 17 441446. (https://doi.org/10.1007/s00198-005-0006-9)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 82

    KozlovAKhabarovaYVershubskyGAteevaYRyzhaenkovV. Vitamin D status of northern indigenous people of Russia leading traditional and ‘modernized’ way of life. International Journal of Circumpolar Health 2014 73 26038. (https://doi.org/10.3402/ijch.v73.26038)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 83

    MeyerHEFalchJASogaardAJHaugE. Vitamin D deficiency and secondary hyperparathyroidism and the association with bone mineral density in persons with Pakistani and Norwegian background living in Oslo, Norway, the Oslo Health Study. Bone 2004 35 412417. (https://doi.org/10.1016/j.bone.2004.04.003)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 84

    IslamMZViljakainenHTKarkkainenMUMSaarnioELaitinenKLamberg-AllardtC. Prevalence of vitamin D deficiency and secondary hyperparathyroidism during winter in pre-menopausal Bangladeshi and Somali immigrant and ethnic Finnish women: associations with forearm bone mineral density. British Journal of Nutrition 2012 107 277283. (https://doi.org/10.1017/S0007114511002893)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 85

    van der MeerIMMiddelkoopBJCBoekeAJPLipsP. Prevalence of vitamin D deficiency among Turkish, Moroccan, Indian and sub-Sahara African populations in Europe and their countries of origin: an overview. Osteoporosis International 2011 22 10091021. (https://doi.org/10.1007/s00198-010-1279-1)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 86

    LipsPDuongTOleksikABlackDCummingsSCoxDNickelsenT. A global study of vitamin D status and parathryoid function in postmenopausal women with osteoporosis: baseline data from the Multiple Outcomes of raloxifene Evaluation Clinical Trial. Journal of Clinical Endocrinology and Metabolism 2001 86 12121221. (https://doi.org/10.1210/jcem.86.3.7327)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 87

    KuchukNOvan SchoorNMPluijmSMChinesALipsP. Vitamin D status, parathyroid function, bone turnover, and BMD in postmenopausal women with osteoporosis: global perspective. Journal of Bone and Mineral Research 2009 24 693701. (https://doi.org/10.1359/jbmr.081209)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 88

    PrenticeA. Nutritional rickets around the world. Journal of Steroid Biochemistry and Molecular Biology 2013 136 201206. (https://doi.org/10.1016/j.jsbmb.2012.11.018)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 89

    HolickMF. Vitamin D deficiency. New England Journal of Medicine 2007 357 266281. (https://doi.org/10.1056/NEJMra070553)

  • 90

    MithalAWahlDABonjourJPBurckhardtPDawson-HughesBEismanJAEl-Hajj FuleihanGJosseRGLipsPMorales-TorresJ et al. Global vitamin D status and determinants of hypovitaminosis D. Osteoporosis International 2009 20 18071820. (https://doi.org/10.1007/s00198-009-0954-6)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 91

    van SchoorNLipsP. Global overview of vitamin D status. Endocrinology and Metabolism Clinics of North America 2017 46 845870. (https://doi.org/10.1016/j.ecl.2017.07.002)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 92

    BassilDRahmeMHoteitMEl-Hajj FuleihanGel-H. Hypovitaminosis D in the Middle East and North Africa: prevalence, risk factors and impact on outcomes. Dermato-Endocrinology 2013 5 274298. (https://doi.org/10.4161/derm.25111)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 93

    HekimsoyZDincGKafescilerSOnurEGuvencYPalaTGucluFOzmenB. Vitamin D status among adults in the Aegean region of Turkey. BMC Public Health 2010 10 782. (https://doi.org/10.1186/1471-2458-10-782)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 94

    BuyukusluNEsinKHizliHSunalNYigitPGaripagaogluM. Clothing preference affects vitamin D status of young women. Nutrition Research 2014 34 688693. (https://doi.org/10.1016/j.nutres.2014.07.012)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 95

    ParlakMKalaySKalayZKirecciAGuneyOKokluE. Severe vitamin D deficiency among pregnant women and their newborns in Turkey. Journal of Maternal-Fetal and Neonatal Medicine 2015 28 548551. (https://doi.org/10.3109/14767058.2014.924103)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 96

    KaraguzelGDilberBCanGOktenADegerOHolickMF. Seasonal vitamin D status of healthy schoolchildren and predictors of low vitamin D status. Journal of Pediatric Gastroenterology and Nutrition 2014 58 654660. (https://doi.org/10.1097/MPG.0000000000000274)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 97

    MasoompourSMSadegholvaadALarijaniBRanjbar-OmraniG. Effects of age and renal function on vitamin D status in men. Archives of Iranian Medicine 2008 11 377381. (https://doi.org/08114/AIM.007)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 98

    HosseinpanahFYarjanliMSheikholeslamiFHeibatollahiMEskandaryPSAziziF. Associations between vitamin D and cardiovascular outcomes; Tehran Lipid and Glucose Study. Atherosclerosis 2011 218 238242. (https://doi.org/10.1016/j.atherosclerosis.2011.05.016)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 99

    HosseinpanahFRambodMHossein-nejadALarijaniBAziziF. Association between vitamin D and bone mineral density in Iranian postmenopausal women. Journal of Bone and Mineral Metabolism 2008 26 8692. (https://doi.org/10.1007/s00774-007-0791-7)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 100

    KaykhaeiMAHashemiMNarouieBShikhzadehARashidiHMoulaeiNGhavamiS. High prevalence of vitamin D deficiency in Zahedan, southeast Iran. Annals of Nutrition and Metabolism 2011 58 3741. (https://doi.org/10.1159/000323749)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 101

    KhalesiNBahaeddiniSMShariatM. Prevalence of maternal vitamin D deficiency in neonates with delayed hypocalcaemia. Acta Medica Iranica 2012 50 740745.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 102

    NasehAAshrafzadehSRassiS. Prevalence of vitamin D deficiency in pregnant mothers in Tehran and investigating its association with serum glucose and insulin. Journal of Maternal-Fetal and Neonatal Medicine 2018 31 23122318. (https://doi.org/10.1080/14767058.2017.1342796)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 103

    TorkamanMAbolghasemiHAmirsalariSBeiraghdarFAfsharpaimanSKavehmaneshZKhosraviMH. Comparison of the vitamin D status of children younger and older than 2 years in Tehran: are supplements really necessary? International Journal of Endocrinology and Metabolism 2016 14 e34676. (https://doi.org/10.5812/ijem.34676)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 104

    Sayed-HassanRAbazidNAlourfiZ. Relationship between 25-hydroxyvitamin D concentrations, serum calcium, and parathyroid hormone in apparently healthy Syrian people. Archives of Osteoporosis 2014 9 176. (https://doi.org/10.1007/s11657-014-0176-1)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 105

    SalibaWBarnettORennertHSRennertG. The risk of all-cause mortality is inversely related to serum 25(OH)D levels. Journal of Clinical Endocrinology and Metabolism 2012 97 27922798. (https://doi.org/10.1210/jc.2012-1747)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 106

    SteinvilALeshem-RubinowEBerlinerSJustoDFinnTIsh-shalomMBiratiEYShalevVSheinbergBRogowskiO. Vitamin D deficiency prevalence and cardiovascular risk in Israel. European Journal of Clinical Investigation 2011 41 263268. (https://doi.org/10.1111/j.1365-2362.2010.02403.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 107

    OrenYShapiraYAgmon-LevinNKivitySZafrirYAltmanALernerAShoenfeldY. Vitamin D insufficiency in a sunny environment: a demographic and seasonal analysis. Israel Medical Association Journal 2010 12 751756.

    • Search Google Scholar
    • Export Citation
  • 108

    KorchiaGAmitaiYMosheGKorchiaLTenenbaumARosenblumJSchechterA. Vitamin D deficiency in children in Jerusalem: the need for updating the recommendation for supplementation. Israel Medical Association Journal 2013 15 333338.

    • Search Google Scholar
    • Export Citation
  • 109

    BatiehaAKhaderYJaddouHHyassatDBatiehaZKhateebMBelbisiAAjlouniK. Vitamin D status in Jordan: dress style and gender discrepancies. Annals of Nutrition and Metabolism 2011 58 1018. (https://doi.org/10.1159/000323097)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 110

    NicholsEKKhatibIMAburtoNJSullivanKMScanlonKSWirthJPSerdulaMK. Vitamin D status and determinants of deficiency among non-pregnant Jordanian women of reproductive age. European Journal of Clinical Nutrition 2012 66 751756. (https://doi.org/10.1038/ejcn.2012.25)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 111

    NicholsEKKhatibIMAburtoNJSerdulaMKScanlonKSWirthJPSullivanKM. Vitamin D status and associated factors of deficiency among Jordanian children of preschool age. European Journal of Clinical Nutrition 2015 69 9095. (https://doi.org/10.1038/ejcn.2014.142)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 112

    MallahEMHamadMFElmanaseerMAQinnaNAIdkaidekNMArafatTAMatalkaKZ. Plasma concentrations of 25-hydroxyvitamin D among Jordanians: effect of biological and habitual factors on vitamin D status. BMC Clinical Pathology 2011 11 8. (https://doi.org/10.1186/1472-6890-11-8)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 113

    Khuri-BulosNLangRDBlevinsMKudybaKLawrenceLDavidsonMFaouriSHalasaNB. Vitamin D deficiency among newborns in Amman, Jordan. Global Journal of Health Science 2013 6 162171. (https://doi.org/10.5539/gjhs.v6n1p162)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 114

    HoteitMAl-ShaarLYazbeckCBou SleimanMGhalayiniTFuleihan GelGel-H. Hypovitaminosis D in a sunny country: time trends, predictors, and implications for practice guidelines. Metabolism 2014 63 968978. (https://doi.org/10.1016/j.metabol.2014.04.009)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 115

    ArabiABaddouraREl-RassiREl-Hajj FuleihanG. Age but not gender modulates the relationship between PTH and vitamin D. Bone 2010 47 408412. (https://doi.org/10.1016/j.bone.2010.05.002)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 116

    AlyahyaKO.VitaminD levels in schoolchildren: a cross-sectional study in Kuwait. BMC Pediatrics 2017 17 213. (https://doi.org/10.1186/s12887-017-0963-0)

  • 117

    MollaAMAl BadawiMHammoudMSMollaAMShukkurMThalibLEliwaMS. Vitamin D status of mothers and their neonates in Kuwait. Pediatrics International 2005 47 649652. (https://doi.org/10.1111/j.1442-200x.2005.02141.x)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 118

    ArdawiMSSibianyAMBakhshTMQariMHMaimaniAA. High prevalence of vitamin D deficiency among healthy Saudi Arabian men: relationship to bone mineral density, parathyroid hormone, bone turnover markers, and lifestyle factors. Osteoporosis International 2012 23 675686. (https://doi.org/10.1007/s00198-011-1606-1)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 119

    Al ShaikhAMAbaalkhailBSolimanAKaddamIAseriKAl-SalehYAl QarniAAl ShuaibiAAl TamimiWMukhtarAM. Prevalence of vitamin D deficiency and calcium homeostasis in Saudi children. Journal of Clinical Research in Pediatric Endocrinology 2016 8 461467. (https://doi.org/10.4274/jcrpe.3301)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 120

    Al-FarisNA. High prevalence of vitamin D deficiency among pregnant Saudi women. Nutrients 2016 8 77. (https://doi.org/10.3390/nu8020077)

  • 121

    RajahJHaqAPettiforJM. Vitamin D and calcium status in urban children attending an ambulatory clinic service in the United Arab Emirates. Dermato-Endocrinology 2012 4 3943. (https://doi.org/10.4161/derm.18250)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 122

    Al AnoutiFThomasJAbdel-WarethLRajahJGrantWBHaqA. Vitamin D deficiency and sun avoidance among university students at Abu Dhabi, United Arab Emirates. Dermato-Endocrinology 2011 3 235239. (https://doi.org/10.4161/derm.3.4.16881)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 123

    GolbaharJAl-SaffarNAltayab DiabDAl-OthmanSDarwishAAl-KafajiG. Predictors of vitamin D deficiency and insufficiency in adult Bahrainis: a cross-sectional study. Public Health Nutrition 2014 17 732738. (https://doi.org/10.1017/S136898001300030X)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 124

    El-MenyarARahilADousaKIbrahimWIbrahimTKhalifaRAbdel RahmanMO. Low vitamin D and cardiovascular risk factors in males and females from a sunny, rich country. Open Cardiovascular Medicine Journal 2012 6 7680. (https://doi.org/10.2174/1874192401206010076)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 125

    BotrosRMSabryIMAbdelbakyRSEidYMNasrMSHendawyLM. Vitamin D deficiency among healthy Egyptian females. Endocrinologia y Nutricion 2015 62 314321. (https://doi.org/10.1016/j.endonu.2015.03.010)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 126

    AyadiIDNouailiEBTalbiEGhdemssiARachedCBahlousAGammoudiAHamoudaSBBouguerraBBouzidK et al. Prevalence of vitamin D deficiency in mothers and their newborns in a Tunisian population. International Journal of Gynaecology and Obstetrics 2016 133 192195. (https://doi.org/10.1016/j.ijgo.2015.09.029)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 127

    DjennaneMLebbahSRouxCDjoudiHCavalierESouberbielleJC. Vitamin D status of schoolchildren in Northern Algeria, seasonal variations and determinants of vitamin D deficiency. Osteoporosis International 2014 25 14931502. (https://doi.org/10.1007/s00198-014-2623-7)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 128

    El MaghraouiAOuzzifZMounachARezqiAAchemlalLBezzaATellalSDehhaouiMGhozlaniI. Hypovitaminosis D and prevalent asymptomatic vertebral fractures in Moroccan postmenopausal women. BMC Women’s Health 2012 12 11. (https://doi.org/10.1186/1472-6874-12-11)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 129

    AtliTGulluSUysalARErdoganG. The prevalence of vitamin D deficiency and effects of ultraviolet light on vitamin D levels in elderly Turkish population. Archives of Gerontology and Geriatrics 2005 40 5360. (https://doi.org/10.1016/j.archger.2004.05.006)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 130

    AlagolFShihadehYBoztepeHTanakolRYarmanSAzizlerliHSandalciO. Sunlight exposure and vitamin D deficiency in Turkish women. Journal of Endocrinological Investigation 2000 23 173177. (https://doi.org/10.1007/BF03343702)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 131

    MishalAA. Effects of different dress styles on vitamin D levels in healthy young Jordanian women. Osteoporosis International 2001 12 931935. (https://doi.org/10.1007/s001980170021)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 132

    MacLaughlinJHolickMF. Aging decreases the capacity of human skin to produce vitamin D3. Journal of Clinical Investigation 1985 76 15361538. (https://doi.org/10.1172/JCI112134)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 133

    LipsPNetelenbosJCJongenMJvan GinkelFCAlthuisALvan SchaikCLvan der VijghWJVermeidenJPvan der MeerC. Histomorphometric profile and vitamin D status in patients with femoral neck fracture. Metabolic Bone Disease and Related Research 1982 4 8593. (https://doi.org/10.1016/0221-8747(82)90021-2)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 134

    BrustadMSandangerTAksnesLLundE. Vitamin D status in a rural population of northern Norway with high fish liver consumption. Public Health Nutrition 2004 7 783789. (https://doi.org/10.1079/PHN2004605)

    • Search Google Scholar
    • Export Citation
  • 135

    BrustadMAlsakerEEngelsenOAksnesLLundE. Vitamin D status of middle-aged women at 65–71 degrees N in relation to dietary intake and exposure to ultraviolet radiation. Public Health Nutrition 2004 7 327335. (https://doi.org/10.1079/PHN2003536)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 136

    AdamiSBertoldoFBragaVFracassiEGattiDGandoliniGMinisolaSBattista RiniG. 25-Hydroxy vitamin D levels in healthy premenopausal wome: association with bone turnover markers and bone mineral density. Bone 2009 45 423426. (https://doi.org/10.1016/j.bone.2009.05.012)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 137

    MatsuokaLYWortsmanJHaddadJGKolmPHollisBW. Racial pigmentation and the cutaneous synthesis of vitamin D. Archives of Dermatology 1991 127 536538. (https://doi.org/10.1001/archderm.1991.04510010104011)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 138

    KielyMBlackLJ. Dietary strategies to maintain adequacy of circulating 25-hydroxyvitamin D concentrations. Scandinavian Journal of Clinical and Laboratory Investigation. Supplementum 2012 243 1423. (https://doi.org/10.3109/00365513.2012.681893)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 139

    ThorgeirsdottirHValgeirsdottirHGunnarsdottirIGisladottirEGunnarsdottirBEThorsdottirI. Icelandic National Nutrition Survey 2010–2011 Main Results. Reykjavik: Directorate of Health2012.

    • Search Google Scholar
    • Export Citation
  • 140

    LandlæknisE. Ráðleggingar um mataræði og næringarefni fyrir fullorðna og börn frá tveggja ára aldri. 2010 ed. Iceland: Landlaeknir2010.

    • Search Google Scholar
    • Export Citation
  • 141

    MeyerHEBrunvandLBrustadMHolvikKJohanssonLPaulsenJE. Tiltak for å sikre en god vitamin D-status i befolkningen pp 188. Ed HelsedirektoratetS-o. Oslo2006.

    • Search Google Scholar
    • Export Citation
  • 142

    BrustadMBraatenTLundE. Predictors for cod-liver oil supplement use – the Norwegian Women and Cancer Study. European Journal of Clinical Nutrition 2004 58 128136. (https://doi.org/10.1038/sj.ejcn.1601759)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 143

    OvesenLAndersenRJakobsenJ. Geographical differences in vitamin D status, with particular reference to European countries. Proceedings of the Nutrition Society 2003 62 813821. (https://doi.org/10.1079/PNS2003297)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 144

    NORDEN. Nordic Nutrition Recommendations 5th ed (NNR5)–vitamin D 2012.

  • 145

    BeckerWPearsonM. Riksmaten 1997–1998. Uppsala: Livsmedelsverket2004.

  • 146

    Enghardt BarbieriHPearsonMBeckerW. Riksmaten-Barn. Livsmedels-och Näringsintag Bland Barn i Sverige. Uppsala: Ord&Form2003.

  • 147

    HelldánARaulioSKosolaMTapanainenHOvaskainenM-LVirtanenS. Finravinto 2012-Tutkimus – The National FINDIET 2012 Survey p 187. Helsinki, Finland2013.

    • Search Google Scholar
    • Export Citation
  • 148

    KyttalaPErkkolaMKronberg-KippilaCTapanainenHVeijolaRSimellOKnipMVirtanenSM. Food consumption and nutrient intake in Finnish 1-6-year-old children Finnish. Public Health Nutrition 2010 13 947956. (https://doi.org/10.1017/S136898001000114X)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 149

    ThuesenBHusemoenLFengerMJakobsenJSchwarzPToftUOvesenLJorgensenTLinnebergA. Determinants of vitamin D status in a general population of Danish adults. Bone 2012 50 605610. (https://doi.org/10.1016/j.bone.2011.12.016)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 150

    BlackLJWaltonJFlynnAKielyM. Adequacy of vitamin D intakes in children and teenagers from the base diet, fortified foods and supplements. Public Health Nutrition 2014 17 721731. (https://doi.org/10.1017/S1368980013000359)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 151

    BlackLJWaltonJFlynnACashmanKDKielyM. Small increments in vitamin D intake by Irish adults over a decade show that strategic initiatives to fortify the food supply are needed. Journal of Nutrition 2015 145 969976. (https://doi.org/10.3945/jn.114.209106)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 152

    HennessyÁBrowneFKielyMWaltonJFlynnA. The role of fortified foods and nutritional supplements in increasing vitamin D intake in Irish preschool children. European Journal of Nutrition 2017 56 12191231. (https://doi.org/10.1007/s00394-016-1171-7)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 153

    United Kingdom Government. National Diet and Nutrition Survey (NDNS) Rolling Program2018.

  • 154

    HillTRO’BrienMMCashmanKDFlynnAKielyM. Vitamin D intakes in 18–64-y-old Irish adults. European Journal of Clinical Nutrition 2004 58 15091517. (https://doi.org/10.1038/sj.ejcn.1602001)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 155

    Roman VinasBRibas BarbaLNgoJGurinovicMNovakovicRCavelaarsAde GrootLCvan’t VeerPMatthysCSerra-MajemL. Projected prevalence of inadequate nutrient intakes in Europe. Annals of Nutrition and Metabolism 2011 59 8495. (https://doi.org/10.1159/000332762)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 156

    LipsPvan GinkelFCJongenMJRubertusFvan der VijghWJNetelenbosJC. Determinants of vitamin D status in patients with hip fracture and in elderly control subjects. American Journal of Clinical Nutrition 1987 46 10051010. (https://doi.org/10.1093/ajcn/46.6.1005)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 157

    Verkaik-KloostermanJDoddKWDekkersALvan ‘t VeerPOckeMC. A three-part, mixed-effects model to estimate the habitual total vitamin D intake distribution from food and dietary supplements in Dutch young children. Journal of Nutrition 2011 141 20552063. (https://doi.org/10.3945/jn.111.142398)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 158

    TouvierMDeschasauxMMontourcyMSuttonACharnauxNKesse-GuyotEAssmannKEFezeuLLatino-MartelPDruesne-PecolloN et al. Determinants of vitamin D status in Caucasian adults: influence of sun exposure, dietary intake, sociodemographic, lifestyle, anthropometric, and genetic factors. Journal of Investigative Dermatology 2015 135 378388. (https://doi.org/10.1038/jid.2014.400)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 159

    JungertASpinnekerANagelANeuhauser-BertholdM. Dietary intake and main food sources of vitamin D as a function of age, sex, vitamin D status, body composition, and income in an elderly German cohort. Food and Nutrition Research 2014 58 18. (https://doi.org/10.3402/fnr.v58.23632)

    • Search Google Scholar
    • Export Citation
  • 160

    RabenbergMScheidt-NaveCBuschMARieckmannNHintzpeterBMensinkGB. Vitamin D status among adults in Germany – results from the German Health Interview and Examination Survey for Adults (DEGS1). BMC Public Health 2015 15 641. (https://doi.org/10.1186/s12889-015-2016-7)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 161

    KoenigJElmadfaI. Status of calcium and vitamin D of different population groups in Austria. International Journal for Vitamin and Nutrition Research 2000 70 214220. (https://doi.org/10.1024/0300-9831.70.5.214)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 162

    NovakovicRCavelaarsAEJMBekkeringGERoman-VinasBNgoJGurinovicMGlibeticMNikolicMGolesorkhiMWarthon MedinaM et al. Micronutrient intake and status in Central and Eastern Europe compared with other European countries, results from the EURRECA network. Public Health Nutrition 2013 16 824840. (https://doi.org/10.1017/s-1368-980012004077)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 163

    JenabMSalviniSvan GilsCHBrustadMShakya-ShresthaSBuijsseBVerhagenHTouvierMBiessyCWallstromP et al. Dietary intakes of retinol, beta-carotene, vitamin D and vitamin E in the European Prospective Investigation into Cancer and Nutrition cohort. European Journal of Clinical Nutrition 2009 63 (Supplement 4) S150S178. (https://doi.org/10.1038/ejcn.2009.79)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 164

    BiliciSSaglamFBeyhanYBarut-UyarBDikmenDGoktasZAttarAJMuckaPUyarMF. Energy expenditure and nutritional status of coal miners: a cross-sectional study. Archives of Environmental and Occupational Health 2016 71 293299. (https://doi.org/10.1080/19338244.2015.1095152)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 165

    EjtahedHSShab-BidarSHosseinpanahFMirmiranPAziziF. Estimation of vitamin D intake based on a scenario for fortification of dairy products with vitamin D in a Tehranian population, Iran. Journal of the American College of Nutrition 2016 35 383391. (https://doi.org/10.1080/07315724.2015.1022269)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 166

    KhashayarPQorbaniMKeshtkarAKhashayarPZiaeeALarijaniB. Awareness of osteoporosis among female head of household: an Iranian experience. Archives of Osteoporosis 2017 12 36. (https://doi.org/10.1007/s11657-017-0330-7)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 167

    SabourHHossein-NezhadAMaghbooliZMadaniFMir