P Lips and others ECTS statement on vitamin D 180:4 P23–P54

Position status
Statement

Current vitamin D status in European and

Middle East countries and strategies to
prevent vitamin D deficiency: a position
statement of the European Calcified Tissue
Society
Paul Lips1, Kevin D Cashman2, Christel Lamberg-Allardt3, Heike Annette Bischoff-Ferrari4, Barbara
Obermayer-Pietsch5, Maria Luisa Bianchi6, Jan Stepan7, Ghada El-Hajj Fuleihan8 and Roger Bouillon9
on behalf of the Working Group on Vitamin D of the European Calcified Tissue Society
1
Endocrine Section, Department of Internal Medicine, Amsterdam University Medical Center, VUMC, Amsterdam, The Netherlands,
2
Cork Centre for Vitamin D and Nutrition Research, School of Food and Nutritional Sciences, Department of Medicine, University
College Cork, Cork, Ireland, 3Calcium Research Unit, Department of Food and Nutritional Sciences, University of Helsinki, Helsinki,
Finland, 4Department of Geriatrics and Aging Research, University Hospital and University of Zurich, Zurich, Switzerland, 5Division of
Endocrinology and Diabetology, Department of Internal Medicine, Medical University Graz, Graz, Austria, 6Bone Metabolism Unit,
European Journal of Endocrinology

Istituto Auxologico Italiano IRCCS, Milano, Italy, 7Institute of Rheumatology, Faculty of Medicine, Charles University,
Prague, Czech Republic, 8Calcium Metabolism and Osteoporosis Program, WHO Collaborating Center for Metabolic
Correspondence
Bone Disorders, American University of Beirut Medical Center, Beirut, Lebanon, and 9Clinic and Laboratory of
should be addressed
Endocrinology, Gasthuisberg, KU Leuven, Leuven, Belgium
to P Lips
(Dedicated to the memory of Prof. Steven Boonen and Prof. Silvano Adami) Email
[email protected]

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.

European Journal of
Endocrinology
(2019) 180, P23–P54

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 Position Statement P Lips and others ECTS statement on vitamin D 180:4 P24
status

Introduction indicator of vitamin D nutritional status, as it reflects

the contributions from diet and dermal production in
The clinical practice committee of the European Calcified
response to ultraviolet B (UVB) sunlight exposure (4).
Tissue Society (ECTS) met during the European Calcified
It is not surprising therefore that serum/plasma 25(OH)
Tissue Symposium at Stockholm in May 2012. The different
D was used as an indicator of vitamin D status recently
guidelines of the Institute of Medicine (IOM) and the
by several authorities in North America and Europe who
Endocrine Society (1, 2) were discussed, including their
were commissioned to establish dietary reference intake
different scopes, the many uncertainties surrounding the
values for vitamin D.
required circulating 25-hydroxyvitamin D (25(OH)D)
The circulating concentration of total 25(OH)D
concentrations, supplementation doses and extra-skeletal
(i.e. comprising the sum of 25(OH)D2 and 25(OH)D3) is used
effects of vitamin D (3). While the IOM’s recommendations
diagnostically and clinically as well as in the derivation of
were directed at population health, the Endocrine Society
dietary reference values for vitamin D. While vitamin D3
guidelines aimed at a clinical care perspective. The members
comes from skin synthesis or animal sources, vitamin D2
agreed that a European statement outlined in a position
is derived from supplements or irradiated foods. As the
paper would be appropriate. A working group was established
biological activity of the C3 epimer of serum 25(OH)D is
to prepare a position statement regarding various aspects
low and its concentration in adults represents only a small
of vitamin D deficiency and prevention for Europe and
fraction of the total 25(OH)D concentration, its separate
the Middle East. Such a document should be appropriate
measurement is not a priority, certainly not in adults.
following the recent reports of the IOM, the guidelines of the
Ideally, measurement of serum 25(OH)D should have a
Endocrine Society, the statement of the Standing Committee
European Journal of Endocrinology

minimal interference from 24,25(OH)2D – the vitamin

of European Doctors and reports from the Scientific Advisory
D metabolite with the highest concentration apart from
Committee on Nutrition (SACN) (https://www.gov.uk
25(OH)D3 (5, 6, 7). Separate measurement of 24,25(OH)2D
/government/publications/sacn-vitamin-d-and-health-report)
may be important in case of suspected genetic CYP24A1
in the UK, the European Food Safety Authority (EFSA)
deficiency (8, 9). Measurement of serum 1α,25(OH)2D
(https://www.efsa.europa.eu/en/efsajournal/pub/4547)     for
can be important for establishing the etiology of hyper-
Europe as well as the ongoing discussions in the American,
or hypocalcemia and some metabolic bone diseases but
European and international journals.
not for the general assessment of the vitamin D status in
The present position paper discusses assessment of
a population or individual. Serum 1α,25(OH)2D may be
vitamin D status and standardization of measurement
high in patients with inflammatory and granulomatous
of 25(OH)D concentration. It includes an overview of
diseases and lymphoproliferative disorders (10, 11).
the vitamin D status and vitamin D intake in different
The impact of pre-analytical factors (e.g. serum versus
European and Middle East countries, the prevalence of
plasma, fasting versus non-fasting state, or time of day)
vitamin D deficiency according to different thresholds,
on circulating 25(OH)D is not fully defined. Several assay
the required circulating 25(OH)D concentrations and
types are currently in use for measurement of circulating
required vitamin D intake (from food and/or supplements)
25(OH)D, each with strengths and weaknesses (12). The
to prevent vitamin D deficiency and possible impact
two most common types of assays are (1) antibody-
on skeletal and non-skeletal outcomes. The perspective
based methods, which use a kit or an automated clinical
of the ECTS Working Group was the whole population,
chemistry platform; and (2) liquid chromatography (LC)-
including risk groups such as children, older persons
based methods with either UV or mass spectrometric (MS)
and immigrants. Data on food fortification policy and
detection. While they will both provide a measure of total
the use of supplements in risk groups are included. The
serum 25(OH)D, mass spectrometry can allow for the
ECTS Working Group discussed strategic options and
separate estimation of 25(OH)D2 and 25(OH)D3 (and in
proposes possible implementation strategies for adults
some cases the C-3 epimers and 24,25(OH)2D) from serum
and elderly subjects in Europe and the Middle East. Finally
samples. The antibody-based methods lack the features
recommendations and a research agenda are presented.
that allow them to distinguish between 25(OH)D2 and
25(OH)D3 (4, 7, 10, 13). Various commercial assays differ
Assessment of serum 25-hydroxyvitamin D because of the nature of the antibody used, some claiming
an advantage that they do not discriminate between
There is a general consensus, also adopted by the ECTS, 25(OH)D2 and 25(OH)D3 (13), whereas others in fact do
that the serum/plasma 25(OH)D concentration is the best underestimate the 25(OH)D2 component and therefore

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 Position Statement P Lips and others ECTS statement on vitamin D 180:4 P25
status

provide correction factors to compensate for high 25(OH) for general implementation of well-validated and accurate
D2 content (2, 14). It is important to note that the majority measurements of vitamin D metabolites (20, 21, 22).
of the data collected over the past 20–30 years have been For reasons of pre-analytical as well as analytical
analyzed using antibody-based assays. LC-based assays factors, as outlined above, inter-laboratory variation in
using a tandem mass spectrometer (LC–MS/MS) allow the serum 25(OH)D may be high (17, 18, 19, 23, 24, 25).
analyst to discriminate between 25(OH)D2 and 25(OH)D3 The international standardization of serum 25(OH)
and other compounds by their unique molecular masses D measurement is also promoted by the Vitamin D
and mass fragments (12). The potential advantages of Standardization Program (VDSP) – a collaborative
LC-based assays include high specificity, high sensitivity initiative between the Office of Dietary Supplements of the
and better reproducibility (<10%). The consensus among National Institutes of Health and the Centers for Disease
analysts is that LC–MS/MS assays will become the ‘gold Control and Prevention (CDC), NIST and a number of the
standard’ for assay performance in the future (15). national health surveys around the world (21, 26). The
However, LC–MS/MS will not be available everywhere, international quality assurance/collaboration schemes,
and antibody-based assays are still being improved and such as DEQAS and VDSP, as well as existing and next
cross-calibrated against LC–MS/MS, so that smaller labs generation standard reference materials for 25(OH)D,
will be able to perform adequate measurements provided can further limit inter-laboratory differences. The impact
they participate in a quality control program. In the of standardization to NIST standards has been amply
circulation, 25(OH)D is bound to serum proteins, and demonstrated by recalibration of the (US) NHANES data
unbound or free 25(OH)D constitutes <1% of the total (27), whereby the J-shaped increased mortality in subjects
European Journal of Endocrinology

concentration. As only free 25(OH)D can enter the cell with high serum 25(OH)D concentration disappeared
for further intra/paracrine production of the active simply because very few subjects had ‘corrected’ 25(OH)
metabolite 1,25(OH)2D, it is plausible that free 25(OH)D D levels above 100 nmol/L. Similarly, a recalibration of
is more important for local actions than total 25(OH)D. European studies in the framework of the EU Framework
The free 25(OH)D concentration can either be calculated 7-funded ODIN project (food-based solutions for optimal
(based on vitamin D-binding protein (DBP), albumin and vitamin D nutrition and health through the life cycle;
total 25(OH)D concentrations and the affinity between https://arquivo.pt/wayback/20160421110252/http://
both components) or can be directly measured. Whether www.odin-vitd.eu/) markedly changed the number of
free 25(OH)D is a better predictor for clinical outcomes vitamin D deficient subjects (28).
than total 25(OH)D is presently unclear (16).
Definitions

Standardization of the measurement of An international consensus on the definition of vitamin D

serum 25(OH)D deficiency and sufficiency is lacking. The IOM has defined
a serum 25(OH)D concentration of 30 nmol/L (divide by
Standard reference materials, inter-laboratory collaboration the conversion factor 2.496 to obtain 12 ng/mL) as the
and quality assurance schemes are important aspects of threshold below which clinical vitamin D deficiency may
overcoming the challenges that the assay methodologies occur (2, 14, 19). It has defined a 25(OH)D concentration
present. An external quality assurance scheme, the of 50 nmol/L (20 ng/mL) as the threshold of sufficiency,
Vitamin D External Quality Assurance Scheme (or DEQAS) that is sufficient for 97.5% of the population in terms of
(www.deqas.org, Charing Cross Hospital in London, UK), bone health, a definition also recently adopted by the
exists since the early 1990s and it has grown steadily, such EFSA (29). The serum concentration of 40 nmol/L fits with
that it now serves as a quarterly monitor of performance the estimated average requirement (EAR), that is sufficient
of analysts and 25(OH)D analytical methods for more for 50% of the population. Serum 25(OH)D levels between
than 1000 laboratories worldwide (5, 17, 18, 19, 20). 30 and 50 nmol/L (12 and 20 ng/mL), referred to by the
The introduction of the National Institute of Standards IOM as ‘inadequacy’, represent an uncertain range and
and Technology (NIST) reference standards, calibrated can be sufficient or not for a certain individual (Table 1).
using a reference LC–MS/MS procedure, offers hope The Endocrine Society has defined serum 25(OH)D of
that the variability of all methods will be diminished in 50 nmol/L (20 ng/mL) as the threshold for deficiency and
the future. Recent data suggest that an improvement is 75 nmol/L (30 ng/mL) as the threshold for sufficiency, that
already occurring (18) but there is still a long way to go is sufficient for 97.5% of the population (1). The 2016 UK

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 Position Statement P Lips and others ECTS statement on vitamin D 180:4 P26
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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.

SACN guidelines defined serum 25(OH)D concentrations countries. These projects utilized available biobanks from
below 25 nmol/L as being deficient for all age groups national nutrition and health surveys and cohorts in Europe
but concluded that there was insufficient evidence to and used a centralized laboratory LC–MS/MS analytical
define a higher 25(OH)D being optimal for bone or global platform for 25(OH)D, which is traceable to the two higher
health (30). order reference measurement procedures (NIST, VDSP) and
The ECTS Working Group defines vitamin D deficiency certified by the Centres for Disease Control and Prevention
as a serum 25(OH)D concentration below 50 nmol/L. A (CDC). The data from these projects together with data from
serum 25(OH)D level below 30 nmol/L is considered severe other studies in different countries in Europe and the Middle
vitamin D deficiency. A serum 25(OH)D concentration of East is summarized in Table 2. We have selected studies from
50 nmol/L and above is considered sufficient. the last 10 years, and, where available, prioritized population-
A problem with these definitions is that they heavily based studies having standardized serum 25(OH)D values
European Journal of Endocrinology

rely on the accuracy of serum 25(OH)D measurement. according to the VDSP program.
The latter depends on standardization and the discussions
on this subject have not been finalized (28).
Northern Europe
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 The prevalence of serum 25(OH)D <30 nmol/L ranged from
be presented in IU/day or in µg/day (1 µg = 40 IU). While 0.4 to 8.4%, and <50 nmol/L from 6.6 to 33.6% in adults,
clinicians often use IU/day, nutritionists usually prefer according to standardized data from the ODIN study,
µg/day. We have chosen the use of µg/day, with frequent and some Nordic studies (28, 36, 37, 38, 39). However,
reference to the conversion factor for ease of the reader. 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
Vitamin D status and prevalence of vitamin in immigrants (42, 43), and in older persons, especially
D deficiency in Europe residents of nursing homes (44, 45). The generally
adequate vitamin D status in the Nordic countries is
Vitamin D status has been studied in many European due to the use of cod liver oil and supplements (46) and
countries in various age groups. Since different studies vitamin D fortification, leading to a great improvement in
use different laboratories and different assays, the data Finland during the last decade (47).
should be compared with caution because, as mentioned
above, the inter-laboratory variation may be high
Western Europe
(19, 23). Another point is the study population which
may be either a population sample (31) or a convenience The prevalence of serum 25(OH)D <30 nmol/L ranged
sample (32). Data from various studies in different from 4.6 to 30.7% and <50 nmol/L from 27.2 to 61.4%
European countries are summarized in Table 2. Recent according to standardized data from ODIN (28). Vitamin
reviews on vitamin D status in Europe or worldwide D status generally was worse in the UK (30.7% < 30 nmol/L
were published by Spiro and Buttriss, Wahl et al. and and 61.4% < 50 nmol/L) than in other countries (25, 28,
Hilger et al. (33, 34, 35). 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62),
The ODIN project (28) as well as a small project funded and recently a rise in the incidence of rickets was observed
by the Nordic Council of Ministers (36) have recently (63). A poor vitamin D status was observed in black and
allowed for the generation of standardized serum 25(OH) Asian people in the UK, in teenagers and adolescents in
D data which facilitates estimating and comparing the the UK (25, 48), in (pregnant) non-Western immigrants
prevalence of vitamin D deficiency in various European (64, 65) and in general in older persons (66).

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 European Journal of Endocrinology

Table 2 Vitamin D status in adults and children in different European countries.

25(OH)D
Country Comments Study population n Age (years) Mean ± s.d. (nmol/L) <25 nmol/L (%) <50 nmol/L (%) References

Iceland Latitude 64° Adult men and 5519 66–96 57.0 ± 17.8 4.2 33.6 Cashman et al.
(Reykjavik) Regionally women 2016 (28)
representative
Norway Latitude 69° Adult men and 12 817 30–87 65.0 ± 17.6 0.3 18.6 Cashman et al.
Position Statement

(Tromso) Regionally women 2016 (28)

representative
Norway (Oslo) Latitude 60° Adult men and 866 30–76 71.0 ± 19.5 0.1 (white) 14.9 (white) Cashman et al.
women (white) 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° Adult men and 4102 29–77 67.7 ± 13.2 0.2 6.6 Cashman et al.
Nationally women 2015 (36)
representative Jaaskelainen
et al. 2017 (47)
P Lips and others

Denmark Latitude 56° Adult men and 3409 19–72 65.0 ± 19.2 0 23.6 Cashman et al.
(Copenhagen) Regionally women 2015 (36)
representative
UK Latitude 50–59° Children, teens 1488 1.5–91 47.4 ± 19.8 15.4 56.4 Cashman et al.
Nationally and adults 2016 (28)
representative
Northern Latitude 55° Girls and boys 1015 12 and 15 66.2 16.7 66.2 Carson et al.
Ireland 2015 (48)
status

Ireland Latitude 51–54° Adults (national 1118 18–84 56.4 ± 22.2 6 (year round) 45 (year round) Cashman et al.
representative 2013 (56)
sample)
Netherlands Latitude 52° LASA 2009 915 61–99 64.7 ± 22.6 2.4 28.5 Cashman et al.
Nationally 2016 (28)
representative
Netherlands Latitude 52° Adults 2625 40–66 59.5 ± 21.7 4.9 33.6 Cashman et al.
Regionally 2016 (28)
representative
ECTS statement on vitamin D

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° Adults 6995 18–79 50.1 ± 18.1 4.2 54.5 Cashman et al.
Nationally 2016 (28)
representative
Germany Latitude 48–52° Children and 10 015 1–17 54.0 ± 19.2 6.0 44.5 Cashman et al.
180:4

Nationally adolescents 2016 (28)

representative
France Varieté study Men and women 892 18–89 60 ± 20 6.3 34.6 Souberbielle
Latitude 43–49° et al. 2016 (54)
P27

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Table 2 Continued.

25(OH)D
Country Comments Study population n Age (years) Mean ± s.d. (nmol/L) <25 nmol/L (%) <50 nmol/L (%) References

Switzerland Latitude 47° MONICA 3276 25–74 46 (median) 6 (<20) >50 Burnand et al.
1992 (55)
Latitude 47° Nursing home Women 246 85 ± 7 23 ± 18 65 Krieg et al.
Men 103 81 ± 8 26 ± 21 48 1998 (58)
Position Statement

Latitude 47° Non-institut. 193 80 ± 9 18 ± 18 90 Theiler et al.

Elderly 1999 (57)

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Spain
Italy Latitude 38–45° Postmenop. 570 59 ± 8 45 ± 20 28 Bettica et al.
women 1999 (69)
Italy Latitude 38–45° Multicenter 700 60–80 76 Isaia et al.
2003 (70)
Greece Latitude 35–40° Adolescents 806 9–14 47.3 ± 12.5 2.2 62.4 Cashman et al.
Regionally 2016 (28)
representative
Greece Latitude 37° Children 222 3–6 54.3 ± 15.7 1.4 40.5 Cashman et al.
Regionally 2016 (28)
P Lips and others

representative
Poland Warsaw Postmenop. 65 72 ± 1 32.5 25 92 Andersen et al.
women 2005 (41)
Regionally Girls 61 12.6 ± 0.5 30.6 33 87
representative
Estonia 59° winter Women 200 49 ± 12 44.6 ± 15.8 8 73 Pludowski et al.
Men 167 49 ± 12 42.7 ± 14.0 2014 (72)
Kull et al.
status

2009 (74)
Summer Women 200 49 ± 12 58.4 ± 17.7 1 29
Men 167 49 ± 12 60.5 ± 18.5
Czech Republic 50° Women 321 53 ± 14 62.5 ± 10 Mayer et al.
Men 239 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.
ECTS statement on vitamin D

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. 120 61.1 ± 8.8 46.9 ± 16.8 14.2 (<30) 63.3 Laktasic et al.
women 2010 (80)
180:4

Belarus 53° Women 168 45–55 72 ± 37 Pludowski et al.

Men 176 55–65 67 ± 35 2014 (72)
Women 178 65–75 65 ± 35
Women 101 >75 46 ± 22
Ukraine 44–52° Women 649 47 (20–59) 29 ± 15 Pludowski et al.
Men 129 44 (20–59) 2014 (72)
P28

27 ± 14
Women 711 69 (60–95) 26 ± 14
Men 86 71 (60–91) 19 ± 9

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 European Journal of Endocrinology

25(OH)D
Country Comments Study population n Age (years) Mean ± s.d. (nmol/L) <25 nmol/L (%) <50 nmol/L (%) References

Russia Older persons 97 70.2 28 ± 10 47 Bakhtiyarova

Hip fracture 63 68.8 22 ± 11 65 et al. 2006 (81)
patients
Russia 57–67° Northern 178 17–59 39.7–47.7 2–53 8–84 Kozlov et al.
indigenous 2014 (82)
Position Statement

Vitamin D status in adults and children in different Middle East countries

Turkey Manisa 119 M 45 ± 17 51.8 ± 38.7 66 Hekimsoy et al.
272 F 45 ± 17 38.1 ± 28.7 79 2010 (93)
Turkey Istanbul students 100 F 21 ± 2 65.7 ± 25 34 Buyukuslu et al.
Covered: 52 ± 20 2014 (94)
Uncovered: 74 ± 8
Turkey Kahramanmaras Pregnant women 97 women 27 ± 5 12.5 ± 8 85 98 Parlak et al.
newborns, 97 97 neonates 0 10.7 ± 6 93 100 2015 (95)
pairs
Turkey Trabzon Schoolchildren 397 M 14.6 ± 1.9 37.3 ± 20.8 28 78 Karaguzel
349 F 14.6 ± 1.8 31.3 ± 17.3 42 87 2014 (96)
Iran Shiraz (latitude Selected by 520 M 20–74 33.7 29.9 (<35 nmol/L) Masoompour
P Lips and others

35 ± 17
30°N) postal code et al. 2008 (97)
number
Iran Tehran (latitude Controls from 251 M + F 56.7 ± 11.7 45 (26–77) 19.1 54 (<37.5 nmol/L) Hosseinpanah
35°N) lipid and et al. 2011 (99)
glucose Study
Iran Zahedan (latitude NA 431 M 20–88 34.4 ± 29.4 NA 85.2 Kaykhaei et al.
30°N) 562 F 2011 (100)
status

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 Torkaman et al.
>2 year: 43 2016 (103)
Syria Damascus (33°N) Healthy 372 34.1 ± 10.0 24.7 ± 16.9 61 Sayed-Hassan
volunteers et al. 2014 (104)
Israel Population based Clalit Health 198 834 M F 0 to >80 51.9 ± 24.5 14.4 49.8 Saliba et al.
(31°N) Services median 60 2012 (105)
Israel Retrospective Maccabi 8175 M F 55 ± 15 M 60 ± 25 NA NA Steinvil et al.
ECTS statement on vitamin D

Population based healthcare 26 699 F M 55 ± 17 F 56.6 ± 24.7 2011 (106)

(31°N) services
Israel (31°N) Volunteers 95 M All ages 57.15 ± 25.2 27.2 78 Oren et al.
100 F 2010 (107)
Israel Jerusalem Healthy children 247 1.5–6 64.2 ± 25.0 28.3 Korchia et al.
primary care 2013 (108)
180:4

Jordan Population based National sample 4590 41.9 ± 13.4 M 183.3 ± 73.3 1.5 Batieha et al.
F 99.5 ± 51.7 14.2 2011 (109)
Jordan National Al Basheer 2032 F 15–49 Median 27.5 60% 95 Nichols et al.
Micronutrient Hospital <30 nmol/L 2012 (110)
Survey
Jordan National Al Basheer 1077 1–5 Median 45 nmol/L 20% 56.5 Nichols et al.
P29

Micronutrient Hospital <30 nmol/L 2015 (111)

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 European Journal of Endocrinology

Table 2 Continued.

25(OH)D
Country Comments Study population n Age (years) Mean ± s.d. (nmol/L) <25 nmol/L (%) <50 nmol/L (%) References

Jordan Healthy volunteers M 99 29 M 44 ± 10 0 76 Mallah et al.

F 201 32 F western 40 ± 8 0 90 2011 (112)
F hijab 31 ± 6 4 98
F niqab 28 ± 4 9 100
Position Statement

Jordan Neonates Al Bashir 3731 0 Median 21.5 ±90 94% Khuri-Bulos et al.
Government 2013 (113)

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Hospital
Amman
Lebanon Beirut Hospital 2008 2002 2008 Hoteit et al. 2014
database (114)
2000–2004 and 349 12.2 ± 4.5 F 42.7 M 48.2 63 58
2007–2008 3024 49.5 ± 11.6 F 57.0 M 54.0 60 44
1762 72.7 ± 5.7 F 59.0 M 54.5 62 40
Lebanon Population based Home-dwelling 157 M 65–85 25.7 (10–96.7) 37 94 Arabi et al. 2010
Beirut (34°N) ambulatory 286 F Mean M 30.2 56 95 (115)
subjects 73 years F 27.3
P Lips and others

Kuwait Schoolchildren 199 7–9.5 Median 30 Alyahya 2017

M 34; F 27 (116)
Kuwait Mothers and Al Adan and 128 pairs 27 Mothers 36.5 40 76 Molla et al. 2005
neonates maternity Neonates 20.5 65 96 (117)
hospitals
Saudi Arabia Riyadh Pregnant women 160 20–49 49.9 (IQR 28) 18 50 Al-Faris 2016
(120)
status

Saudi Arabia Population based 40 (PHCCs) M < 50: 550 20–74 31.3 ± 17.5 52.6 89.9 Ardawi et al.
Jeddah (22°N) M > 50: 284 26.8 ± 15.0 41.9 83.8 2012 (118)

Saudi Arabia Schools all over School children 1013 M 6–15 28 ± 11 M 25 M 93 Al Shaikh et al.
country 1097 F F 64 F 98 2016 (119)
United Arab Abu Dhabi University 70 M 21 ± 4 M 27.3 ± 15.7 94 Al Anouti et al.
Em students 208 F F 24.2 ± 14.9 2011 (122)
United Arab Abu Dhabi Pediatric 183 5.3 ± 3.7 53.6 ± 33.4 17 ±57 Rajah et al. 2012
Em outpatients (121)
ECTS statement on vitamin D

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 547 49 ± 13 36.0 ± 27.5 46 El-Menyar et al.
study in 547 2012 (124)
hospital
patients
180:4

Egypt Cairo and Port Women Lactating 51 26 ± 5 30 73 Botros et al.

Said Pregnant 50 26 ± 5 37 54 2015 (125)
Non pregnant 31 ± 8 27 72
208
Elderly 38 58 ± 4 66 40
Geriatric 57 76 ± 7 37 77
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 European Journal of Endocrinology

25(OH)D
Country Comments Study population n Age (years) Mean ± s.d. (nmol/L) <25 nmol/L (%) <50 nmol/L (%) References

Tunisia Tunis Mothers and 87 mothers 31 ± 5 17 ± 13 87 (<30) 97 Ayadi et al. 2016

newborns 87 neonates 0 15 ± 4 78 (<30) 98 (126)
Algeria Tizi-Ouzou Healthy children 435 5–15 Sept: 71.4 8.1 (<30) 29.9 Djennane et al.
March: 52.9 17.4 (<30) 41.4 2014 (127)
Morocco Rabat Postmenopaual 178 58.8 ± 8.2 39.5 ± 29.0 51.6 El Maghraoui
women et al. 2012
Position Statement

(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° Norwegian 866 30–76 71.0 ± 19.5 0.1 14.9 Cashman et al.
Pakistani 176 27.6 ± 12.3 52.3 92.0 2015 (36)
Finland Latitude 60–63° Ethnic (all): 1310 18–64 45.5 ± 21.9 18.2 63.7 Cashman et al.
Representative of White Russian 466 62.8 ± 21.0 2.5 28.7 2016 (28)
immigrant Kurdish 500 33.7 ± 15.6 34.2 85.6
populations Somalian 364 40.5 ± 16.6 15.7 76.4
Finland Latitude 60 Bangladeshi 34 20–48 42.9 ± 16.1 0 70.6 Islam et al. 2012
Somali 48 36.8 ± 11.8 8.3 81.3 (84)
Finnish 61 3.3 44.3
P Lips and others

54.1 ± 19.1
Denmark Latitude 55 Pakistani Children 37 12.2 10.9 81 95 Andersen et al.
Premenopausal 36.2 12.0 84 97 2008 (43)
women 115
Men 95 38.3 20.7 65 95
Netherlands Adult women 613: 18–65 Van der Meer
and men et al. 2008 (64)
Dutch 67 6
status

Turkish 27 41
Moroccan 30 37
Surinam Asian 24 51
Surinam Creole 27 45
African 33 19

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.
ECTS statement on vitamin D
180:4
P31

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 Position Statement P Lips and others ECTS statement on vitamin D 180:4 P32
status

Southern Europe 12.5% of the participants and 40% was deficient (serum
25(OH)D <50 nmol/L) (28).
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 Vitamin D status and prevalence of vitamin
25 nmol/L in Greece while it was around 45 nmol/L in the D deficiency in the Middle East
Nordic countries (31). Other studies in these countries
Population-based studies are rare. The prevalence of
usually show mean serum 25(OH)D concentrations below
vitamin D deficiency and rickets is high in the Middle
50 nmol/L and higher percentages of serum 25(OH)D
East despite abundant sunshine (25, 88, 89, 90, 91, 92)
<30 nmol/L than in Northern and Western Europe (67, 68,
(Table 2). The median or mean serum 25(OH)D in almost
69, 70, 71). Standardized data from infants and children
all surveys was between 25 and 50 nmol/L, with lower
in Greece (ODIN) showed serum 25(OH)D <30 nmol/L in
values in women than in men, that also depend on
4.2–6.9%, and <50 nmol/L in 40.5–62.4% (28).
clothing style (93, 94, 95, 96, 97, 98, 99, 100, 101, 102,
103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114,
Eastern Europe 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126,
127, 128, 129, 130, 131). In a recent systematic review,
Standardized data from adults are not available. In
the prevalence of vitamin D deficiency in the Middle East
general, a review and individual studies showed a mean
varied between 30 and 90% depending on the type of
serum 25(OH)D usually lower than 50 nmol/L, and a
European Journal of Endocrinology

study, country, age group and assay used (92). Vitamin

poorer vitamin D status than in Northern and Western
D status was poor in several surveys in Saudi Arabia
Europe (72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82).
(118, 119), probably due to a very traditional lifestyle.
Vitamin D status is better in Israel.
Immigrants in Europe In general, vitamin D deficiency is much more
prevalent in the Middle East than in Northern and
Studies from Norway, Finland, Denmark and the
Western Europe. Risk groups for severe deficiency include
Netherlands confirm a very poor vitamin D status in non-
children, adolescents and pregnant women.
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 Determinants of vitamin D status and risk
or lower in Turkish, Moroccan and Surinamese people in groups for vitamin D deficiency
comparison with a mean serum 25(OH)D of 67 nmol/L in
Demographic, anthropometric and lifestyle factors are
locally born people (64).
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
European population studies
the main determinants, but these are modified by other
As mentioned early, the Seneca study was performed in factors. Vitamin D status deteriorates with aging above
eight countries but serum 25(OH)D was measured in one 70 years due to decreased sun exposure and cutaneous
central laboratory to avoid variation between different synthesis (132), and is poor in the institutionalized,
laboratories (31). Some studies reporting baseline 75% of them being severely vitamin D deficient (serum
data from randomized clinical trials in patients with 25(OH)D <25 nmol/L), and in patients with hip fracture
osteoporosis also used a central laboratory facility, making (66, 133). The good vitamin D status in the Nordic
comparisons between countries more reliable (raloxifene countries is explained by the frequent consumption
and bazedoxifene studies) (86, 87). A general trend in of cod liver oil and vitamin D supplements (134, 135).
these data is that vitamin D status usually is much better Furthermore, fortification of milk and milk products
in Nordic countries than around the Mediterranean. over the last 10 years has considerably improved vitamin
The European ODIN study used standardized data from D status in Finland (47). On the other side, strong
epidemiological studies in Europe. Severe vitamin D sunshine in Southern Europe and the Middle East may
deficiency (serum 25(OH)D <30 nmol/L) was observed in lead to decreased exposure (136), and skin pigmentation

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 Position Statement P Lips and others ECTS statement on vitamin D 180:4 P33
status

Causes Consequences Prevention

Sun Figure 1
Causes, consequences and prevention of
Vitamin D-related gene vitamin D deficiency. The red arrows lead
polymorphisms
Oily fish to vitamin D deficiency, the green arrows
Vitamin D
deficiency
can prevent it. Vitamin D-related gene
Low sun exposure polymorphisms indicate gene
Cod liver oil
polymorphisms in the vitamin D metabolic
High PTH
pathway that decrease vitamin D
Poor diet bioavailability. Low sun exposure may also
Mineralisation Bone loss Food fortification:
defect (milk, juice, flour, oil) be due to clothing style, skin pigmentation
No supplements
and sunscreen use. Poor diet means no
fish, no dairy products, no vitamin
× Supplements for
risk groups
D-fortified foods. A full color version of
this figure is available at https://doi.
org/10.1530/EJE-18-0736.

decreases vitamin D synthesis (137). Vitamin D status in Northern Europe

the Middle East is strongly dependent on clothing style,
European Journal of Endocrinology

The mean intake of vitamin D in Northern Europe varies

with decreasing vitamin D status going from Western-
between 4 and 14 µg/day (41, 43, 139, 140, 141, 142, 143,
style clothing to hijab and niqab (129, 130, 131). A
144, 145, 146, 147, 148, 149), with high values found in
low calcium intake is common in the Middle East (92).
Norway, due to the consumption of oily fish and cod liver
It increases the risk of rickets, and it leads to secondary
oil. In Iceland, the difference between users and non-
hyperparathyroidism and bone loss. Pollution and urban
users of cod liver oil was more than 9 µg/day. In Sweden,
living are other factors.
fish and fortified milk products were important sources.
Risk groups for vitamin D deficiency are children,
In Finland, the fortification of fluid milk products was
adolescents, pregnant women and older persons.
recently increased to 10 µg/L. Vitamin D supplement of
Vitamin D status usually is very poor in immigrants
10 µg/day was recommended for children younger than
from non-Western countries, compared with native
3 years, and 7.5 µg/day for children and adolescents aged
people (28, 64, 83, 84, 85), fatty fish and supplements
3–18 years. The recent Finrisk–Findiet survey has shown
being the most important determinants (64). This is
that the dietary vitamin D intake has increased to above
even worse in pregnant non-Western immigrants, who
10 µg/day in men and nearly as much in women (47, 147).
displayed mean serum 25(OH)D concentrations around
The mean dietary vitamin D intake was around 3 µg/day
25 nmol/L (65).
in Denmark.

Vitamin D intake in Europe and the Western Europe

Middle East
The mean vitamin D intake in Western Europe varies
Measurements of vitamin D content of food requires between 1.5 and 5 µg/day, far below the EAR of
special expertise due to its low concentration, the possible 10 µg/day (150, 151, 152, 153, 154, 155, 156, 157, 158,
presence of vitamin D esters with uncertain bioavailability, 159, 160, 161).
and the presence of 25(OH)D in some food items. Most of
the data presented below is based on methodology which
Southern Europe
estimated vitamin D only. Studies on vitamin D intake
in Europe have been nicely summarized by Spiro and Food consumption surveys presented in Table 3 showed
Buttriss (33), and Kiely and Black (138). An overview of vitamin D intakes from below 1 µg/day to about 3 µg/day
the data is presented in Table 3. in Italy, Spain and Portugal.

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 Position Statement P Lips and others ECTS statement on vitamin D 180:4 P34
status

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 µg Thorgeirsdottir et al.

13.5 µg (with cod liver oil) 2012 (139)
Norway Volunteers 32 9.6 µg Brustad et al. 2004 (134)
Norkost M: 15 µg Norkost (144)
F: 12.9 µg
Sweden Riksmaten 7.1 µg Riksmaten (145)

Finland National Diet Survey 1708 25–74 M: 11 µg Helldán et al. 2013 (147)
Findiet F: 9 µg
OM: 14 µg
OW: 19 µg
Denmark Dan Nat Survey 3.9
3.1
United Kingdom NDNS rolling survey M: 210 4–10 2.2 (median) Department of Health
(2008/2009 to M: 238 11–18 2.1 2011 (153)
2009/2010) M: 346 19–64 2.8
M: 96 >65 3.9
F: 213 4–10 2
F: 215 11–18 1.7
F: 461 19–64 2.6
F: 128 >65 3.1 (median)
European Journal of Endocrinology

Ireland National Adult 1274 18–64 3.5 (median) Black et al. 2015 (151)
Nutrition Survey 6.4 (mean)
Ireland Irish Preschool Children 500 1–4 2–2.5 µg (median) Hennessy et al.
Survey 2016 (152)
Ireland Irish Children’s and 594 5–8 1.9 (median) Black et al. 2014 (150)
Teens’ National 441 9–12 2.1 (median)
Nutrition Surveys 13–17 2.4 (median)
Netherlands Hip fract pat controls 125 75.9 2.8 Lips et al. 1987 (156)
74 75.6 2.9
Food cons survey M: 4.8
F: 3.6
Germany Nat Nutr Survey M: 4.4
F: 3.4
Portugal Epiporto M: 3.4 Spiro & Buttriss
F: 3.3 2014 (33)
Spain ENCAT 2002–2003 M: 0.7 Spiro & Buttriss
F: 0.7 2014 (33)
Italy INN-CA 1996 M: 2.5 Spiro & Buttriss
F: 2.4 2014 (33)
10 European European Prospective M: 13 025 35–74 5.5 Jenab et al. 2009 (163)
countries Investigation into F: 23 009 35–74 3.6
(EPIC) Cancer and Nutrition
Southern (EPIC) study M: 4530 35–74 4.2
F: 7372 35–74 5.1
Central M: 3807 35–74 4.7
F: 8561 35–74 3.4
Northern M: 4688 35–74 7.4
F: 7076 35–74 5.0
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 5524 18–70 M: 2.5 ± 4.3 Ejtahed et al.
Glucose Study F: 3.8 ± 3.1 2016 (165)
Iran Iranian Multicentric F: 581 42.4 ± 12.2 1.5 ± 1.2 Khashayar et al.
Osteoporosis Study 2017 (166)
Iran Pregnant 2.3±1.9 Sabour et al.
women 2006 (167)
Iran Children 1.4 Feizabad et al. 2017 (168)

(Continued)

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 Position Statement P Lips and others ECTS statement on vitamin D 180:4 P35
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Table 3 Continued.

Country Study population n Age (years) Vitamin D intake (µg/day) References

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 F 39.4 ± 5.6 2.2 ± 1.5 Gannage-Yared et al.
M 41.3 ± 5.5 3.2 ± 2.0 2000 (171)
Lebanon 128 pregnant 10.6 ± 10.9 (FFQ) Papazian et al. 2016
women 8.9 ± 2.5 (24 h recall) (172)
Qatar 60 young 29 3.0 Salameh et al. 2016 (173)
women
United Arab 350 adolescent 15.3 ± 2 8.5 Narchi et al. 2015 (174)
Emirates females
Saudi Arabia University students 19–25 53% < 15 µg/day Alzaheb & Al-Amer
Tabuk 2017 (175)
Tunisia 225 boys 8 Bezrati et al. 2016 (176)
Tunisia 87 pregnant 2.2 Ayadi et al. 2016 (126)
women

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

Eastern Europe in the section on Food fortification with vitamin D. These

drawbacks may explain the wide variability between
European Journal of Endocrinology

The mean vitamin D intake varied between 2 and

countries and the lack of a consistent pattern by age.
5 µg/day, according to a recent review (162).
The mean vitamin D intake ranged between 1 and 4 µg/
day, with some exceptions in selected groups of children,
European studies
adolescents and pregnant women, probably due to
National dietary and food consumption surveys as well vitamin D supplements (126, 164, 165, 166, 167, 168,
as smaller studies use various methods of data collection, 169, 170, 171, 172, 173, 174, 175, 176). These intakes are
analysis and reporting, making meaningful comparison well below the RDA of 10–20 µg/day, depending on age
of vitamin D intakes problematic (155). Some studies and reproductive stage (2, 177).
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/ Genetic factors
day in girls and 3.4–9.5 µg/day in older women (41)
Genetic factors may contribute to up to 28% of inter-
The European Prospective Investigation into Cancer
individual variability in serum 25(OH)D concentrations,
and Nutrition (EPIC) compared vitamin D intakes in ten
while clinical correlates such as season, vitamin D intake
European countries. The mean vitamin D intake was 5.5
and waist circumference explain another 24% of variability
and 3.6 µg/day in men and women respectively with the
(178). Studies have applied the candidate gene approach
highest intake in the Northern countries (163).
to relatively common single nucleotide polymorphisms
In conclusion, mean vitamin D intake in most
which play an important biological role in vitamin D
European countries is rather low, in most countries less
metabolism, transport, degradation and downstream
than 5 μg/day (200 IU/day). Vitamin D intake is highest in
pathways, to evaluate their impact on circulating 25(OH)
the Nordic countries and poor in Southern Europe.
D concentrations (Fig. 1). These include genes involved
in cholesterol synthesis (DHCR7), 1-α-hydroxylase
Vitamin D intake in the Middle East (CYP27B1), 25-hydroxylase (CYP2R1), vitamin D transport
(GC (group specific component), identical to DBP) and to
Population-based studies on vitamin D intake are scarce. a lesser extent also 24-hydroxylase (CYP24A1) (179, 180,
The used food frequency and 24 h recall questionnaires 181, 182). Similar effects of polymorphisms of these genes
varied and these tools were mostly validated in (especially DBP/GC) were confirmed in several studies
Western populations, with little or no adaptation to (183). The combined effects of these genes do not explain
the Mediterranean/Middle Eastern diet. Vitamin D more than about 5% of the variability and considerably less
fortification varies widely between countries, as detailed than the seasonal variation in serum 25(OH)D (179, 184).

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 Position Statement P Lips and others ECTS statement on vitamin D 180:4 P36
status

25(OH)D and all other metabolites of vitamin D are rickets in children and osteomalacia in adults. While
bound to a high capacity, high affinity serum DBP or rickets is rare in almost all European countries, it is still
GC. A smaller proportion is loosely bound to albumin. reported in the Middle East, in some Asian countries and in
Therefore the free concentration of 25(OH)D represents immigrants of those countries in Europe (88). In general,
less than 0.1% of the total concentration. Genetic rickets in Europe is mostly reported in non-Western
polymorphisms of DBP are associated with different DBP immigrants, mainly coming from Africa and Asia and in
concentrations but this depends on the antibody used for persons consuming macrobiotic or vegan diets (191, 192).
measuring DBP. When polyclonal anti-DBP antibodies are This can be explained by the fact that oily fish and dairy
used, subjects with GC2 genotype have a slightly lower products are the major dietary source of vitamin D and
DBP concentration compared to others (185), associated calcium, both being absent in these diets. Milder vitamin
with lower 25(OH)D concentrations. A monoclonal D deficiency results in secondary hyperparathyroidism,
antibody method found much (about 50%) lower DBP increased bone turnover and accelerated bone loss,
concentrations in GC 1f–1f homozygotes (mainly African- osteoporosis and fractures (66). The vitamin D endocrine
Americans) than in subjects with other genotypes (186). system primarily tries to maintain a normal serum calcium
Subsequent studies using mass spectrometry to measure homeostasis whereby its role on bone can be either
serum DBP, however, did not find a significant difference beneficial or deleterious depending on calcium intake and
in DBP according to race (187, 188), creating serious availability (193, 194). Many cross-sectional studies and
doubt (189) on the conclusions based on the monoclonal especially randomized controlled trials have demonstrated
antibody (186). As the free concentration of 25(OH)D is a beneficial role of vitamin D supplementation, in a
European Journal of Endocrinology

dependent on both DBP concentration and affinity it is sufficient dose of daily 20 µg (800 IU) vitamin D (195, 196,
yet not possible to conclude whether clinical correlates 197) and in combination with calcium supplements (198,
and thresholds for vitamin D deficiency depend on 199), among seniors (institutionalized and community-
genetic polymorphisms of DBP. An assay to measure the dwelling) at risk for vitamin D deficiency and with a
free 25(OH)D concentration is available, but currently it is lower than recommended calcium intake, showing a
uncertain whether the measurement of this metabolite in reduction of falls as well as hip and other fractures (3,
its free state has clinical implications (189, 190). 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
Impact of vitamin D on bone health in adolescents and non-elderly adults requires
additional controlled intervention studies. The 2018
A beneficial effect of vitamin D on musculoskeletal health meta-analysis on the musculoskeletal benefits of vitamin
is well established, as severe vitamin D deficiency causes D monotherapy on BMD, fractures and falls by Bolland

Table 4 Dietary reference intakes for vitamin D in µg/day according to different European countries, the Institute of Medicine
and the Endocrine Society.

<1 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 10 15 15 15 15 20 15 IOM 2011 (2)
Medicine
Endocrine 10–25 15–25 15–25 15–25 37.5–50 37.5–50 15–25** Holick et al. 2011 (1)
Society 37.5–50

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

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 Position Statement P Lips and others ECTS statement on vitamin D 180:4 P37
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and colleagues suggests no benefit on these outcomes, but range for serum 25(OH)D and fall prevention may be
they did not analyze clinical trials with vitamin D and between 50 and 75 nmol/L (20 and 30 ng/mL) for optimal
calcium vs double placebo (205). 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
Extra-skeletal health (222, 224). Among somewhat younger postmenopausal
women (mean age 66 year), a most desirable range of
The presence of the vitamin D receptor (VDR) in serum 25(OH)D for optimal fall prevention was suggested
most cells and tissues, as well as the expression of the to be 80–95 nmol/L (32–38 ng/mL) based on a multidose
1α-hydroxylation enzyme CYP27B1 in many cells and the vitamin D trial (225). Notably, both trials suggested that
large number of genes under the control of 1α,25(OH)2D a serum 25(OH)D higher than 113 nmol/L (45 ng/mL) was
suggest a broader role of the vitamin D endocrine system associated with a significantly increased risk of falling
beyond bone and calcium homeostasis (206, 207, 208). compared to a 25(OH)D range of 80–95 nmol/L (221).
Moreover, such potential effects on non-classical or non- An additional aspect with potential impact on muscles
skeletal outcomes are in line with data from association and falls as well as bone density is the relationship between
studies between low vitamin D status and cardiovascular vitamin D status and sex steroid levels in men with a
diseases, diabetes and the metabolic syndrome, parallel seasonal variation of both hormones (226, 227,
inflammatory, infectious and immune disorders, as well 228, 229). While it has been demonstrated that vitamin
as a variety of cancers. A low vitamin D status was also D increases testosterone production in human primary
European Journal of Endocrinology

associated with increased mortality risks as extensively testicular cells (230), clinical trials were controversial
reviewed (3, 27, 206, 209). Whether skeletal or cardiac (231, 232) and a pooled analysis did not show an increase
muscles are target tissues for the vitamin D endocrine (233). Meta-analyses of RCTs on cardiovascular outcomes,
system has been debated. The presence of the VDR in and glycaemic control and type 2 diabetes have shown
skeletal muscle tissue has been questioned recently by disappointing effects (208, 234, 235, 236). This was
Wang and DeLuca suggesting that the VDR is undetectable confirmed by a Mendelian randomization study (237).
in muscle tissue (210), in contrast with many earlier However, a recent meta-analysis of RCTs of vitamin D on
studies (211, 212, 213, 214, 215), including the most acute respiratory infection showed that vitamin D in a
recent one using a new multi-step immunofluorescent daily or weekly dose reduced the risk of acute respiratory
technique to detect the VDR in muscle biopsy tissue from infection by 12%, the results being larger in those with
older female subjects (216). Recently, others found VDR baseline serum 25(OH)D <25 nmol/L (238). A large 4 year
to be expressed albeit at low (mRNA and protein) levels RCT of vitamin D 2000 IU/day and calcium 1500 mg/day
(217). VDR null mice (systemic or cardiac muscle-specific in postmenopausal women showed a borderline (P = 0.06)
deletion), however, show a clear muscle phenotype and decrease in cancer incidence (239). A recent Mendelian
many in vitro studies also show clear coherent positive randomization study showed an association between
effects of 1α,25(OH)2D on muscle cell precursors. Severe genetically lowered serum 25(OH)D concentrations and
vitamin D deficiency is frequently associated with muscle higher ovarian cancer susceptibility (240).
weakness/hypotonia and an increased risk of falling In Mendelian randomization studies, the use of 25(OH)
(218). Several double-blind intervention studies also show D measurements in relation to GC, CYP2R1, DHCR7
a significant average reduction of 19% in fall frequency genotypes and a binary study outcome variable such as
when elderly vitamin D deficient subjects receive a mortality has revealed associations of genotypes with
vitamin D supplement, but meta-analyses of these studies 25(OH)D concentrations, and of 25(OH)D concentrations
came to divergent conclusions depending on the quality and mortality, but the statistical association of genotypes
of fall assessment, and the inclusion of trials with or and binary outcome mortality was ambiguous (241).
without blinding (2, 219, 220). The overall interpretation Thus, a direct influence of genotypes on clinical outcomes
of the presently available data suggest that correction of was not always visible (208). Further studies on mortality
severe vitamin D deficiency improves muscle function and causes and low vitamin D status showed an association
reduces the risk of falls (3, 220). High intermittent dosing with cancer and all-cause mortality but not with
of vitamin D or doses resulting in high serum 25(OH)D cardiovascular mortality (241).
levels (above 125 nmol/L, 50 ng/mL) may, however, result Recently, the results of two megatrials have become
in increased risk of falls (221, 222) so that the therapeutic available. The VIDA trial in 5110 subjects compared

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 Position Statement P Lips and others ECTS statement on vitamin D 180:4 P38
status

vitamin D 100 000 IU/month with placebo and found above may have additional health benefits in reducing
no effect of vitamin D on cardiovascular disease (242). the risk of common cancers, autoimmune diseases, type
The VITAL trial comparing vitamin D 2000 IU/day with 2 diabetes, cardiovascular disease and infectious diseases
placebo in more than 25 000 subjects, concluded that (246, 247, 248). In contrast, the IOM concludes that
vitamin D did not result in a lower incidence of invasive there is no evidence that a 25(OH)D threshold greater
cancer or cardiovascular events than placebo (243). The than 50 nmol/L (20 ng/mL) has any additional benefit to
baseline mean serum 25(OH)D was rather high in these health (2), based on the results of RCTs. More recently
trials, 63 and 75 nmol/L, respectively. From all this data, it several other organizations (249), including the European
can be concluded that the prevention of chronic diseases Standing Committee of Medical Doctors (250) and several
is not a reason to start vitamin D supplementation in a scientists (3) supported the conclusions of IOM on
vitamin D replete population (244). 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
Optimal levels of 25-hydroxyvitamin D 1,25(OH)2D or PTH concentrations, intestinal calcium
absorption or bone mineral density. The required intake of
Although a great degree of consensus exists concerning vitamin D to achieve such serum 25(OH)D concentrations
the essential role of vitamin D on bone health, and some has been evaluated in numerous studies and an intake
controversy on its effect on muscle strength and falls, in the range of 600–1000 IU of vitamin D3 per day
there is less consensus about the optimal or required (15–25 µg/day) is adequate for achieving concentration
European Journal of Endocrinology

concentration of 25(OH)D to achieve these effects. As levels of ≥50 nmol/L in more than 97% of postmenopausal
there is no proven causality for the frequent association Caucasian or Afro-American women (223). Similar results
between vitamin D status and many other extra-skeletal were found in some European RCTs of young children,
effects, no threshold concentration can be defined for children, teenagers, young adults and older adults (251,
these putative protective effects. 252, 253, 254, 255, 256). Whether a higher dosage is
The ECTS Working Group has defined severe vitamin needed for populations with lower baseline 25(OH)D
D deficiency as a serum 25(OH)D lower than 30 nmol/L concentrations has not yet been established but evidence
(12 ng/mL) as such concentrations and even more so from two randomized clinical trials from Lebanon, one
concentrations below 15 nmol/L are associated with in children and another in elderly, suggest that this is
rickets or osteomalacia (245). The ECTS has defined the case for countries in the Middle East (257, 258).
vitamin D deficiency as a serum 25(OH)D concentration However, calculations of the required vitamin D to
below 50 nmol/L, a concentration that according to the replace the daily metabolic clearance of 25(OH)D suggest
IOM covers the needs of nearly all healthy individuals that 600–1000 IU/day should be sufficient to maintain
in the population in relation to bone health (2) (see serum 25(OH)D concentrations above 50 nmol/L (3). An
‘Definitions’ section), similar to the EFSA (29). In contrast, intake of 800 IU/day (20 µg/day) has also been proven to
an extensive analysis in the UK (30) concluded that serum be efficient in reducing the risks of fractures and falls in
25(OH)D concentrations should be above 25 nmol/L at all elderly Caucasian women (3, 196, 200, 218). The recent
ages as to avoid rickets or osteomalacia, and that these individual participant data meta-analysis in the ODIN
concentrations can be achieved in all otherwise healthy study concluded that higher doses are required in order
subjects, even when deprived from sunlight, by a daily to reach a serum 25(OH)D concentration of 50 nmol/L in
vitamin D intake of 10 µg (30). These experts did not find 97.5% of the population (259).
sufficient hard data to define higher serum 25(OH)D or Whether higher concentrations of 25(OH)D would
recommend higher vitamin D intake as to improve bone translate into additional skeletal and extra-skeletal effects
quality or provide extra-skeletal health benefits. as suggested by some cross-sectional or observational
At the other end of the spectrum, a 25(OH)D studies needs to be investigated in additional RCTs. The
concentration of 75 nmol/L (30 ng/mL) or higher is presently available usually small RCTs using doses of
recommended by the Endocrine Society (1). Regarding vitamin D above 2000 IU/day, however, have not proven
general health endpoints, the Endocrine Society states additional benefits so far (3). Fortunately, several large
that while evidence from RCTs is lacking, numerous scale, long-term RCTs are ongoing (Table 5) and are
epidemiological studies have suggested that a serum expected to better define efficacy and optimal dosages
25(OH)D concentration of 75 nmol/L (30 ng/mL) and of vitamin D for a variety of other major non-skeletal

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 Position Statement P Lips and others ECTS statement on vitamin D 180:4 P39
status

outcomes (3, 260). The negative results of the VIDA societies and resembles the Endocrine Society guideline
and VITAL trials suggest that vitamin D is not effective (269). When recommended intakes are compared with
with regard to cardiovascular disease and cancer when the actual intake, the values only approach each other
baseline 25(OH)D is high (242, 243). Very high dosages in the Nordic countries, Norway, Sweden and Finland
of vitamin D or very high serum 25(OH)D concentrations (144, 147).
may be detrimental. First, vitamin D toxicity can occur Recommendations for supplement use have explicitly
(261, 262, 263), characterized by increased urinary been made for small children in the Nordic countries,
calcium excretion, hypercalcemia and ectopic soft tissue the DACH countries, the UK, Ireland, the Netherlands
calcification, but only exists as a iatrogenic disease when and Turkey. Specific recommendations for supplement
serum 25(OH)D exceeds 250 nmol/L. However, large, use in other age groups have been made in Finland and
intermittent pulse doses of vitamin D (300 000 IU or more) the Netherlands. Two guidelines, from Saudi Arabia and
have been found to be associated with increased risks of United Arabic Emirates, recommended 800–2000 IU/day,
fractures and falls (221, 264). In cross-sectional studies depending on age category and reproductive status (270,
a U-shaped relationship has been found between serum 271). The former was developed with the ESCEO group,
25(OH)D concentrations and cancer or mortality whereby and both were exclusively based on expert opinion and
not only low but also the highest concentrations were review of the evidence from studies conducted in Western
found to pose risks (209). Therefore as has been observed populations. The actual use of supplements is high in the
for other fat-soluble vitamins too much as well as too Nordic countries and very low in Southern Europe (33)
little has to be avoided. Also, vitamin D hypersensitivity and the Middle East (177).
European Journal of Endocrinology

due to mutation in the gene encoding for the vitamin D

catabolizing enzyme 24-hydroxylase (CYP24A1) should
not be neglected (265, 266). Strategic options
A recent review (267) proposes a desirable
concentration range of 50–100 nmol/L (20–40 ng/mL), The principal goal of a strategy aiming to improve vitamin
provided precise and accurate assays are used. This D status is to prevent vitamin D deficient bone disease,
range allows practitioners to tailor treatment, taking for example rickets in children and fractures in adults
into account season, lifestyle factors and individual and older persons. Strategic options may vary between
vitamin D intake. Most children reach the desirable target nihilism and interventions to achieve a serum 25(OH)
concentrations by a daily intake of 400–600 IU (10–15 µg/ D level above a threshold. The null option to prevent
day), and adults by an intake of 800 IU/day (20 µg/day). fractures in adults was advocated by the US Preventive
This is in line with results from randomized dose-ranging Services Task Force (272). This was based on the opinion
clinical trials (223, 251). Additional data is needed to of the task force that the evidence for an effect of vitamin
validate the above proposed concentration range and D on fracture prevention in older persons was insufficient
vitamin D doses, especially in children, pregnant women (273). The IOM has set the required serum 25(OH)D
and non-Caucasian populations. 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
Recommendations on vitamin D intake in (600 IU) for 1–70 year olds and 20 µg (800 IU) for older
Europe and the Middle East subjects per day, when sun exposure is minimal. The
mean vitamin D intake in most European countries with
As stated in the Introduction, the focus of guidelines may the exception of the Nordic countries is well below the
be different, varying from public health, as in the IOM minimal requirement to achieve the 25(OH)D threshold
guidelines, to individual patients, as in the Endocrine of 50 nmol/L unless there is regular access to sunlight
Society guideline. Most national guidelines are made or to vitamin D supplements including cod liver oil
from a public health perspective. A summary of guidelines (Table 3). Depending on the lifestyle and nutritional
and recommendations is presented in Table 4. Recently, habits, the required vitamin D supplementation may vary
a more detailed overview of present guidelines for more for different segments of the population and for different
than 40 countries was published (268). countries. For example, in Norway, vitamin D status is
Most guidelines resemble those of the IOM. The adequate in a large part of the population, due to sun
guideline of Central Europe was made by professional exposure on a skin with little pigment, high consumption

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 Position Statement P Lips and others ECTS statement on vitamin D 180:4 P40
status

of fish and cod liver oil and adequate dietary calcium

Bassuk et al. 2016 (299)

Scragg et al. 2017 (242)

Neale et al. 2016 (300)

intake. In contrast, vitamin D status in Southern Italy may
Khaw et al. 2017 (298)

Manson et al. 2018

be poor due to low sun exposure on a more pigmented

NCT01646437*

NCT01463813*
NCT01745263*

NCT02880982*
skin, little access to vitamin D-rich food (oily fish or cod
liver oil), and a low dietary calcium intake. This means
References

that implementation strategies have to be tailored to the

(243)
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
No effect on CVD
No effect on falls
and fractures,

recommendations for vitamin D intake (1) up to 37.5–

and cancer

50 µg/day (1500–2000 IU/day) in adults (Table 4). The

Dec 2019
Jan 2019

ECTS Working Group does not support this option for the
Results

CVD

2022
general European population.

Results are expected between 2015 and 2020. Investigators: R Scragg, JE Manson, S Yusuf, TP Tuomainen, H Bischoff-Ferrari, R Neale, A Martineau.
Tuberculosis, astma, acute resp
Fract, functional decline, blood
pressure, cognitive decline,

Implementation strategies

Several concepts on implementation exist based either on

individual responsibility or on public responsibility. In the
CVD, fract, cancer

CVD, DM, cancer

European Journal of Endocrinology

Fract, CVD, ARI

first situation this may lead to vitamin D supplementation

Cancer, CVD

CVD, cancer

infection

infection

on an individual basis, based on requirements as stated

Outcome

by national regulatory bodies or professional societies.

In the second situation, a more active public health
approach, supported by the ECTS, is required involving
Megatrials with multiple outcomes with expected results in the coming 5 years.

2000 IU/omega-3/physical exercise

recommendations for lifestyle including sunshine

60 000 IU/month/polycaps/aspirin

exposure, healthy nutrition, food fortification and vitamin

3200 vs 1600 IU/day vs placebo
2000 IU/day/fish oil/placebo

D supplementation. Implementation can occur through

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

guidelines, professional organizations, special clinics for

young children or other risk groups, and publications in the
100 000 IU/month

lay press. Providing vitamin D supplements for free is a very

60 000 IU/month
10 000 IU/week

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).
Dose

Vitamin D can be supplemented as vitamin D3,

vitamin D2 and 25-hydroxyvitamin D (calcifediol). In
three clinical trials, using assays that well differentiated
Factorial design

Factorial design

Factorial design
DB, two groups

DB, two groups

D2 and D3 metabolites, vitamin D3 appeared to be

Study design

somewhat more effective than vitamin D2 in increasing

2/2/2

2/2/2

serum 25(OH)D (275, 276, 277). Most RCTs have used

2/2

vitamin D3 and currently this is more readily available.

Regarding calcifediol, this metabolite appears 2–3 times
Number of

more effective in increasing serum 25(OH)D than vitamin

children
subjects

D3 (224). Calcifediol might be of value in patients with

28 875

18 000

25 000
5110

5500

2152

5400

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,
DO-HEALTH
Consortium

D-HEALTH

weekly, monthly and with larger intervals up to one year.

VIDIKids
Table 5

TIPS-3

Daily, weekly and monthly doses have been compared in

VITAL

FIND
VIDA

two studies. In one of these, in 48 women serum 25(OH)

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 Position Statement P Lips and others ECTS statement on vitamin D 180:4 P41
status

D was similar after 2 months in all dosing groups (278). recommends an intake of 15 µg/day for pregnant women
The other study in 338 nursing home residents showed a (285). Based on a Cochrane meta-analysis, the WHO
similar increase of serum 25(OH) D with daily or weekly recommends against routine vitamin D supplementation
doses, while monthly doses were less effective (279). in pregnancy (286). A more recent update of the
A yearly dose of 500 000 IU was given in an Australian Cochrane analysis was more positive about potential
clinical trial to prevent hip fractures, but the fall and benefits of vitamin D supplementation in pregnancy, but
fracture incidence in the vitamin D group were higher the authors concluded that evidence is not sufficient yet
than in the placebo group (221). A yearly intramuscular for a general supplementation advice in pregnancy (287).
dose of vitamin D (300 000 IU) given in a UK study also Recommendations from a WHO-sponsored symposium
was not effective (264). during the 2015 Vitamin D Workshop (288) endorsed a
Absorption with a meal containing some fat appears correction of widespread vitamin D deficiency of pregnant
to improve vitamin D absorption (280). While loading women in line with the recommendations for all adult
doses have been recommended in case of deficiency by females (10–15 µg/day), as part of antenatal care in general.
some experts, there is no evidence of the clinical value of Special risk groups such as pregnant women in the Middle
such loading doses. 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
Public health options majority of mothers failed to achieve the required serum
25(OH)D level even with doses by far exceeding current
European Journal of Endocrinology

The use of cod liver oil was very common in Western recommendations (92). However, it is questionable whether
Europe to prevent rickets, and still is very widespread in vitamin D doses of 15–20 µg/day (600–800 IU/day) actually
the Nordic countries. A recent meta-analysis demonstrated are too low, or rather that compliance to these doses
that at a dose as low as 400 IU/day (10 μg/day) vitamin may not have been adequate. In a recent dose-finding
D prevents the occurrence of rickets (281). The advice to trial, doses of 600–800 IU/day were sufficient to achieve a
use vitamin D drops 10 µg/day (400 IU/day) in infants and 25(OH)D concentration of more than 50 nmol/L in 97%
children below 4 years was and still is common practice of postmenopausal women (223) similar to findings in an
in the Netherlands and several other Western European earlier study in Dutch institutionalized elderly (251).
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 Food fortification with vitamin D
the institution of a population-based preventive program
in 2005 (274). The free distribution of vitamin D drops As mentioned above, the dietary intakes of children and
to all newborn infants visiting primary care facilities in adults in European countries, as well as beyond Europe,
Turkey has decreased the prevalence of rickets from 6% have been comprehensively reviewed recently (33, 138,
in 1998 to 0.1% in 2008 in children under 3 years of age 289). In brief, intakes of vitamin D in national surveys
(274, 282). A similar experience has been reported from throughout Europe (e.g. UK, Ireland, Denmark and
Finland, Canada and New Zealand (47, 283, 284). France) are typically below 5 μg/day, except for the Nordic
The IOM increased its RDAs for vitamin D 7 years countries, and vary according to contribution from
ago, ranging from 10 to 20 µg/day, considerably lower nutritional supplements, country-specific fortification
than those of the Endocrine Society (1, 14). There were practices, sex and age; with the nutritional supplements
also recent global consensus recommendations on being the main source of variation. Overall, it is clear
prevention and management of nutritional rickets (285): that the current dietary supply of vitamin D makes it
supplementation with 10 µg/day (400 IU/day) is adequate unfeasible for most children and adults in Europe to meet
to prevent rickets and is recommended for all infants from the IOM’s EAR of 10 µg/day (400 IU/day), let alone the
birth to 12 months of age, independent of their mode of RDA of 15 µg/day (600 IU/day), which were established
feeding. Beyond 12 months of age, all children and adults on the assumption of minimal or absent UVB-induced
need to meet their nutritional requirement for vitamin D dermal supply. It has been emphasized that there is only
through diet and/or supplementation, which is at least a limited number of public health strategies available to
15 µg/day (600 IU/day), similar to the recommendation correct low dietary vitamin D intake (289, 290). A brief
of the IOM. The global consensus of rickets also overview will be provided here:

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 Position Statement P Lips and others ECTS statement on vitamin D 180:4 P42
status

1. Improving intake of naturally occurring vitamin D-rich exception of ecological products. This fortification
foods. This is the least likely strategy to increase has had a positive impact on the vitamin D intake
dietary vitamin D intake because there are very few and status in adults, whose mean vitamin D intake
food sources that are rich in vitamin D, such as oily now is about 10 µg, where close to 40–50% comes
fish, with limited availability. Furthermore, most of from fortified milk products (147). The vitamin D
these are not frequently consumed by many in the status has also improved as demonstrated recently
population (290). when a comparison of standardized serum 25(OH)
2. Vitamin D supplementation. Supplementation with D data from two nationally representative surveys
vitamin D has been shown to significantly improve of Finnish adults 11 years apart showed that less
vitamin D intake across a variety of age, race, ethnic than 6% had a 25(OH)D concentration lower than
and gender groups as well as improving vitamin 50 nmol/L in the autumn/early winter months in
D status per se. However, the population intake of 2011 compared to the situation in 2000 when about
vitamin D from supplements is quite low (291). This 50% had concentrations lower than 50 nmol/L (47).
is mainly due to the relatively low vitamin D content Also of note, the prevalence of severe vitamin D
of most supplements compared to the requirement deficiency (<30 nmol/L) decreased from 13% to 0.6%
as discussed earlier. While not highly effective at over the 11 year period (47).
a population level due to the low percentage of
compliance in the general population for most The ECTS Working Group acknowledges the valuable
European countries, vitamin D supplementation may contribution of fortified milk to vitamin D intakes,
European Journal of Endocrinology

be appropriate in high-risk groups such as infants particularly in children, and the continued need for
and young children, pregnant women and older fortification of milk and other dairy products. However,
persons (250). Actually, vitamin D supplements are fortification, including bio-fortification, of a wider
systematically recommended for young children range of foods offers more possibilities. Well-designed
from 0 to 3 years in several countries and also for all sustainable fortification strategies, which use a range
institutionalized elderly subjects (249). of foods to accommodate diversity, have the potential
3. Vitamin D fortification (mandatory or voluntarily) of to increase vitamin D intakes across the population
food. While supplements are an effective method for distribution and minimize the prevalence of a low serum
individuals to increase their intake, food fortification 25(OH)D concentration (294, 295). To provide evidence,
represents the best opportunity to increase the we need to model European food and vitamin D intake
vitamin D supply to the population (138, 289, 292). data to ascertain which food vehicles and what level of
Fortification of foods with vitamin D in the United vitamin D addition will ensure an effective but safe rise
States and Canada has an important effect on the in serum 25(OH)D concentration in all segments of
mean daily intake of vitamin D by the average the European population. The benefits and limitations
adult, but it does not yet reach the required levels of of bio-fortification of various foods are investigated in
vitamin D intake (293). This may relate to the level of the EU Framework 7 ODIN project. This includes plant
fortification, types and choice of food vehicles and the and animal-based food via UVB irradiation of yeast and
issue of mandatory or optional/voluntary fortification. mushrooms (296), and addition of the most effective forms
It was recently demonstrated that the 95th percentile of vitamin D (vitamin D3 or calcifediol in some cases) to
of intake of vitamin D from voluntary fortified the feeds of the animals with ultimate inclusion in the
foods in Europe is low (291). Finland has focused on tissue for use as foods. Data from the project suggests that
improving vitamin D status in the whole population a combination of traditional fortification of dairy foods
by extensive fortification. In April 2010, The National together with the newer approach of bio-fortification of
Nutrition Council launched a new recommendation foods with vitamin D can allow for an mean intake within
that the earlier fortification levels should be doubled the population of 10 µg/day conforming to the EAR (2) as
to 1.0 µg/100 g (40 IU/100 g) for all fluid milk products published by the IOM.
and that 20 µg/100 g (800 IU/100 g) should be used for In Middle East countries food fortification is sporadic
spreadable fats. These recommendations were based and the use of supplements is low (177). Furthermore,
on simulations of the effect of fortification. Especially dairy products are only consumed by a minority of
the dairy industry responded immediately and the population. Fortification of wheat flour may have
almost all fluid milk products were fortified, with the potential to alleviate vitamin D deficiency in countries

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 Position Statement P Lips and others ECTS statement on vitamin D 180:4 P43
status

such as India and Jordan, where pasteurized milk is not as fortification of flour and oil with vitamin D as well
widely consumed (297). The Gulf Countries Council as bio-fortification of animal-derived food products,
mandates a wheat flour standard (GS194) that includes such as eggs, red meats and cultured fish, should be
vitamin D fortification of flour, and several countries considered carefully as additional means of increasing
have initiated it. These include Jordan, Palestine and vitamin D intake in the population.
Saudi Arabia that initiated flour fortification with vitamin •• Vitamin D supplements are recommended
D at 13.8 µg (550 IU) per kg of flour, a very cost-effective for special risk groups in order to increase the
public health intervention to prevent rickets, estimated serum 25(OH)D concentration above 50 nmol/L in all
to incur a cost of 0.04–0.05 US$ per metric ton of flour countries of Europe and the Middle East.
(Personal communication Quentin Johnson, Food •• A vitamin D supplement of 10 µg/day
Fortification Initiative, www.ffinetwork.org and Ayoub (400 IU/day) is advised for all children of
Al Jawaldeh WHO Eastern Mediterranean Region). The 0–1 year and preferably 0–3 year to eradicate rickets.
United States Agency for International Development •• A vitamin D supplement of 10–15 µg/day (400–
adds 13.8 µg (550 IU) of vitamin D/kg of vegetable oil 600 IU/day) is advised for all pregnant women.
standard, 0.4–0.6 µg (16–23 IU) per g of oil for their •• A vitamin D supplement of 10–20 µg/day
food aid programs. Such initiatives will help countries (400–800 IU/day) is advised- to all older
like Yemen, Iraq and now Syrian refugees in Lebanon, institutionalized subjects and should be considered
Jordan, Iraq and Turkey. World Food Program standards for all older persons above 70 year.
include vitamin D in both cereal flours and vegetable oil •• A vitamin D supplement of 10 µg/day (400 IU/day)
European Journal of Endocrinology

for their emergency programs, an important point in the should be considered for non-Western immigrants and
Middle East refugee context. While these initiatives will refugees.
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 Research agenda
standards may include vitamin A and D, but these are
mostly voluntary or by covenant at the moment. More •• Effects of food fortification (milk, oil, flour/bread, juice,
on micronutrient fortification of foods in developing bio-fortified foods) have to be studied per fortified food
countries can be found on http://www.gainhealth. item in different countries with regard to different
org/programs/initiatives/#global-tracking. risk groups in the population such as young children,
pregnant women, older persons and non-Western
immigrants and compared with the effects of vitamin
Recommendations D supplementation.
•• Further study is needed on vitamin D requirement in
The ECTS Working Group recommends the following:
the Middle East (257, 258) and on measures to prevent
•• A reliable estimation of vitamin D status, such vitamin D deficiency.
as performed in the ODIN project, should be performed •• The impact of individual participant data (IPD) meta-
in all European countries and the Middle East (28). This regression analysis on the required vitamin D intake
requires utilization of protocol to conduct retrospective compared to standard meta-regression has to be
standardization of the available serum 25(OH)D data studied, as the latter suggests that the requirement may
as well as a greater effort to standardize assays for be higher (259). The IPD approach could be applied to
accurate measurement of 25(OH)D into the future. All other population subgroups, such as pregnant women
publications and reports on vitamin D status should and ethnic groups.
include such standardized data. •• Regular monitoring of vitamin D intake (using
•• Fortification of foods is the preferred strategy comprehensive vitamin D food composition data) and
to increase vitamin D intake and status over all vitamin D status by standardized 25(OH)D assays should
segments of the population, provided that adequate be organized in all European and Middle East countries
quality assurance monitoring is performed. Milk, and should guide future intervention strategies.
yogurt and other milk products are to be fortified •• The occurrence of rickets should be monitored in all
with around 10 µg/L (400 IU/L). Other options such European and Middle East countries.

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 Position Statement P Lips and others ECTS statement on vitamin D 180:4 P44
status

•• When the results of ongoing large randomized vitamin receive the highest priority by public health authorities
D trials (Table 5) become available, the optimal serum and health care providers.
25(OH)D concentration and the corresponding
vitamin D intake should be adjusted.
Declaration of interest
•• Genetic studies are recommended to investigate the Paul Lips: He received lecture fee from Abiogen. He chaired the vitamin
individual vulnerability for vitamin D deficiency. D Workshop in 2015. Kevin D Cashman: He was a member of the UK
Mendelian randomization studies can elucidate the SACN vitamin D working group. Heike Annette Bischoff-Ferrari: During
the last 3 years HABF received investigator-initiated grant support from
long-term impact of vitamin D deficiency on cancer DSM Nutritional Products and WILD, received speaker fees from Pfizer,
and autoimmune disease outcomes, as to guide clinical Roche Diagnostics, Meda, Sandoz and Sanofi. Maria Luisa Bianchi: She
decision-making in case RCTs are not available and received consultancy honoraria from Alexion Pharmaceuticals and Kyowa
Kirin. Roger Bouillon: He received lecture fees (over the last 2 years) from
cannot be performed for whatever reason. 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.
Conclusion

In order to compare vitamin D status between different Funding

countries and to get a reliable estimate of the prevalence This research did not receive any specific grant from any funding agency in
the public, commercial or not-for-profit sector.
of vitamin D deficiency, standardized 25(OH)D assays
should be used in population-based surveys. This should
European Journal of Endocrinology

include all ongoing studies and whenever possible, also

representative samples of older major published surveys References
and trials. The prevalence of a low serum 25(OH)D 1 Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA,
Heaney RP, Murad MH, Weaver CM & Endocrine Society. Evaluation,
concentration (<50 nmol/L) is high, that is more than treatment, and prevention of vitamin D deficiency: an Endocrine
50% during winter, in many European and Middle Society clinical practice guideline. Journal of Clinical Endocrinology and
East countries. Even more worrying is the presence of Metabolism 2011 96 1911–1930. (https://doi.org/10.1210/jc.2011-0385)
2 Institute of Medicine. Dietary Reference Intakes for Calcium and
severe vitamin D deficiency (below 25/30 nmol/L) in Vitamin D. Washington DC: The National Academies Press, 2011.
specific risk groups. The spectrum ranges from adequate 3 Bouillon R, van Schoor NM, Gielen E, Boonen S, Mathieu C,
vitamin D status in the Nordic countries to severe Vanderschueren D & Lips P. Optimal vitamin D status: a critical
analysis on the basis of evidence-based medicine. Journal of Clinical
deficiency in the Middle East. Vitamin D status usually Endocrinology and Metabolism 2013 98 E1283–E1304. (https://doi.
is poor in non-Western immigrants. According to current org/10.1210/jc.2013-1195)
evidence, the desirable serum 25(OH)D concentration 4 Seamans KM & Cashman KD. Existing and potentially novel
functional markers of vitamin D status: a systematic review. American
is set at 50 nmol/L or higher. While most experts agree Journal of Clinical Nutrition 2009 89 1997S–2008S. (https://doi.
on this concentration, it is uncertain whether higher org/10.3945/ajcn.2009.27230D)
concentrations provide additional benefit. When the 5 Carter GD, Jones JC, Shannon J, Williams EL, Jones G, Kaufmann M
& Sempos C. 25-Hydroxyvitamin D assays: potential interference
results of ongoing randomized clinical trials are available, from other circulating vitamin D metabolites. Journal of Steroid
the required serum 25(OH)D concentration may have to Biochemistry and Molecular Biology 2016 164 134–138. (https://doi.
be modified, depending on the outcome. It will require a org/10.1016/j.jsbmb.2015.12.018)
6 Jongen MJ, van der Vijgh WJ, Willems HJ, Netelenbos JC &
tremendous effort to improve vitamin D status in Europe Lips P. Simultaneous determination of 25-hydroxyvitamin D,
and the Middle East and reduce the percentage of the 24,25-dihydroxyvitamin D, and 1,25-dihydroxyvitamin D in plasma
population with a serum 25(OH)D concentration below or serum. Clinical Chemistry 1981 27 1757–1760.
7 Cashman KD, Hayes A, Galvin K, Merkel J, Jones G, Kaufmann M,
50 nmol/L. This may translate into targeted approaches Hoofnagle AN, Carter GD, Durazo-Arvizu RA & Sempos CT.
such as prudent sun exposure, adequate nutrition, food Significance of serum 24,25-dihydroxyvitamin D in the assessment
fortification policy and vitamin D supplementation of vitamin D status: a double-edged sword? Clinical Chemistry 2015
61 636–645. (https://doi.org/10.1373/clinchem.2014.234955)
for high-risk groups. Elimination of nutritional rickets 8 Kaufmann M, Gallagher JC, Peacock M, Schlingmann KP,
should receive the highest priority. As there is near Konrad M, DeLuca HF, Sigueiro R, Lopez B, Mourino A,
universal agreement that serum 25(OH)D concentrations Maestro M et al. Clinical utility of simultaneous quantitation of
25-hydroxyvitamin D and 24,25-dihydroxyvitamin D by LC-MS/
should exceed 25/30 nmol/L; at whatever age, strategies MS involving derivatization with DMEQ-TAD. Journal of Clinical
to eliminate this deficiency, particularly in children, Endocrinology and Metabolism 2014 99 2567–2574. (https://doi.
pregnant women, older persons and immigrants, should org/10.1210/jc.2013-4388)

https://eje.bioscientifica.com
Downloaded from Bioscientifica.com at 11/19/2020 10:31:03AM
via American University of Beirut
 Position Statement P Lips and others ECTS statement on vitamin D 180:4 P45
status

9 Molin A, Baudoin R, Kaufmann M, Souberbielle JC, Ryckewaert A, Endocrinology and Metabolism 2004 89 3152–3157. (https://doi.
Vantyghem MC, Eckart P, Bacchetta J, Deschenes G, Kesler- org/10.1210/jc.2003-031979)
Roussey G et al. CYP24A1 mutations in a cohort of hypercalcemic 23 Lips P, Chapuy MC, Dawson-Hughes B, Pols HA & Holick MF.
patients: evidence for a recessive trait. Journal of Clinical An international comparison of serum 25-hydroxyvitamin D
Endocrinology and Metabolism 2015 100 E1343–E1352. (https://doi. measurements. Osteoporosis International 1999 9 394–397. (https://
org/10.1210/jc.2014-4387) doi.org/10.1007/s001980050162)
10 Lips P. Relative value of 25(OH)D and 1,25(OH)2D measurements. 24 Sempos CT, Vesper HW, Phinney KW, Thienpont LM, Coates PM
Journal of Bone and Mineral Research 2007 22 1668–1671. (https://doi. & Vitamin D Standardization Program (VDSP). Vitamin D status
org/10.1359/jbmr.070716) as an international issue: national surveys and the problem of
11 Abreu MT, Kantorovich V, Vasiliauskas EA, Gruntmanis U, standardization. Scandinavian Journal of Clinical and Laboratory
Matuk R, Daigle K, Chen S, Zehnder D, Lin YC, Yang H et al. Investigation. Supplementum 2012 243 32–40. (https://doi.org/10.3109
Measurement of vitamin D levels in inflammatory bowel disease /00365513.2012.681935)
patients reveals a subset of Crohn’s disease patients with elevated 25 Prentice A. Vitamin D deficiency: a global perspective. Nutrition
1,25-dihydroxyvitamin D and low bone mineral density. Gut 2004 Reviews 2008 66 S153–S164. (https://doi.org/10.1111/j.1753-
53 1129–1136. (https://doi.org/10.1136/gut.2003.036657) 4887.2008.00100.x)
12 Makin HLJ, Jones G, Kaufmann M & Calverley MJ. Analysis of 26 Binkley N & Carter GD. Toward clarity in clinical vitamin D status
vitamin D, their metabolites and analogs. In Steroid Analysis, 2nd assessment: 25(OH)D assay standardization. Endocrinology and
ed., Chapter 11, pp 967–1096. Eds HLJ Makin & DB Gower. Springer Metabolism Clinics of North America 2017 46 885–899. (https://doi.
Science and Business Media, Berlin 2010. org/10.1016/j.ecl.2017.07.012)
13 Hollis BW & Napoli JL. Improved radioimmunoassay for vitamin D 27 Sempos CT, Durazo-Arvizu RA, Dawson-Hughes B, Yetley EA,
and its use in assessing vitamin D status. Clinical Chemistry 1985 31 Looker AC, Schleicher RL, Cao G, Burt V, Kramer H, Bailey RL et al.
1815–1819. Is there a reverse J-shaped association between 25-hydroxyvitamin
14 Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, D and all-cause mortality? Results from the U.S. nationally
Durazo-Arvizu RA, Gallagher JC, Gallo RL, Jones G et al. The 2011 representative NHANES. Journal of Clinical Endocrinology and
report on dietary reference intakes for calcium and vitamin D from Metabolism 2013 98 3001–3009. (https://doi.org/10.1210/jc.2013-
European Journal of Endocrinology

the Institute of Medicine: what clinicians need to know. Journal of 1333)

Clinical Endocrinology and Metabolism 2011 96 53–58. (https://doi. 28 Cashman KD, Dowling KG, Skrabakova Z, Gonzalez-Gross M,
org/10.1210/jc.2010-2704) Valtuena J, De Henauw S, Moreno L, Damsgaard CT, Michaelsen KF,
15 De la Hunty A, Wallace AM, Gibson S, Viljakainen H, Lamberg- Molgaard C et al. Vitamin D deficiency in Europe: pandemic?
Allardt C & Ashwell M. UK Food Standards Agency Workshop American Journal of Clinical Nutrition 2016 103 1033–1044. (https://
Consensus Report: the choice of method for measuring doi.org/10.3945/ajcn.115.120873)
25-hydroxyvitamin D to estimate vitamin D status for the UK 29 European Food Safety Authority EEFS. Scientific opinion on dietary
National Diet and Nutrition Survey. British Journal of Nutrition 2010 reference values for vitamin D. EFSA Journal 2016 14 4547.
104 612–619. (https://doi.org/10.1017/S000711451000214X) 30 Scientific Advisory Committee on Nutrition. Draft SACN vitamin D
16 Bikle D, Bouillon R, Thadhani R & Schoenmakers I. Vitamin D and health report (Internet). Report Pdf, 2015.
metabolites in captivity? Should we measure free or total 25(OH) 31 van der Wielen RP, Lowik MR, van den Berg H, de Groot LC, Haller J,
D to assess vitamin D status? Journal of Steroid Biochemistry and Moreiras O & van Staveren WA. Serum vitamin D concentrations
Molecular Biology 2017 173 105–116. (https://doi.org/10.1016/j. among elderly people in Europe. Lancet 1995 346 207–210. (https://
jsbmb2017.01.007) doi.org/10.1016/S0140-6736(95)91266-5)
17 Carter GD, Berry JL, Gunter E, Jones G, Jones JC, Makin HLJ, Sufi S & 32 McKenna MJ. Differences in vitamin D status between countries in
Wheeler MJ. Proficiency testing of 25-hydroxyvitamin D (25-OHD) young adults and the elderly. American Journal of Medicine 1992 93
assays. Journal of Steroid Biochemistry and Molecular Biology 2010 121 69–77. (https://doi.org/10.1016/0002-9343(92)90682-2)
176–179. (https://doi.org/10.1016/j.jsbmb.2010.03.033) 33 Spiro A & Buttriss JL. Vitamin D: an overview of vitamin D status
18 Carter GD & Jones JC. Use of a common standard improves and intake in Europe. Nutrition Bulletin 2014 39 322–350. (https://
the performance of liquid chromatography-tandem mass doi.org/10.1111/nbu.12108)
spectrometry methods for serum 25-hydroxyvitamin-D. Annals 34 Wahl DA, Cooper C, Ebeling PR, Eggersdorfer M, Hilger J, Hoffman K,
of Clinical Biochemistry 2009 46 79–81. (https://doi.org/10.1258/ Josse R, Kanis JA, Mithal A, Pierroz DD et al. A global representation
acb.2008.008135) of vitamin D status in healthy populations. Archives of Osteoporosis
19 Barake M, Daher RT, Salti I, Cortas NK, Al-Shaar L, Habib RH 2012 7 155–172. (https://doi.org/10.1007/s11657-012-0093-0)
& Fuleihan Gel-H. 25-Hydroxyvitamin D assay variations 35 Hilger J, Friedel A, Herr R, Rausch T, Roos F, Wahl DA, Pierroz DD,
and impact on clinical decision making. Journal of Clinical Weber P & Hoffmann K. A systematic review of vitamin D status in
Endocrinology and Metabolism 2012 97 835–843. (https://doi. populations worldwide. British Journal of Nutrition 2014 111 23–45.
org/10.1210/jc.2011-2584) (https://doi.org/10.1017/S0007114513001840)
20 Carter GD, Berry J, Durazo-Arvizu R, Gunter E, Jones G, Jones J, 36 Cashman KD, Dowling KG, Skrabakova Z, Kiely M, Lamberg-
Makin HLJ, Pattni P, Sempos CT, Twomey P et al. Hydroxyvitamin Allardt C, Durazo-Arvizu RA, Sempos CT, Koskinen S, Lundqvist A,
D assays: an historical perspective from DEQAS. Journal of Steroid Sundvall J et al. Standardizing serum 25-hydroxyvitamin D data from
Biochemistry and Molecular Biology 2018 177 30–35. (https://doi. four Nordic population samples using the Vitamin D Standardization
org/10.1016/j.jsbmb.2017.07.018) Program protocols: shedding new light on vitamin D status in Nordic
21 Binkley N, Sempos CT & Vitamin D Standardization Program (VDSP). individuals. Scandinavian Journal of Clinical and Laboratory Investigation
Standardizing vitamin D assays: the way forward. Journal of Bone 2015 75 549–561. (https://doi.org/10.3109/00365513.2015.1057898)
and Mineral Research 2014 29 1709–1714. (https://doi.org/10.1002/ 37 Buchebner D, McGuigan F, Gerdhem P, Malm J, Ridderstrale M &
jbmr.2252) Akesson K. Vitamin D insufficiency over 5 years is associated with
22 Binkley N, Krueger D, Cowgill CS, Plum L, Lake E, Hansen KE, increased fracture risk-an observational cohort study of elderly
DeLuca HF & Drezner MK. Assay variation confounds the diagnosis women. Osteoporosis International 2014 25 2767–2775. (https://doi.
of hypovitaminosis D: a call for standardization. Journal of Clinical org/10.1007/s00198-014-2823-1)

https://eje.bioscientifica.com
Downloaded from Bioscientifica.com at 11/19/2020 10:31:03AM
via American University of Beirut
 Position Statement P Lips and others ECTS statement on vitamin D 180:4 P46
status

38 Melhus H, Snellman G, Gedeborg R, Byberg L, Berglund L, Nutrition Research 2015 35 716–725. (https://doi.org/10.1016/j.
Mallmin H, Hellman P, Blomhoff R, Hagstrom E, Arnlov J nutres.2015.06.005)
et al. Plasma 25-hydroxyvitamin D levels and fracture risk in a 52 Chapuy MC, Preziosi P, Maamer M, Arnaud S, Galan P, Hercberg S &
community-based cohort of elderly men in Sweden. Journal of Meunier PJ. Prevalence of vitamin D insufficiency in an adult normal
Clinical Endocrinology and Metabolism 2010 95 2637–2645. (https:// population. Osteoporosis International 1997 7 439–443. (https://doi.
doi.org/10.1210/jc.2009-2699) org/10.1007/s001980050030)
39 Brembeck P, Winkvist A & Olausson H. Determinants of vitamin 53 Chapuy MC, Schott AM, Garnero P, Hans D, Delmas PD &
D status in pregnant fair-skinned women in Sweden. British Meunier PJ. Healthy elderly French women living at home have
Journal of Nutrition 2013 110 856–864. (https://doi.org/10.1017/ secondary hyperparathyroidism and high bone turnover in winter.
S0007114512005855) EPIDOS Study Group. Journal of Clinical Endocrinology and Metabolism
40 Eriksson S & Strandvik B. Vitamin D status in healthy children 1996 81 1129–1133. (https://doi.org/10.1210/jcem.81.3.8772587)
in Sweden still satisfactory. Changed supplementation and new 54 Souberbielle JC, Massart C, Brailly-Tabard S, Cavalier E & Chanson P.
knowledge motivation for further studies. Läkartidningen 2016 107 Prevalence and determinants of vitamin D deficiency in healthy
2474–2477. French adults: the VARIETE study. Endocrine 2016 53 543–550.
41 Andersen R, Molgaard C, Skovgaard LT, Brot C, Cashman KD, (https://doi.org/10.1007/s12020-016-0960-3)
Chabros E, Charzewska J, Flynn A, Jakobsen J, Karkkainen M et al. 55 Burnand B, Sloutskis D, Gianoli F, Cornuz J, Rickenbach M,
Teenage girls and elderly women living in northern Europe have low Paccaud F & Burckhardt P. Serum 25-hydroxyvitamin D: distribution
winter vitamin D status. European Journal of Clinical Nutrition 2005 59 and determinants in the Swiss population. American Journal of
533–541. (https://doi.org/10.1038/sj.ejcn.1602108) Clinical Nutrition 1992 56 537–542. (https://doi.org/10.1093/
42 Holvik K, Meyer HE, Haug E & Brunvand L. Prevalence and ajcn/56.3.537)
predictors of vitamin D deficiency in five immigrant groups living 56 Cashman KD, Muldowney S, McNulty B, Nugent A, FitzGerald AP,
in Oslo, Norway: the Oslo Immigrant Health Study. European Kiely M, Walton J, Gibney MJ & Flynn A. Vitamin D status of Irish
Journal of Clinical Nutrition 2005 59 57–63. (https://doi.org/10.1038/ adults: findings from the National Adult Nutrition Survey. British
sj.ejcn.1602033) Journal of Nutrition 2013 109 1248–1256. (https://doi.org/10.1017/
43 Andersen R, Molgaard C, Skovgaard LT, Brot C, Cashman KD, S0007114512003212)
European Journal of Endocrinology

Jakobsen J, Lamberg-Allardt C & Ovesen L. Pakistani immigrant 57 Theiler R, Stahelin HB, Tyndall A, Binder K, Somorjai G &
children and adults in Denmark have severely low vitamin D status. Bischoff HA. Calcidiol, calcitriol and parathyroid hormone serum
European Journal of Clinical Nutrition 2008 62 625–634. (https://doi. concentrations in institutionalized and ambulatory elderly in
org/10.1038/sj.ejcn.1602753) Switzerland. International Journal for Vitamin and Nutrition Research
44 Holvik K, Ahmed LA, Forsmo S, Gjesdal CG, Grimnes G, 1999 69 96–105. (https://doi.org/10.1024/0300-9831.69.2.96)
Samuelsen SO, Schei B, Blomhoff R, Tell GS & Meyer HE. Low serum 58 Krieg MA, Cornuz J, Jacquet AF, Thiebaud D & Burckhardt P.
levels of 25-hydroxyvitamin D predict hip fracture in the elderly: a Influence of anthropometric parameters and biochemical markers
NOREPOS study. Journal of Clinical Endocrinology and Metabolism 2013 of bone metabolism on quantitative ultrasound of bone in the
98 3341–3350. (https://doi.org/10.1210/jc.2013-1468) institutionalized elderly. Osteoporosis International 1998 8 115–120.
45 Holvik K, Brunvand L, Brustad M & Meyer HE. Vitamin D Status in the (https://doi.org/10.1007/BF02672506)
Norwegian Population. Oslo: The Norwegian Academy of Science and 59 Bischoff-Ferrari HA, Can U, Staehelin HB, Platz A, Henschkowski J,
Letters, 2008. Michel BA, Dawson-Hughes B & Theiler R. Severe vitamin D
46 Steingrimsdottir L, Gunnarsson O, Indridason OS, Franzson L & deficiency in Swiss hip fracture patients. Bone 2008 42 597–602.
Sigurdsson G. Relationship between serum parathyroid hormone (https://doi.org/10.1016/j.bone.2007.10.026)
levels, vitamin D sufficiency, and calcium intake. JAMA 2005 294 60 Bischof MG, Heinze G & Vierhapper H. Vitamin D status and its
2336–2341. (https://doi.org/10.1001/jama.294.18.2336) relation to age and body mass index. Hormone Research 2006 66
47 Jaaskelainen T, Itkonen ST, Lundqvist A, Erkkola M, Koskela T, 211–215. (https://doi.org/10.1159/000094932)
Lakkala K, Dowling KG, Hull GL, Kroger H, Karppinen J et al. 61 Amrein K, Zajic P, Schnedl C, Waltensdorfer A, Fruhwald S, Holl A,
The positive impact of general vitamin D food fortification Purkart T, Wunsch G, Valentin T, Grisold A et al. Vitamin D status and
policy on vitamin D status in a representative adult Finnish its association with season, hospital and sepsis mortality in critical
population: evidence from an 11-y follow-up based on standardized illness. Critical Care 2014 18 R47. (https://doi.org/10.1186/cc13790)
25-hydroxyvitamin D data. American Journal of Clinical Nutrition 2017 62 Kudlacek S, Schneider B, Peterlik M, Leb G, Klaushofer K, Weber K,
105 1512–1520. (https://doi.org/10.3945/ajcn.116.151415) Woloszczuk W, Willvonseder R & Austrian Study Group on
48 Carson EL, Pourshahidi LK, Hill TR, Cashman KD, Strain JJ, Normative Values of Bone. Assessment of vitamin D and calcium
Boreham CA & Mulhern MS. Vitamin D, muscle function, and status in healthy adult Austrians. European Journal of Clinical
cardiorespiratory fitness in adolescents from the Young Hearts Study. Investigation 2003 33 323–331. (https://doi.org/10.1046/j.1365-
Journal of Clinical Endocrinology and Metabolism 2015 100 4621–4628. 2362.2003.01127.x)
(https://doi.org/10.1210/jc.2015-2956) 63 Goldrace M, Hall N & Yeates DG. Hospitalisation for children with
49 van Schoor NM, Knol DL, Deeg DJ, Peters FP, Heijboer AC & rickets in England: a historical perspective. Lancet 2014 383 597–598.
Lips P. Longitudinal changes and seasonal variations in serum (https://doi.org/10.1016/S0140-6736(14)60211-7)
25-hydroxyvitamin D levels in different age groups: results of the 64 van der Meer IM, Boeke AJP, Lips P, Grootjans-Geerts I, Wuister JD,
Longitudinal Aging Study Amsterdam. Osteoporosis International 2014 Deville WLJM, Wielders JPM, Bouter LM & Middelkoop BJC. Fatty
25 1483–1491. (https://doi.org/10.1007/s00198-014-2651-3) fish and supplements are the greatest modifiable contributors to
50 Bouillon RA, Auwerx JH, Lissens WD & Pelemans WK. Vitamin the serum 25-hydroxyvitamin D concentration in a multiethnic
D status in the elderly: seasonal substrate deficiency causes population. Clinical Endocrinology 2008 68 466–472. (https://doi.
1,25-dihydroxycholecalciferol deficiency. American Journal of Clinical org/10.1111/j.1365-2265.2007.03066.x)
Nutrition 1987 45 755–763. (https://doi.org/10.1093/ajcn/45.4.755) 65 van der Meer IM, Karamali NS, Boeke AJ, Lips P, Middelkoop BJ,
51 Hoge A, Donneau AF, Streel S, Kolh P, Chapelle JP, Albert A, Verhoeven I & Wuister JD. High prevalence of vitamin D deficiency
Cavalier E & Guillaume M. Vitamin D deficiency is common among in pregnant non-western women in the Hague, Netherlands.
adults in Wallonia (Belgium, 51 degrees 30′ North): findings from American Journal of Clinical Nutrition 2006 84 350–353; quiz 468.
the Nutrition, Environment and Cardio-Vascular Health study. (https://doi.org/10.1093/ajcn/84.1.350)

https://eje.bioscientifica.com
Downloaded from Bioscientifica.com at 11/19/2020 10:31:03AM
via American University of Beirut
 Position Statement P Lips and others ECTS statement on vitamin D 180:4 P47
status

66 Lips P. Vitamin D deficiency and secondary hyperparathyroidism in 81 Bakhtiyarova S, Lesnyak O, Kyznesova N, Blankenstein MA & Lips P.
the elderly: consequences for bone loss and fractures and therapeutic Vitamin D status among patients with hip fracture and elderly
implications. Endocrine Reviews 2001 22 477–501. (https://doi. control subjects in Yekaterinburg, Russia. Osteoporosis International
org/10.1210/edrv.22.4.0437) 2006 17 441–446. (https://doi.org/10.1007/s00198-005-0006-9)
67 Quesada JM, Jans I, Benito P, Jimenez JA & Bouillon R. Vitamin D 82 Kozlov A, Khabarova Y, Vershubsky G, Ateeva Y & Ryzhaenkov V.
status of elderly people in Spain. Age and Ageing 1989 18 392–397. Vitamin D status of northern indigenous people of Russia leading
(https://doi.org/10.1093/ageing/18.6.392) traditional and ‘modernized’ way of life. International Journal of
68 Navarro-Valverde C & Quesada-Gomez JM. Vitamin D deficiency in Circumpolar Health 2014 73 26038. (https://doi.org/10.3402/ijch.
Spain. Reality or myth? Revista de Osteoporosis y Metabolismo Mineral v73.26038)
2014 6 (Supplement 1) S5–S10. (https://doi.org/10.4321/S1889- 83 Meyer HE, Falch JA, Sogaard AJ & Haug E. Vitamin D deficiency
836X2014000500002) and secondary hyperparathyroidism and the association with
69 Bettica P, Bevilacqua M, Vago T & Norbiato G. High prevalence bone mineral density in persons with Pakistani and Norwegian
of hypovitaminosis D among free-living postmenopausal women background living in Oslo, Norway, the Oslo Health Study. Bone 2004
referred to an osteoporosis outpatient clinic in northern Italy for 35 412–417. (https://doi.org/10.1016/j.bone.2004.04.003)
initial screening. Osteoporosis International 1999 9 226–229. (https:// 84 Islam MZ, Viljakainen HT, Karkkainen MUM, Saarnio E, Laitinen K
doi.org/10.1007/s001980050141) & Lamberg-Allardt C. Prevalence of vitamin D deficiency and
70 Isaia G, Giorgino R, Rini GB, Bevilacqua M, Maugeri D & Adami S. secondary hyperparathyroidism during winter in pre-menopausal
Prevalence of hypovitaminosis D in elderly women in Italy: clinical Bangladeshi and Somali immigrant and ethnic Finnish women:
consequences and risk factors. Osteoporosis International 2003 14 associations with forearm bone mineral density. British Journal
577–582. (https://doi.org/10.1007/s00198-003-1390-7) of Nutrition 2012 107 277–283. (https://doi.org/10.1017/
71 Challa A, Ntourntoufi A, Cholevas V, Bitsori M, Galanakis E & S0007114511002893)
Andronikou S. Breastfeeding and vitamin D status in Greece during 85 van der Meer IM, Middelkoop BJC, Boeke AJP & Lips P. Prevalence
the first 6 months of life. European Journal of Pediatrics 2005 164 of vitamin D deficiency among Turkish, Moroccan, Indian and sub-
724–729. (https://doi.org/10.1007/s00431-005-1757-1) Sahara African populations in Europe and their countries of origin:
72 Pludowski P, Grant WB, Bhattoa HP, Bayer M, Povoroznyuk V, an overview. Osteoporosis International 2011 22 1009–1021. (https://
European Journal of Endocrinology

Rudenka E, Ramanau H, Varbiro S, Rudenka A, Karczmarewicz E doi.org/10.1007/s00198-010-1279-1)

et al. Vitamin D status in central Europe. International 86 Lips P, Duong T, Oleksik A, Black D, Cummings S, Cox D &
Journal of Endocrinology 2014 2014 589587. (https://doi. Nickelsen T. A global study of vitamin D status and parathryoid
org/10.1155/2014/589587) function in postmenopausal women with osteoporosis: baseline data
73 Holecki M, Zahorska-Markiewicz B, Chudek J & Wiecek A. Changes from the Multiple Outcomes of raloxifene Evaluation Clinical Trial.
in bone mineral density and bone turnover markers in obese women Journal of Clinical Endocrinology and Metabolism 2001 86 1212–1221.
after short-term weight loss therapy during a 5-year follow-up. Polskie (https://doi.org/10.1210/jcem.86.3.7327)
Archiwum Medycyny Wewnetrznej 2010 120 248–254. 87 Kuchuk NO, van Schoor NM, Pluijm SM, Chines A & Lips P.
74 Kull MJ, Kallikorm R, Tamm A & Lember M. Seasonal variance of Vitamin D status, parathyroid function, bone turnover, and BMD
25-(OH) vitamin D in the general population of Estonia, a northern in postmenopausal women with osteoporosis: global perspective.
European country. BMC Public Health 2009 9 22. (https://doi. Journal of Bone and Mineral Research 2009 24 693–701. (https://doi.
org/10.1186/1471-2458-9-22) org/10.1359/jbmr.081209)
75 Mayer OJ, Filipovsky J, Seidlerova J, Vanek J, Dolejsova M, Vrzalova J 88 Prentice A. Nutritional rickets around the world. Journal of Steroid
& Cifkova R. The association between low 25-hydroxyvitamin D Biochemistry and Molecular Biology 2013 136 201–206. (https://doi.
and increased aortic stiffness. Journal of Human Hypertension 2012 26 org/10.1016/j.jsbmb.2012.11.018)
650–655. (https://doi.org/10.1038/jhh.2011.94) 89 Holick MF. Vitamin D deficiency. New England Journal of Medicine
76 Kocjan T, Tan TM-M, Conway GS & Prelevic G. Vitamin D status in 2007 357 266–281. (https://doi.org/10.1056/NEJMra070553)
patients with osteopenia or osteoporosis – an audit of an endocrine 90 Mithal A, Wahl DA, Bonjour JP, Burckhardt P, Dawson-Hughes B,
clinic. International Journal for Vitamin and Nutrition Research 2006 76 Eisman JA, El-Hajj Fuleihan G, Josse RG, Lips P, Morales-Torres J
307–313. (https://doi.org/10.1024/0300-9831.76.5.307) et al. Global vitamin D status and determinants of hypovitaminosis
77 Viragh E, Horvath D, Locsei Z, Kovacs L, Jager R, Varga B, Kovacs LG D. Osteoporosis International 2009 20 1807–1820. (https://doi.
& Salamonne TE. Vitamin D supply among healthy blood donors in org/10.1007/s00198-009-0954-6)
Vas County, Hungary. Orvosi Hetilap 2012 153 1629–1637. (https:// 91 van Schoor N & Lips P. Global overview of vitamin D status.
doi.org/10.1556/OH.2012.29459) Endocrinology and Metabolism Clinics of North America 2017 46
78 Bhattoa HP, Bettembuk P, Ganacharya S & Balogh A. Prevalence and 845–870. (https://doi.org/10.1016/j.ecl.2017.07.002)
seasonal variation of hypovitaminosis D and its relationship to bone 92 Bassil D, Rahme M, Hoteit M & El-Hajj Fuleihan Gel-H.
metabolism in community dwelling postmenopausal Hungarian Hypovitaminosis D in the Middle East and North Africa: prevalence,
women. Osteoporosis International 2004 15 447–451. (https://doi. risk factors and impact on outcomes. Dermato-Endocrinology 2013 5
org/10.1007/s00198-003-1566-1) 274–298. (https://doi.org/10.4161/derm.25111)
79 Bhattoa HP, Nagy E, More C, Kappelmayer J, Balogh A, Kalina E 93 Hekimsoy Z, Dinc G, Kafesciler S, Onur E, Guvenc Y, Pala T,
& Antal-Szalmas P. Prevalence and seasonal variation of Guclu F & Ozmen B. Vitamin D status among adults in the Aegean
hypovitaminosis D and its relationship to bone metabolism in region of Turkey. BMC Public Health 2010 10 782. (https://doi.
healthy Hungarian men over 50 years of age: the HunMen Study. org/10.1186/1471-2458-10-782)
Osteoporosis International 2013 24 179–186. (https://doi.org/10.1007/ 94 Buyukuslu N, Esin K, Hizli H, Sunal N, Yigit P & Garipagaoglu M.
s00198-012-1920-2) Clothing preference affects vitamin D status of young women.
80 Laktasic-Zerjavic N, Korsic M, Crncevic-Orlic Z, Kovac Z, Polasek O Nutrition Research 2014 34 688–693. (https://doi.org/10.1016/j.
& Soldo-Juresa D. Vitamin D status, dependence on age, and nutres.2014.07.012)
seasonal variations in the concentration of vitamin D in Croatian 95 Parlak M, Kalay S, Kalay Z, Kirecci A, Guney O & Koklu E. Severe
postmenopausal women initially screened for osteoporosis. Clinical vitamin D deficiency among pregnant women and their newborns
Rheumatology 2010 29 861–867. (https://doi.org/10.1007/s10067- in Turkey. Journal of Maternal-Fetal and Neonatal Medicine 2015 28
010-1409-3) 548–551. (https://doi.org/10.3109/14767058.2014.924103)

https://eje.bioscientifica.com
Downloaded from Bioscientifica.com at 11/19/2020 10:31:03AM
via American University of Beirut
 Position Statement P Lips and others ECTS statement on vitamin D 180:4 P48
status

96 Karaguzel G, Dilber B, Can G, Okten A, Deger O & Holick MF. 111 Nichols EK, Khatib IM, Aburto NJ, Serdula MK, Scanlon KS,
Seasonal vitamin D status of healthy schoolchildren and predictors Wirth JP & Sullivan KM. Vitamin D status and associated factors
of low vitamin D status. Journal of Pediatric Gastroenterology of deficiency among Jordanian children of preschool age. European
and Nutrition 2014 58 654–660. (https://doi.org/10.1097/ Journal of Clinical Nutrition 2015 69 90–95. (https://doi.org/10.1038/
MPG.0000000000000274) ejcn.2014.142)
97 Masoompour SM, Sadegholvaad A, Larijani B & Ranjbar-Omrani G. 112 Mallah EM, Hamad MF, Elmanaseer MA, Qinna NA,
Effects of age and renal function on vitamin D status in men. Idkaidek NM, Arafat TA & Matalka KZ. Plasma concentrations of
Archives of Iranian Medicine 2008 11 377–381. (https://doi.org/08114/ 25-hydroxyvitamin D among Jordanians: effect of biological and
AIM.007) habitual factors on vitamin D status. BMC Clinical Pathology 2011 11
98 Hosseinpanah F,. Yarjanli M, Sheikholeslami F, Heibatollahi M, 8. (https://doi.org/10.1186/1472-6890-11-8)
Eskandary PS & Azizi F. Associations between vitamin D and 113 Khuri-Bulos N, Lang RD, Blevins M, Kudyba K, Lawrence L,
cardiovascular outcomes; Tehran Lipid and Glucose Study. Davidson M, Faouri S & Halasa NB. Vitamin D deficiency among
Atherosclerosis 2011 218 238–242. (https://doi.org/10.1016/j. newborns in Amman, Jordan. Global Journal of Health Science 2013 6
atherosclerosis.2011.05.016) 162–171. (https://doi.org/10.5539/gjhs.v6n1p162)
99 Hosseinpanah F, Rambod M, Hossein-nejad A, Larijani B & Azizi F. 114 Hoteit M, Al-Shaar L, Yazbeck C, Bou Sleiman M, Ghalayini T
Association between vitamin D and bone mineral density in Iranian & Fuleihan Gel Gel-H. Hypovitaminosis D in a sunny country:
postmenopausal women. Journal of Bone and Mineral Metabolism 2008 time trends, predictors, and implications for practice guidelines.
26 86–92. (https://doi.org/10.1007/s00774-007-0791-7) Metabolism 2014 63 968–978. (https://doi.org/10.1016/j.
100 Kaykhaei MA, Hashemi M, Narouie B, Shikhzadeh A, Rashidi H, metabol.2014.04.009)
Moulaei N & Ghavami S. High prevalence of vitamin D deficiency in 115 Arabi A, Baddoura R, El-Rassi R & El-Hajj Fuleihan G. Age but not
Zahedan, southeast Iran. Annals of Nutrition and Metabolism 2011 58 gender modulates the relationship between PTH and vitamin D. Bone
37–41. (https://doi.org/10.1159/000323749) 2010 47 408–412. (https://doi.org/10.1016/j.bone.2010.05.002)
101 Khalesi N, Bahaeddini SM & Shariat M. Prevalence of maternal 116 Alyahya KO. Vitamin D levels in schoolchildren: a cross-sectional
vitamin D deficiency in neonates with delayed hypocalcaemia. Acta study in Kuwait. BMC Pediatrics 2017 17 213. (https://doi.
Medica Iranica 2012 50 740–745. org/10.1186/s12887-017-0963-0)
European Journal of Endocrinology

102 Naseh A, Ashrafzadeh S & Rassi S. Prevalence of vitamin D deficiency 117 Molla AM, Al Badawi M, Hammoud MS, Molla AM, Shukkur M,
in pregnant mothers in Tehran and investigating its association with Thalib L & Eliwa MS. Vitamin D status of mothers and their neonates
serum glucose and insulin. Journal of Maternal-Fetal and Neonatal in Kuwait. Pediatrics International 2005 47 649–652. (https://doi.
Medicine 2018 31 2312–2318. (https://doi.org/10.1080/14767058.201 org/10.1111/j.1442-200x.2005.02141.x)
7.1342796) 118 Ardawi MS, Sibiany AM, Bakhsh TM, Qari MH & Maimani AA. High
103 Torkaman M, Abolghasemi H, Amirsalari S, Beiraghdar F, prevalence of vitamin D deficiency among healthy Saudi Arabian
Afsharpaiman S, Kavehmanesh Z & Khosravi MH. Comparison of the men: relationship to bone mineral density, parathyroid hormone,
vitamin D status of children younger and older than 2 years in Tehran: bone turnover markers, and lifestyle factors. Osteoporosis International
are supplements really necessary? International Journal of Endocrinology 2012 23 675–686. (https://doi.org/10.1007/s00198-011-1606-1)
and Metabolism 2016 14 e34676. (https://doi.org/10.5812/ijem.34676) 119 Al Shaikh AM, Abaalkhail B, Soliman A, Kaddam I, Aseri K,
104 Sayed-Hassan R, Abazid N & Alourfi Z. Relationship between Al-Saleh Y, Al Qarni A, Al Shuaibi A, Al Tamimi W & Mukhtar AM.
25-hydroxyvitamin D concentrations, serum calcium, and Prevalence of vitamin D deficiency and calcium homeostasis in Saudi
parathyroid hormone in apparently healthy Syrian people. children. Journal of Clinical Research in Pediatric Endocrinology 2016 8
Archives of Osteoporosis 2014 9 176. (https://doi.org/10.1007/ 461–467. (https://doi.org/10.4274/jcrpe.3301)
s11657-014-0176-1) 120 Al-Faris NA. High prevalence of vitamin D deficiency among
105 Saliba W, Barnett O, Rennert HS & Rennert G. The risk of all-cause pregnant Saudi women. Nutrients 2016 8 77. (https://doi.
mortality is inversely related to serum 25(OH)D levels. Journal of org/10.3390/nu8020077)
Clinical Endocrinology and Metabolism 2012 97 2792–2798. (https:// 121 Rajah J, Haq A & Pettifor JM. Vitamin D and calcium status in
doi.org/10.1210/jc.2012-1747) urban children attending an ambulatory clinic service in the United
106 Steinvil A, Leshem-Rubinow E, Berliner S, Justo D, Finn T, Ish- Arab Emirates. Dermato-Endocrinology 2012 4 39–43. (https://doi.
shalom M, Birati EY, Shalev V, Sheinberg B & Rogowski O. Vitamin org/10.4161/derm.18250)
D deficiency prevalence and cardiovascular risk in Israel. European 122 Al Anouti F, Thomas J, Abdel-Wareth L, Rajah J, Grant WB & Haq A.
Journal of Clinical Investigation 2011 41 263–268. (https://doi. Vitamin D deficiency and sun avoidance among university students
org/10.1111/j.1365-2362.2010.02403.x) at Abu Dhabi, United Arab Emirates. Dermato-Endocrinology 2011 3
107 Oren Y, Shapira Y, Agmon-Levin N, Kivity S, Zafrir Y, Altman A, 235–239. (https://doi.org/10.4161/derm.3.4.16881)
Lerner A & Shoenfeld Y. Vitamin D insufficiency in a sunny 123 Golbahar J, Al-Saffar N, Altayab Diab D, Al-Othman S, Darwish A &
environment: a demographic and seasonal analysis. Israel Medical Al-Kafaji G. Predictors of vitamin D deficiency and insufficiency in
Association Journal 2010 12 751–756. adult Bahrainis: a cross-sectional study. Public Health Nutrition 2014
108 Korchia G, Amitai Y, Moshe G, Korchia L, Tenenbaum A, 17 732–738. (https://doi.org/10.1017/S136898001300030X)
Rosenblum J & Schechter A. Vitamin D deficiency in children 124 El-Menyar A, Rahil A, Dousa K, Ibrahim W, Ibrahim T, Khalifa R &
in Jerusalem: the need for updating the recommendation for Abdel Rahman MO. Low vitamin D and cardiovascular risk factors in
supplementation. Israel Medical Association Journal 2013 15 333–338. males and females from a sunny, rich country. Open Cardiovascular
109 Batieha A, Khader Y, Jaddou H, Hyassat D, Batieha Z, Khateeb M, Medicine Journal 2012 6 76–80. (https://doi.org/10.2174/1874192401
Belbisi A & Ajlouni K. Vitamin D status in Jordan: dress style and 206010076)
gender discrepancies. Annals of Nutrition and Metabolism 2011 58 125 Botros RM, Sabry IM, Abdelbaky RS, Eid YM, Nasr MS &
10–18. (https://doi.org/10.1159/000323097) Hendawy LM. Vitamin D deficiency among healthy Egyptian
110 Nichols EK, Khatib IM, Aburto NJ, Sullivan KM, Scanlon KS, Wirth JP females. Endocrinologia y Nutricion 2015 62 314–321. (https://doi.
& Serdula MK. Vitamin D status and determinants of deficiency org/10.1016/j.endonu.2015.03.010)
among non-pregnant Jordanian women of reproductive age. 126 Ayadi ID, Nouaili EB, Talbi E, Ghdemssi A, Rached C, Bahlous A,
European Journal of Clinical Nutrition 2012 66 751–756. (https://doi. Gammoudi A, Hamouda SB, Bouguerra B, Bouzid K et al. Prevalence
org/10.1038/ejcn.2012.25) of vitamin D deficiency in mothers and their newborns in a Tunisian

https://eje.bioscientifica.com
Downloaded from Bioscientifica.com at 11/19/2020 10:31:03AM
via American University of Beirut
 Position Statement P Lips and others ECTS statement on vitamin D 180:4 P49
status

population. International Journal of Gynaecology and Obstetrics 2016 Proceedings of the Nutrition Society 2003 62 813–821. (https://doi.
133 192–195. (https://doi.org/10.1016/j.ijgo.2015.09.029) org/10.1079/PNS2003297)
127 Djennane M, Lebbah S, Roux C, Djoudi H, Cavalier E & 144 NORDEN. Nordic Nutrition Recommendations, 5th ed (NNR5)–vitamin
Souberbielle JC. Vitamin D status of schoolchildren in Northern D, 2012.
Algeria, seasonal variations and determinants of vitamin D 145 Becker W & Pearson M. Riksmaten 1997–1998. Uppsala:
deficiency. Osteoporosis International 2014 25 1493–1502. (https://doi. Livsmedelsverket, 2004.
org/10.1007/s00198-014-2623-7) 146 Enghardt Barbieri H, Pearson M & Becker W. Riksmaten-Barn.
128 El Maghraoui A, Ouzzif Z, Mounach A, Rezqi A, Achemlal L, Livsmedels-och Näringsintag Bland Barn i Sverige. Uppsala: Ord&Form,
Bezza A, Tellal S, Dehhaoui M & Ghozlani I. Hypovitaminosis 2003.
D and prevalent asymptomatic vertebral fractures in Moroccan 147 Helldán A, Raulio S, Kosola M, Tapanainen H, Ovaskainen M-L &
postmenopausal women. BMC Women’s Health 2012 12 11. (https:// Virtanen S. Finravinto 2012-Tutkimus – The National FINDIET 2012
doi.org/10.1186/1472-6874-12-11) Survey, p 187. Helsinki, Finland, 2013.
129 Atli T, Gullu S, Uysal AR & Erdogan G. The prevalence of vitamin 148 Kyttala P, Erkkola M, Kronberg-Kippila C, Tapanainen H, Veijola R,
D deficiency and effects of ultraviolet light on vitamin D levels in Simell O, Knip M & Virtanen SM. Food consumption and
elderly Turkish population. Archives of Gerontology and Geriatrics 2005 nutrient intake in Finnish 1-6-year-old children Finnish. Public
40 53–60. (https://doi.org/10.1016/j.archger.2004.05.006) Health Nutrition 2010 13 947–956. (https://doi.org/10.1017/
130 Alagol F, Shihadeh Y, Boztepe H, Tanakol R, Yarman S, Azizlerli H & S136898001000114X)
Sandalci O. Sunlight exposure and vitamin D deficiency in Turkish 149 Thuesen B, Husemoen L, Fenger M, Jakobsen J, Schwarz P, Toft U,
women. Journal of Endocrinological Investigation 2000 23 173–177. Ovesen L, Jorgensen T & Linneberg A. Determinants of vitamin
(https://doi.org/10.1007/BF03343702) D status in a general population of Danish adults. Bone 2012 50
131 Mishal AA. Effects of different dress styles on vitamin D levels in 605–610. (https://doi.org/10.1016/j.bone.2011.12.016)
healthy young Jordanian women. Osteoporosis International 2001 12 150 Black LJ, Walton J, Flynn A & Kiely M. Adequacy of vitamin D
931–935. (https://doi.org/10.1007/s001980170021) intakes in children and teenagers from the base diet, fortified foods
132 MacLaughlin J & Holick MF. Aging decreases the capacity of human and supplements. Public Health Nutrition 2014 17 721–731. (https://
skin to produce vitamin D3. Journal of Clinical Investigation 1985 76 doi.org/10.1017/S1368980013000359)
European Journal of Endocrinology

1536–1538. (https://doi.org/10.1172/JCI112134) 151 Black LJ, Walton J, Flynn A, Cashman KD & Kiely M. Small increments
133 Lips P, Netelenbos JC, Jongen MJ, van Ginkel FC, Althuis AL, van in vitamin D intake by Irish adults over a decade show that strategic
Schaik CL, van der Vijgh WJ, Vermeiden JP & van der Meer C. initiatives to fortify the food supply are needed. Journal of Nutrition
Histomorphometric profile and vitamin D status in patients with 2015 145 969–976. (https://doi.org/10.3945/jn.114.209106)
femoral neck fracture. Metabolic Bone Disease and Related Research 152 Hennessy Á, Browne F, Kiely M, Walton J & Flynn A. The role of
1982 4 85–93. (https://doi.org/10.1016/0221-8747(82)90021-2) fortified foods and nutritional supplements in increasing vitamin D
134 Brustad M, Sandanger T, Aksnes L & Lund E. Vitamin D status intake in Irish preschool children. European Journal of Nutrition 2017
in a rural population of northern Norway with high fish liver 56 1219–1231. (https://doi.org/10.1007/s00394-016-1171-7)
consumption. Public Health Nutrition 2004 7 783–789. (https://doi. 153 United Kingdom Government. National Diet and Nutrition Survey
org/10.1079/PHN2004605) (NDNS) Rolling Program, 2018.
135 Brustad M, Alsaker E, Engelsen O, Aksnes L & Lund E. Vitamin D 154 Hill TR, O’Brien MM, Cashman KD, Flynn A & Kiely M. Vitamin
status of middle-aged women at 65–71 degrees N in relation to D intakes in 18–64-y-old Irish adults. European Journal of
dietary intake and exposure to ultraviolet radiation. Public Health Clinical Nutrition 2004 58 1509–1517. (https://doi.org/10.1038/
Nutrition 2004 7 327–335. (https://doi.org/10.1079/PHN2003536) sj.ejcn.1602001)
136 Adami S, Bertoldo F, Braga V, Fracassi E, Gatti D, Gandolini G, 155 Roman Vinas B, Ribas Barba L, Ngo J, Gurinovic M, Novakovic R,
Minisola S & Battista Rini G. 25-Hydroxy vitamin D levels in healthy Cavelaars A, de Groot LC, van’t Veer P, Matthys C & Serra-Majem L.
premenopausal wome: association with bone turnover markers Projected prevalence of inadequate nutrient intakes in Europe.
and bone mineral density. Bone 2009 45 423–426. (https://doi. Annals of Nutrition and Metabolism 2011 59 84–95. (https://doi.
org/10.1016/j.bone.2009.05.012) org/10.1159/000332762)
137 Matsuoka LY, Wortsman J, Haddad JG, Kolm P & Hollis BW. Racial 156 Lips P, van Ginkel FC, Jongen MJ, Rubertus F, van der Vijgh WJ &
pigmentation and the cutaneous synthesis of vitamin D. Archives Netelenbos JC. Determinants of vitamin D status in patients with
of Dermatology 1991 127 536–538. (https://doi.org/10.1001/ hip fracture and in elderly control subjects. American Journal of
archderm.1991.04510010104011) Clinical Nutrition 1987 46 1005–1010. (https://doi.org/10.1093/
138 Kiely M & Black LJ. Dietary strategies to maintain adequacy of ajcn/46.6.1005)
circulating 25-hydroxyvitamin D concentrations. Scandinavian 157 Verkaik-Kloosterman J, Dodd KW, Dekkers AL, van ‘t Veer P &
Journal of Clinical and Laboratory Investigation. Supplementum 2012 Ocke MC. A three-part, mixed-effects model to estimate the
243 14–23. (https://doi.org/10.3109/00365513.2012.681893) habitual total vitamin D intake distribution from food and dietary
139 Thorgeirsdottir H, Valgeirsdottir H, Gunnarsdottir I, Gisladottir E, supplements in Dutch young children. Journal of Nutrition 2011 141
Gunnarsdottir BE & Thorsdottir I. Icelandic National Nutrition Survey 2055–2063. (https://doi.org/10.3945/jn.111.142398)
2010–2011 Main Results. Reykjavik: Directorate of Health, 2012. 158 Touvier M, Deschasaux M, Montourcy M, Sutton A, Charnaux N,
140 Landlæknis E. Ráðleggingar um mataræði og næringarefni fyrir fullorðna Kesse-Guyot E, Assmann KE, Fezeu L, Latino-Martel P, Druesne-
og börn frá tveggja ára aldri., 2010 ed. Iceland: Landlaeknir, 2010. Pecollo N et al. Determinants of vitamin D status in Caucasian
141 Meyer HE, Brunvand L, Brustad M, Holvik K, Johansson L & adults: influence of sun exposure, dietary intake, sociodemographic,
Paulsen JE. Tiltak for å sikre en god vitamin D-status i befolkningen, pp lifestyle, anthropometric, and genetic factors. Journal of Investigative
1–88. Ed S-o Helsedirektoratet. Oslo, 2006. Dermatology 2015 135 378–388. (https://doi.org/10.1038/
142 Brustad M, Braaten T & Lund E. Predictors for cod-liver oil jid.2014.400)
supplement use – the Norwegian Women and Cancer Study. 159 Jungert A, Spinneker A, Nagel A & Neuhauser-Berthold M. Dietary
European Journal of Clinical Nutrition 2004 58 128–136. (https://doi. intake and main food sources of vitamin D as a function of age,
org/10.1038/sj.ejcn.1601759) sex, vitamin D status, body composition, and income in an elderly
143 Ovesen L, Andersen R & Jakobsen J. Geographical differences in German cohort. Food and Nutrition Research 2014 58 1–8. (https://doi.
vitamin D status, with particular reference to European countries. org/10.3402/fnr.v58.23632)

https://eje.bioscientifica.com
Downloaded from Bioscientifica.com at 11/19/2020 10:31:03AM
via American University of Beirut
 Position Statement P Lips and others ECTS statement on vitamin D 180:4 P50
status

160 Rabenberg M, Scheidt-Nave C, Busch MA, Rieckmann N, International Journal of Women’s Health 2016 8 529–535. (https://doi.
Hintzpeter B & Mensink GB. Vitamin D status among adults org/10.2147/IJWH.S107707)
in Germany – results from the German Health Interview and 174 Narchi H, Kochiyil J, Al Hamad S, Yasin J, Laleye L & Al Dhaheri A.
Examination Survey for Adults (DEGS1). BMC Public Health 2015 15 Hypovitaminosis D in adolescent females – an analytical cohort study
641. (https://doi.org/10.1186/s12889-015-2016-7) in the United Arab Emirates. Paediatrics and International Child Health
161 Koenig J & Elmadfa I. Status of calcium and vitamin D of different 2015 35 36–43. (https://doi.org/10.1179/2046905514Y.0000000144)
population groups in Austria. International Journal for Vitamin and 175 Alzaheb RA & Al-Amer O. Prevalence and predictors of
Nutrition Research 2000 70 214–220. (https://doi.org/10.1024/0300- hypovitaminosis D among female university students in Tabuk,
9831.70.5.214) Saudi Arabia. Clinical Medicine Insights: Women’s Health 2017 10
162 Novakovic R, Cavelaars AEJM, Bekkering GE, Roman-Vinas B, 1179562X17702391. (https://doi.org/10.1177/1179562X17702391)
Ngo J, Gurinovic M, Glibetic M, Nikolic M, Golesorkhi M, Warthon 176 Bezrati I, Ben Fradj MKB, Ouerghi N, Feki M, Chaouachi A &
Medina M et al. Micronutrient intake and status in Central and Kaabachi N. Vitamin D inadequacy is widespread in Tunisian active
Eastern Europe compared with other European countries, results boys and is related to diet but not to adiposity or insulin resistance.
from the EURRECA network. Public Health Nutrition 2013 16 Libyan Journal of Medicine 2016 11 31258. (https://doi.org/10.3402/
824–840. (https://doi.org/10.1017/s-1368-980012004077) ljm.v11.31258)
163 Jenab M, Salvini S, van Gils CH, Brustad M, Shakya-Shrestha S, 177 Hwalla N, Al Dhaheri AS, Radwan H, Alfawaz HA, Fouda MA,
Buijsse B, Verhagen H, Touvier M, Biessy C, Wallstrom P et al. Dietary Al-Daghri NM, Zaghloul S & Blumberg JB. The prevalence of
intakes of retinol, beta-carotene, vitamin D and vitamin E in the micronutrient deficiencies and inadequacies in the Middle East and
European Prospective Investigation into Cancer and Nutrition approaches to interventions. Nutrients 2017 9 E229. (https://doi.
cohort. European Journal of Clinical Nutrition 2009 63 (Supplement 4) org/10.3390/nu9030229)
S150–S178. (https://doi.org/10.1038/ejcn.2009.79) 178 Shea MK, Benjamin EJ, Dupuis J, Massaro JM, Jacques PF,
164 Bilici S, Saglam F, Beyhan Y, Barut-Uyar B, Dikmen D, Goktas Z, D’Agostino RB Sr, Ordovas JM, O’Donnell CJ, Dawson-Hughes B,
Attar AJ, Mucka P & Uyar MF. Energy expenditure and nutritional Vasan RS et al. Genetic and non-genetic correlates of vitamins K and
status of coal miners: a cross-sectional study. Archives of Environmental D. European Journal of Clinical Nutrition 2009 63 458–464. (https://
and Occupational Health 2016 71 293–299. (https://doi.org/10.1080/1 doi.org/10.1038/sj.ejcn.1602959)
European Journal of Endocrinology

9338244.2015.1095152) 179 Wang TJ, Zhang F, Richards JB, Kestenbaum B, van Meurs JB, Berry D,
165 Ejtahed HS, Shab-Bidar S, Hosseinpanah F, Mirmiran P & Azizi F. Kiel DP, Streeten EA, Ohlsson C, Koller DL et al. Common genetic
Estimation of vitamin D intake based on a scenario for fortification determinants of vitamin D insufficiency: a genome-wide association
of dairy products with vitamin D in a Tehranian population, Iran. study. Lancet 2010 376 180–188. (https://doi.org/10.1016/S0140-
Journal of the American College of Nutrition 2016 35 383–391. (https:// 6736(10)60588-0)
doi.org/10.1080/07315724.2015.1022269) 180 Ahn J, Yu K, Stolzenberg-Solomon R, Simon KC, McCullough ML,
166 Khashayar P, Qorbani M, Keshtkar A, Khashayar P, Ziaee A & Gallicchio L, Jacobs EJ, Ascherio A, Helzlsouer K, Jacobs KB et al.
Larijani B. Awareness of osteoporosis among female head of Genome-wide association study of circulating vitamin D levels.
household: an Iranian experience. Archives of Osteoporosis 2017 12 Human Molecular Genetics 2010 19 2739–2745. (https://doi.
36. (https://doi.org/10.1007/s11657-017-0330-7) org/10.1093/hmg/ddq155)
167 Sabour H, Hossein-Nezhad A, Maghbooli Z, Madani F, Mir E 181 Signorello LB, Shi J, Cai Q, Zheng W, Williams SM, Long J, Cohen SS,
& Larijani B. Relationship between pregnancy outcomes and Li G, Hollis BW, Smith JR et al. Common variation in vitamin D
maternal vitamin D and calcium intake: a cross-sectional study. pathway genes predicts circulating 25-hydroxyvitamin D levels
Gynecological Endocrinology 2006 22 585–589. (https://doi. among African Americans. PLoS ONE 2011 6 e28623. (https://doi.
org/10.1080/09513590601005409) org/10.1371/journal.pone.0028623)
168 Feizabad E, Hossein-Nezhad A, Maghbooli Z, Ramezani M, 182 Anderson LN, Cotterchio M, Knight JA, Borgida A, Gallinger S &
Hashemian R & Moattari S. Impact of air pollution on vitamin D Cleary SP. Genetic variants in vitamin D pathway genes and risk
deficiency and bone health in adolescents. Archives of Osteoporosis of pancreas cancer; results from a population-based case-control
2017 12 34. (https://doi.org/10.1007/s11657-017-0323-6) study in Ontario, Canada. PLoS ONE 2013 8 e66768. (https://doi.
169 Kelishadi R, Moeini R, Poursafa P, Farajian S, Yousefy H & Okhovat- org/10.1371/journal.pone.0066768)
Souraki AA. Independent association between air pollutants and 183 Trummer O, Schwetz V, Walter-Finell D, Lerchbaum E, Renner W,
vitamin D deficiency in young children in Isfahan, Iran. Paediatrics Gugatschka M, Dobnig H, Pieber TR & Obermayer-Pietsch B. Allelic
and International Child Health 2014 34 50–55. (https://doi.org/10.117 determinants of vitamin D insufficiency, bone mineral density, and
9/2046905513Y.0000000080) bone fractures. Journal of Clinical Endocrinology and Metabolism 2012
170 Zaghloul S, Al-Hooti SN, Al-Hamad N, Al-Zenki S, Alomirah H, 97 E1234–E1240. (https://doi.org/10.1210/jc.2011-3088)
Alayan I, Al-Attar H, Al-Othman A, Al-Shami E, Al-Somaie M et al. 184 Bouillon R. Genetic and environmental determinants of vitamin D
Evidence for nutrition transition in Kuwait: over-consumption of status. Lancet 2010 376 148–149. (https://doi.org/10.1016/S0140-
macronutrients and obesity. Public Health Nutrition 2013 16 596–607. 6736(10)60635-6)
(https://doi.org/10.1017/S1368980012003941) 185 Bouillon R, Jones K & Schoenmakers I. Vitamin D-binding protein
171 Gannage-Yared MH, Chemali R, Yaacoub N & Halaby G. and vitamin D in blacks and whites. New England Journal of Medicine
Hypovitaminosis D in a sunny country: relation to lifestyle and bone 2014 370 879. (https://doi.org/10.1056/NEJMc1315850)
markers. Journal of Bone and Mineral Research 2000 15 1856–1862. 186 Powe CE, Evans MK, Wenger J, Zonderman AB, Berg AH, Nalls M,
(https://doi.org/10.1359/jbmr.2000.15.9.1856) Tamez H, Zhang D, Bhan I, Karumanchi SA et al. Vitamin D-binding
172 Papazian T, Hout H, Sibai D, Helou N, Younes H, El Osta N & protein and vitamin D status of black Americans and white
Khabbaz LR. Development, reproducibility and validity of a food Americans. New England Journal of Medicine 2013 369 1991–2000.
frequency questionnaire among pregnant women adherent to the (https://doi.org/10.1056/NEJMoa1306357)
Mediterranean dietary pattern. Clinical Nutrition 2016 35 1550–1556. 187 Henderson CM, Lutsey PL, Misialek JR, Laha TJ, Selvin E, Eckfeldt JH
(https://doi.org/10.1016/j.clnu.2016.04.015) & Hoofnagle AN. Measurement by a novel LC-MS/MS methodology
173 Salameh K, Al-Janahi NS, Reedy AM & Dawodu A. Prevalence reveals similar serum concentrations of vitamin D-binding protein in
and risk factors for low vitamin D status among breastfeeding blacks and whites. Clinical Chemistry 2016 62 179–187. (https://doi.
mother-infant dyads in an environment with abundant sunshine. org/10.1373/clinchem.2015.244541)

https://eje.bioscientifica.com
Downloaded from Bioscientifica.com at 11/19/2020 10:31:03AM
via American University of Beirut
 Position Statement P Lips and others ECTS statement on vitamin D 180:4 P51
status

188 Nielson CM, Jones KS, Chun RF, Jacobs JM, Wang Y, Hewison M, 202 Drake MT. Vitamin D and the goldilocks principle: too little, too
Adams JS, Swanson CM, Lee CG, Vanderschueren D et al. Free much, or just right? Journal of Clinical Endocrinology and Metabolism
25-hydroxyvitamin D: impact of vitamin D binding protein assays 2014 99 1164–1166. (https://doi.org/10.1210/jc.2014-1350)
on racial-genotypic associations. Journal of Clinical Endocrinology 203 Autier P, Boniol M, Pizot C & Mullie P. Vitamin D status and ill
and Metabolism 2016 101 2226–2234. (https://doi.org/10.1210/ health: a systematic review. Lancet. Diabetes and Endocrinology 2014 2
jc.2016-1104) 76–89. (https://doi.org/10.1016/S2213-8587(13)70165-7)
189 Bouillon R. The power of mass spectroscopy as arbiter for 204 Bolland MJ, Grey A, Gamble GD & Reid IR. The effect of vitamin D
immunoassays. Clinical Chemistry 2016 62 6–8. (https://doi. supplementation on skeletal, vascular, or cancer outcomes: a trial
org/10.1373/clinchem.2015.248484) sequential meta-analysis. Lancet Diabetes and Endocrinology 2014 2
190 Schwartz JB, Lai J, Lizaola B, Kane L, Markova S, Weyland P, 307–320. (https://doi.org/10.1016/S2213-8587(13)70212-2)
Terrault NA, Stotland N & Bikle D. A comparison of measured and 205 Bolland MJ, Grey A & Avenell A. Effects of vitamin D
calculated free 25(OH) vitamin D levels in clinical populations. supplementation on musculoskeletal health: a systematic review,
Journal of Clinical Endocrinology and Metabolism 2014 99 1631–1637. meta-analysis, and trial sequential analysis. Lancet. Diabetes and
(https://doi.org/10.1210/jc.2013-3874) Endocrinology 2018 6 847–858. (https://doi.org/10.1016/S2213-
191 Dagnelie PC, Vergote FJVR, Vanstaveren WA, Vandenberg H, 8587(18)30265-1)
Dingjan PG & Hautvast JGAJ. High prevalence of rickets in infants 206 Bouillon R, Carmeliet G, Verlinden L, van Etten E, Verstuyf A,
on macrobiotic diets. American Journal of Clinical Nutrition 1990 51 Luderer HF, Lieben L, Mathieu C & Demay M. Vitamin D and human
202–208. (https://doi.org/10.1093/ajcn/51.2.202) health: lessons from vitamin D receptor null mice. Endocrine Reviews
192 Beck-Nielsen SS, Jensen TK, Gram J, Brixen K & Brock-Jacobsen B. 2008 29 726–776. (https://doi.org/10.1210/er.2008-0004)
Nutritional rickets in Denmark: a retrospective review of children’s 207 Rosen CJ, Adams JS, Bikle DD, Black DM, Demay MB, Manson JE,
medical records from 1985 to 2005. European Journal of Pediatrics Murad MH & Kovacs CS. The nonskeletal effects of vitamin D: an
2009 168 941–949. (https://doi.org/10.1007/s00431-008-0864-1) Endocrine Society scientific statement. Endocrine Reviews 2012 33
193 Lieben L, Masuyama R, Torrekens S, Van Looveren R, Schrooten J, 456–492. (https://doi.org/10.1210/er.2012-1000)
Baatsen P, Lafage-Proust MH, Dresselaers T, Feng JQ, Bonewald LF 208 Bouillon R, Marcocci C, Carmeliet G, Bikle D, White JH, Dawson-
et al. Normocalcemia is maintained in mice under conditions of Hughes B, Lips P, Munns CF, Lazaretti-Castro M, Giustina A et al.
European Journal of Endocrinology

calcium malabsorption by vitamin D-induced inhibition of bone Skeletal and extra-skeletal actions of vitamin D: current evidence and
mineralization. Journal of Clinical Investigation 2012 122 1803–1815. outstanding questions. Endocrine Reviews 2018 Epub. (https://doi.
(https://doi.org/10.1172/JCI45890) org/10.1210/er.2018-00126)
194 Eisman JA & Bouillon R. Vitamin D: direct effects of vitamin 209 Rejnmark L, Avenell A, Masud T, Anderson F, Meyer HE, Sanders KM,
D metabolites on bone: lessons from genetically modified Salovaara K, Cooper C, Smith HE, Jacobs ET et al. Vitamin D with
mice. BoneKEy Reports 2014 3 499. (https://doi.org/10.1038/ calcium reduces mortality: patient level pooled analysis of 70 528
bonekey.2013.233) patients from eight major vitamin D trials. Journal of Clinical
195 Bischoff-Ferrari HA, Willett WC, Wong JB, Giovannucci E, Endocrinology and Metabolism 2012 97 2670–2681. (https://doi.
Dietrich T & Dawson-Hughes B. Fracture prevention with vitamin org/10.1210/jc.2011-3328)
D supplementation: a meta-analysis of randomized controlled 210 Wang Y & DeLuca HF. Is the vitamin D receptor found in the
trials. JAMA 2005 293 2257–2264. (https://doi.org/10.1001/ muscle? Endocrinology 2011 152 354–363. (https://doi.org/10.1210/
jama.293.18.2257) en.2010-1109)
196 Bischoff-Ferrari HA, Willett WC, Orav EJ, Lips P, Meunier PJ, 211 Bischoff HA, Borchers M, Gudat F, Duermueller U, Theiler R,
Lyons RA, Flicker L, Wark J, Jackson RD, Cauley JA et al. A pooled Stahelin HB & Dick W. In situ detection of 1,25-dihydroxyvitamin
analysis of vitamin D dose requirements for fracture prevention. New D3 receptor in human skeletal muscle tissue. Histochemical Journal
England Journal of Medicine 2012 367 40–49. (https://doi.org/10.1056/ 2001 33 19–24. (https://doi.org/10.1023/A:1017535728844)
NEJMoa1109617) 212 Bischoff-Ferrari HA, Borchers M, Gudat F, Durmuller U, Stahelin HB
197 Bischoff-Ferrari HA, Willett WC, Wong JB, Stuck AE, Staehelin HB, & Dick W. Vitamin D receptor expression in human muscle tissue
Orav EJ, Thoma A, Kiel DP & Henschkowski J. Prevention of decreases with age. Journal of Bone and Mineral Research 2004 19
nonvertebral fractures with oral vitamin D and dose dependency: 265–269. (https://doi.org/10.1359/jbmr.2004.19.2.265)
a meta-analysis of randomized controlled trials. Archives of 213 Boland R. Role of vitamin D in skeletal muscle function. Endocrine
Internal Medicine 2009 169 551–561. (https://doi.org/10.1001/ Reviews 1986 7 434–448. (https://doi.org/10.1210/edrv-7-4-434)
archinternmed.2008.600) 214 Costa EM, Blau HM & Feldman D. 1,25-Dihydroxyvitamin D3
198 Boonen S, Lips P, Bouillon R, Bischoff-Ferrari HA, Vanderschueren D receptors and hormonal responses in cloned human skeletal muscle
& Haentjens P. Need for additional calcium to reduce the risk of cells. Endocrinology 1986 119 2214–2220. (https://doi.org/10.1210/
hip fracture with vitamin D supplementation: evidence from a endo-119-5-2214)
comparative metaanalysis of randomized controlled trials. Journal of 215 Simpson RU, Thomas GA & Arnold AJ. Identification of
Clinical Endocrinology and Metabolism 2007 92 1415–1423. (https:// 1,25-dihydroxyvitamin D3 receptors and activities in muscle. Journal
doi.org/10.1210/jc.2006-1404) of Biological Chemistry 1985 260 8882–8891.
199 Avenell A, Mak JC & O’Connell D. Vitamin D and vitamin D 216 Ceglia L, da Silva Morais M, Park LK, Morris E, Harris SS,
analogues for preventing fractures in post-menopausal women and Bischoff-Ferrari HA, Fielding RA & Dawson-Hughes B. Multi-step
older men. Cochrane Database of Systematic Reviews 2014 CD000227. immunofluorescent analysis of vitamin D receptor loci and myosin
(https://doi.org/10.1002/14651858.CD000227.pub4) heavy chain isoforms in human skeletal muscle. Journal of Molecular
200 Lips P, Gielen E & van Schoor NM. Vitamin D supplements with or Histology 2010 41 137–142. (https://doi.org/10.1007/s10735-010-9270-x)
without calcium to prevent fractures. BoneKEy Reports 2014 3 512. 217 Girgis CM, Mokbel N, Cha KM, Houweling PJ, Abboud M, Fraser DR,
(https://doi.org/10.1038/bonekey.2014.7) Mason RS, Clifton-Bligh RJ & Gunton JE. The vitamin D receptor
201 Boonen S, Bischoff-Ferrari HA, Cooper C, Lips P, Ljunggren O, (VDR) is expressed in skeletal muscle of male mice and modulates
Meunier PJ & Reginster JY. Addressing the musculoskeletal 25-hydroxyvitamin D (25OHD) uptake in myofibers. Endocrinology
components of fracture risk with calcium and vitamin D: a review of 2014 155 3227–3237. (https://doi.org/10.1210/en.2014-1016)
the evidence. Calcified Tissue International 2006 78 257–270. (https:// 218 Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, Orav JE,
doi.org/10.1007/s00223-005-0009-8) Stuck AE, Theiler R, Wong JB, Egli A, Kiel DP & Henschkowski J.

https://eje.bioscientifica.com
Downloaded from Bioscientifica.com at 11/19/2020 10:31:03AM
via American University of Beirut
 Position Statement P Lips and others ECTS statement on vitamin D 180:4 P52
status

Fall prevention with supplemental and active forms of vitamin D: a 233 Jorde R, Grimnes G, Hutchinson MS, Kjaergaard M, Kamycheva E
meta-analysis of randomised controlled trials. BMJ 2009 339 b3692. & Svartberg J. Supplementation with vitamin D does not increase
(https://doi.org/10.1136/bmj.b3692) serum testosterone levels in healthy males. Hormone and Metabolic
219 Bolland MJ, Grey A, Gamble GD & Reid IR. Vitamin D Research 2013 45 675–681. (https://doi.org/10.1055/s-003311345139)
supplementation and falls: a trial sequential meta-analysis. Lancet 234 Pittas AG, Chung M, Trikalinos T, Mitri J, Brendel M, Patel K,
Diabetes and Endocrinology 2014 2 573–580. (https://doi.org/10.1016/ Lichtenstein AH, Lau J & Balk EM. Systematic review: vitamin D and
S2213-8587(14)70068-3) cardiometabolic outcomes. Annals of Internal Medicine 2010 152
220 Bischoff-Ferrari HA. Relevance of vitamin D in muscle health. Reviews 307–314. (https://doi.org/10.7326/0003-4819-152-5-201003020-00009)
in Endocrine and Metabolic Disorders 2012 13 71–77. (https://doi. 235 Krul-Poel YH, Ter Wee MM, Lips P & Simsek S. MANAGEMENT of
org/10.1007/s11154-011-9200-6) ENDOCRINE DISEASE: The effect of vitamin D supplementation
221 Sanders KM, Stuart AL, Williamson EJ, Simpson JA, Kotowicz MA, on glycaemic control in patients with type 2 diabetes mellitus: a
Young D & Nicholson GC. Annual high-dose oral vitamin D and falls systematic review and meta-analysis. European Journal of Endocrinology
and fractures in older women: a randomized controlled trial. JAMA 2017 176 R1–R14. (https://doi.org/10.1530/EJE-16-0391)
2010 303 1815–1822. (https://doi.org/10.1001/jama.2010.594) 236 Lips P, Eekhoff M, van Schoor N, Oosterwerff M, de Jongh R, Krul-
222 Bischoff-Ferrari HA, Dawson-Hughes B, Orav EJ, Staehelin HB, Poel Y & Simsek S. Vitamin D and type 2 diabetes. Journal of Steroid
Meyer OW, Theiler R, Dick W, Willett WC & Egli A. Monthly high- Biochemistry and Molecular Biology 2017 173 280–285. (https://doi.
dose vitamin D treatment for the prevention of functional decline: a org/10.1016/j.jsbmb.2016.11.021)
randomized clinical trial. JAMA Internal Medicine 2016 176 175–183. 237 Manousaki D, Mokry LE, Ross S, Goltzman D & Richards JB.
(https://doi.org/10.1001/jamainternmed.2015.7148) Mendelian randomization studies do not support a role for vitamin
223 Gallagher JC, Sai A, Templin T & Smith L. Dose response to vitamin D in coronary artery disease. Circulation: Cardiovascular Genetics 2016
D supplementation in postmenopausal women: a randomized 9 349–356. (https://doi.org/10.1161/CIRCGENETICS.116.001396)
trial. Annals of Internal Medicine 2012 156 425–437. (https://doi. 238 Martineau AR, Jolliffe DA, Hooper RL, Greenberg L, Aloia JF, Bergman P,
org/10.7326/0003-4819-156-6-201203200-00005) Dubnov-Raz G, Esposito S, Ganmaa D, Ginde AA et al. Vitamin
224 Bischoff-Ferrari HA, Dawson-Hughes B, Orav EJ, Staehelin HB, D supplementation to prevent acute respiratory tract infections:
Meyer OW, Theiler R, Dick W, Willett WC & Egli A. Monthly high- systematic review and meta-analysis of individual participant data. BMJ
European Journal of Endocrinology

dose vitamin D treatment for the prevention of functional decline: a 2017 356 i6583. (https://doi.org/10.1136/bmj.i6583)
randomized clinical trial. JAMA Internal Medicine 2016 176 175–183. 239 Lappe J, Watson P, Travers-Gustafson D, Recker R, Garland C,
(https://doi.org/10.1001/jamainternmed.2015.7148) Gorham E, Baggerly K & McDonnell SL. Effect of vitamin D and
225 Smith LM, Gallagher JC & Suiter C. Medium doses of daily vitamin calcium supplementation on cancer incidence in older women: a
D decrease falls and higher doses of daily vitamin D3 increase randomized clinical trial. JAMA 2017 317 1234–1243. (https://doi.
falls: a randomized clinical trial. Journal of Steroid Biochemistry and org/10.1001/jama.2017.2115)
Molecular Biology 2017 173 317–322. (https://doi.org/10.1016/j. 240 Ong JS, Cuellar-Partida G, Lu Y, Australian Ovarian Cancer S,
jsbmb.2017.03.015) Fasching PA, Hein A, Burghaus S, Beckmann MW, Lambrechts D,
226 Wehr E, Pilz S, Boehm BO, Marz W & Obermayer-Pietsch B. Van Nieuwenhuysen E et al. Association of vitamin D levels and risk
Association of vitamin D status with serum androgen levels in men. of ovarian cancer: a Mendelian randomization study. International
Clinical Endocrinology 2010 73 243–248. (https://doi.org/10.1111/ Journal of Epidemiology 2016 45 1619–1630. (https://doi.org/10.1093/
j.1365-2265.2009.03777.x) ije/dyw207)
227 Tak YJ, Lee JG, Kim YJ, Park NC, Kim SS, Lee S, Cho BM, Kong EH, 241 Afzal S, Brondum-Jacobsen P, Bojesen SE & Nordestgaard BG.
Jung DW & Yi YH. Serum 25-hydroxyvitamin D levels and Genetically low vitamin D concentrations and increased mortality:
testosterone deficiency in middle-aged Korean men: a cross-sectional Mendelian randomisation analysis in three large cohorts. BMJ 2014
study. Asian Journal of Andrology 2015 17 324–328. (https://doi. 349 g6330. (https://doi.org/10.1136/bmj.g6330)
org/10.4103/1008-682X.142137) 242 Scragg R, Stewart AW, Waayer D, Lawes CMM, Toop L, Sluyter J,
228 Anic GM, Albanes D, Rohrmann S, Kanarek N, Nelson WG, Murphy J, Khaw KT & Camargo CA Jr. Effect of monthly high-dose
Bradwin G, Rifai N, McGlynn KA, Platz EA & Mondul AM. vitamin D supplementation on cardiovascular disease in the vitamin
Association between serum 25-hydroxyvitamin D and serum sex D assessment study: a randomized clinical trial. JAMA Cardiology
steroid hormones among men in NHANES. Clinical Endocrinology 2017 2 608–616. (https://doi.org/10.1001/jamacardio.2017.0175)
2016 85 258–266. (https://doi.org/10.1111/cen.13062) 243 Manson JE, Cook NR, Lee IM, Christen W, Bassuk SS, Mora S,
229 Lee DM, Tajar A, Pye SR, Boonen S, Vanderschueren D, Bouillon R, Gibson H, Gordon D, Copeland T, D’Agostino D et al. Vitamin D
O’Neill TW, Bartfai G, Casanueva FF, Finn JD et al. Association of supplements and prevention of cancer and cardiovascular disease.
hypogonadism with vitamin D status: the European Male Ageing New England Journal of Medicine 2019 380 33–44. (https://doi.
Study. European Journal of Endocrinology 2012 166 77–85. (https://doi. org/10.1056/NEJMoa1809944)
org/10.1530/EJE-11-0743) 244 Meyer HE, Holvik K & Lips P. Should vitamin D supplements be
230 Hofer D, Munzker J, Schwetz V, Ulbing M, Hutz K, Stiegler P, recommended to prevent chronic diseases? BMJ 2015 350 h321.
Zigeuner R, Pieber TR, Muller H & Obermayer-Pietsch B. Testicular (https://doi.org/10.1136/bmj.h321)
synthesis and vitamin D action. Journal of Clinical Endocrinology 245 Need AG, O’Loughlin PD, Morris HA, Coates PS, Horowitz M &
and Metabolism 2014 99 3766–3773. (https://doi.org/10.1210/ Nordin BE. Vitamin D metabolites and calcium absorption in severe
jc.2014-1690) vitamin D deficiency. Journal of Bone and Mineral Research 2008 23
231 Pilz S, Frisch S, Koertke H, Kuhn J, Dreier J, Obermayer-Pietsch B, 1859–1863. (https://doi.org/10.1359/jbmr.080607)
Wehr E & Zittermann A. Effect of vitamin D supplementation on 246 Lappe JM, Travers-Gustafson D, Davies KM, Recker RR & Heaney RP.
testosterone levels in men. Hormone and Metabolic Research 2011 43 Vitamin D and calcium supplementation reduces cancer risk: results
223–225. (https://doi.org/10.1055/s-0030-1269854) of a randomized trial. American Journal of Clinical Nutrition 2007 85
232 Heijboer AC, Oosterwerff M, Schroten NF, Eekhoff EM, Chel VG, 1586–1591. (https://doi.org/10.1093/ajcn/85.6.1586)
de Boer RA, Blankenstein MA & Lips P. Vitamin D supplementation 247 Wang TJ, Pencina MJ, Booth SL, Jacques PF, Ingelsson E,
and testosterone concentrations in male human subjects. Clinical Lanier K, Benjamin EJ, D’Agostino RB, Wolf M & Vasan RS.
Endocrinology 2015 83 105–110. (https://doi.org/10.1111/cen.12711) Vitamin D deficiency and risk of cardiovascular disease.

https://eje.bioscientifica.com
Downloaded from Bioscientifica.com at 11/19/2020 10:31:03AM
via American University of Beirut
 Position Statement P Lips and others ECTS statement on vitamin D 180:4 P53
status

Circulation 2008 117 503–511. (https://doi.org/10.1161/ 262 Lee JP, Tansey M, Jetton JG & Krasowski MD. Vitamin D toxicity:
CIRCULATIONAHA.107.706127) a 16-year retrospective study at an Academic Medical Center.
248 Grant WB, Cross HS, Garland CF, Gorham ED, Moan J, Peterlik M, Laboratory Medicine 2018 49 123–129. (https://doi.org/10.1093/
Porojnicu AC, Reichrath J & Zittermann A. Estimated benefit of labmed/lmx077)
increased vitamin D status in reducing the economic burden of disease 263 Taylor PN & Davies JS. A review of the growing risk of vitamin
in Western Europe. Progress in Biophysics and Molecular Biology 2009 99 D toxicity from inappropriate practice. British Journal of Clinical
104–113. (https://doi.org/10.1016/j.pbiomolbio.2009.02.003) Pharmacology 2018 84 1121–1127. (https://doi.org/10.1111/bcp.13573)
249 Weggemans RM, Kromhout D & van Weel C. New dietary reference 264 Smith H, Anderson F, Raphael H, Maslin P, Crozier S & Cooper C.
values for vitamin D in the Netherlands. European Journal of Clinical Effect of annual intramuscular vitamin D on fracture risk in elderly
Nutrition 2013 67 685–685. (https://doi.org/10.1038/ejcn.2013.55) men and women, a population-based, randomized, double-blind,
250 Standing Committee of European Doctors. Vitamin D: Nutritional placebo-controlled trial. Rheumatology 2007 46 1852–1857. (https://
Policy in Europe. Brussels, 2010. www.cpme.eu doi.org/10.1093/rheumatology/kem240)
251 Lips P, Wiersinga A, van Ginkel FC, Jongen MJ, Netelenbos JC, 265 Schlingmann KP, Kaufmann M, Weber S, Irwin A, Goos C, John U,
Hackeng WH, Delmas PD & van der Vijgh WJ. The effect of vitamin Misselwitz J, Klaus G, Kuwertz-Broking E, Fehrenbach H et al.
D supplementation on vitamin D status and parathyroid function in Mutations in CYP24A1 and idiopathic infantile hypercalcemia.
elderly subjects. Journal of Clinical Endocrinology and Metabolism 1988 New England Journal of Medicine 2011 365 410–421. (https://doi.
67 644–650. (https://doi.org/10.1210/jcem-67-4-644) org/10.1056/NEJMoa1103864)
252 Mortensen C, Damsgaard CT, Hauger H, Ritz C, Lanham-New SA, 266 Jacobs TP, Kaufman M, Jones G, Kumar R, Schlingmann KP, Shapses S
Smith TJ, Hennessy Á, Dowling K, Cashman KD, Kiely M et al. & Bilezikian JP. A lifetime of hypercalcemia and hypercalciuria,
Estimation of the dietary requirement for vitamin D in white finally explained. Journal of Clinical Endocrinology and Metabolism
children aged 4–8 y: a randomized, controlled, dose-response trial. 2014 99 708–712. (https://doi.org/10.1210/jc.2013-3802)
American Journal of Clinical Nutrition 2016 104 1310–1317. (https:// 267 El-Hajj Fuleihan G, Bouillon R, Clarke B, Chakhtoura M, Cooper C,
doi.org/10.3945/ajcn.116.136697) McClung MR & Singh R. Serum 25-hydroxyvitamin D levels:
253 Cashman KD, FitzGerald AP, Viljakainen HT, Jakobsen J, variability, knowledge gaps and the concept of a desirable range.
Michaelsen KF, Lamberg-Allardt C & Molgaard C. Estimation of the Journal of Bone and Mineral Research 2015 30 1119–1133. (https://doi.
European Journal of Endocrinology

dietary requirement for vitamin D in healthy adolescent white girls. org/10.1002/jbmr.2536)

American Journal of Clinical Nutrition 2011 93 549–555. (https://doi. 268 Bouillon R. Comparative analysis of nutritional guidelines for
org/10.3945/ajcn.110.006577) vitamin D. Nature Reviews Endocrinology 2017 13 466–479. (https://
254 Smith TJ, Tripkovic L, Damsgaard CT, Molgaard C, Ritz C, Wilson- doi.org/10.1038/nrendo.2017.31)
Barnes SL, Dowling KG, Hennessy Á, Cashman KD, Kiely M et al. 269 Pludowski P, Karczmarewicz E, Bayer M, Carter G, Chlebna-Sokol D,
Estimation of the dietary requirement for vitamin D in adolescents Czech-Kowalska J, Debski R, Decsi T, Dobrzanska A, Franek E et al.
aged 14–18 y: a dose-response, double-blind, randomized placebo- Practical guidelines for the supplementation of vitamin D and the
controlled trial. American Journal of Clinical Nutrition 2016 104 treatment of deficits in Central Europe – recommended vitamin
1301–1309. (https://doi.org/10.3945/ajcn.116.138065) D intakes in the general population and groups at risk of vitamin
255 Cashman KD, Hill TR, Lucey AJ, Taylor N, Seamans KM, D deficiency. Endokrynologia Polska 2013 64 319–327. (https://doi.
Muldowney S, Fitzgerald AP, Flynn A, Barnes MS, Horigan G et al. org/10.5603/EP.2013.0012)
Estimation of the dietary requirement for vitamin D in healthy 270 Haq A, Wimalawansa SJ, Pludowski P & Anouti FA. Clinical practice
adults. American Journal of Clinical Nutrition 2008 88 1535–1542. guidelines for vitamin D in the United Arab Emirates. Journal of
(https://doi.org/10.3945/ajcn.2008.26594) Steroid Biochemistry and Molecular Biology 2018 175 4–11. (https://doi.
256 Cashman KD, Wallace JM, Horigan G, Hill TR, Barnes MS, Lucey AJ, org/10.1016/j.jsbmb.2016.09.021)
Bonham MP, Taylor N, Duffy EM, Seamans K et al. Estimation of the 271 Al-Daghri NM, Al-Saleh Y, Aljohani N, Sulimani R, Al-Othman AM,
dietary requirement for vitamin D in free-living adults >=64 y of age. Alfawaz H, Fouda M, Al-Amri F, Shahrani A, Alharbi M et al. Vitamin
American Journal of Clinical Nutrition 2009 89 1366–1374. (https:// D status correction in Saudi Arabia: an expert’s consensus under
doi.org/10.3945/ajcn.2008.27334) the auspices of the European Society for Clinical and Economic
257 Chakhtoura M, Akl EA, El Ghandour S, Shawwa K, Arabi A, Aspects of Osteoporosis, osteoarthritis, and musculoskeletal Diseases
Mahfoud Z, Habib RH, Hoballah H & El-Hajj Fuleihan G. Impact of (ESCEO). Archives of Osteoporosis 2017 12 1. (https://doi.org/10.1007/
vitamin D replacement in adults and elderly in the Middle East and s11657-016-0295-y)
North Africa: a systematic review and meta-analysis of randomized 272 LeBlanc ES, Zakher B, Daeges M, Pappas M & Chou R. Screening for
controlled trials. Osteoporosis International 2017 28 35–46. (https:// vitamin D deficiency: a systematic review for the U.S. Preventive
doi.org/10.1007/s00198-016-3837-7) Services Task Force. Annals of Internal Medicine 2015 162 109–122.
258 Chakhtoura M, El Ghandour S, Shawwa K, Akl EA, Arabi A, (https://doi.org/10.7326/M14-1659)
Mahfoud Z, Habib R, Hoballah H & El-Hajj Fuleihan G. Vitamin D 273 Moyer VA & U.S. Preventive Services Task Force. Vitamin D and
replacement in children, adolescents and pregnant women in the calcium supplementation to prevent fractures in adults: U.S.
Middle East and North Africa: a systematic review and meta-analysis Preventive Services Task Force recommendation statement. Annals of
of randomized controlled trials. Metabolism 2017 70 160–176. Internal Medicine 2013 158 691–696. (https://doi.org/10.7326/0003-
(https://doi.org/10.1016/j.metabol.2017.02.009) 4819-158-9-201305070-00603)
259 Cashman KD, Ritz C, Kiely M & Odin C. Improved dietary guidelines 274 Hatun Ş, Ozkan B & Bereket A. Vitamin D deficiency and prevention:
for vitamin D: application of individual participant data (IPD)-level Turkish experience. ACTA Paediatrica 2011 100 1195–1199. (https://
meta-regression analyses. Nutrients 2017 9. (https://doi.org/10.3390/ doi.org/10.1111/j.1651-2227.2011.02383.x)
nu9050469) 275 Binkley N, Gemar D, Engelke J, Gangnon R, Ramamurthy R,
260 Manson JE & Bassuk SS. Vitamin D research and clinical practice: at Krueger D & Drezner MK. Evaluation of ergocalciferol or
a crossroads. JAMA 2015 313 1311–1312. (https://doi.org/10.1001/ cholecalciferol dosing, 1600 IU daily or 50 000 IU monthly in older
jama.2015.1353) adults. Journal of Clinical Endocrinology and Metabolism 2011 96
261 Galior K, Grebe S & Singh R. Development of vitamin D toxicity 981–988. (https://doi.org/10.1210/jc.2010-0015)
from overcorrection of vitamin D deficiency: a review of case reports. 276 Tripkovic L, Wilson LR, Hart K, Johnsen S, de Lusignan S, Smith CP,
Nutrients 2018 10 E953. (https://doi.org/10.3390/nu10080953) Bucca G, Penson S, Chope G, Elliott R et al. Daily supplementation

https://eje.bioscientifica.com
Downloaded from Bioscientifica.com at 11/19/2020 10:31:03AM
via American University of Beirut
 Position Statement P Lips and others ECTS statement on vitamin D 180:4 P54
status

with 15 mug vitamin D2 compared with vitamin D3 to increase Molecular Biology 2016 164 156–160. (https://doi.org/10.1016/j.
wintertime 25-hydroxyvitamin D status in healthy South Asian and jsbmb.2015.11.004)
white European women: a 12-wk randomized, placebo-controlled 289 Cashman KD & Kiely M. EURRECA-estimating vitamin D
food-fortification trial. American Journal of Clinical Nutrition 2017 106 requirements for deriving dietary reference values. Critical Reviews in
481–490. (https://doi.org/10.3945/ajcn.116.138693) Food Science and Nutrition 2013 53 1097–1109. (https://doi.org/10.10
277 Shieh A, Chun RF, Ma C, Witzel S, Meyer B, Rafison B, Swinkels L, 80/10408398.2012.742862)
Huijs T, Pepkowitz S, Holmquist B et al. Effects of high-dose vitamin 290 Cashman KD & Kiely M. Recommended dietary intakes for vitamin
D2 Versus D3 on total and free 25-hydroxyvitamin D and markers of D: where do they come from, what do they achieve and how can
calcium balance. Journal of Clinical Endocrinology and Metabolism 2016 we meet them? Journal of Human Nutrition and Dietetics 2014 27
101 3070–3078. (https://doi.org/10.1210/jc.2016-1871) 434–442. (https://doi.org/10.1111/jhn.12226)
278 Ish-Shalom S, Segal E, Salganik T, Raz B, Bromberg IL & Vieth R. 291 Flynn A, Hirvonen T, Mensink GB, Ocke MC, Serra-Majem L, Stos K,
Comparison of daily, weekly, and monthly vitamin D3 in ethanol Szponar L, Tetens I, Turrini A, Fletcher R et al. Intake of selected
dosing protocols for two months in elderly hip fracture patients. nutrients from foods, from fortification and from supplements in
Journal of Clinical Endocrinology and Metabolism 2008 93 3430–3435. various European countries. Food and Nutrition Research 2009 53
(https://doi.org/10.1210/jc.2008-0241) 1–51. (https://doi.org/10.3402/fnr.v53i0.2038)
279 Chel V, Wijnhoven HA, Smit JH, Ooms M & Lips P. Efficacy of 292 Cashman KD. Vitamin D: dietary requirements and food fortification
different doses and time intervals of oral vitamin D supplementation as a means of helping achieve adequate vitamin D status. Journal of
with or without calcium in elderly nursing home residents. Steroid Biochemistry and Molecular Biology 2015 148 19–26. (https://
Osteoporosis International 2008 19 663–671. (https://doi.org/10.1007/ doi.org/10.1016/j.jsbmb.2015.01.023)
s00198-007-0465-2) 293 Calvo MS & Whiting SJ. Survey of current vitamin D food
280 Dawson-Hughes B, Harris SS, Lichtenstein AH, Dolnikowski G, fortification practices in the United States and Canada. Journal of
Palermo NJ & Rasmussen H. Dietary fat increases vitamin D-3 Steroid Biochemistry and Molecular Biology 2013 136 211–213. (https://
absorption. Journal of the Academy of Nutrition and Dietetics 2015 115 doi.org/10.1016/j.jsbmb.2012.09.034)
225–230. (https://doi.org/10.1016/j.jand.2014.09.014) 294 Black LJ, Seamans KM, Cashman KD & Kiely M. An updated
281 Lerch C & Meissner T. Interventions for the prevention of nutritional systematic review and meta-analysis of the efficacy of vitamin D food
European Journal of Endocrinology

rickets in term born children. Cochrane Database of Systematic Reviews fortification. Journal of Nutrition 2012 142 1102–1108. (https://doi.
2007 17 CD006164. (https://doi.org/10.1002/14651858.CD006164. org/10.3945/jn.112.158014)
pub2) 295 Cashman KD & Kiely M. Tackling inadequate vitamin D intakes
282 Cesur Y, Caksen H, Gundem A, Kirimi E & Odabas D. Comparison within the population: fortification of dairy products with vitamin
of low and high dose of vitamin D treatment in nutritional D may not be enough. Endocrine 2016 51 38–46. (https://doi.
vitamin D deficiency rickets. Journal of Pediatric Endocrinology org/10.1007/s12020-015-0711-x)
and Metabolism 2003 16 1105–1109. (https://doi.org/10.1515/ 296 Cashman KD, Kiely M, Seamans KM & Urbain P. Effect of
JPEM.2003.16.8.1105) ultraviolet light-exposed mushrooms on vitamin D status: liquid
283 Ward LM, Gaboury I, Ladhani M & Zlotkin S. Vitamin D-deficiency chromatography-tandem mass spectrometry reanalysis of biobanked
rickets among children in Canada. CMAJ 2007 177 161–166. (https:// sera from a randomized controlled trial and a systematic review plus
doi.org/10.1503/cmaj.061377) meta-analysis. Journal of Nutrition 2016 146 565–575. (https://doi.
284 Wheeler BJ, Dickson NP, Houghton LA, Ward LM & Taylor BJ. org/10.3945/jn.115.223784)
Incidence and characteristics of vitamin D deficiency rickets in New 297 Babu US & Calvo MS. Modern India and the vitamin D dilemma:
Zealand children: a New Zealand Paediatric Surveillance Unit study. evidence for the need of a national food fortification program.
Australian and New Zealand Journal of Public Health 2015 39 380–383. Molecular Nutrition and Food Research 2010 54 1134–1147. (https://
(https://doi.org/10.1111/1753-6405.12390) doi.org/10.1002/mnfr.200900480)
285 Munns CF, Shaw N, Kiely M, Specker BL, Thacher TD, Ozono K, 298 Khaw KT, Stewart AW, Waayer D, Lawes CMM, Toop L,
Michigami T, Tiosano D, Mughal MZ, Makitie O et al. Global Camargo CA Jr & Scragg R. Effect of monthly high-dose vitamin D
consensus recommendations on prevention and management of supplementation on falls and non-vertebral fractures: secondary
nutritional rickets. Journal of Clinical Endocrinology and and post-hoc outcomes from the randomised, double-blind,
Metabolism 2016 101 394–415. (https://doi.org/10.1210/ placebo-controlled ViDA trial. Lancet. Diabetes and Endocrinology
jc.2015-2175) 2017 5 438–447. (https://doi.org/10.1016/S2213-8587
286 De-Regil LM, Palacios C, Ansary A, Kulier R & Pena-Rosas JP. Vitamin (17)30103-1)
D supplementation for women during pregnancy. Cochrane Database 299 Bassuk SS, Manson JE, Lee IM, Cook NR, Christen WG, Bubes VY,
of Systematic Reviews 2012 2 CD008873. Gordon DS, Copeland T, Friedenberg G, D’Agostino DM et al.
287 De-Regil LM, Palacios C, Lombardo LK & Pena-Rosas JP. Vitamin D Baseline characteristics of participants in the vitamin D and
supplementation for women during pregnancy. Cochrane Database of OmegA-3 TriaL (VITAL). Contemporary Clinical Trials 2016 47
Systematic Reviews 2016 1 CD008873. 235–243. (https://doi.org/10.1016/j.cct.2015.12.022)
288 Schoenmakers I, Pettifor JM, Pena-Rosas JP, Lamberg-Allardt C, 300 Neale RE, Armstrong BK, Baxter C, Duarte Romero B, Ebeling P,
Shaw N, Jones KS, Lips P, Glorieux FH & Bouillon R. Prevention English DR, Kimlin MG, McLeod DS, O’Connell RL, van der
and consequences of vitamin D deficiency in pregnant and Pols JC et al. The D-Health Trial: a randomized trial of vitamin
lactating women and children: a symposium to prioritise vitamin D for prevention of mortality and cancer. Contemporary Clinical
D on the global agenda. Journal of Steroid Biochemistry and Trials 2016 48 83–90. (https://doi.org/10.1016/j.cct.2016.04.005)

Received 4 September 2018

Revised version received 11 December 2018
Accepted 31 January 2019

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