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; https://arquivo.pt/wayback/20160421110252/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).
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) |
|---|---|---|---|---|---|
| <25/30 | Deficient | Deficient | Deficient | Deficient | Severely deficient |
| 25–50 | Uncertain* | Deficient | Deficient | Deficient | |
| 50–75 | Sufficient | Insufficient | Sufficient | Sufficient | |
| >75 | Sufficient |
*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).
Vitamin D status in adults and children in different European countries.
| Country | Comments | Study population | n | Age (years) | 25(OH)D | References | ||
|---|---|---|---|---|---|---|---|---|
| Mean ± s.d. (nmol/L) | <25 nmol/L (%) | <50 nmol/L (%) | ||||||
| Iceland (Reykjavik) | Latitude 64°Regionally representative | Adult men and women | 5519 | 66–96 | 57.0 ± 17.8 | 4.2 | 33.6 | Cashman et al. 2016 ( 28 ) |
| Norway (Tromso) | Latitude 69°Regionally representative | Adult men and women | 12 817 | 30–87 | 65.0 ± 17.6 | 0.3 | 18.6 | Cashman et al. 2016 ( 28 ) |
| Norway (Oslo) | Latitude 60° | Adult men and women | 866 | 30–76 | 71.0 ± 19.5 (white) | 0.1 (white) | 14.9 (white) | Cashman et al. 2015 ( 36 ) |
| Sweden | Latitude 58° | Older men | 1194 | 71 | 68.7 ± 19.1 | 0.8 | 17 | Melhus et al. 2010 (38) |
| Sweden | Latitude 56° | OPRA women | 995 | 80 (80–81) | 78 ± 30 | 0 ??? | 16 | Buchebner et al. 2014 (37) |
| Finland | Latitude 60–70°Nationally representative | Adult men and women | 4102 | 29–77 | 67.7 ± 13.2 | 0.2 | 6.6 | Cashman et al. 2015 ( 36)Jaaskelainen et al. 2017 ( 47) |
| Denmark (Copenhagen) | Latitude 56°Regionally representative | Adult men and women | 3409 | 19–72 | 65.0 ± 19.2 | 0 | 23.6 | Cashman et al. 2015 ( 36 ) |
| UK | Latitude 50–59°Nationally representative | Children, teens and adults | 1488 | 1.5–91 | 47.4 ± 19.8 | 15.4 | 56.4 | Cashman et al. 2016 ( 28 ) |
| Northern Ireland | Latitude 55° | Girls and boys | 1015 | 12 and 15 | 66.2 | 16.7 | 66.2 | Carson et al. 2015 ( 48 ) |
| Ireland | Latitude 51–54° | Adults (national representative sample) | 1118 | 18–84 | 56.4 ± 22.2 | 6 (year round) | 45 (year round) | Cashman et al. 2013 ( 56 ) |
| Netherlands | Latitude 52°Nationally representative | LASA 2009 | 915 | 61–99 | 64.7 ± 22.6 | 2.4 | 28.5 | Cashman et al. 2016 ( 28 ) |
| Netherlands | Latitude 52°Regionally representative | Adults | 2625 | 40–66 | 59.5 ± 21.7 | 4.9 | 33.6 | Cashman et al. 2016 ( 28 ) |
| Belgium | Latitude 51° | Adults | 697 | 42.7 (32–53) | 49.3 (35–65) | 7.3 | 51.1 | Hoge et al. 2015 (51) |
| Germany | Latitude 47–55°Nationally representative | Adults | 6995 | 18–79 | 50.1 ± 18.1 | 4.2 | 54.5 | Cashman et al. 2016 ( 28 ) |
| Germany | Latitude 48–52°Nationally representative | Children and adolescents | 10 015 | 1–17 | 54.0 ± 19.2 | 6.0 | 44.5 | Cashman et al. 2016 ( 28 ) |
| France | Varieté studyLatitude 43–49° | Men and women | 892 | 18–89 | 60 ± 20 | 6.3 | 34.6 | Souberbielle et al. 2016 (54) |
| Switzerland | Latitude 47° | MONICA | 3276 | 25–74 | 46 (median) | 6 (<20) | >50 | Burnand et al. 1992 (55) |
| Latitude 47° | Nursing home | Women 246Men 103 | 85 ± 781 ± 8 | 23 ± 1826 ± 21 | 6548 | Krieg et al. 1998 (58) | ||
| Latitude 47° | Non-institut.Elderly | 193 | 80 ± 9 | 18 ± 18 | 90 | Theiler et al. 1999 (57) | ||
| Spain | ||||||||
| Italy | Latitude 38–45° | Postmenop. women | 570 | 59 ± 8 | 45 ± 20 | 28 | Bettica et al. 1999 (69) | |
| Italy | Latitude 38–45° | Multicenter | 700 | 60–80 | 76 | Isaia et al. 2003 (70) | ||
| Greece | Latitude 35–40°Regionally representative | Adolescents | 806 | 9–14 | 47.3 ± 12.5 | 2.2 | 62.4 | Cashman et al. 2016 ( 28 ) |
| Greece | Latitude 37°Regionally representative | Children | 222 | 3–6 | 54.3 ± 15.7 | 1.4 | 40.5 | Cashman et al. 2016 ( 28 ) |
| Poland | Warsaw | Postmenop. women | 6561 | 72 ± 112.6 ± 0.5 | 32.530.6 | 2533 | 9287 | Andersen et al. 2005 (41) |
| Regionally representative | Girls | |||||||
| Estonia | 59° winter | WomenMen | 200167 | 49 ± 1249 ± 12 | 44.6 ± 15.842.7 ± 14.0 | 8 | 73 | Pludowski et al. 2014 (72)Kull et al. 2009 (74) |
| Summer | WomenMen | 200167 | 49 ± 1249 ± 12 | 58.4 ± 17.760.5 ± 18.5 | 1 | 29 | ||
| Czech Republic | 50° | WomenMen | 321239 | 53 ± 14 | 62.5 ± 10 | Mayer et al. 2012 (75) | ||
| Slovakia | 49° | Women | 162 | 32.7 ± 4.4 | 81.5 ± 31.5 | 15 | Pludowski et al. 2014 (72) | |
| Slovenia | Latitude 46° | 448 | 17–89 | 30.5 | 66.4 | Kocjan et al. 2006 (76) | ||
| Hungary | 47° | Women | 319 | 65 (41–91) | 48.4 (12.5–135) | 56.7 (w + m) | Bhattoa et al. 2004 (78) | |
| Men | 206 | 60 (51–81) | 72.8 (11–185) | Bhattoa et al. 2013 (79) | ||||
| Croatia | Latitude 45° | Postmenop. women | 120 | 61.1 ± 8.8 | 46.9 ± 16.8 | 14.2 (<30) | 63.3 | Laktasic et al. 2010 (80) |
| Belarus | 53° | WomenMenWomenWomen | 168176178101 | 45–5555–6565–75>75 | 72 ± 3767 ± 3565 ± 3546 ± 22 | Pludowski et al. 2014 (72) | ||
| Ukraine | 44–52° | WomenMenWomenMen | 64912971186 | 47 (20–59)44 (20–59)69 (60–95)71 (60–91) | 29 ± 1527 ± 1426 ± 1419 ± 9 | Pludowski et al. 2014 (72) | ||
| Russia | Older personsHip fracture patients | 9763 | 70.268.8 | 28 ± 1022 ± 11 | 4765 | Bakhtiyarova et al. 2006 (81) | ||
| Russia | 57–67° | Northern indigenous | 178 | 17–59 | 39.7–47.7 | 2–53 | 8–84 | Kozlov et al. 2014 (82) |
| Vitamin D status in adults and children in different Middle East countries | ||||||||
| Turkey | Manisa | 119 M272 F | 45 ± 1745 ± 17 | 51.8 ± 38.738.1 ± 28.7 | 6679 | Hekimsoy et al. 2010 (93) | ||
| Turkey | Istanbul | students | 100 F | 21 ± 2 | 65.7 ± 25Covered: 52 ± 20Uncovered: 74 ± 8 | 34 | Buyukuslu et al. 2014 (94) | |
| Turkey | Kahramanmaras | Pregnant women newborns, 97 pairs | 97 women97 neonates | 27 ± 50 | 12.5 ± 810.7 ± 6 | 8593 | 98100 | Parlak et al. 2015 (95) |
| Turkey | Trabzon | Schoolchildren | 397 M349 F | 14.6 ± 1.914.6 ± 1.8 | 37.3 ± 20.831.3 ± 17.3 | 2842 | 7887 | Karaguzel 2014 (96) |
| Iran | Shiraz (latitude 30°N) | Selected by postal code number | 520 M | 20–74 | 35 ± 17 | 33.7 | 29.9 (<35 nmol/L) | Masoompour et al. 2008 (97) |
| Iran | Tehran (latitude 35°N) | Controls from lipid and glucose Study | 251 M + F | 56.7 ± 11.7 | 45 (26–77) | 19.1 | 54 (<37.5 nmol/L) | Hosseinpanah et al. 2011 (99) |
| Iran | Zahedan (latitude 30°N) | NA | 431 M562 F | 20–88 | 34.4 ± 29.4 | NA | 85.2 | Kaykhaei et al. 2011 (100) |
| Iran | Tehran | Pregnant women | 149 | 27.9 ± 4.3 | 38.9 ± 16.6 | 38% <30 | Naseh et al. 2018 (102) | |
| Iran | Tehran | Pediatric clinic | 286 | 4.5 ± 2.8 | 50 ± 38 | <2 year: 8>2 year: 43 | Torkaman et al. 2016 (103) | |
| Syria | Damascus (33°N) | Healthy volunteers | 372 | 34.1 ± 10.0 | 24.7 ± 16.9 | 61 | Sayed-Hassan et al. 2014 (104) | |
| Israel | Population based (31°N) | Clalit Health Services | 198 834 M F | 0 to >80 median 60 | 51.9 ± 24.5 | 14.4 | 49.8 | Saliba et al. 2012 (105) |
| Israel | RetrospectivePopulation based (31°N) | Maccabi healthcare services | 8175 M26 699 F | F 55 ± 15M 55 ± 17 | M 60 ± 25F 56.6 ± 24.7 | NA | NA | Steinvil et al. 2011 (106) |
| Israel | (31°N) | Volunteers | 95 M100 F | All ages | 57.15 ± 25.2 | 27.2 | 78 | Oren et al. 2010 (107) |
| Israel | Jerusalem | Healthy children primary care | 247 | 1.5–6 | 64.2 ± 25.0 | 28.3 | Korchia et al. 2013 (108) | |
| Jordan | Population based | National sample | 4590 | 41.9 ± 13.4 | M 183.3 ± 73.3F 99.5 ± 51.7 | 1.514.2 | Batieha et al. 2011 (109) | |
| Jordan | National Micronutrient Survey | Al Basheer Hospital | 2032 F | 15–49 | Median 27.5 | 60% <30 nmol/L | 95 | Nichols et al. 2012 (110) |
| Jordan | National Micronutrient Survey | Al Basheer Hospital | 1077 | 1–5 | Median 45 nmol/L | 20% <30 nmol/L | 56.5 | Nichols et al. 2015 (111) |
| Jordan | Healthy volunteers | M 99F 201 | 2932 | M 44 ± 10F western 40 ± 8F hijab 31 ± 6F niqab 28 ± 4 | 0049 | 769098100 | Mallah et al. 2011 (112) | |
| Jordan | Neonates | Al Bashir Government Hospital Amman | 3731 | 0 | Median 21.5 | ±90 | 94% | Khuri-Bulos et al. 2013 (113) |
| Lebanon | Beirut | Hospital database | 2008 | 2002 2008 | Hoteit et al. 2014 (114) | |||
| 2000–2004 and 2007–2008 | 34930241762 | 12.2 ± 4.549.5 ± 11.672.7 ± 5.7 | F 42.7 M 48.2F 57.0 M 54.0F 59.0 M 54.5 | 63 5860 4462 40 | ||||
| Lebanon | Population basedBeirut (34°N) | Home-dwelling ambulatory subjects | 157 M286 F | 65–85Mean 73 years | 25.7 (10–96.7)M 30.2F 27.3 | 3756 | 9495 | Arabi et al. 2010 (115) |
| Kuwait | Schoolchildren | 199 | 7–9.5 | Median 30M 34; F 27 | Alyahya 2017 (116) | |||
| Kuwait | Mothers and neonates | Al Adan and maternity hospitals | 128 pairs | 27 | Mothers 36.5Neonates 20.5 | 4065 | 7696 | Molla et al. 2005 (117) |
| Saudi Arabia | Riyadh | Pregnant women | 160 | 20–49 | 49.9 (IQR 28) | 18 | 50 | Al-Faris 2016 (120) |
| Saudi Arabia | Population basedJeddah (22°N) | 40 (PHCCs) | M < 50: 550M > 50: 284 | 20–74 | 31.3 ± 17.526.8 ± 15.0 | 52.641.9 | 89.983.8 | Ardawi et al. 2012 (118) |
| Saudi Arabia | Schools all over country | School children | 1013 M1097 F | 6–15 | 28 ± 11 | M 25F 64 | M 93F 98 | Al Shaikh et al. 2016 (119) |
| United Arab Em | Abu Dhabi | University students | 70 M208 F | 21 ± 4 | M 27.3 ± 15.7F 24.2 ± 14.9 | 94 | Al Anouti et al. 2011 (122) | |
| United Arab Em | Abu Dhabi | Pediatric outpatients | 183 | 5.3 ± 3.7 | 53.6 ± 33.4 | 17 | ±57 | Rajah et al. 2012 (121) |
| Bahrein | Manama | Blood donors | 500 | 33.7 ± 10.1 | 27.9 ± 19.3 | 49.4 | 86.4 | Golbahar et al. 2014 (123) |
| Qatar | Doha | Retrospective study in 547 hospital patients | 547 | 49 ± 13 | 36.0 ± 27.5 | 46 | El-Menyar et al. 2012 (124) | |
| Egypt | Cairo and Port Said | Women | Lactating 51Pregnant 50Non pregnant 208Elderly 38Geriatric 57 | 26 ± 526 ± 531 ± 858 ± 476 ± 7 | 3037276637 | 7354724077 | Botros et al. 2015 (125) | |
| Tunisia | Tunis | Mothers and newborns | 87 mothers87 neonates | 31 ± 50 | 17 ± 1315 ± 4 | 87 (<30)78 (<30) | 9798 | Ayadi et al. 2016 (126) |
| Algeria | Tizi-Ouzou | Healthy children | 435 | 5–15 | Sept: 71.4March: 52.9 | 8.1 (<30)17.4 (<30) | 29.941.4 | Djennane et al. 2014 (127) |
| Morocco | Rabat | Postmenopaual women | 178 | 58.8 ± 8.2 | 39.5 ± 29.0 | 51.6 | El 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° | NorwegianPakistani | 866176 | 30–76 | 71.0 ± 19.527.6 ± 12.3 | 0.152.3 | 14.992.0 | Cashman et al. 2015 ( 36 ) |
| Finland | Latitude 60–63°Representative of immigrant populations | Ethnic (all):White Russian KurdishSomalian | 1310466500364 | 18–64 | 45.5 ± 21.962.8 ± 21.033.7 ± 15.640.5 ± 16.6 | 18.22.534.215.7 | 63.728.785.676.4 | Cashman et al. 2016 ( 28 ) |
| Finland | Latitude 60 | BangladeshiSomaliFinnish | 344861 | 20–48 | 42.9 ± 16.136.8 ± 11.854.1 ± 19.1 | 08.33.3 | 70.681.344.3 | Islam et al. 2012 (84) |
| Denmark | Latitude 55 | Pakistani | Children 37Premenopausal women 115Men 95 | 12.236.238.3 | 10.912.020.7 | 818465 | 959795 | Andersen et al. 2008 (43) |
| Netherlands | Adult women and men | 613: | 18–65 | Van der Meer et al. 2008 (64) | ||||
| DutchTurkishMoroccanSurinam AsianSurinam CreoleAfrican | 672730242733 | 64137514519 | ||||||
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.
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
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
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.
Vitamin D intake in European and Middle East countries.
| Country | Study population | n | Age (years) | Vitamin D intake (µg/day) | References |
|---|---|---|---|---|---|
| Iceland | 3.9 µg13.5 µg (with cod liver oil) | Thorgeirsdottir et al. 2012 (139) | |||
| Norway | VolunteersNorkost | 32 | 9.6 µgM: 15 µgF: 12.9 µg | Brustad et al. 2004 (134)Norkost (144) | |
| Sweden | Riksmaten | 7.1 µg | Riksmaten (145) | ||
| Finland | National Diet SurveyFindiet | 1708 | 25–74 | M: 11 µgF: 9 µgOM: 14 µgOW: 19 µg | Helldán et al. 2013 (147) |
| Denmark | Dan Nat Survey | 3.93.1 | |||
| United Kingdom | NDNS rolling survey (2008/2009 to 2009/2010) | M: 210 M: 238 M: 346M: 96F: 213F: 215F: 461F: 128 | 4–1011–1819–64>654–1011–1819–64>65 | 2.2 (median)2.12.83.921.72.63.1 (median) | Department of Health 2011 (153) |
| Ireland | National Adult Nutrition Survey | 1274 | 18–64 | 3.5 (median)6.4 (mean) | Black et al. 2015 (151) |
| Ireland | Irish Preschool Children Survey | 500 | 1–4 | 2–2.5 µg (median) | Hennessy et al. 2016 (152) |
| Ireland | Irish Children’s and Teens’ National Nutrition Surveys | 594441 | 5–89–1213–17 | 1.9 (median)2.1 (median)2.4 (median) | Black et al. 2014 (150) |
| Netherlands | Hip fract pat controls | 12574 | 75.975.6 | 2.82.9 | Lips et al. 1987 (156) |
| Food cons survey | M: 4.8F: 3.6 | ||||
| Germany | Nat Nutr Survey | M: 4.4F: 3.4 | |||
| Portugal | Epiporto | M: 3.4F: 3.3 | Spiro & Buttriss 2014 (33) | ||
| Spain | ENCAT 2002–2003 | M: 0.7F: 0.7 | Spiro & Buttriss 2014 (33) | ||
| Italy | INN-CA 1996 | M: 2.5F: 2.4 | Spiro & Buttriss 2014 (33) | ||
| 10 European countries (EPIC) | European Prospective Investigation into Cancer and Nutrition (EPIC) study | M: 13 025 F: 23 009 | 35–7435–74 | 5.53.6 | Jenab et al. 2009 (163) |
| Southern | M: 4530 F: 7372 | 35–7435–74 | 4.25.1 | ||
| Central | M: 3807 F: 8561 | 35–7435–74 | 4.73.4 | ||
| Northern | M: 4688 F: 7076 | 35–7435–74 | 7.45.0 | ||
| Middle East | |||||
| Turkey | Mining facility | 135 coal miners | 32.6 ± 7.4 | 2.1 ± 1.3 | Bilici et al. 2016 (164) |
| Iran | Tehran Lipid and Glucose Study | 5524 | 18–70 | M: 2.5 ± 4.3F: 3.8 ± 3.1 | Ejtahed et al. 2016 (165) |
| Iran | Iranian Multicentric Osteoporosis Study | F: 581 | 42.4 ± 12.2 | 1.5 ± 1.2 | Khashayar et al. 2017 (166) |
| Iran | Pregnant women | 2.3±1.9 | Sabour et al. 2006 (167) | ||
| Iran | Children | 1.4 | Feizabad et al. 2017 (168) | ||
| Iran | 100 children | 4–10 | 11.7 | Kelishadi et al. 2014 (169) | |
| Kuwait | Repres. national sample | 1049 | 1–2.9 | Zaghloul et al. 2013 (170) | |
| Lebanon | Beirut | FM | 39.4 ± 5.641.3 ± 5.5 | 2.2 ± 1.53.2 ± 2.0 | Gannage-Yared et al. 2000 (171) |
| Lebanon | 128 pregnant women | 10.6 ± 10.9 (FFQ)8.9 ± 2.5 (24 h recall) | Papazian et al. 2016 (172) | ||
| Qatar | 60 young women | 29 | 3.0 | Salameh et al. 2016 (173) | |
| United Arab Emirates | 350 adolescent females | 15.3 ± 2 | 8.5 | Narchi et al. 2015 (174) | |
| Saudi Arabia | University students Tabuk | 19–25 | 53% < 15 µg/day | Alzaheb & Al-Amer 2017 (175) | |
| Tunisia | 225 boys | 8 | Bezrati et al. 2016 (176) | ||
| Tunisia | 87 pregnant women | 2.2 | Ayadi 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).
Megatrials with multiple outcomes with expected results in the coming 5 years.
| Consortium | Number of subjects | Study design | Dose | Outcome | Results | References |
|---|---|---|---|---|---|---|
| VIDA | 5110 | DB, two groups | 100 000 IU/month | Fract, CVD, ARI | No effect on falls and fractures, CVD | Khaw et al. 2017 (298)Scragg et al. 2017 (242) |
| VITAL | 28 875 | Factorial design 2/2 | 2000 IU/day/fish oil/placebo | Cancer, CVD | No effect on CVD and cancer | Bassuk et al. 2016 (299)Manson et al. 2018 (243) |
| TIPS-3 | 5500 | Factorial design 2/2/2 | 60 000 IU/month/polycaps/aspirin | CVD, fract, cancer | Jan 2019 | Nbib1646437* |
| FIND | 18 000 | 3200 vs 1600 IU/day vs placebo | CVD, cancer | Dec 2019 | Nbib1463813* | |
| DO-HEALTH | 2152 | Factorial design 2/2/2 | 2000 IU/omega-3/physical exercise | Fract, functional decline, blood pressure, cognitive decline, infection | Nbib1745263* | |
| D-HEALTH | 25 000 | 60 000 IU/month | CVD, DM, cancer | Neale et al. 2016 (300) | ||
| VIDIKids | 5400 children | DB, two groups | 10 000 IU/week | Tuberculosis, astma, acute resp infection | 2022 | Nbib2880982* |
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).
Dietary reference intakes for vitamin D in µg/day according to different European countries, the Institute of Medicine and the Endocrine Society.
| <1 year | 1–3 years | 4–10 years | 11–18 years | Adults | Older | Pregnant | References* | |
|---|---|---|---|---|---|---|---|---|
| Nordic NR | 10 | 10 | 10 | 10 | 10 | 20 | 20 | NORDEN 2014 (144) |
| UK | 8.5–10 | 10 | 10 | 10 | 10 | 10 | 10 | SACN 2015 (30) |
| Ireland | 7.0–8.5 | 10 | 0–10 | 0–15 | 0–10 | 10 | 10 | FSAI 1999*** |
| Netherlands | 10 | 10 | 0–10 | 0–10 | 0–10 | 20 | 10 | Weggemans et al. 2013 (249) |
| Belgium | 10 | 10 | 10 | 10–15 | 10–15 | 15 | 20 | Spiro and Buttriss 2014 (33) |
| France | 20–25 | 10 | 5 | 5 | 5 | 5 | 10 | Spiro and Buttriss 2014 (33) |
| DACH | 10 | 20 | 20 | 20 | 20 | 20 | 20 | Spiro and Buttriss 2014 (33) |
| Spain | 10 | 15 | 15 | 15 | 15 | 20 | 15 | Spiro and Buttriss 2014 (33) |
| Central Europe | 10 | 15–25 | 15–25 | 15–25 | 20–50 | 20–50 | 20–50 | Pludowski et al. 2013 (269) |
| EFSA 2016 | 10 | 15 | 15 | 15 | 15 | 15 | 15 | EFSA 2016 (29) |
| Institute of Medicine | 10 | 15 | 15 | 15 | 15 | 20 | 15 | IOM 2011 (2) |
| Endocrine Society | 10–25 | 15–25 | 15–25 | 15–25 | 37.5–50 | 37.5–50 | 15–25**37.5–50 | Holick 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:
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↑
Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM & Endocrine Society. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism 2011 96 1911–1930. (https://doi.org/10.1210/jc.2011-0385)
- 2↑
Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. Washington DC: The National Academies Press, 2011.
- 3↑
Bouillon R, van Schoor NM, Gielen E, Boonen S, Mathieu C, Vanderschueren D & Lips P. Optimal vitamin D status: a critical analysis on the basis of evidence-based medicine. Journal of Clinical Endocrinology and Metabolism 2013 98 E1283–E1304. (https://doi.org/10.1210/jc.2013-1195)
- 4↑
Seamans KM & Cashman KD. Existing and potentially novel functional markers of vitamin D status: a systematic review. American Journal of Clinical Nutrition 2009 89 1997S–2008S. (https://doi.org/10.3945/ajcn.2009.27230D)
- 5↑
Carter GD, Jones JC, Shannon J, Williams EL, Jones G, Kaufmann M & Sempos C. 25-Hydroxyvitamin D assays: potential interference from other circulating vitamin D metabolites. Journal of Steroid Biochemistry and Molecular Biology 2016 164 134–138. (https://doi.org/10.1016/j.jsbmb.2015.12.018)
- 6↑
Jongen MJ, van der Vijgh WJ, Willems HJ, Netelenbos JC & Lips P. Simultaneous determination of 25-hydroxyvitamin D, 24,25-dihydroxyvitamin D, and 1,25-dihydroxyvitamin D in plasma or serum. Clinical Chemistry 1981 27 1757–1760.
- 7↑
Cashman KD, Hayes A, Galvin K, Merkel J, Jones G, Kaufmann M, Hoofnagle AN, Carter GD, Durazo-Arvizu RA & Sempos CT. Significance of serum 24,25-dihydroxyvitamin D in the assessment of vitamin D status: a double-edged sword? Clinical Chemistry 2015 61 636–645. (https://doi.org/10.1373/clinchem.2014.234955)
- 8↑
Kaufmann M, Gallagher JC, Peacock M, Schlingmann KP, Konrad M, DeLuca HF, Sigueiro R, Lopez B, Mourino A & Maestro M 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 2567–2574. (https://doi.org/10.1210/jc.2013-4388)
- 9↑
Molin A, Baudoin R, Kaufmann M, Souberbielle JC, Ryckewaert A, Vantyghem MC, Eckart P, Bacchetta J, Deschenes G & Kesler-Roussey G et al. CYP24A1 mutations in a cohort of hypercalcemic patients: evidence for a recessive trait. Journal of Clinical Endocrinology and Metabolism 2015 100 E1343–E1352. (https://doi.org/10.1210/jc.2014-4387)
- 10↑
Lips P. Relative value of 25(OH)D and 1,25(OH)2D measurements. Journal of Bone and Mineral Research 2007 22 1668–1671. (https://doi.org/10.1359/jbmr.070716)
- 11↑
Abreu MT, Kantorovich V, Vasiliauskas EA, Gruntmanis U, Matuk R, Daigle K, Chen S, Zehnder D, Lin YC & Yang H 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 1129–1136. (https://doi.org/10.1136/gut.2003.036657)
- 12↑
Makin HLJ, Jones G, Kaufmann M & Calverley MJ. Analysis of vitamin D, their metabolites and analogs. In Steroid Analysis, 2nd ed., Chapter 11, pp 967–1096. Eds Makin HLJ & Gower DB. Springer Science and Business Media, Berlin 2010.
- 13↑
Hollis BW & Napoli JL. Improved radioimmunoassay for vitamin D and its use in assessing vitamin D status. Clinical Chemistry 1985 31 1815–1819.
- 14↑
Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, Durazo-Arvizu RA, Gallagher JC, Gallo RL & Jones G 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 53–58. (https://doi.org/10.1210/jc.2010-2704)
- 15↑
De la Hunty A, Wallace AM, Gibson S, Viljakainen H, Lamberg-Allardt C & Ashwell M. 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 104 612–619. (https://doi.org/10.1017/S000711451000214X)
- 16↑
Bikle D, Bouillon R, Thadhani R & Schoenmakers I. 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 173 105–116. (https://doi.org/10.1016/j.jsbmb2017.01.007)
- 17↑
Carter GD, Berry JL, Gunter E, Jones G, Jones JC, Makin HLJ, Sufi S & Wheeler MJ. Proficiency testing of 25-hydroxyvitamin D (25-OHD) assays. Journal of Steroid Biochemistry and Molecular Biology 2010 121 176–179. (https://doi.org/10.1016/j.jsbmb.2010.03.033)
- 18↑
Carter GD & Jones JC. 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 79–81. (https://doi.org/10.1258/acb.2008.008135)
- 19↑
Barake M, Daher RT, Salti I, Cortas NK, Al-Shaar L, Habib RH, Fuleihan Gel-H. 25-Hydroxyvitamin D assay variations and impact on clinical decision making. Journal of Clinical Endocrinology and Metabolism 2012 97 835–843. (https://doi.org/10.1210/jc.2011-2584)
- 20↑
Carter GD, Berry J, Durazo-Arvizu R, Gunter E, Jones G, Jones J, Makin HLJ, Pattni P, Sempos CT & Twomey P et al. Hydroxyvitamin D assays: an historical perspective from DEQAS. Journal of Steroid Biochemistry and Molecular Biology 2018 177 30–35. (https://doi.org/10.1016/j.jsbmb.2017.07.018)
- 21↑
Binkley N, Sempos CT & Vitamin D Standardization Program (VDSP). Standardizing vitamin D assays: the way forward. Journal of Bone and Mineral Research 2014 29 1709–1714. (https://doi.org/10.1002/jbmr.2252)
- 22↑
Binkley N, Krueger D, Cowgill CS, Plum L, Lake E, Hansen KE, DeLuca HF & Drezner MK. Assay variation confounds the diagnosis of hypovitaminosis D: a call for standardization. Journal of Clinical Endocrinology and Metabolism 2004 89 3152–3157. (https://doi.org/10.1210/jc.2003-031979)
- 23↑
Lips P, Chapuy MC, Dawson-Hughes B, Pols HA & Holick MF. An international comparison of serum 25-hydroxyvitamin D measurements. Osteoporosis International 1999 9 394–397. (https://doi.org/10.1007/s001980050162)
- 24↑
Sempos CT, Vesper HW, Phinney KW, Thienpont LM, Coates PM & 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 32–40. (https://doi.org/10.3109/00365513.2012.681935)
- 25↑
Prentice A. Vitamin D deficiency: a global perspective. Nutrition Reviews 2008 66 S153–S164. (https://doi.org/10.1111/j.1753-4887.2008.00100.x)
- 26↑
Binkley N & Carter GD. Toward clarity in clinical vitamin D status assessment: 25(OH)D assay standardization. Endocrinology and Metabolism Clinics of North America 2017 46 885–899. (https://doi.org/10.1016/j.ecl.2017.07.012)
- 27↑
Sempos CT, Durazo-Arvizu RA, Dawson-Hughes B, Yetley EA, Looker AC, Schleicher RL, Cao G, Burt V, Kramer H & Bailey RL 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 3001–3009. (https://doi.org/10.1210/jc.2013-1333)
- 28↑
Cashman KD, Dowling KG, Skrabakova Z, Gonzalez-Gross M, Valtuena J, De Henauw S, Moreno L, Damsgaard CT, Michaelsen KF & Molgaard C et al. Vitamin D deficiency in Europe: pandemic? American Journal of Clinical Nutrition 2016 103 1033–1044. (https://doi.org/10.3945/ajcn.115.120873)
- 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 Pdf, 2015.
- 31↑
van der Wielen RP, Lowik MR, van den Berg H, de Groot LC, Haller J, Moreiras O & van Staveren WA. Serum vitamin D concentrations among elderly people in Europe. Lancet 1995 346 207–210. (https://doi.org/10.1016/S0140-6736(95)91266-5)
- 32↑
McKenna MJ. Differences in vitamin D status between countries in young adults and the elderly. American Journal of Medicine 1992 93 69–77. (https://doi.org/10.1016/0002-9343(92)90682-2)
- 33↑
Spiro A & Buttriss JL. Vitamin D: an overview of vitamin D status and intake in Europe. Nutrition Bulletin 2014 39 322–350. (https://doi.org/10.1111/nbu.12108)
- 34↑
Wahl DA, Cooper C, Ebeling PR, Eggersdorfer M, Hilger J, Hoffman K, Josse R, Kanis JA, Mithal A & Pierroz DD et al. A global representation of vitamin D status in healthy populations. Archives of Osteoporosis 2012 7 155–172. (https://doi.org/10.1007/s11657-012-0093-0)
- 35↑
Hilger J, Friedel A, Herr R, Rausch T, Roos F, Wahl DA, Pierroz DD, Weber P & Hoffmann K. A systematic review of vitamin D status in populations worldwide. British Journal of Nutrition 2014 111 23–45. (https://doi.org/10.1017/S0007114513001840)
- 36↑
Cashman KD, Dowling KG, Skrabakova Z, Kiely M, Lamberg-Allardt C, Durazo-Arvizu RA, Sempos CT, Koskinen S, Lundqvist A & Sundvall J 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 75 549–561. (https://doi.org/10.3109/00365513.2015.1057898)
- 37↑
Buchebner D, McGuigan F, Gerdhem P, Malm J, Ridderstrale M & Akesson K. Vitamin D insufficiency over 5 years is associated with increased fracture risk-an observational cohort study of elderly women. Osteoporosis International 2014 25 2767–2775. (https://doi.org/10.1007/s00198-014-2823-1)
- 38↑
Melhus H, Snellman G, Gedeborg R, Byberg L, Berglund L, Mallmin H, Hellman P, Blomhoff R, Hagstrom E & Arnlov J 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 2637–2645. (https://doi.org/10.1210/jc.2009-2699)
- 39↑
Brembeck P, Winkvist A & Olausson H. Determinants of vitamin D status in pregnant fair-skinned women in Sweden. British Journal of Nutrition 2013 110 856–864. (https://doi.org/10.1017/S0007114512005855)
- 40↑
Eriksson S & Strandvik B. Vitamin D status in healthy children in Sweden still satisfactory. Changed supplementation and new knowledge motivation for further studies. Läkartidningen 2016 107 2474–2477.
- 41↑
Andersen R, Molgaard C, Skovgaard LT, Brot C, Cashman KD, Chabros E, Charzewska J, Flynn A, Jakobsen J & Karkkainen M et al. Teenage girls and elderly women living in northern Europe have low winter vitamin D status. European Journal of Clinical Nutrition 2005 59 533–541. (https://doi.org/10.1038/sj.ejcn.1602108)
- 42↑
Holvik K, Meyer HE, Haug E & Brunvand L. 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 57–63. (https://doi.org/10.1038/sj.ejcn.1602033)
- 43↑
Andersen R, Molgaard C, Skovgaard LT, Brot C, Cashman KD, Jakobsen J, Lamberg-Allardt C & Ovesen L. Pakistani immigrant children and adults in Denmark have severely low vitamin D status. European Journal of Clinical Nutrition 2008 62 625–634. (https://doi.org/10.1038/sj.ejcn.1602753)
- 44↑
Holvik K, Ahmed LA, Forsmo S, Gjesdal CG, Grimnes G, Samuelsen SO, Schei B, Blomhoff R, Tell GS & Meyer HE. Low serum levels of 25-hydroxyvitamin D predict hip fracture in the elderly: a NOREPOS study. Journal of Clinical Endocrinology and Metabolism 2013 98 3341–3350. (https://doi.org/10.1210/jc.2013-1468)
- 45↑
Holvik K, Brunvand L, Brustad M & Meyer HE. Vitamin D Status in the Norwegian Population. Oslo: The Norwegian Academy of Science and Letters, 2008.
- 46↑
Steingrimsdottir L, Gunnarsson O, Indridason OS, Franzson L & Sigurdsson G. Relationship between serum parathyroid hormone levels, vitamin D sufficiency, and calcium intake. JAMA 2005 294 2336–2341. (https://doi.org/10.1001/jama.294.18.2336)
- 47↑
Jaaskelainen T, Itkonen ST, Lundqvist A, Erkkola M, Koskela T, Lakkala K, Dowling KG, Hull GL, Kroger H & Karppinen J 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 1512–1520. (https://doi.org/10.3945/ajcn.116.151415)
- 48↑
Carson EL, Pourshahidi LK, Hill TR, Cashman KD, Strain JJ, Boreham CA & Mulhern MS. Vitamin D, muscle function, and cardiorespiratory fitness in adolescents from the Young Hearts Study. Journal of Clinical Endocrinology and Metabolism 2015 100 4621–4628. (https://doi.org/10.1210/jc.2015-2956)
- 49↑
van Schoor NM, Knol DL, Deeg DJ, Peters FP, Heijboer AC & Lips P. 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 1483–1491. (https://doi.org/10.1007/s00198-014-2651-3)
- 50↑
Bouillon RA, Auwerx JH, Lissens WD & Pelemans WK. Vitamin D status in the elderly: seasonal substrate deficiency causes 1,25-dihydroxycholecalciferol deficiency. American Journal of Clinical Nutrition 1987 45 755–763. (https://doi.org/10.1093/ajcn/45.4.755)
- 51↑
Hoge A, Donneau AF, Streel S, Kolh P, Chapelle JP, Albert A, Cavalier E & Guillaume M. 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 35 716–725. (https://doi.org/10.1016/j.nutres.2015.06.005)
- 52↑
Chapuy MC, Preziosi P, Maamer M, Arnaud S, Galan P, Hercberg S & Meunier PJ. Prevalence of vitamin D insufficiency in an adult normal population. Osteoporosis International 1997 7 439–443. (https://doi.org/10.1007/s001980050030)
- 53↑
Chapuy MC, Schott AM, Garnero P, Hans D, Delmas PD & Meunier PJ. 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 1129–1133. (https://doi.org/10.1210/jcem.81.3.8772587)
- 54↑
Souberbielle JC, Massart C, Brailly-Tabard S, Cavalier E & Chanson P. Prevalence and determinants of vitamin D deficiency in healthy French adults: the VARIETE study. Endocrine 2016 53 543–550. (https://doi.org/10.1007/s12020-016-0960-3)
- 55↑
Burnand B, Sloutskis D, Gianoli F, Cornuz J, Rickenbach M, Paccaud F & Burckhardt P. Serum 25-hydroxyvitamin D: distribution and determinants in the Swiss population. American Journal of Clinical Nutrition 1992 56 537–542. (https://doi.org/10.1093/ajcn/56.3.537)
- 56↑
Cashman KD, Muldowney S, McNulty B, Nugent A, FitzGerald AP, Kiely M, Walton J, Gibney MJ & Flynn A. Vitamin D status of Irish adults: findings from the National Adult Nutrition Survey. British Journal of Nutrition 2013 109 1248–1256. (https://doi.org/10.1017/S0007114512003212)
- 57↑
Theiler R, Stahelin HB, Tyndall A, Binder K, Somorjai G & Bischoff HA. Calcidiol, calcitriol and parathyroid hormone serum concentrations in institutionalized and ambulatory elderly in Switzerland. International Journal for Vitamin and Nutrition Research 1999 69 96–105. (https://doi.org/10.1024/0300-9831.69.2.96)
- 58↑
Krieg MA, Cornuz J, Jacquet AF, Thiebaud D & Burckhardt P. Influence of anthropometric parameters and biochemical markers of bone metabolism on quantitative ultrasound of bone in the institutionalized elderly. Osteoporosis International 1998 8 115–120. (https://doi.org/10.1007/BF02672506)
- 59↑
Bischoff-Ferrari HA, Can U, Staehelin HB, Platz A, Henschkowski J, Michel BA, Dawson-Hughes B & Theiler R. Severe vitamin D deficiency in Swiss hip fracture patients. Bone 2008 42 597–602. (https://doi.org/10.1016/j.bone.2007.10.026)
- 60↑
Bischof MG, Heinze G & Vierhapper H. Vitamin D status and its relation to age and body mass index. Hormone Research 2006 66 211–215. (https://doi.org/10.1159/000094932)
- 61↑
Amrein K, Zajic P, Schnedl C, Waltensdorfer A, Fruhwald S, Holl A, Purkart T, Wunsch G, Valentin T & Grisold A 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)
- 62↑
Kudlacek S, Schneider B, Peterlik M, Leb G, Klaushofer K, Weber K, Woloszczuk W, Willvonseder R & 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 33 323–331. (https://doi.org/10.1046/j.1365-2362.2003.01127.x)
- 63↑
Goldrace M, Hall N & Yeates DG. Hospitalisation for children with rickets in England: a historical perspective. Lancet 2014 383 597–598. (https://doi.org/10.1016/S0140-6736(14)60211-7)
- 64↑
van der Meer IM, Boeke AJP, Lips P, Grootjans-Geerts I, Wuister JD, Deville WLJM, Wielders JPM, Bouter LM & Middelkoop BJC. Fatty fish and supplements are the greatest modifiable contributors to the serum 25-hydroxyvitamin D concentration in a multiethnic population. Clinical Endocrinology 2008 68 466–472. (https://doi.org/10.1111/j.1365-2265.2007.03066.x)
- 65↑
van der Meer IM, Karamali NS, Boeke AJ, Lips P, Middelkoop BJ, Verhoeven I & Wuister JD. High prevalence of vitamin D deficiency in pregnant non-western women in the Hague, Netherlands. American Journal of Clinical Nutrition 2006 84 350–353; quiz 468. (https://doi.org/10.1093/ajcn/84.1.350)
- 66↑
Lips P. Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications. Endocrine Reviews 2001 22 477–501. (https://doi.org/10.1210/edrv.22.4.0437)
- 67↑
Quesada JM, Jans I, Benito P, Jimenez JA & Bouillon R. Vitamin D status of elderly people in Spain. Age and Ageing 1989 18 392–397. (https://doi.org/10.1093/ageing/18.6.392)
- 68↑
Navarro-Valverde C & Quesada-Gomez JM. Vitamin D deficiency in Spain. Reality or myth? Revista de Osteoporosis y Metabolismo Mineral 2014 6 (Supplement 1) S5–S10. (https://doi.org/10.4321/S1889-836X2014000500002)
- 69↑
Bettica P, Bevilacqua M, Vago T & Norbiato G. 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 9 226–229. (https://doi.org/10.1007/s001980050141)
- 70↑
Isaia G, Giorgino R, Rini GB, Bevilacqua M, Maugeri D & Adami S. Prevalence of hypovitaminosis D in elderly women in Italy: clinical consequences and risk factors. Osteoporosis International 2003 14 577–582. (https://doi.org/10.1007/s00198-003-1390-7)
- 71↑
Challa A, Ntourntoufi A, Cholevas V, Bitsori M, Galanakis E & Andronikou S. Breastfeeding and vitamin D status in Greece during the first 6 months of life. European Journal of Pediatrics 2005 164 724–729. (https://doi.org/10.1007/s00431-005-1757-1)
- 72↑
Pludowski P, Grant WB, Bhattoa HP, Bayer M, Povoroznyuk V, Rudenka E, Ramanau H, Varbiro S, Rudenka A & Karczmarewicz E et al. Vitamin D status in central Europe. International Journal of Endocrinology 2014 2014 589587. (https://doi.org/10.1155/2014/589587)
- 73↑
Holecki M, Zahorska-Markiewicz B, Chudek J & Wiecek A. 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 120 248–254.
- 74↑
Kull MJ, Kallikorm R, Tamm A & Lember M. 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)
- 75↑
Mayer OJ, Filipovsky J, Seidlerova J, Vanek J, Dolejsova M, Vrzalova J & Cifkova R. The association between low 25-hydroxyvitamin D and increased aortic stiffness. Journal of Human Hypertension 2012 26 650–655. (https://doi.org/10.1038/jhh.2011.94)
- 76↑
Kocjan T, Tan TM-M, Conway GS & Prelevic G. Vitamin D status in patients with osteopenia or osteoporosis – an audit of an endocrine clinic. International Journal for Vitamin and Nutrition Research 2006 76 307–313. (https://doi.org/10.1024/0300-9831.76.5.307)
- 77↑
Viragh E, Horvath D, Locsei Z, Kovacs L, Jager R, Varga B, Kovacs LG & Salamonne TE. Vitamin D supply among healthy blood donors in Vas County, Hungary. Orvosi Hetilap 2012 153 1629–1637. (https://doi.org/10.1556/OH.2012.29459)
- 78↑
Bhattoa HP, Bettembuk P, Ganacharya S & Balogh A. Prevalence and seasonal variation of hypovitaminosis D and its relationship to bone metabolism in community dwelling postmenopausal Hungarian women. Osteoporosis International 2004 15 447–451. (https://doi.org/10.1007/s00198-003-1566-1)
- 79↑
Bhattoa HP, Nagy E, More C, Kappelmayer J, Balogh A, Kalina E & Antal-Szalmas P. 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 24 179–186. (https://doi.org/10.1007/s00198-012-1920-2)
- 80↑
Laktasic-Zerjavic N, Korsic M, Crncevic-Orlic Z, Kovac Z, Polasek O & Soldo-Juresa D. 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 29 861–867. (https://doi.org/10.1007/s10067-010-1409-3)
- 81↑
Bakhtiyarova S, Lesnyak O, Kyznesova N, Blankenstein MA & Lips P. Vitamin D status among patients with hip fracture and elderly control subjects in Yekaterinburg, Russia. Osteoporosis International 2006 17 441–446. (https://doi.org/10.1007/s00198-005-0006-9)
- 82↑
Kozlov A, Khabarova Y, Vershubsky G, Ateeva Y & Ryzhaenkov V. 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)
- 83↑
Meyer HE, Falch JA, Sogaard AJ & Haug E. 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 35 412–417. (https://doi.org/10.1016/j.bone.2004.04.003)
- 84↑
Islam MZ, Viljakainen HT, Karkkainen MUM, Saarnio E, Laitinen K & Lamberg-Allardt C. 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 107 277–283. (https://doi.org/10.1017/S0007114511002893)
- 85↑
van der Meer IM, Middelkoop BJC, Boeke AJP & Lips P. 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 1009–1021. (https://doi.org/10.1007/s00198-010-1279-1)
- 86↑
Lips P, Duong T, Oleksik A, Black D, Cummings S, Cox D & Nickelsen T. 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 1212–1221. (https://doi.org/10.1210/jcem.86.3.7327)
- 87↑
Kuchuk NO, van Schoor NM, Pluijm SM, Chines A & Lips P. Vitamin D status, parathyroid function, bone turnover, and BMD in postmenopausal women with osteoporosis: global perspective. Journal of Bone and Mineral Research 2009 24 693–701. (https://doi.org/10.1359/jbmr.081209)
- 88↑
Prentice A. Nutritional rickets around the world. Journal of Steroid Biochemistry and Molecular Biology 2013 136 201–206. (https://doi.org/10.1016/j.jsbmb.2012.11.018)
- 89↑
Holick MF. Vitamin D deficiency. New England Journal of Medicine 2007 357 266–281. (https://doi.org/10.1056/NEJMra070553)
- 90↑
Mithal A, Wahl DA, Bonjour JP, Burckhardt P, Dawson-Hughes B, Eisman JA, El-Hajj Fuleihan G, Josse RG, Lips P & Morales-Torres J et al. Global vitamin D status and determinants of hypovitaminosis D. Osteoporosis International 2009 20 1807–1820. (https://doi.org/10.1007/s00198-009-0954-6)
- 91↑
van Schoor N & Lips P. Global overview of vitamin D status. Endocrinology and Metabolism Clinics of North America 2017 46 845–870. (https://doi.org/10.1016/j.ecl.2017.07.002)
- 92↑
Bassil D, Rahme M, Hoteit M, El-Hajj Fuleihan Gel-H. Hypovitaminosis D in the Middle East and North Africa: prevalence, risk factors and impact on outcomes. Dermato-Endocrinology 2013 5 274–298. (https://doi.org/10.4161/derm.25111)
- 93↑
Hekimsoy Z, Dinc G, Kafesciler S, Onur E, Guvenc Y, Pala T, Guclu F & Ozmen B. 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)
- 94↑
Buyukuslu N, Esin K, Hizli H, Sunal N, Yigit P & Garipagaoglu M. Clothing preference affects vitamin D status of young women. Nutrition Research 2014 34 688–693. (https://doi.org/10.1016/j.nutres.2014.07.012)
- 95↑
Parlak M, Kalay S, Kalay Z, Kirecci A, Guney O & Koklu E. Severe vitamin D deficiency among pregnant women and their newborns in Turkey. Journal of Maternal-Fetal and Neonatal Medicine 2015 28 548–551. (https://doi.org/10.3109/14767058.2014.924103)
- 96↑
Karaguzel G, Dilber B, Can G, Okten A, Deger O & Holick MF. Seasonal vitamin D status of healthy schoolchildren and predictors of low vitamin D status. Journal of Pediatric Gastroenterology and Nutrition 2014 58 654–660. (https://doi.org/10.1097/MPG.0000000000000274)
- 97↑
Masoompour SM, Sadegholvaad A, Larijani B & Ranjbar-Omrani G. Effects of age and renal function on vitamin D status in men. Archives of Iranian Medicine 2008 11 377–381. (https://doi.org/08114/AIM.007)
- 98↑
Hosseinpanah F, Yarjanli M, Sheikholeslami F, Heibatollahi M, Eskandary PS & Azizi F. Associations between vitamin D and cardiovascular outcomes; Tehran Lipid and Glucose Study. Atherosclerosis 2011 218 238–242. (https://doi.org/10.1016/j.atherosclerosis.2011.05.016)
- 99↑
Hosseinpanah F, Rambod M, Hossein-nejad A, Larijani B & Azizi F. Association between vitamin D and bone mineral density in Iranian postmenopausal women. Journal of Bone and Mineral Metabolism 2008 26 86–92. (https://doi.org/10.1007/s00774-007-0791-7)
- 100↑
Kaykhaei MA, Hashemi M, Narouie B, Shikhzadeh A, Rashidi H, Moulaei N & Ghavami S. High prevalence of vitamin D deficiency in Zahedan, southeast Iran. Annals of Nutrition and Metabolism 2011 58 37–41. (https://doi.org/10.1159/000323749)
- 101↑
Khalesi N, Bahaeddini SM & Shariat M. Prevalence of maternal vitamin D deficiency in neonates with delayed hypocalcaemia. Acta Medica Iranica 2012 50 740–745.
- 102↑
Naseh A, Ashrafzadeh S & Rassi S. 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 2312–2318. (https://doi.org/10.1080/14767058.2017.1342796)
- 103↑
Torkaman M, Abolghasemi H, Amirsalari S, Beiraghdar F, Afsharpaiman S, Kavehmanesh Z & Khosravi MH. 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)
- 104↑
Sayed-Hassan R, Abazid N & Alourfi Z. 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)
- 105↑
Saliba W, Barnett O, Rennert HS & Rennert G. The risk of all-cause mortality is inversely related to serum 25(OH)D levels. Journal of Clinical Endocrinology and Metabolism 2012 97 2792–2798. (https://doi.org/10.1210/jc.2012-1747)
- 106↑
Steinvil A, Leshem-Rubinow E, Berliner S, Justo D, Finn T, Ish-shalom M, Birati EY, Shalev V, Sheinberg B & Rogowski O. Vitamin D deficiency prevalence and cardiovascular risk in Israel. European Journal of Clinical Investigation 2011 41 263–268. (https://doi.org/10.1111/j.1365-2362.2010.02403.x)
- 107↑
Oren Y, Shapira Y, Agmon-Levin N, Kivity S, Zafrir Y, Altman A, Lerner A & Shoenfeld Y. Vitamin D insufficiency in a sunny environment: a demographic and seasonal analysis. Israel Medical Association Journal 2010 12 751–756.
- 108↑
Korchia G, Amitai Y, Moshe G, Korchia L, Tenenbaum A, Rosenblum J & Schechter A. Vitamin D deficiency in children in Jerusalem: the need for updating the recommendation for supplementation. Israel Medical Association Journal 2013 15 333–338.
- 109↑
Batieha A, Khader Y, Jaddou H, Hyassat D, Batieha Z, Khateeb M, Belbisi A & Ajlouni K. Vitamin D status in Jordan: dress style and gender discrepancies. Annals of Nutrition and Metabolism 2011 58 10–18. (https://doi.org/10.1159/000323097)
- 110↑
Nichols EK, Khatib IM, Aburto NJ, Sullivan KM, Scanlon KS, Wirth JP & Serdula MK. Vitamin D status and determinants of deficiency among non-pregnant Jordanian women of reproductive age. European Journal of Clinical Nutrition 2012 66 751–756. (https://doi.org/10.1038/ejcn.2012.25)
- 111↑
Nichols EK, Khatib IM, Aburto NJ, Serdula MK, Scanlon KS, Wirth JP & Sullivan KM. Vitamin D status and associated factors of deficiency among Jordanian children of preschool age. European Journal of Clinical Nutrition 2015 69 90–95. (https://doi.org/10.1038/ejcn.2014.142)
- 112↑
Mallah EM, Hamad MF, Elmanaseer MA, Qinna NA, Idkaidek NM, Arafat TA & Matalka KZ. 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)
- 113↑
Khuri-Bulos N, Lang RD, Blevins M, Kudyba K, Lawrence L, Davidson M, Faouri S & Halasa NB. Vitamin D deficiency among newborns in Amman, Jordan. Global Journal of Health Science 2013 6 162–171. (https://doi.org/10.5539/gjhs.v6n1p162)
- 114↑
Hoteit M, Al-Shaar L, Yazbeck C, Bou Sleiman M, Ghalayini T, Fuleihan Gel Gel-H. Hypovitaminosis D in a sunny country: time trends, predictors, and implications for practice guidelines. Metabolism 2014 63 968–978. (https://doi.org/10.1016/j.metabol.2014.04.009)
- 115↑
Arabi A, Baddoura R, El-Rassi R & El-Hajj Fuleihan G. Age but not gender modulates the relationship between PTH and vitamin D. Bone 2010 47 408–412. (https://doi.org/10.1016/j.bone.2010.05.002)
- 116↑
Alyahya KO. & Vitamin D levels in schoolchildren: a cross-sectional study in Kuwait. BMC Pediatrics 2017 17 213. (https://doi.org/10.1186/s12887-017-0963-0)
- 117↑
Molla AM, Al Badawi M, Hammoud MS, Molla AM, Shukkur M, Thalib L & Eliwa MS. Vitamin D status of mothers and their neonates in Kuwait. Pediatrics International 2005 47 649–652. (https://doi.org/10.1111/j.1442-200x.2005.02141.x)
- 118↑
Ardawi MS, Sibiany AM, Bakhsh TM, Qari MH & Maimani AA. 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 23 675–686. (https://doi.org/10.1007/s00198-011-1606-1)
- 119↑
Al Shaikh AM, Abaalkhail B, Soliman A, Kaddam I, Aseri K, Al-Saleh Y, Al Qarni A, Al Shuaibi A, Al Tamimi W & Mukhtar AM. Prevalence of vitamin D deficiency and calcium homeostasis in Saudi children. Journal of Clinical Research in Pediatric Endocrinology 2016 8 461–467. (https://doi.org/10.4274/jcrpe.3301)
- 120↑
Al-Faris NA. High prevalence of vitamin D deficiency among pregnant Saudi women. Nutrients 2016 8 77. (https://doi.org/10.3390/nu8020077)
- 121↑
Rajah J, Haq A & Pettifor JM. Vitamin D and calcium status in urban children attending an ambulatory clinic service in the United Arab Emirates. Dermato-Endocrinology 2012 4 39–43. (https://doi.org/10.4161/derm.18250)
- 122↑
Al Anouti F, Thomas J, Abdel-Wareth L, Rajah J, Grant WB & Haq A. Vitamin D deficiency and sun avoidance among university students at Abu Dhabi, United Arab Emirates. Dermato-Endocrinology 2011 3 235–239. (https://doi.org/10.4161/derm.3.4.16881)
- 123↑
Golbahar J, Al-Saffar N, Altayab Diab D, Al-Othman S, Darwish A & Al-Kafaji G. Predictors of vitamin D deficiency and insufficiency in adult Bahrainis: a cross-sectional study. Public Health Nutrition 2014 17 732–738. (https://doi.org/10.1017/S136898001300030X)
- 124↑
El-Menyar A, Rahil A, Dousa K, Ibrahim W, Ibrahim T, Khalifa R & Abdel Rahman MO. Low vitamin D and cardiovascular risk factors in males and females from a sunny, rich country. Open Cardiovascular Medicine Journal 2012 6 76–80. (https://doi.org/10.2174/1874192401206010076)
- 125↑
Botros RM, Sabry IM, Abdelbaky RS, Eid YM, Nasr MS & Hendawy LM. Vitamin D deficiency among healthy Egyptian females. Endocrinologia y Nutricion 2015 62 314–321. (https://doi.org/10.1016/j.endonu.2015.03.010)
- 126↑
Ayadi ID, Nouaili EB, Talbi E, Ghdemssi A, Rached C, Bahlous A, Gammoudi A, Hamouda SB, Bouguerra B & Bouzid K et al. Prevalence of vitamin D deficiency in mothers and their newborns in a Tunisian population. International Journal of Gynaecology and Obstetrics 2016 133 192–195. (https://doi.org/10.1016/j.ijgo.2015.09.029)
- 127↑
Djennane M, Lebbah S, Roux C, Djoudi H, Cavalier E & Souberbielle JC. Vitamin D status of schoolchildren in Northern Algeria, seasonal variations and determinants of vitamin D deficiency. Osteoporosis International 2014 25 1493–1502. (https://doi.org/10.1007/s00198-014-2623-7)
- 128↑
El Maghraoui A, Ouzzif Z, Mounach A, Rezqi A, Achemlal L, Bezza A, Tellal S, Dehhaoui M & Ghozlani I. 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)
- 129↑
Atli T, Gullu S, Uysal AR & Erdogan G. 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 53–60. (https://doi.org/10.1016/j.archger.2004.05.006)