0% found this document useful (0 votes)

28 views17 pages

Ec 18 0432

Uploaded by

Firnanda Sulfadli

We take content rights seriously. If you suspect this is your content, claim it here.

Available Formats

Download as PDF, TXT or read online on Scribd

0% found this document useful (0 votes)

28 views17 pages

Ec 18 0432

Uploaded by

Firnanda Sulfadli

We take content rights seriously. If you suspect this is your content, claim it here.

Available Formats

Download as PDF, TXT or read online on Scribd

You are on page 1/ 17

S Pilz et al.

Vitamin D testing and 8:2 R27–R43

treatment

REVIEW

Vitamin D testing and treatment: a narrative

review of current evidence
Stefan Pilz1, Armin Zittermann2, Christian Trummer1, Verena Theiler-Schwetz1, Elisabeth Lerchbaum1,
Martin H Keppel3, Martin R Grübler4, Winfried März5,6,7 and Marlene Pandis1
1
Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
2
Clinic for Thoracic and Cardiovascular Surgery, Herz- und Diabeteszentrum NRW, Ruhr University Bochum, Bad Oeynhausen, Germany
3
University Institute for Medical and Chemical Laboratory Diagnostics, Paracelsus Medical University, Salzburg, Austria
4
Department of Cardiology, Swiss Cardiovascular Center Bern, Bern University Hospital, University of Bern, Bern, Switzerland
5
Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
6
Medical Clinic V (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, Ruperto-Carola University of
Heidelberg, Heidelberg, Germany
7
Synlab Medical Center of Human Genetics Mannheim, Mannheim, Germany

Correspondence should be addressed to S Pilz: [email protected]

Abstract
Vitamin D testing and treatment is a subject of controversial scientific discussions, and it Key Words
is challenging to navigate through the expanding vitamin D literature with heterogeneous ff guideline
and partially opposed opinions and recommendations. In this narrative review, we aim ff vitamin D
to provide an update on vitamin D guidelines and the current evidence on the role of ff evidence-based medicine
vitamin D for human health with its subsequent implications for patient care and public ff recommendation
health issues. Vitamin D is critical for bone and mineral metabolism, and it is established
that vitamin D deficiency can cause rickets and osteomalacia. While many guidelines
recommend target serum 25-hydroxyvitamin D (25[OH]D) concentrations of ≥50 nmol/L
(20 ng/mL), the minimum consensus in the scientific community is that serum 25(OH)D
concentrations below 25–30 nmol/L (10–12 ng/mL) must be prevented and treated. Using
this latter threshold of serum 25(OH)D concentrations, it has been documented that there
is a high worldwide prevalence of vitamin D deficiency that may require public health
actions such as vitamin D food fortification. On the other hand, there is also reason for
concern that an exploding rate of vitamin D testing and supplementation increases costs
and might potentially be harmful. In the scientific debate on vitamin D, we should consider
that nutrient trials differ from drug trials and that apart from the opposed positions
regarding indications for vitamin D treatment we still have to better characterize the
Endocrine Connections
precise role of vitamin D for human health. (2019) 8, R27–R43

Introduction
Vitamin D is critical for bone and mineral metabolism low 25-hydroxyvitamin D (25[OH]D) concentrations are
and is effective in the prevention and treatment of rickets associated with various acute and chronic diseases, thus
and osteomalacia (1, 2, 3, 4, 5). Given that vitamin D raising a high interest in vitamin D (15, 16). Randomized
receptors (VDRs) are expressed in almost every tissue controlled trials (RCTs) have, however, largely failed to
and cell, there have been numerous investigations on show significant effects of vitamin D supplementation on
potential extra-skeletal effects of vitamin D (6, 7, 8, 9, various health outcomes (17, 18, 19, 20). As a consequence,
10, 11, 12, 13, 14). Epidemiological studies showed that there are nowadays controversial scientific discussions

https://ec.bioscientifica.com © 2019 The authors This work is licensed under a Creative Commons
https://doi.org/10.1530/EC-18-0432 Published by Bioscientifica Ltd Attribution-NonCommercial 4.0 International License.
S Pilz et al. Vitamin D testing and 8:2 R28
treatment

and heterogeneous approaches in clinical routine and to vitamin D-binding protein (DBP) and to a lesser extent
in public health actions regarding vitamin D testing and to albumin and lipoproteins with only a small fraction
treatment (17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28). (less than 1%) circulating in its unbound (free) form (34).
In this brief narrative review, we give an overview Although some tissues can take up DBP-bound vitamin
on clinical and nutritional vitamin D guidelines and D metabolites by the megalin–cubilin system, most cells
summarize the current evidence on the role of vitamin seem to be dependent on free vitamin D metabolites that
D for human health with its subsequent implications for diffuse through the cell membrane to get access to the
patient care and public health issues. We start with a brief intracellularly located VDR. Therefore, measurements of
introduction on vitamin D physiology and its clinical free 25(OH)D might be useful in special conditions with
effects and summarize nutritional clinical vitamin D significantly altered DBP levels (e.g. pregnancy, liver
guidelines. Then, we provide some insights and guidance cirrhosis or hormonal contraceptive intake), but more
regarding vitamin D testing and supplementation, data are needed to clarify the clinical significance of free
followed by a critical appraisal of vitamin D research. 25(OH)D (34, 35). Vitamin D catabolism is initiated by
Finally, we present our conclusions with an outlook on 24-hydroxylation of vitamin D metabolites that are
future directions in the field of vitamin D. finally excreted in the bile and urine. For a more detailed
description of vitamin D metabolism, we refer the reader
to other excellent reviews (1, 6, 14, 22) (Fig. 1).

Vitamin D physiology
Vitamin D was initially described as a substance that
Clinical effects of vitamin D
was able to cure rickets and was termed ‘D’ as it was
the fourth in the sequence of vitamins discovered (29). Physiologic effects of vitamin D and its metabolites are
The main two isoforms are vitamin D3 (cholecalciferol) mainly exerted by binding to the VDR with subsequent
and vitamin D2 (ergocalciferol) that share a similar downstream regulation of hundreds of genes, but there
metabolism so that we will not differentiate between are also non-genomic rapid effects including a direct
these isoforms unless otherwise stated. It has been stabilizing effect on the endothelium (1, 36). Vitamin
roughly estimated that ultraviolet-B (UV-B)-induced D has a critical role in the regulation of calcium and
production of vitamin D in the skin accounts for about phosphate metabolism by effects on the intestine, bone
80% of vitamin D supply, whereas dietary intake (e.g. and the kidneys. Breaking it down to a simple concept,
fish, eggs or vitamin D-fortified food) plays usually only an adequate vitamin D status is required to maintain
a minor role (30). The vitamin D supply from different normal calcium and phosphate levels and prevents
sources is of course subject to significant variation based secondary hyperparathyroidism. In this context, vitamin
on genetic, environmental and lifestyle factors (30, 31, 32, D is particularly important for optimal intestinal
33). Classification of vitamin D status is based on serum calcium absorption and exerts major effects on bone
25(OH)D that is mainly derived from hydroxylation of by maintaining mineral homeostasis but also by direct
vitamin D in the liver. Compared to vitamin D, 25(OH) pleiotropic effects on bone cells (37, 38). Historically, the
D has a much higher serum concentration and a longer discovery of vitamin D was essential for the successful
half-life (about 3 weeks versus 1 day) and is therefore prevention and treatment of epidemic rickets in the early
considered the best parameter to indicate vitamin D 20th century (39). This was achieved by increasing the
supply from all different sources. 1,25-dihydroxyvitamin vitamin D supply to the general population by public
D (1,25[OH]2D) is the so-called active vitamin D hormone health actions such as intake of cod liver oil, UV radiation,
or calcitriol that has the highest affinity to the almost vitamin D food fortification and, finally, also vitamin D
ubiquitously expressed VDR. Serum concentrations of supplementation (39). Nutritional rickets is characterized
1,25(OH)2D are mainly derived from renal hydroxylation by bone deformities (Fig. 2) as a result of reduced apoptosis
of 25(OH)D and are rather dependent on regulators of of hypertrophic chondrocytes in the growth plate
mineral metabolism (e.g. parathyroid hormone (PTH), and reduced mineralization (2, 3, 4, 5, 39). Additional
phosphate or fibroblast growth factor-23 (FGF-23)) or symptoms are muscle weakness and developmental
kidney function, than on substrate availability of 25(OH) delay, and in severe cases, rickets may be fatal due to life-
D, so that they do not well reflect vitamin D supply. In threatening heart failure and cardiac arrest (2, 3, 4, 5, 39).
the circulation, vitamin D metabolites are mainly bound While vitamin D deficiency can cause rickets in bones with

Figure 1
Vitamin D endogenous synthesis and metabolism.
Endogenous vitamin D synthesis occurs primarily
through sunlight exposure which produces
pre-vitamin D3. It is hydroxylated in the liver and
then in the kidney, producing 1,25D (1,25
dihydroxyvitamin D), the physiologically active
form of vitamin D which acts in target sites in
bone and immune cells, as well as liver cells.
Abbreviations: CYP (cytochrome P450), UV-B
(ultraviolet-B), hν (denotes photochemical
reaction). Reproduced from Keane et al. (14)
under the terms of the CC Attribution 4.0
International (CC BY 4.0) licence.

open growth plates, osteomalacia constitutes defective Beyond musculoskeletal effects, several studies
mineralization of existing bone leading to reduced bone investigated the potential extra-skeletal actions of
stiffness and is frequently associated with bone pain and vitamin D. Cell culture and animal studies as well as
muscle weakness (4, 40). Treatment of nutritional rickets observational data support the hypothesis that vitamin D
and osteomalacia with vitamin D plus calcium is associated is critical for a variety of common diseases including for
with great improvements of bone mineral density (BMD), example, cardiovascular, autoimmune, and neurological
but data from RCTs and meta-analyses on vitamin D diseases, infections, pregnancy complications and cancer
supplementation in unselected populations show either (1, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20). By
no or only slight increases in BMD (41, 42, 43, 44, 45). contrast, RCTs have largely shown no effect of vitamin
In subgroup analyses of RCTs, it has been documented D supplementation on nonskeletal health outcomes
that moderate improvements of BMD by vitamin D (7, 17, 18, 19, 20, 58, 59, 60, 61, 62, 63, 64, 65, 66).
supplementation may be restricted to individuals with Nevertheless, some meta-analyses of RCTs documented
25(OH)D serum concentrations ≤30 nmol/L (multiply by beneficial vitamin D effects on certain health outcomes
2.496 to convert ng/mL to nmol/L) with no significant such as respiratory tract infections, asthma exacerbations,
effect at higher 25(OH)D levels (43, 44). On the other hand, some pregnancy outcomes and mortality (67, 68, 69, 70,
vitamin D deficiency is not necessarily associated with 71, 72). These data should, however, be interpreted with
rickets or osteomalacia, suggesting that other factors such caution due to some limitations such as heterogeneity,
as those related to phosphate and calcium homeostasis different sources of potential bias, data quality of original
play a role and apparently determine the individual trials and partially small effect sizes.
sensitivity to detrimental effects of vitamin D deficiency. Of particular interest is the association between
Regarding the effects of vitamin D supplementation on vitamin D status and cancer, with several observational
falls and fractures, the current meta-analyses of RCTs draw studies showing an inverse association between serum
inconsistent conclusions with either a neutral or a small 25(OH)D concentrations and cancer incidence as well
beneficial effect (46, 47, 48, 49, 50, 51, 52, 53, 54, 55, as mortality (73, 74, 75, 76, 77). Meta-analyses of RCTs
56, 57). Beyond methodological issues of meta-analyses, largely report a moderate, yet significant reduction in
these inconsistent results may be attributed to the fact cancer mortality by vitamin D supplementation (19, 20,
that only sensitive persons may significantly benefit, for 65, 72). Vitamin D effects on cancer were also evaluated
example, those with low 25(OH)D receiving an adequate in the VITamin D and OmegA-3 TriaL (VITAL), a RCT in
dose of vitamin D and those at high fracture/fall risk such 25,871 older participants in the United States who were
as institutionalized individuals (46, 47, 48, 49, 50, 51, 52, randomized to 50 µg (1 µg equals 40 international units
53, 54, 55, 56, 57). (IU)) of vitamin D daily or placebo (78). After a median

mortality, but they do not confirm the reductions in

cancer incidence such as those for breast cancer that
would have been expected from previous observational
studies (73, 74, 75, 76, 77, 78).

Vitamin D guidelines
Several vitamin D guidelines and guidance papers have
been published with heterogeneous and partially opposed
opinions and recommendations regarding vitamin D
requirements (79, 80, 81, 82, 83, 84). To avoid confusion
and misinterpretations, it is essential to differentiate
nutritional vitamin D guidelines targeted for the general
population from clinical vitamin D guidelines intended
for patients care.
Nutritional vitamin D guidelines use the terms
dietary reference intakes (DRIs) or dietary reference values
(DRVs) to describe the distribution of dietary vitamin
D requirements in the population (84). Understanding
of DRV/DRI in terms of their definition (Table 1), the
process of their development, as well as their intended
implications is essential for their use as public health
policy instruments (84, 85). For deeper insights into these
issues we refer the reader to other excellent publications,
but we wish to briefly describe some of the key aspects
Figure 2
Three children with rickets (reproduced, with permission, from Wellcome of DRV/DRI (84, 85). A critical point regarding vitamin
Library, London. Wellcome Images [email protected] http:// D requirements is that they are currently mainly based
wellcomeimages.org; Three children with rickets; anon., Friends’ Relief
on musculoskeletal outcomes for which serum 25(OH)
Mission, Vienna XII, n.d.; Photograph circa 1920–1930; reproduced under
the terms of the CC Attribution 4.0 International (CC BY 4.0) licence). D concentrations have been used to characterize the
dose–response relationship. As part of this process, the
follow-up time of 5.3 years, the hazard ratios (with Institute of Medicine (IOM) in North America has defined
95% confidence intervals (95% CI)) were 0.83 (0.67–1.02) target serum 25(OH)D concentrations at the estimated
for death from cancer, 1.02 (0.79–1.31) for breast cancer, average requirement (EAR) and at the recommended
0.88 (0.72–1.07) for prostate cancer, and 1.09 (0.73–1.62) dietary allowance (RDA) that should meet the vitamin
for colorectal cancer. In analyses excluding 1 year and D requirements in 50 and 97.5% of the population,
2 years of follow-up, neither of which was pre-specified, respectively (86). The EAR and the RDA for vitamin D,
the hazard ratios (95% CI) for death from cancer were that is, the dietary intakes of vitamin D to achieve the
0.79 (0.63–0.99) and 0.75 (0.59–0.96), respectively. ‘EAR-like’ and ‘RDA-like’ serum 25(OH)D concentrations,
Furthermore, in a subgroup analysis of study participants were then calculated according to meta-regression analyses
with a BMI below 25 kg/m2, cancer mortality was of ‘winter’ vitamin D RCTs. Winter RCTs were chosen
significantly reduced by vitamin D supplementation because DRV/DRI apply to conditions with minimal
with a hazard ratio (95% CI) of 0.76 (0.63–0.90). In the or no sunlight exposure with consequently hardly any
entire study cohort, the mean ± standard deviation serum UV-B-induced endogenous vitamin D synthesis in the
25(OH)D concentration at baseline was 77 ± 25 nmol/L, skin. Major health agencies have used similar approaches,
and follow-up measurements in a subgroup of participants and the resulting DRV/DRI for vitamin D are listed in
after 1 year indicated an increase in serum 25(OH)D Tables 2 and 3 (86, 87, 88, 89, 90, 91). While the RDA is
concentrations in the treatment group of 30 nmol/L. traditionally adopted for planning intakes of individuals,
The findings from the VITAL trial support a potential as it meets the vitamin D requirements of 97.5% of
beneficial effect of vitamin D supplementation on cancer individuals within a population, it must be differentiated

Table 1 Definitions for the constituent dietary reference intakes and dietary reference values (reproduced from Cashman (85)
under the terms of the CC Attribution 4.0 International (CC BY 4.0) licence).

Institute of Medicine’s Dietary Reference Intakes European Food Safety Authority’s Dietary Reference Values

Estimated average requirement (EAR): The average daily Average requirement (AR): The level of (nutrient) intake estimated to
nutrient intake level that is estimated to meet the satisfy the physiological requirement or metabolic demand, as defined
requirements of half of the healthy individuals in a by the specified criterion for adequacy for that nutrient, in half of the
particular life stage and gender group people in a population group, given a normal distribution of
requirement
Recommended dietary allowance (RDA): The average daily Population reference intake (PRI): The level of (nutrient) intake that is
dietary intake level that is sufficient to meet the adequate for virtually all people in a population group. On the
nutrient requirements of nearly all (97.5 percent) assumption that the individual requirements for a nutrient are
healthy individuals in a particular life stage and normally distributed within a population and the inter-individual
gender group variation is known, the PRI is calculated on the basis of the AR plus
twice its standard deviation (s.d.). This will meet the requirements of
97.5% of the individuals in the population
Adequate intake (AI): The recommended average daily Adequate intake (AI): The value estimated when a PRI cannot be
intake level of a nutrient based on observed or established because an AR cannot be determined. An AI is the average
experimentally determined approximations or observed or experimentally determined approximations or estimates
estimates of intakes that are assumed to be adequate of nutrient intake by a population group (or groups) of apparently
for a group (or groups) of apparently healthy people; healthy people that is assumed to be adequate
used when the RDA cannot be determined
Tolerable upper intake level (UL): The highest average Tolerable upper intake level (UL): The maximum level of total chronic daily
daily nutrient intake level that is likely to pose no risk intake of a nutrient (from all sources) judged to be unlikely to pose a
of adverse health effects to almost all individuals in risk of adverse health effects to humans
the general population. As intake increases above the
UL, the potential risk of adverse effects may increase

between the individual and the population perspective. ≥50 nmol/L in 97.5% of the population, whereas 12.7 µg
When taking care of an individual, the RDA is the intake (508 IU) per day were calculated according to the use of
target for this individual, but in terms of public health the lower end of the 95% CI of the mean response using
actions, the goal is not, and should not be, to assure that aggregate data (84, 85). Such statistical considerations are
97.5% of the population exceeds the RDA equivalent crucial for the understanding and dealing with DRV/DRI.
serum concentration, that is, 50 nmol/L when using the A simplified summary of nutritional guidelines is that
IOM RDA. Shifting the population vitamin D intake target serum 25(OH)D concentrations range from ≥25 to
distribution to the point at which 97.5% of the population ≥50 nmol/L corresponding to a daily vitamin D intake of
exceed the RDA like serum 25(OH)D concentration 10–20 µg (400–800 IU). General populations around the
would consequently shift the higher end of the intake world generally fail to meet these vitamin D intakes and
distribution toward potentially harmful levels (84, 92). In target serum 25(OH)D concentrations pointing to the
this context, it should also be noted that the RDA was need for public health actions such as systematic vitamin
calculated based on meta-regression analyses indicating D food fortification (93, 94, 95, 96, 97, 98). In Europe, for
that the lower end of the 95% CI for the median intake is example, serum 25(OH)D concentrations <30 nmol/L and
≥50 nmol/L, that is, we can be sure that at least 50% of the <50 nmol/L are reported in 13.0 and 40.4% of the general
individuals will achieve ≥50 nmol/L at an RDA vitamin population, respectively (93). Therefore, some countries
D intake. Such conventional meta-regression analyses have already introduced systematic vitamin D food
using aggregate (group) data are suitable for establishing fortification to improve vitamin D intakes in the general
EARs as they well indicate mean responses and CI around population (99, 100, 101, 102, 103). While systematic
these mean responses. They are not ideal for calculating vitamin D food fortification in countries such as the
RDAs, because they do not adequately capture between- United States or Canada has improved vitamin D status in
individual variability as it can be done using regression the general population, further actions have to be taken
analyses based on individual participant data (IPD) to optimize their food fortification approaches (80). In
(84, 85). Using the same dataset for different statistical Finland, however, systematic vitamin D food fortification
approaches, it has been documented in IPD analyses that was highly effective by reducing the prevalence of
a vitamin D intake of about 30 µg (1200 IU) per day is individuals with serum 25(OH)D concentrations
required to achieve a serum 25(OH)D concentration of <30 nmol/L below 1% (99).

Table 2 Dietary reference values (DRV)/dietary reference intakes (DRI) for vitamin D (reproduced from Pilz et al. (81) under the
terms of the CC Attribution 4.0 International (CC BY 4.0) licence).

Germany, Austria Nordic European

and Switzerland countries
Country (health authority) United States and Canada (IOM) Europe (EFSA) (DACH) UK (SACN) (NORDEN)

DRV/DRI EAR RDA AI AI RNI RI

Target 25(OH)D in nmol/L 40 50 50 50 25 50

Age group Vitamin D intakes in µg (international units, IU) per day (1 µg = 40 IU)

0–6 months 10 (400) 10 (400) 8.5–10 (300–400)

7–12 months 10 (400) 10 (400) 10 (400) 8.5–10 (300–400) 10 (400)
1–3 years 10 (400) 15 (600) 15 (600) 20 (800) 10 (400) 10 (400)
4–6 years 10 (400) 15 (600) 15 (600) 20 (800) 10 (400) 10 (400)
7–8 years 10 (400) 15 (600) 15 (600) 20 (800) 10 (400) 10 (400)
9–10 years 10 (400) 15 (600) 15 (600) 20 (800) 10 (400) 10 (400)
11–14 years 10 (400) 15 (600) 15 (600) 20 (800) 10 (400) 10 (400)
15–17 years 10 (400) 15 (600) 15 (600) 20 (800) 10 (400) 10 (400)
18–69 years 10 (400) 15 (600) 15 (600) 20 (800) 10 (400) 10 (400)
70–74 years 10 (400) 20 (600) 15 (600) 20 (800) 10 (400) 10 (400)
75 years and older 10 (400) 20 (600) 15 (600) 20 (800) 10 (400) 20 (800)
Pregnancy 10 (400) 15 (600) 15 (600) 20 (800) 10 (400) 10 (400)
Lactation 10 (400) 15 (600) 15 (600) 20 (800) 10 (400) 10 (400)

IOM, Institute of Medicine; EFSA, European Food Safety Authority; DACH, Germany, Austria and Switzerland; SACN, Scientific Advisory Committee on
Nutrition; EAR, Estimated Average Requirement; RDA, Recommended Dietary Allowance; AI, Adequate Intake; RNI, Reference; Nutrient Intake; RI,
Recommended Intake; 25(OH)D, 25-hydroxyvitamin D.

Apart from nutritional guidelines on vitamin D nutritional rickets, the minimum recommended dose is
requirements in the general population, there are also 50 µg (2000 IU) of vitamin D per day for a minimum of
clinical vitamin D guidelines that aim to guide clinicians, 3 months plus oral calcium intake of 500 mg per day (5).
when taking care of specific patient populations Regarding vitamin D supplementation of osteoporosis
or individuals. A selection of these guidelines is patients, the recommendations are not fully consistent but
presented in this paragraph. The ‘Global Consensus 20 µg (800 IU) of vitamin D per day can be recommended
Recommendation on Prevention and Management of in the general management of osteoporosis patients (104,
Nutritional Rickets’ recommends for the prevention of 105, 106). Higher vitamin D intakes up to 50 µg (2000 IU)
rickets the supplementation of 10 µg (400 IU) of vitamin of vitamin D per day may also be used in specific patients
D daily from birth to 12 months, and thereafter, vitamin but do not represent the common consensus of major
D intakes through diet and supplements to meet the osteoporosis guidelines (104, 105, 106). Some experts
nutritional requirement according to the IOM report argue that in older individuals (aged ≥65 years), a general
(i.e. 15–20 µg (600–800 IU) per day) (5). For treatment of intake of a daily vitamin D supplement with 20 µg (800 IU)

Table 3 Tolerable upper intake levels for vitamin D (adapted from Pilz et al. (80) under the terms of the CC Attribution 4.0
International (CC BY 4.0) licence).

Country (health authority) United States and Canada (IOM) Europe (EFSA)

Age group Vitamin D in µg (international units, IU) per day (1 µg = 40 IU)

0–6 months 25 (1000) 25 (1000)
6–12 months 37.5 (1500) 35 (1400)*
1–3 years 62.5 (2500) 50 (2000)
4–8 years 75 (3000) 50 (2000)
9–10 years 100 (4000) 50 (2000)
11–17 years 100 (4000) 100 (4000)
18 years and older 100 (4000) 100 (4000)
Pregnancy 100 (4000) 100 (4000)
Lactation 100 (4000) 100 (4000)

EFSA, European Food Safety Authority; IOM, Institute of Medicine. *recently updated (180)

is a reasonable approach to ensure a sufficient vitamin Table 4 Indications for 25-hydroxyvitamin D measurements
D status (82). In patients with chronic kidney disease (candidates for screening) (reproduced, with permission, from
(CKD), it is suggested by the ‘Kidney Disease: Improving Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley
Global Outcomes (KDIGO) 2017 Clinical Practice DA, Heaney RP, Hassan Murad M & Weaver CM; Evaluation,
Guideline’ that vitamin D deficiency and insufficiency be Treatment, and Prevention of Vitamin D Deficiency: an
corrected by vitamin D supplementation using treatment Endocrine Society Clinical Practice Guideline; Journal of Clinical
strategies recommended for the general population (107). Endocrinology & Metabolism; 2011; 96(7) 1911–1930; by
Parathyroid diseases also require particular attention permission of Oxford University Press (24)).
regarding vitamin D status and represent an indication
Rickets
for measurement of serum 25(OH)D concentrations (108, Osteomalacia
109, 110). Patients with primary hyperparathyroidism and Osteoporosis
25(OH)D concentrations <50 nmol/L should be repleted Chronic kidney disease
Hepatic failure
with vitamin D doses (e.g. 15–25 µg (600–1000 IU) daily)
Malabsorption syndromes
aiming to bring 25(OH)D ≥50 nmol/L at a minimum, but Cystic fibrosis
a goal of 75 nmol/L also is reasonable (108). In primary Inflammatory bowel disease
hypoparathyroidism, it is also recommended to ensure Crohn’s disease
Bariatric surgery
a serum 25(OH)D concentration >50 nmol/L with a
Radiation enteritis
suggested supplemental vitamin D dose of 10–20 µg Hyperparathyroidism
(400–800 IU) per day (109, 110). One major vitamin Medications
D guideline for patient care is the ‘Endocrine Society Antiseizure medications
Glucocorticoids
Clinical Practice Guideline’ for evaluation, treatment
AIDS medications
and prevention of vitamin D deficiency that supports Antifungals, e.g. ketoconazole
the IOM recommendations for vitamin D intake to Cholestyramine
maximize bone health and muscle function in the African–American and Hispanic children and adults
Pregnant and lactating women
general population (24). However, the ‘Endocrine Society Older adults with history of falls
Clinical Practice Guideline’ significantly differs from the Older adults with history of nontraumatic fractures
IOM report as it is suggested to measure serum 25(OH) Obese children and adults (BMI 30 kg/m2)
D concentrations in individuals at risk of vitamin D Granuloma-forming disorders
Sarcoidosis
deficiency (Table 4). If vitamin D deficiency, classified Tuberculosis
as serum 25(OH)D <50 nmol/L, is detected in such Histoplasmosis
individuals, it is recommended to supplement vitamin Coccidiomycosis
Berylliosis
D to achieve serum 25(OH)D concentrations of at least
Some lymphomas
75 nmol/L. In detail, vitamin D-deficient adults should
be treated with 1250 µg (50,000 IU) vitamin D once a
requirements in general populations and in certain
week for 8 weeks or its equivalent of 150 µg (6000 IU)
patient populations or at-risk individuals is an unresolved
daily, followed by a maintenance dose of 37.5–50 µg
issue (23, 24, 25, 26).
(1500–2000 IU) daily. In obese patients, patients with
malabsorption syndromes (in particular patients after
bariatric surgery), and patients on medications affecting
Practical vitamin D testing
vitamin D metabolism, a higher dose (e.g. two to three
and supplementation
times higher) is suggested to treat vitamin D deficiency.
There has been an intensive scientific debate on the There is a consensus that population-wide screening
differences in the recommendations regarding vitamin for vitamin D deficiency by measuring serum 25(OH)D
D requirements from the IOM report and the Endocrine concentrations in asymptomatic low-risk patients should
Society Clinical Practice guideline that is beyond the not be done (111, 112, 113, 114). There is, however,
scope of this review (23, 24, 25, 26). In simple terms, the no consensus on indications for 25(OH)D testing in
IOM report does not conclude that there is additional patients at risk of vitamin D deficiency with suggested
benefit of achieving serum 25(OH)D concentrations of indications ranging from almost no testing to relatively
75 nmol/L when compared to 50 nmol/L. Furthermore, wide testing according to the Endocrine Society Clinical
whether or which differences exist regarding vitamin D Practice Guideline (Table 4). Making the long story short,

no study has shown the effectiveness of 25(OH)D as well as by vitamin D RCTs showing that a vitamin
screening in certain groups so that any recommendations D supplement with 20 µg (800 IU) per day is sufficient
regarding 25(OH)D testing have a relatively low evidence to achieve serum 25(OH)D concentrations ≥50 nmol/L
base and are mostly derived from expert opinions. A high in almost all participants (117, 118, 119). In pregnant
suspicion or diagnosis of rickets or osteomalacia does women, it was calculated that a daily overall vitamin D
definitely justify the measurement of serum 25(OH)D intake of about 30 µg (1200 IU) ensured that almost all
concentrations. As mentioned earlier, several guidelines women had serum 25(OH)D concentrations ≥50 nmol/L
and experts argue that serum 25(OH)D concentrations and that cord 25(OH)D concentrations were >25 nmol/L
should be measured in patients with hyper- and in 99% and ≥30 nmol/L in 95% of the newborns (120).
hypoparathyroidism as well as in CKD patients (107, 108, Regarding the precise vitamin D intake serum 25(OH)
109, 110). Although serum 25(OH)D concentrations are D dose–response curve, there are slightly inconsistent
widely measured in patients with osteoporosis, there is results in the literature (88, 91). As a frequently quoted
some controversy on whether such a testing should be rough summary, it can be estimated that per intake of about
done in all patients, just selected high-risk patients or 2.5 µg (100 IU) of vitamin D per day, the serum 25(OH)D
not at all. While there is definitely uncertainty regarding concentrations may increase by about 2.5–5 nmol/L but
precise indications for vitamin D testing in at-risk with quite significant variability of such estimates in the
individuals, there is evidence available that an uncritical literature (88, 91). Although not clearly established, there
high use of serum 25(OH)D measurements is performed are data indicating that the dose–response curve is not
in clinical routine that significantly increases healthcare linear and flattens at higher intakes (88, 91). Furthermore,
costs (112, 113, 114, 115). Clinicians should be aware that several studies suggest that achieved increases in serum
laboratory measurements of serum 25(OH)D have shown 25(OH)D are significantly higher in individuals with
significant inter-assay and inter-laboratory differences lower compared to higher baseline levels and are lower
leading to efforts for standardization and a pressure in persons with a higher BMI (88, 91). Although there
toward well-validated gold standard measurements by is no clear recommendation to perform follow-up
mass spectrometry (115). There is, of course, a seasonal measurements of serum 25(OH)D after starting with a
variation in serum 25(OH)D concentrations with the daily vitamin D supplement, it bears mentioning that
highest levels at the end of summer and the lowest re-measurements of serum 25(OH)D should not be done
levels at the end of winter, but the tracking of serum earlier than after 8 weeks on treatment because this is
25(OH)D concentrations over time reveals that a single approximately the time required to reach a steady state
measurement of serum 25(OH)D at a given time point (88, 91). Of note, some studies indicate that it may take
provides an estimate of future 25(OH)D levels (even even 12 weeks or longer to reach a steady state in serum
if years apart) which is similar to the tracking of blood 25(OH)D (121).
pressure or blood lipids (116). It should be noted that daily, weekly or monthly
Apart from testing issues and the uncertainty regarding vitamin D dosing regimens can be used because they result
target concentrations, it is crucial to be aware on the dose– in the same serum 25(OH)D concentrations (122, 123).
response relationship of vitamin D intakes and serum Nevertheless, some experts recommend to prefer daily
25(OH)D concentrations. It should be considered that doses as vitamin D itself may be biologically relevant, but
the average nutritional vitamin D intake in the general has only a half-life of about a day and because some RCTs
population is typically below 5 µg (200 IU) per day (80, 98). on intermittent high-dose vitamin D supplementation
Using data from vitamin D RCTs in winter, Cashman et al. have reported adverse effects such as increased falls and
have calculated in an IPD regression analysis that with fractures (124, 125, 126, 127). In detail, an annual dose
an overall (diet plus supplements) vitamin D intake of of 12,500 µg (500,000 IU) of vitamin D for 3–5 years in
10 µg (400 IU) per day, the percentages of individuals with 2256 community-dwelling women aged 70 years or older
serum 25(OH)D concentrations ≥25, ≥30 and ≥50 nmol/L, resulted in an increased risk of fractures and falls with
would be 97.5, 95 and about 50%, respectively (84, 85). To incident rate ratios (with 95% CI) compared to placebo
ensure that 97.5% of the individuals would achieve serum of 1.15 (1.02–1.30; P = 0.03) and 1.26 (1.00–1.59; P = 0.47),
25(OH)D concentrations ≥50 nmol/L would require an respectively (124). Interestingly, post hoc analyses showed
overall vitamin D intake of approximately 30 µg (1200 IU) that increased risk of falls was exacerbated in the 3-month
per day (84, 85). These estimates are, for example, period following the annual vitamin D dose, with a
supported by studies on food fortification in Finland similar trend for fractures (124). This also means that

risk was particularly increased during the period with the vitamin D intoxication does, however, usually only occur
highest serum 25(OH)D concentrations during the year at serum 25(OH)D concentrations above 375 nmol/L
in the intervention group with a median concentration, and is very rare (80, 127, 131). Nevertheless, in view of
1 month after the annual dose, that was slightly higher limited data on high serum 25(OH)D concentrations
than 120 nmol/L including 24% of the participants with and some observational studies reporting U- or J-shaped
levels ≥150 nmol/L (124). Importantly, another RCT over curves on the association between serum 25(OH)D and
1 year in 200 community-dwelling men and women aged outcomes such as mortality, the IOM report classified
70 years and older with a prior fall reported that risk of serum 25(OH)D concentrations greater than 125 nmol/L,
falls was significantly increased in participants allocated if sustained, as potentially harmful (25). It has been
to monthly doses of 1500 µg (60,000 IU) of vitamin argued that the increased risk at high serum 25(OH)
D compared to monthly doses of 600 µg (24,000 IU) D concentrations might have been partially attributed
of vitamin D (mean number of falls per participant: to patients with previous vitamin D deficiency who
1.47 vs 0.94; P = 0.02) (125). By contrast, other RCTs therefore received vitamin D supplements, but whenever
on intermittent high-dose vitamin D supplementation discussing associations between serum 25(OH)D and
such as the Vitamin D Assessment (ViDA) Study in 5108 outcome, it must be stressed that such data should be
older individuals randomized to 2500 µg (100,000 IU) based on surveys with standardization of 25(OH)D
of vitamin D per month or placebo did not report on measurements. Current meta-analyses of observational
increased risk of fractures or falls (128, 129). In line with studies do not report on significantly elevated risk
this, a recent meta-analysis on vitamin D supplementation of adverse events at serum 25(OH)D concentrations
and musculoskeletal health outcomes did not find higher than 125 nmol/L, so that it is still unclear which
differences for daily versus intermittent vitamin D doses serum 25(OH)D concentrations should be used as a
(57). Interestingly, there are also data suggesting that threshold level for vitamin D toxicity (132, 133). To
there may be a U-shaped association of serum 25(OH) get some deeper insights into the association of serum
D and risk of falls (130). Anyway, we believe that some 25(OH)D concentrations and clinical outcomes such as
caution is warranted with intermittent high-dose vitamin mortality, we show the results of an IPD meta-analysis
D supplementation and with potential adverse effects of on standardized serum 25(OH)D concentrations in Fig. 3
very high serum 25(OH)D concentrations. (16). Importantly, in the VITAL trial, there were no safety
From a clinical perspective, vitamin D intoxication concerns with regard to hypercalcemia, kidney stones
is characterized by hypercalcemia, which is preceded or kidney failure with a daily supplementation of 50 µg
by hypercalciuria (80, 127). Hypercalcemia induced by (2000 IU) vitamin D (78).

Figure 3
Dose–response trend of hazard ratios of death
from all causes by standardized
25-hydroxyvitamin D. Dose–response trend of
hazard ratios of all-cause mortality by
standardized 25-hydroxyvitamin D were adjusted
for age, sex, BMI and season of blood drawing
concentrations. Hazard ratios (blue line with 95%
confidence interval as the dotted blue lines) are
referring to the 25-hydroxyvitamin D
concentration of 83.4 nmol/L (i.e. the median
25-hydroxyvitamin D concentration for the group
with 25-hydroxyvitamin D concentrations from 75
to 99.99 nmol/L). Reproduced from Gaksch et al.
(16) under the terms of the CC0 1.0 Universal
(CC0 1.0) Public Domain Dedication.

Apart from oral intake, vitamin D can also be fail and is not a ‘wonder drug’ (160). Unfortunately, many
administered intramuscularly with a similar, yet delayed, vitamin D RCTs have a similar study design as previous
increase compared to oral intakes (134, 135, 136). disappointing nutrient trials with no selection of sensitive
Transdermal applications of vitamin D do also raise (e.g. vitamin D deficient) individuals, and may, therefore
serum 25(OH)D, but more data on this topic are needed likewise show no effect or might even be harmful (158,
(137, 138). Apart from vitamin D, there are also 25(OH) 159, 161). Subgroup analyses of vitamin D-deficient
D preparations available for treatment that are about individuals, even if showing beneficial effects, will likewise
3.2–5-fold as effective as vitamin D in raising serum 25(OH) not be widely accepted and will definitely not be able to
D concentrations (139, 140). Regarding vitamin D3 and D2, compete with drug trials results that are not derived from
most experts argue to rather prefer vitamin D3, as it is the unselected participants but rather from very large cohorts
endogenous form that may be more potent in increasing of carefully selected and ‘sensitive’ populations (158).
serum 25(OH)D concentrations compared to vitamin D2 Assessment of calcium intake is also crucial in vitamin
(141). The lower affinity to DBP of vitamin D2 metabolites D RCTs because it seems that individuals with a poor
compared to vitamin D3 metabolites may contribute to calcium intake may be more sensitive to adverse effects of
a more rapid clearance of vitamin D2 (142, 143, 144). vitamin D deficiency and vice versa.
Reviewing the current literature on this topic, Bouillon It is important to point out that EBM is not exclusively
et al. concluded that vitamin D2 can be considered as a based on RCTs but also on other study designs including,
good analog of vitamin D3 rather than as being truly apart from classic observational studies, also Mendelian
bioequivalent (144). As part of the discussion on optimal Randomization (MR) studies (157). These MR studies
strategies for vitamin D supplementation, it should also be evaluate whether genetically determined serum 25(OH)D
emphasized that a healthy lifestyle with moderate sunlight levels are associated with outcome and have the advantage
exposure, a healthy diet (including fish) and avoiding or over RCTs that they assess lifelong exposure (162, 163).
treating obesity can also effectively increase serum 25(OH) While observational studies on vitamin D have been very
D concentrations (145, 146, 147, 148, 149). useful to generate hypotheses that have to be further
tested in RCTs or MR studies, they are definitely prone
to bias or reverse causation as for example, DBP decreases
Critical appraisal of vitamin D research
due to critical illness thus consequently decreasing total
Several vitamin D RCTs have been published and are serum 25(OH)D (164). It is also important to note that
currently ongoing that have or will substantially increase serum 25(OH)D concentrations in observational studies
our knowledge on vitamin D. Robert Heaney and other are mainly derived from sunlight-induced vitamin D
scientists pointed out that the evidence-based medicine synthesis in the skin, while interventional studies rather
(EBM) guidelines, developed specifically for drugs, supplement vitamin D than increasing UV-induced
have been applied to nutrients and their trials without vitamin D synthesis that may also exert vitamin
considering major differences between nutrients and D-independent effects on human health. Moreover, there
drugs (150, 151, 152, 153, 154, 155, 156, 157). One key are still several knowledge gaps regarding the role and
point is that the dose–response curve of nutrient intake regulation of DBP or regarding data on potential vitamin
and outcomes is generally not linear, and it requires an D toxicity at high serum 25(OH)D concentrations (164,
accurate interpretation and study design of nutrient 165, 166, 167). As an important task for future vitamin
trials considering this dose–response curve. Assessment D research, Sempos et al. have proposed to develop an
of nutrient status at baseline and study end and aiming international ‘Rickets Registry’ based on standardized
for a change in nutrient intake that is associated with serum 25(OH)D and a standardized case definition of
a significant change in outcomes on the dose–response rickets (166).
curve is important. RCTs including participants regardless Better education for professionals and the lay public
of their prevailing vitamin D status or with high serum is also required to reduce the overuse of high-dose
25(OH)D concentrations may miss to report significant vitamin D supplements (in particular doses that exceed
vitamin D effects in ‘sensitive’ populations such as vitamin the tolerable upper intake levels according to Table 3) in
D-deficient individuals (158, 159). It should appear logical those who do not need it and to improve the underuse
that when even established treatments such as aspirin are of vitamin D supplements in those individuals in whom
not effective in terms of improved clinical outcomes when it is indicated (168, 169, 170, 171, 172, 173). Infrequent
given to everyone in the population, vitamin D will also use of vitamin D supplements in individuals with a low

socioeconomic status has to be considered (170, 171, dose–response analyses of RCTs (24, 49, 56). Even
172, 173). Importantly, rickets is still a worldwide public if following more conservative approaches, there is
health problem causing morbidity and mortality and is an imperative requirement for vitamin D treatment
even increasing in Europe with immigrants from Middle in individuals with serum 25(OH)D concentrations
East, Africa and Asia being at particularly high risk <25–30 nmol/L, a level that can be prevented by a
(174). Prevalence and incidence of vitamin D deficiency- supplemental vitamin D dose of 10 µg (400 IU) per day.
associated nutritional rickets is difficult to assess due to We believe that upcoming large vitamin D RCTs will
incomplete reporting and inconsistent case definition, likewise not show significant beneficial effects as they
but even if conservative estimates of only a few single- did not target vitamin D-deficient or sensitive high-risk
digit cases per 100,000 is true, vitamin D-deficient individuals, but will provide important safety data for
rickets and the therewith associated infant deaths are relatively high doses of vitamin D supplementation in the
preventable and require adequate public health actions general older population (158, 161, 178, 179).
(174, 175, 176, 177).

Declaration of interest
The authors declare that there is no conflict of interest that could be
perceived as prejudicing the impartiality of this review.
Conclusions
It is established that vitamin D deficiency can cause rickets
Funding
and osteomalacia with a significant risk increase at serum
This work did not receive any specific grant from any funding agency in the
25(OH)D concentrations <25–30 nmol/L, pointing to the public, commercial or not-for-profit sector.
need for prevention and treatment of such low serum
25(OH)D concentrations on an individual and population
Author contribution statement
level. Adequate vitamin D supplementation may also All authors contributed to the drafting and critical review of this manuscript.
have moderate beneficial effects on BMD, fractures and
falls. These effects seem to be only evident in vitamin
D-sensitive populations, that is, in particular in those with References
serum 25(OH)D concentrations <30 nmol/L and older 1 Christakos S, Dhawan P, Verstuyf A, Verlinden L & Carmeliet G.
Vitamin D: metabolism, molecular mechanism of action, and
or at-risk individuals. Importantly, high calcium intake pleiotropic effects. Physiological Reviews 2016 96 365–408. (https://
may partially compensate for reduced serum 25(OH) doi.org/10.1152/physrev.00014.2015)
D concentrations. Meta-analyses of RCTs indicated that 2 Carpenter TO, Shaw NJ, Portale AA, Ward LM, Abrams SA &
Pettifor JM. Rickets. Nature Reviews Disease Primers 2017 3 17101.
vitamin D supplementation may also reduce extra-skeletal (https://doi.org/10.1038/nrdp.2017.101)
outcomes such as infections, asthma exacerbations, 3 Uday S, Fratzl-Zelman N, Roschger P, Klaushofer K, Chikermane A,
pregnancy outcomes and mortality, but more data are Saraff V, Tulchinsky T, Thacher TD, Marton T & Högler W. Cardiac,
bone and growth plate manifestations in hypocalcemic infants:
required to clearly establish causality. Anyway, effect sizes revealing the hidden body of the vitamin D deficiency iceberg. BMC
on any of these outcomes, if truly present, are only small Pediatrics 2018 18 183. (https://doi.org/10.1186/s12887-018-1159-y)
but may eventually be significant on a population level. 4 Uday S & Högler W. Nutritional rickets and osteomalacia in the
twenty-first century: revised concepts, public health, and prevention
Clinicians are confronted with an overwhelming testing strategies. Current Osteoporosis Reports 2017 15 293–302. (https://doi.
and self-supplementation of vitamin D in the general org/10.1007/s11914-017-0383-y)
population. It is therefore recommended that vitamin D 5 Munns CF, Shaw N, Kiely M, Specker BL, Thacher TD, Ozono K,
Michigami T, Tiosano D, Mughal MZ, Mäkitie O, et al. Global
testing should not be misused as a universal population- consensus recommendations on prevention and management of
wide screening tool, but rather be applied only in selected nutritional rickets. Journal of Clinical Endocrinology and Metabolism
individuals at high risk of vitamin D deficiency. Being 2016 101 394–415. (https://doi.org/10.1210/jc.2015-2175)
6 Bouillon R, Carmeliet G, Verlinden L, van Etten E, Verstuyf A,
aware of inconsistent guidelines and recommendations, Luderer HF, Lieben L, Mathieu C & Demay M. Vitamin D and human
we suggest that a reasonable approach for clinicians is to health: lessons from vitamin D receptor null mice. Endocrine Reviews
supplement vitamin D in those individuals with measured 2008 29 726–776. (https://doi.org/10.1210/er.2008-0004)
7 Rosen CJ, Adams JS, Bikle DD, Black DM, Demay MB, Manson JE,
serum 25(OH)D <50 nmol/L and osteoporosis patients. A Murad MH & Kovacs CS. The nonskeletal effects of vitamin D: an
supplemental dose of 20 µg (800 IU) of vitamin D per day Endocrine Society scientific statement. Endocrine Reviews 2012 33
should be sufficient for almost all individuals to safely 456–492. (https://doi.org/10.1210/er.2012-1000)
8 Pilz S, Verheyen N, Grübler MR, Tomaschitz A & März W. Vitamin
achieve serum 25(OH)D concentrations ≥50 nmol/L D and cardiovascular disease prevention. Nature Reviews Cardiology
and to exert beneficial clinical effects according to some 2016 13 404–417. (https://doi.org/10.1038/nrcardio.2016.73)

9 Holick MF. The vitamin D deficiency pandemic: approaches for treatment, and prevention of vitamin D deficiency: an Endocrine
diagnosis, treatment and prevention. Reviews in Endocrine and Society clinical practice guideline. Journal of Clinical Endocrinology and
Metabolic Disorders 2017 18 153–165. (https://doi.org/10.1007/ Metabolism 2011 96 1911–1930. (https://doi.org/10.1210/jc.2011-0385)
s11154-017-9424-1) 25 Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK,
10 Trummer C, Pilz S, Schwetz V, Obermayer-Pietsch B & Lerchbaum E. Durazo-Arvizu RA, Gallagher JC, Gallo RL, Jones G, et al. The 2011
Vitamin D, PCOS and androgens in men: a systematic review. Endocrine report on dietary reference intakes for calcium and vitamin D from
Connections 2018 7 R95–R113. (https://doi.org/10.1530/EC-18-0009) the Institute of Medicine: what clinicians need to know. Journal of
11 Muscogiuri G, Altieri B, Annweiler C, Balercia G, Pal HB, Boucher BJ, Clinical Endocrinology and Metabolism 2011 96 53–58. (https://doi.
Cannell JJ, Foresta C, Grübler MR, Kotsa K, et al. Vitamin D and org/10.1210/jc.2010-2704)
chronic diseases: the current state of the art. Archives of Toxicology 26 Rosen CJ, Abrams SA, Aloia JF, Brannon PM, Clinton SK, Durazo-
2017 91 97–107. (https://doi.org/10.1007/s00204-016-1804-x) Arvizu RA, Gallagher JC, Gallo RL, Jones G, Kovacs CS, et al. IOM
12 Zittermann A, Pilz S, Hoffmann H & März W. Vitamin D and airway committee members respond to Endocrine Society vitamin D
infections: a European perspective. European Journal of Medical guideline. Journal of Clinical Endocrinology and Metabolism 2012 97
Research 2016 21 14. (https://doi.org/10.1186/s40001-016-0208-y) 1146–1152. (https://doi.org/10.1210/jc.2011-2218)
13 Wagner CL & Hollis BW. The implications of vitamin D status 27 Reid IR. Calcium and vitamin D: to supplement or not? Cleveland
During pregnancy on mother and her developing child. Frontiers in Clinic Journal of Medicine 2018 85 693–698. (https://doi.org/10.3949/
Endocrinology 2018 9 500. (https://doi.org/10.3389/fendo.2018.00500) ccjm.85a.18026)
14 Keane JT, Elangovan H, Stokes RA & Gunton JE. Vitamin D and 28 Pludowski P, Holick MF, Grant WB, Konstantynowicz J,
the liver-correlation or cause? Nutrients 2018 10 496. (https://doi. Mascarenhas MR, Haq A, Povoroznyuk V, Balatska N, Barbosa AP,
org/10.3390/nu10040496) Karonova T, et al. Vitamin D supplementation guidelines. Journal of
15 Chowdhury R, Kunutsor S, Vitezova A, Oliver-Williams C, Steroid Biochemistry and Molecular Biology 2018 175 125–135. (https://
Chowdhury S, Kiefte-de-Jong JC, Khan H, Baena CP, Prabhakaran D, doi.org/10.1016/j.jsbmb.2017.01.021)
Hoshen MB, et al. Vitamin D and risk of cause specific death: 29 Deluca HF History of the discovery of vitamin D and its active
systematic review and meta-analysis of observational cohort and metabolites. BoneKEy Reports 2014 3 479. (https://doi.org/10.1038/
randomised intervention studies. BMJ 2014 348 g1903. (https://doi. bonekey.2013.213)
org/10.1136/bmj.g1903) 30 Macdonald HM, Mavroeidi A, Fraser WD, Darling AL, Black AJ,
16 Gaksch M, Jorde R, Grimnes G, Joakimsen R, Schirmer H, Aucott L, O'Neill F, Hart K, Berry JL, Lanham-New SA, et al. Sunlight
Wilsgaard T, Mathiesen EB, Njølstad I, Løchen ML, März W, et al. and dietary contributions to the seasonal vitamin D status of cohorts
Vitamin D and mortality: individual participant data meta-analysis of healthy postmenopausal women living at northerly latitudes:
of standardized 25-hydroxyvitamin D in 26916 individuals from a a major cause for concern? Osteoporosis International 2011 22
European consortium. PLoS ONE 2017 12 e0170791. (https://doi. 2461–2472. (https://doi.org/10.1007/s00198-010-1467-z)
org/10.1371/journal.pone.0170791) 31 Jiang X, O'Reilly PF, Aschard H, Hsu YH, Richards JB, Dupuis J,
17 Autier P, Boniol M, Pizot C & Mullie P. Vitamin D status and ill Ingelsson E, Karasik D, Pilz S, Berry D, et al. Genome-wide association
health: a systematic review. Lancet Diabetes and Endocrinology 2014 2 study in 79,366 European-ancestry individuals informs the genetic
76–89. (https://doi.org/10.1016/S2213-8587(13)70165-7) architecture of 25-hydroxyvitamin D levels. Nature Communications
18 Swart KM, Lips P, Brouwer IA, Jorde R, Heymans MW, Grimnes G, 2018 9 260. (https://doi.org/10.1038/s41467-017-02662-2)
Grübler MR, Gaksch M, Tomaschitz A, Pilz S, et al. Effects of vitamin 32 Bouillon R. Genetic and racial differences in the vitamin D endocrine
D supplementation on markers for cardiovascular disease and type 2 system. Endocrinology and Metabolism Clinics of North America 2017 46
diabetes: an individual participant data meta-analysis of randomized 1119–1135. (https://doi.org/10.1016/j.ecl.2017.07.014)
controlled trials. American Journal of Clinical Nutrition 2018 107 33 Martinaityte I, Kamycheva E, Didriksen A, Jakobsen J & Jorde R.
1043–1053. (https://doi.org/10.1093/ajcn/nqy078) Vitamin D stored in fat tissue during a 5-year intervention affects
19 Autier P, Mullie P, Macacu A, Dragomir M, Boniol M, Coppens K, serum 25-hydroxyvitamin D levels the following year. Journal of
Pizot C & Boniol M. Effect of vitamin D supplementation on Clinical Endocrinology and Metabolism 2017 102 3731–3738. (https://
non-skeletal disorders: a systematic review of meta-analyses doi.org/10.1210/jc.2017-01187)
and randomised trials. Lancet Diabetes and Endocrinology 2017 5 34 Bikle DD, Malmstroem S & Schwartz J. Current controversies:
986–1004. (https://doi.org/10.1016/S2213-8587(17)30357-1) are free vitamin metabolite levels a more accurate assessment of
20 Rejnmark L, Bislev LS, Cashman KD, Eiríksdottir G, Gaksch M, vitamin D status than total levels? Endocrinology and Metabolism
Grübler M, Grimnes G, Gudnason V, Lips P, Pilz S, et al. Non-skeletal Clinics of North America 2017 46 901–918. (https://doi.org/10.1016/j.
health effects of vitamin D supplementation: a systematic review on ecl.2017.07.013)
findings from meta-analyses summarizing trial data. PLoS ONE 2017 35 Pilz S, Obeid R, Schwetz V, Trummer C, Pandis M, Lerchbaum E,
12 e0180512. (https://doi.org/10.1371/journal.pone.0180512) Pieber TR, Obermayer-Pietsch B, Wilhelm M, Hahn A, et al.
21 Bolland MJ, Avenell A & Grey A. Should adults take vitamin D Hormonal contraceptive use is associated With higher total but
supplements to prevent disease? BMJ 2016 355 i6201. (https://doi. unaltered free 25-hydroxyvitamin D serum concentrations. Journal of
org/10.1136/bmj.i6201) Clinical Endocrinology and Metabolism 2018 103 2385–2391. (https://
22 Ebeling P, Adler R, Jones G, Liberman UA, Mazziotti G, Minisola S, doi.org/10.1210/jc.2018-00336)
Munns C, Napoli N, Pittas A, Giustina A, et al. MANAGEMENT of 36 Gibson CC, Davis CT, Zhu W, Bowman-Kirigin JA, Walker AE, Tai Z,
ENDOCRINE DISEASE: Therapeutics of vitamin D. European Journal of Thomas KR, Donato AJ, Lesniewski LA & Li DY. Dietary vitamin
Endocrinology 2018 179 R239–R259. (https://doi.org/10.1530/EJE-18- D and its metabolites non-genomically stabilize the endothelium.
0151) PLoS ONE 2015 10 e0140370. (https://doi.org/10.1371/journal.
23 Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, pone.0140370)
Heaney RP, Murad MH & Weaver CM. Guidelines for preventing and 37 Anderson PH. Vitamin D activity and metabolism in bone. Current
treating vitamin D deficiency and insufficiency revisited. Journal of Osteoporosis Reports 2017 15 443–449. (https://doi.org/10.1007/
Clinical Endocrinology and Metabolism 2012 97 1153–1158. (https:// s11914-017-0394-8)
doi.org/10.1210/jc.2011-2601) 38 van de Peppel J & van Leeuwen JP. Vitamin D and gene networks in
24 Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, human osteoblasts. Frontiers in Physiology 2014 5 137. (https://doi.
Heaney RP, Murad MH, Weaver CM & Endocrine Society. Evaluation, org/10.3389/fphys.2014.00137)

39 Rajakumar K, Greenspan SL, Thomas SB & Holick MF. Solar 54 Weaver CM, Alexander DD, Boushey CJ, Dawson-Hughes B,
ultraviolet radiation and vitamin D: a historical perspective. American Lappe JM, LeBoff MS, Liu S, Looker AC, Wallace TC & Wang DD.
Journal of Public Health 2007 97 1746–1754. (https://doi.org/10.2105/ Calcium plus vitamin D supplementation and risk of fractures: an
AJPH.2006.091736) updated meta-analysis from the National Osteoporosis Foundation.
40 Bhan A, Rao AD & Rao DS. Osteomalacia as a result of vitamin D Osteoporosis International 2016 27 367–376. (https://doi.org/10.1007/
deficiency. Endocrinology and Metabolism Clinics of North America 2010 s00198-015-3386-5)
39 321–331. (https://doi.org/10.1016/j.ecl.2010.02.001) 55 Avenell A, Mak JC & O'Connell D. Vitamin D and vitamin D
41 Reid IR. Vitamin D effect on bone mineral density and fractures. analogues for preventing fractures in post-menopausal women
Endocrinology and Metabolism Clinics of North America 2017 46 and older men. Cochrane Database of Systematic Reviews 2014 4
935–945. (https://doi.org/10.1016/j.ecl.2017.07.005) CD000227. (https://doi.org/10.1002/14651858.CD000227.pub4)
42 Reid IR, Bolland MJ & Grey A. Effects of vitamin D supplements on 56 Bischoff-Ferrari HA, Willett WC, Orav EJ, Lips P, Meunier PJ,
bone mineral density: a systematic review and meta-analysis. Lancet Lyons RA, Flicker L, Wark J, Jackson RD, Cauley JA, et al. A pooled
2014 383 146–155. (https://doi.org/10.1016/S0140-6736(13)61647-5) analysis of vitamin D dose requirements for fracture prevention. New
43 Macdonald HM, Reid IR, Gamble GD, Fraser WD, Tang JC & England Journal of Medicine 2012 367 40–49. (https://doi.org/10.1056/
Wood AD. 25-Hydroxyvitamin D threshold for the effects of vitamin NEJMoa1109617)
D supplements on bone density: secondary analysis of a randomized 57 Bolland MJ, Grey A & Avenell A. Effects of vitamin D
controlled trial. Journal of Bone and Mineral Research 2018 33 supplementation on musculoskeletal health: a systematic review,
1464–1469. (https://doi.org/10.1002/jbmr.3442) meta-analysis, and trial sequential analysis. Lancet Diabetes and
44 Reid IR, Horne AM, Mihov B, Gamble GD, Al-Abuwsi F, Singh M, Endocrinology 2018 6 847–858. (https://doi.org/10.1016/S2213-
Taylor L, Fenwick S, Camargo CA, Stewart AW, et al. Effect of 8587(18)30265-1)
monthly high-dose vitamin D on bone density in community- 58 Scragg R, Stewart AW, Waayer D, Lawes CMM, Toop L, Sluyter J,
dwelling older adults substudy of a randomized controlled trial. Murphy J, Khaw KT & Camargo CA Jr. Effect of monthly high-dose
Journal of Internal Medicine 2017 282 452–460. (https://doi. vitamin D supplementation on cardiovascular disease in the vitamin
org/10.1111/joim.12651) D assessment study: a randomized clinical trial. JAMA Cardiology
45 Al-Ali H & Fuleihan GE. Nutritional osteomalacia: substantial 2017 2 608–616. (https://doi.org/10.1001/jamacardio.2017.0175)
clinical improvement and gain in bone density posttherapy. Journal 59 Lappe J, Watson P, Travers-Gustafson D, Recker R, Garland C,
of Clinical Densitometry 2000 3 97–101. (https://doi.org/10.1385/ Gorham E, Baggerly K & McDonnell SL. Effect of vitamin D and
JCD:3:1:097) calcium supplementation on cancer incidence in older women: a
46 Bolland MJ, Grey A, Gamble GD & Reid IR. Vitamin D randomized clinical trial. JAMA 2017 317 1234–1243. (https://doi.
supplementation and falls: a trial sequential meta-analysis. Lancet org/10.1001/jama.2017.2115)
Diabetes and Endocrinology 2014 2 573–580. (https://doi.org/10.1016/ 60 Kubiak J, Thorsby PM, Kamycheva E & Jorde R. Vitamin D
S2213-8587(14)70068-3) supplementation does not improve CVD risk factors in vitamin
47 Murad MH, Elamin KB, Abu Elnour NO, Elamin MB, Alkatib AA, D-insufficient subjects. Endocrine Connections 2018 7 840–849.
Fatourechi MM, Almandoz JP, Mullan RJ, Lane MA, Liu H, et al. (https://doi.org/10.1530/EC-18-0144)
Clinical review: the effect of vitamin D on falls: a systematic review 61 Roth DE, Morris SK, Zlotkin S, Gernand AD, Ahmed T, Shanta SS,
and meta-analysis. Journal of Clinical Endocrinology and Metabolism Papp E, Korsiak J, Shi J, Islam MM, et al. Vitamin D supplementation
2011 96 2997–3006. (https://doi.org/10.1210/jc.2011-1193) in pregnancy and lactation and infant growth. New England
48 Bolland MJ, Grey A & Reid IR. Differences in overlapping meta- Journal of Medicine 2018 379 535–546. (https://doi.org/10.1056/
analyses of vitamin D supplements and falls. Journal of Clinical NEJMoa1800927)
Endocrinology and Metabolism 2014 99 4265–4272. (https://doi. 62 Sluyter JD, Camargo CA, Waayer D, Lawes CMM, Toop L, Khaw KT
org/10.1210/jc.2014-2562) & Scragg R. Effect of monthly, high-dose, long-term vitamin D on
49 Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, Orav JE, lung function: a randomized controlled trial. Nutrients 2017 9 1353.
Stuck AE, Theiler R, Wong JB, Egli A, Kiel DP & Henschkowski J. (https://doi.org/10.3390/nu9121353)
Fall prevention with supplemental and active forms of vitamin D: a 63 Saleem J, Zakar R, Zakar MZ, Belay M, Rowe M, Timms PM, Scragg R
meta-analysis of randomised controlled trials. BMJ 2009 339 b3692. & Martineau AR. High-dose vitamin D3 in the treatment of severe
(https://doi.org/10.1136/bmj.b3692) acute malnutrition: a multicenter double-blind randomized
50 Cameron ID, Gillespie LD, Robertson MC, Murray GR, Hill KD, controlled trial. American Journal of Clinical Nutrition 2018 107
Cumming RG & Kerse N. Interventions for preventing falls in older 725–733. (https://doi.org/10.1093/ajcn/nqy027)
people in care facilities and hospitals. Cochrane Database of Systematic 64 Hibbs AM, Ross K, Kerns LA, Wagner C, Fuloria M, Groh-Wargo S,
Reviews 2012 12 CD005465. (https://doi.org/10.1002/14651858. Zimmerman T, Minich N & Tatsuoka C. Effect of vitamin D
CD005465.pub3) supplementation on recurrent wheezing in black infants who were
51 Bischoff-Ferrari HA, Dawson-Hughes B & Willett WC. Issues of trial born preterm: the D-wheeze randomized clinical trial. JAMA 2018
selection and subgroup considerations in the recent meta-analysis of 319 2086–2094. (https://doi.org/10.1001/jama.2018.5729)
Zhao and colleagues on fracture reduction by calcium and vitamin 65 Goulão B, Stewart F, Ford JA, MacLennan G & Avenell A. Cancer and
D supplementation in community-dwelling older adults. Osteoporosis vitamin D supplementation: a systematic review and meta-analysis.
International 2018 29 2151–2152. (https://doi.org/10.1007/s00198- American Journal of Clinical Nutrition 2018 107 652–663. (https://doi.
018-4587-5) org/10.1093/ajcn/nqx047)
52 Kahwati LC, Weber RP, Pan H, Gourlay M, LeBlanc E, Coker- 66 Beveridge LA, Khan F, Struthers AD, Armitage J, Barchetta I,
Schwimmer M & Viswanathan M. Vitamin D, calcium, or combined Bressendorff I, Cavallo MG, Clarke R, Dalan R, Dreyer G, et al. Effect
supplementation for the primary prevention of fractures in of vitamin D supplementation on markers of vascular function: A
community-dwelling adults: evidence report and systematic review systematic review and individual participant meta-analysis. Journal
for the US Preventive Services Task Force. JAMA 2018 319 of the American Heart Association 2018 7 e008273. (https://doi.
1600–1612. (https://doi.org/10.1001/jama.2017.21640) org/10.1161/JAHA.117.008273)
53 Zhao JG, Zeng XT, Wang J & Liu L. Association Between calcium or 67 Martineau AR, Jolliffe DA, Hooper RL, Greenberg L, Aloia JF,
vitamin D supplementation and fracture incidence in community- Bergman P, Dubnov-Raz G, Esposito S, Ganmaa D, Ginde AA,
dwelling older adults: a systematic review and meta-analysis. JAMA et al. Vitamin D supplementation to prevent acute respiratory
2017 318 2466–2482. (https://doi.org/10.1001/jama.2017.19344) tract infections: systematic review and meta-analysis of individual

participant data. BMJ 2017 356 i6583. (https://doi.org/10.1136/bmj. Epling JW Jr, Kemper AR, et al. Vitamin D, calcium, or combined
i6583) supplementation for the primary prevention of fractures in
68 Jolliffe DA, Greenberg L, Hooper RL, Griffiths CJ, Camargo CA Jr, community-dwelling adults: US Preventive Services Task Force
Kerley CP, Jensen ME, Mauger D, Stelmach I, Urashima M, et al. Recommendation Statement. JAMA 2018 319 1592–1599. (https://
Vitamin D supplementation to prevent asthma exacerbations: a doi.org/10.1001/jama.2018.3185)
systematic review and meta-analysis of individual participant data. 82 Brouwer-Brolsma EM, Bischoff-Ferrari HA, Bouillon R, Feskens EJ,
Lancet Respiratory Medicine 2017 5 881–890. (https://doi.org/10.1016/ Gallagher CJ, Hyppönen E, Llewellyn DJ, Stoecklin E, Dierkes J,
S2213-2600(17)30306-5) Kies AK, et al. Vitamin D: do we get enough? A discussion between
69 Bi WG, Nuyt AM, Weiler H, Leduc L, Santamaria C & Wei SQ. vitamin D experts in order to make a step towards the harmonisation
Association between vitamin D supplementation during pregnancy of dietary reference intakes for vitamin D across Europe. Osteoporosis
and offspring growth, morbidity, and mortality: a systematic review International 2013 24 1567–1577. (https://doi.org/10.1007/s00198-
and meta-analysis. JAMA Pediatrics 2018 172 635–645. (https://doi. 012-2231-3)
org/10.1001/jamapediatrics.2018.0302) 83 Pilz S, Trummer C, Pandis M, Schwetz V, Aberer F, Grübler M,
70 Roth DE, Leung M, Mesfin E, Qamar H, Watterworth J & Papp E. Verheyen N, Tomaschitz A & März W. Vitamin D: current guidelines
Vitamin D supplementation during pregnancy: state of the evidence and future outlook. Anticancer Research 2018 38 1145–1151. (https://
from a systematic review of randomised trials. BMJ 2017 359 j5237. doi.org/10.21873/anticanres.12333)
(https://doi.org/10.1136/bmj.j5237) 84 Cashman KD. Vitamin D requirements for the future-lessons learned
71 Putzu A, Belletti A, Cassina T, Clivio S, Monti G, Zangrillo A & and charting a path forward. Nutrients 2018 10 533. (https://doi.
Landoni G. Vitamin D and outcomes in adult critically ill patients. org/10.3390/nu10050533)
A systematic review and meta-analysis of randomized trials. Journal 85 Cashman KD, Ritz C, Kiely M & Odin Collaborators. Improved
of Critical Care 2017 38 109–114. (https://doi.org/10.1016/j. dietary guidelines for vitamin D: application of individual
jcrc.2016.10.029) participant data (IPD)-level meta-regression analyses. Nutrients 2017
72 Bjelakovic G, Gluud LL, Nikolova D, Whitfield K, Wetterslev J, 9 469. (https://doi.org/10.3390/nu9050469)
Simonetti RG, Bjelakovic M & Gluud C. Vitamin D supplementation 86 Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK,
for prevention of mortality in adults. Cochrane Database of Systematic Durazo-Arvizu RA, Gallagher JC, Gallo RL, Jones G, et al. The 2011
Reviews 2014 1 CD007470. (https://doi.org/10.1002/14651858. report on dietary reference intakes for calcium and vitamin D from
CD007470.pub3) the Institute of Medicine: what clinicians need to know. Journal of
73 McDonnell SL, Baggerly CA, French CB, Baggerly LL, Garland CF, Clinical Endocrinology and Metabolism 2011 96 53–58. (https://doi.
Gorham ED, Hollis BW, Trump DL & Lappe JM. Breast cancer risk org/10.1210/jc.2010-2704)
markedly lower with serum 25-hydroxyvitamin D concentrations 87 Institute of Medicine (US). Committee to review dietary reference
≥60 vs <20 ng/mL (150 vs 50 nmol/L): pooled analysis of two intakes for vitamin D and calcium. In Dietary Reference Intakes for
randomized trials and a prospective cohort. PLoS ONE 2018 13 Calcium and Vitamin D. Eds AC Ross, CL Taylor, AL Yaktine & HB Del
e0199265. (https://doi.org/10.1371/journal.pone.0199265) Valle. Washington DC, USA: National Academies Press, 2011.
74 McDonnell SL, Baggerly C, French CB, Baggerly LL, Garland CF, 88 EFSA NDA Panel (EFSA Panel on Dietetic Products, Nutrition and
Gorham ED, Lappe JM & Heaney RP. Serum 25-hydroxyvitamin D Allergies). Scientific opinion on dietary reference values for vitamin
concentrations ≥40 ng/mL are associated with >65% lower cancer D. EFSA Journal 2016 14 4547.
risk: pooled analysis of randomized trial and prospective cohort 89 Nordic Council of Ministers. Nordic Nutrition Recommendation 2012.
study. PLoS ONE 2016 11 e0152441. (https://doi.org/10.1371/journal. Integrating Nutrition and Physical Activity. Copenhagen, Denmark:
pone.0152441) Nordic Council of Ministers, 2014.
75 Grant WB & Boucher BJ. Randomized controlled trials of vitamin 90 German Nutrition Society. New reference values for vitamin D.
D and cancer incidence: a modeling study. PLoS ONE 2017 12 Annals of Nutrition and Metabolism 2012 60 241–246. (https://doi.
e0176448. (https://doi.org/10.1371/journal.pone.0176448) org/10.1159/000337547)
76 Pilz S, Dobnig H, Winklhofer-Roob B, Riedmüller G, Fischer JE, 91 Scientific Advisory Committee on Nutrition. Report on vitamin D
Seelhorst U, Wellnitz B, Boehm BO & März W. Low serum levels and health. London, UK: SACN & Public Health England, 2016.
of 25-hydroxyvitamin D predict fatal cancer in patients referred to (available at: https://www.gov.uk/government/groups/scientific-
coronary angiography. Cancer Epidemiology, Biomarkers and Prevention advisory-committee-on-nutrition)
2008 17 1228–1233. (https://doi.org/10.1158/1055-9965.EPI-08- 92 Allen L, de Benoist B, Dary O & Hurrell R. Guidelines on Food
0002) Fortification with Micronutrients. Geneva, Switzerland: WHO/Food and
77 Giovannucci E, Liu Y, Rimm EB, Hollis BW, Fuchs CS, Stampfer MJ & Agriculture Organization of the United Nations, 2006. (available at:
Willett WC. Prospective study of predictors of vitamin D status and http://www.who.int/iris/handle/10665/43412)
cancer incidence and mortality in men. Journal of the National Cancer 93 Cashman KD, Dowling KG, Škrabáková Z, Gonzalez-Gross M,
Institute 2006 98 451–459. (https://doi.org/10.1093/jnci/djj101) Valtueña J, De Henauw S, Moreno L, Damsgaard CT, Michaelsen KF,
78 Manson JE, Cook NR, Lee IM, Christen W, Bassuk SS, Mora S, Mølgaard C, et al. Vitamin D deficiency in Europe: pandemic?
Gibson H, Gordon D, Copeland T, D’Agostino D, et al. Vitamin D American Journal of Clinical Nutrition 2016 103 1033–1044. (https://
supplements and prevention of cancer and cardiovascular disease. doi.org/10.3945/ajcn.115.120873)
New England Journal of Medicine 2019 380 33–44. doi:10.1056/ 94 van Schoor N & Lips P. Global overview of vitamin D status.
NEJMoa1809944. Endocrinology and Metabolism Clinics of North America 2017 46
79 Bouillon R. Comparative analysis of nutritional guidelines for 845–870. (https://doi.org/10.1016/j.ecl.2017.07.002)
vitamin D. Nature Reviews Endocrinology 2017 13 466–479. (https:// 95 Schleicher RL, Sternberg MR, Lacher DA, Sempos CT, Looker AC,
doi.org/10.1038/nrendo.2017.31) Durazo-Arvizu RA, Yetley EA, Chaudhary-Webb M, Maw KL,
80 Pilz S, März W, Cashman KD, Kiely ME, Whiting SJ, Holick MF, Pfeiffer CM, et al. The vitamin D status of the US population
Grant WB, Pludowski P, Hiligsmann M, Trummer C, et al. Rationale from 1988 to 2010 using standardized serum concentrations of
and plan for vitamin D food fortification: a review and guidance. 25-hydroxyvitamin D shows recent modest increases. American
Frontiers in Endocrinology 2018 9 373. (https://doi.org/10.3389/ Journal of Clinical Nutrition 2016 104 454–461. (https://doi.
fendo.2018.00373) org/10.3945/ajcn.115.127985)
81 US Preventive Services Task Force, Grossman DC, Curry SJ, 96 Schleicher RL, Sternberg MR, Looker AC, Yetley EA, Lacher DA,
Owens DK, Barry MJ, Caughey AB, Davidson KW, Doubeni CA, Sempos CT, Taylor CL, Durazo-Arvizu RA, Maw KL, Chaudhary-

Webb M, et al. National estimates of serum total 25-hydroxyvitamin European Society of Endocrinology Clinical Guideline: treatment
D and metabolite concentrations measured by liquid of chronic hypoparathyroidism in adults. European Journal of
chromatography-tandem mass spectrometry in the US population Endocrinology 2015 173 G1–G20. (https://doi.org/10.1530/EJE-15-
during 2007–2010. Journal of Nutrition 2016 146 1051–1061. (https:// 0628)
doi.org/10.3945/jn.115.227728) 110 Brandi ML, Bilezikian JP, Shoback D, Bouillon R, Clarke BL,
97 Manios Y, Moschonis G, Lambrinou CP, Tsoutsoulopoulou K, Thakker RV, Khan AA & Potts JT Jr. Management of
Binou P, Karachaliou A, Breidenassel C, Gonzalez-Gross M, Kiely M hypoparathyroidism: summary statement and guidelines. Journal of
& Cashman KD. A systematic review of vitamin D status in southern Clinical Endocrinology and Metabolism 2016 101 2273–2283. (https://
European countries. European Journal of Nutrition 2018 57 2001–2036. doi.org/10.1210/jc.2015-3907)
(https://doi.org/10.1007/s00394-017-1564-2) 111 Avenell A, Bolland MJ & Grey A. 25-Hydroxyvitamin D – should labs
98 Spiro A & Buttriss JL. Vitamin D: an overview of vitamin D status be measuring it? Annals of Clinical Biochemistry 2018 [epub]. (https://
and intake in Europe. Nutrition Bulletin 2014 39 322–350. (https:// doi.org/10.1177/0004563218796858)
doi.org/10.1111/nbu.12108) 112 Rockwell M, Kraak V, Hulver M & Epling J. Clinical management of
99 Jääskeläinen T, Itkonen ST, Lundqvist A, Erkkola M, Koskela T, low vitamin D: a scoping review of physicians’ practices. Nutrients
Lakkala K, Dowling KG, Hull GL, Kröger H, Karppinen J, et al. 2018 10 493. (https://doi.org/10.3390/nu10040493)
The positive impact of general vitamin D food fortification 113 Basatemur E, Hunter R, Horsfall L, Sutcliffe A & Rait G. Costs of
policy on vitamin D status in a representative adult Finnish vitamin D testing and prescribing among children in primary care.
population: evidence from an 11-y follow-up based on standardized European Journal of Pediatrics 2017 176 1405–1409. (https://doi.
25-hydroxyvitamin D data. American Journal of Clinical Nutrition 2017 org/10.1007/s00431-017-2986-9)
105 1512–1520. (https://doi.org/10.3945/ajcn.116.151415) 114 Woodford HJ, Barrett S & Pattman S. Vitamin D: too much testing
100 Calvo MS & Whiting SJ. Survey of current vitamin D food and treating? Clinical Medicine 2018 18 196–200. (https://doi.
fortification practices in the United States and Canada. Journal of org/10.7861/clinmedicine.18-3-196)
Steroid Biochemistry and Molecular Biology 2013 136 211–213. (https:// 115 Binkley N, Dawson-Hughes B, Durazo-Arvizu R, Thamm M,
doi.org/10.1016/j.jsbmb.2012.09.034) Tian L, Merkel JM, Jones JC, Carter GD & Sempos CT. Vitamin D
101 Wilson LR, Tripkovic L, Hart KH & Lanham-New SA. Vitamin D measurement standardization: the way out of the chaos. Journal of
deficiency as a public health issue: using vitamin D2 or vitamin D3 Steroid Biochemistry and Molecular Biology 2017 173 117–121. (https://
in future fortification strategies. Proceedings of the Nutrition Society doi.org/10.1016/j.jsbmb.2016.12.002)
2017 76 392–399. (https://doi.org/10.1017/S0029665117000349) 116 Jorde R, Sneve M, Hutchinson M, Emaus N, Figenschau Y &
102 Moulas AN & Vaiou M. Vitamin D fortification of foods and Grimnes G. Tracking of serum 25-hydroxyvitamin D levels during
prospective health outcomes. Journal of Biotechnology 2018 285 14 years in a population-based study and during 12 months in
91–101. (https://doi.org/10.1016/j.jbiotec.2018.08.010) an intervention study. American Journal of Epidemiology 2010 171
103 Itkonen ST, Erkkola M & Lamberg-Allardt CJE. Vitamin D 903–908. (https://doi.org/10.1093/aje/kwq005)
fortification of fluid milk products and their contribution to vitamin 117 Pilz S, Hahn A, Schön C, Wilhelm M & Obeid R. Effect of two
D intake and vitamin D status in observational studies – a review. different multimicronutrient supplements on vitamin D status in
Nutrients 2018 10 E1054. (https://doi.org/10.3390/nu10081054) women of childbearing age: a randomized trial. Nutrients 2017 9 30.
104 Compston J, Cooper A, Cooper C, Gittoes N, Gregson C, Harvey N, (https://doi.org/10.3390/nu9010030)
Hope S, Kanis JA, McCloskey EV, Poole KES, et al. UK clinical 118 Lehmann U, Riedel A, Hirche F, Brandsch C, Girndt M, Ulrich C,
guideline for the prevention and treatment of osteoporosis. Archives Seibert E, Henning C, Glomb MA, Dierkes J, et al. Vitamin D3
of Osteoporosis 2017 12 43. (https://doi.org/10.1007/s11657-017- supplementation: response and predictors of vitamin D3 metabolites
0324-5) – a randomized controlled trial. Clinical Nutrition 2016 35 351–358.
105 Kanis JA, McCloskey EV, Johansson H, Cooper C, Rizzoli R, (https://doi.org/10.1016/j.clnu.2015.04.021)
Reginster JY, on behalf of the Scientific Advisory Board of the 119 Gallagher JC, Sai A, Templin T 2nd & Smith L. Dose response
European Society for Clinical and Economic Aspects of Osteoporosis to vitamin D supplementation in postmenopausal women: a
and Osteoarthritis (ESCEO) & The Committee of Scientific Advisors randomized trial. Annals of Internal Medicine 2012 156 425–437.
of the International Osteoporosis Foundation (IOF). European (https://doi.org/10.7326/0003-4819-156-6-201203200-00005)
guidance for the diagnosis and management of osteoporosis in 120 O'Callaghan KM, Hennessy Á, Hull GLJ, Healy K, Ritz C, Kenny LC,
postmenopausal women. Osteoporosis International 2013 24 23–57. Cashman KD & Kiely ME. Estimation of the maternal vitamin D
(https://doi.org/10.1007/s00198-012-2074-y) intake that maintains circulating 25-hydroxyvitamin D in late
106 Dawson-Hughes B, Mithal A, Bonjour JP, Boonen S, Burckhardt P, gestation at a concentration sufficient to keep umbilical cord sera
Fuleihan GE, Josse RG, Lips P, Morales-Torres J & Yoshimura N. ≥25–30 nmol/L: a dose-response, double-blind, randomized placebo-
IOF position statement: vitamin D recommendations for older controlled trial in pregnant women at northern latitude. American
adults. Osteoporosis International 2010 21 1151–1154. (https://doi. Journal of Clinical Nutrition 2018 108 77–91. (https://doi.org/10.1093/
org/10.1007/s00198-010-1285-3) ajcn/nqy064)
107 Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD 121 Bacon CJ, Gamble GD, Horne AM, Scott MA & Reid IR. High-
Update Work Group. KDIGO 2017 Clinical Practice Guideline Update dose oral vitamin D3 supplementation in the elderly. Osteoporosis
for the diagnosis, evaluation, prevention, and treatment of chronic International 2009 20 1407–1415. (https://doi.org/10.1007/s00198-
kidney disease–mineral and bone disorder (CKD-MBD). Kidney 008-0814-9)
International Supplements 2017 7 1–59. (https://doi.org/10.1016/j. 122 Jorde R & Grimnes G. Serum cholecalciferol may be a better marker
kisu.2017.04.001) of vitamin D status than 25-hydroxyvitamin D. Medical Hypotheses
108 Bilezikian JP, Brandi ML, Eastell R, Silverberg SJ, Udelsman R, 2018 111 61–65. (https://doi.org/10.1016/j.mehy.2017.12.017)
Marcocci C & Potts JT Jr. Guidelines for the management of 123 Ish-Shalom S, Segal E, Salganik T, Raz B, Bromberg IL & Vieth R.
asymptomatic primary hyperparathyroidism: summary statement Comparison of daily, weekly, and monthly vitamin D3 in ethanol
from the fourth International Workshop. Journal of Clinical dosing protocols for two months in elderly hip fracture patients.
Endocrinology and Metabolism 2014 99 3561–3569. (https://doi. Journal of Clinical Endocrinology and Metabolism 2008 93 3430–3435.
org/10.1210/jc.2014-1413) (https://doi.org/10.1210/jc.2008-0241)
109 Bollerslev J, Rejnmark L, Marcocci C, Shoback DM, Sitges-Serra A, 124 Sanders KM, Stuart AL, Williamson EJ, Simpson JA, Kotowicz MA,
van Biesen W, Dekkers OM & European Society of Endocrinology. Young D & Nicholson GC. Annual high-dose oral vitamin D and falls

and fractures in older women: a randomized controlled trial. JAMA controlled pilot study. International Journal of Biological and Medical
2010 303 1815–1822. (https://doi.org/10.1001/jama.2010.594) Science 2014 10 21–24.
125 Bischoff-Ferrari HA, Dawson-Hughes B, Orav EJ, Staehelin HB, 139 Quesada-Gomez JM & Bouillon R. Is calcifediol better than
Meyer OW, Theiler R, Dick W, Willett WC & Egli A. Monthly high- cholecalciferol for vitamin D supplementation? Osteoporosis
dose vitamin D treatment for the prevention of functional decline: a International 2018 29 1697–1711. (https://doi.org/10.1007/s00198-
randomized clinical trial. JAMA Internal Medicine 2016 176 175–183. 018-4520-y)
(https://doi.org/10.1001/jamainternmed.2015.7148) 140 Hayes A & Cashman KD. Food-based solutions for vitamin D
126 Smith H, Anderson F, Raphael H, Maslin P, Crozier S & Cooper C. deficiency: putting policy into practice and the key role for research.
Effect of annual intramuscular vitamin D on fracture risk in elderly Proceedings of the Nutrition Society 2017 76 54–63. (https://doi.
men and women – a population-based, randomized, double-blind, org/10.1017/S0029665116000756)
placebo-controlled trial. Rheumatology 2007 46 1852–1857. (https:// 141 Tripkovic L, Lambert H, Hart K, Smith CP, Bucca G, Penson S,
doi.org/10.1093/rheumatology/kem240) Chope G, Hyppönen E, Berry J, Vieth R, et al. Comparison of
127 European Food Safety Authority. Scientific opinion on the tolerable vitamin D2 and vitamin D3 supplementation in raising serum
upper intake level of vitamin D. EFSA Journal 2012 10 2813. 25-hydroxyvitamin D status: a systematic review and meta-analysis.
128 Khaw KT, Stewart AW, Waayer D, Lawes CMM, Toop L, American Journal of Clinical Nutrition 2012 95 1357–1364. (https://
Camargo CA Jr & Scragg R. Effect of monthly high-dose vitamin D doi.org/10.3945/ajcn.111.031070)
supplementation on falls and non-vertebral fractures: secondary and 142 Chun RF, Hernandez I, Pereira R, Swinkles L, Huijs T, Zhou R,
post-hoc outcomes from the randomised, double-blind, placebo- Liu NQ, Shieh A, Guemes M, Mallya SM, et al. Differential responses
controlled ViDA trial. Lancet Diabetes and Endocrinology 2017 5 to vitamin D2 and vitamin D3 are associated With variations in free
438–447. (https://doi.org/10.1016/S2213-8587(17)30103-1) 25-hydroxyvitamin D. Endocrinology 2016 157 3420–3430. (https://
129 Trivedi DP, Doll R & Khaw KT. Effect of four monthly oral vitamin doi.org/10.1210/en.2016-1139)
D3 (cholecalciferol) supplementation on fractures and mortality 143 Shieh A, Chun RF, Ma C, Witzel S, Meyer B, Rafison B, Swinkels L,
in men and women living in the community: randomised double Huijs T, Pepkowitz S, Holmquist B, et al. Effects of high-dose vitamin
blind controlled trial. BMJ 2003 326 469. (https://doi.org/10.1136/ D2 Versus D3 on total and free 25-hydroxyvitamin D and markers of
bmj.326.7387.469) calcium balance. Journal of Clinical Endocrinology and Metabolism 2016
130 Smith LM, Gallagher JC & Suiter C. Medium doses of daily vitamin 101 3070–3078. (https://doi.org/10.1210/jc.2016-1871)
D decrease falls and higher doses of daily vitamin D3 increase 144 Bouillon R, Verlinden L & Verstuyf A. Is vitamin D2 really
falls: a randomized clinical trial. Journal of Steroid Biochemistry and bioequivalent to vitamin D3? Endocrinology 2016 157 3384–3387.
Molecular Biology 2017 173 317–322. (https://doi.org/10.1016/j. (https://doi.org/10.1210/en.2016-1528)
jsbmb.2017.03.015) 145 Jager N, Schöpe J, Wagenpfeil S, Bocionek P, Saternus R, Vogt T &
131 Marcinowska-Suchowierska E, Kupisz-Urbańska M, Łukaszkiewicz J, Reichrath J. The impact of UV-dose, body surface area exposed and
Płudowski P & Jones G Vitamin D toxicity – a clinical perspective. other factors on cutaneous vitamin D synthesis measured as serum
Frontiers in Endocrinology 2018 9 550. (https://doi.org/10.3389/ 25(OH)D concentration: systematic review and meta-analysis.
fendo.2018.00550) Anticancer Research 2018 38 1165–1171. (https://doi.org/10.21873/
132 Schöttker B, Jorde R, Peasey A, Thorand B, Jansen EH, Groot Ld, anticanres.12336)
Streppel M, Gardiner J, Ordóñez-Mena JM, Perna L, et al. Vitamin 146 Seckmeyer G, Schrempf M, Wieczorek A, Riechelmann S,
D and mortality: meta-analysis of individual participant data from Graw K, Seckmeyer S & Zankl M. A novel method to calculate
a large consortium of cohort studies from Europe and the United solar UV exposure relevant to vitamin D production in humans.
States. BMJ 2014 348 g3656. (https://doi.org/10.1136/bmj.g3656) Photochemistry and Photobiology 2013 89 974–983. (https://doi.
133 Garland CF, Kim JJ, Mohr SB, Gorham ED, Grant WB, org/10.1111/php.12074)
Giovannucci EL, Baggerly L, Hofflich H, Ramsdell JW, Zeng K, 147 Lehmann U, Gjessing HR, Hirche F, Mueller-Belecke A,
et al. Meta-analysis of all-cause mortality according to serum Gudbrandsen OA, Ueland PM, Mellgren G, Lauritzen L, Lindqvist H,
25-hydroxyvitamin D. American Journal of Public Health 2014 104 Hansen AL, et al. Efficacy of fish intake on vitamin D status: a
e43–e50. (https://doi.org/10.2105/AJPH.2014.302034) meta-analysis of randomized controlled trials. American Journal
134 Whyte MP, Haddad JG Jr, Walters DD & Stamp TC. Vitamin D of Clinical Nutrition 2015 102 837–847. (https://doi.org/10.3945/
bioavailability: serum 25-hydroxyvitamin D levels in man after ajcn.114.105395)
oral, subcutaneous, intramuscular, and intravenous vitamin D 148 Himbert C, Ose J, Delphan M & Ulrich CM. A systematic review of
administration. Journal of Clinical Endocrinology and Metabolism 1979 the interrelation between diet- and surgery-induced weight loss and
48 906–911. (https://doi.org/10.1210/jcem-48-6-906) vitamin D status. Nutrition Research 2017 38 13–26. (https://doi.
135 Wylon K, Drozdenko G, Krannich A, Heine G, Dölle S & Worm M. org/10.1016/j.nutres.2016.12.004)
Pharmacokinetic evaluation of a single intramuscular high dose 149 Vimaleswaran KS, Berry DJ, Lu C, Tikkanen E, Pilz S, Hiraki LT,
versus an oral long-term supplementation of cholecalciferol. Cooper JD, Dastani Z, Li R, Houston DK, et al. Causal relationship
PLoS ONE 2017 12 e0169620. (https://doi.org/10.1371/journal. between obesity and vitamin D status: bi-directional Mendelian
pone.0169620) randomization analysis of multiple cohorts. PLoS Medicine 2013 10
136 Gupta N, Farooqui KJ, Batra CM, Marwaha RK & Mithal A. e1001383. (https://doi.org/10.1371/journal.pmed.1001383)
Effect of oral versus intramuscular vitamin D replacement in 150 Lappe JM & Heaney RP. Why randomized controlled trials of calcium
apparently healthy adults with vitamin D deficiency. Indian Journal and vitamin D sometimes fail. Dermato-Endocrinology 2012 4 95–100.
of Endocrinology and Metabolism 2017 21 131–136. (https://doi. (https://doi.org/10.4161/derm.19833)
org/10.4103/2230-8210.196007) 151 Heaney RP. Vitamin D – baseline status and effective dose. New
137 Bubshait DA, Al-Dakheel DA & Alanii FM. Topical vitamin D3: a England Journal of Medicine 2012 367 77–78. (https://doi.org/10.1056/
randomized controlled trial (RCT). Clinical Nutrition ESPEN 2018 27 NEJMe1206858)
16–19. (https://doi.org/10.1016/j.clnesp.2018.05.009) 152 Heaney RP. Nutrients, endpoints, and the problem of proof.
138 Sadat-Ali M, Bubshait DA, Al-Turki HA, Al-Dakheel DA & Journal of Nutrition 2008 138 1591–1595. (https://doi.org/10.1093/
Al-Olayani WS. Topical delivery of vitamin d3: a randomized jn/138.9.1591)

153 Heaney RP. The nutrient problem. Nutrition Reviews 2012 70 exceeding 1000 or 4000 international units daily, 1999–2014. JAMA
165–169. (https://doi.org/10.1111/j.1753-4887.2011.00469.x) 2017 317 2448–2450. (https://doi.org/10.1001/jama.2017.4392)
154 Heaney RP. Guidelines for optimizing design and analysis of clinical 169 Dwyer JT, Coates PM & Smith MJ. Dietary supplements: regulatory
studies of nutrient effects. Nutrition Reviews 2014 72 48–54. (https:// challenges and research resources. Nutrients 2018 10 41. (https://doi.
doi.org/10.1111/nure.12090) org/10.3390/nu10010041)
155 Hébert JR, Frongillo EA, Adams SA, Turner-McGrievy GM, Hurley TG, 170 Darling AL, Blackbourn DJ, Ahmadi KR & Lanham-New SA. Vitamin
Miller DR & Ockene IS. Perspective: randomized controlled trials are D supplement use and associated demographic, dietary and lifestyle
not a panacea for diet-related research. Advances in Nutrition 2016 7 factors in 8024 South Asians aged 40–69 years: analysis of the UK
423–432. (https://doi.org/10.3945/an.115.011023) biobank cohort. Public Health Nutrition 2018 21 2678–2688. (https://
156 Ioannidis JPA The challenge of reforming nutritional epidemiologic doi.org/10.1017/S1368980018001404)
research. JAMA 2018 320 969–970. (https://doi.org/10.1001/ 171 Weernink MG, van Wijk RM, Groothuis-Oudshoorn CG,
jama.2018.11025) Lanting CI, Grant CC, van Vlimmeren LA & Boere-Boonekamp MM.
157 Scragg R. Limitations of vitamin D supplementation trials: why Insufficient vitamin D supplement use during pregnancy and early
observational studies will continue to help determine the role of childhood: a risk factor for positional skull deformation. Maternal
vitamin D in health. Journal of Steroid Biochemistry and Molecular and Child Nutrition 2016 12 177–188. (https://doi.org/10.1111/
Biology 2018 177 6–9. (https://doi.org/10.1016/j.jsbmb.2017.06.006) mcn.12153)
158 Pilz S, Rutters F & Dekker JM. Disease prevention: vitamin 172 Looman M, van den Berg C, Geelen A, Samlal RAK, Heijligenberg R,
D trials. Science 2012 338 883. (https://doi.org/10.1126/ Klein Gunnewiek JMT, Balvers MGJ, Leendertz-Eggen CL,
science.338.6109.883-c) Wijnberger LDE, Feskens EJM, et al. Supplement use and
159 Scragg R. Emerging evidence of thresholds for beneficial effects from dietary sources of folate, vitamin D, and n-3 fatty acids during
vitamin D supplementation. Nutrients 2018 10 561. (https://doi. preconception: the GLIMP2 study. Nutrients 2018 10 962. (https://
org/10.3390/nu10050561) doi.org/10.3390/nu10080962)
160 McNeil JJ, Nelson MR, Woods RL, Lockery JE, Wolfe R, Reid CM, 173 Jun S, Cowan AE, Tooze JA, Gahche JJ, Dwyer JT, Eicher-Miller HA,
Kirpach B, Shah RC, Ives DG, Storey E, et al. Effect of aspirin on Bhadra A, Guenther PM, Potischman N, Dodd KW, et al. Dietary
all-cause mortality in the healthy elderly. New England Journal of supplement use among U.S. Children by family income, food
Medicine 2018 379 1519–1528. doi:10.1056/NEJMoa1803955. security level, and nutrition assistance program participation status
161 Kupferschmidt K. Uncertain verdict as vitamin D goes on in 2011–2014. Nutrients 2018 10 1212. (https://doi.org/10.3390/
trial. Science 2012 337 1476–1478. (https://doi.org/10.1126/ nu10091212)
science.337.6101.1476) 174 Creo AL, Thacher TD, Pettifor JM, Strand MA & Fischer PR.
162 Trajanoska K, Morris JA, Oei L, Zheng HF, Evans DM, Kiel DP, Nutritional rickets around the world: an update. Paediatrics and
Ohlsson C, Richards JB & Rivadeneira F. GEFOS/GENOMOS International Child Health 2017 37 84–98. (https://doi.org/10.1080/20
consortium and the 23andMe research team. Assessment of the 469047.2016.1248170)
genetic and clinical determinants of fracture risk: genome wide 175 Creo AL, Tebben PJ, Fischer PR, Thacher TD & Pittock ST. Cardiac
association and Mendelian randomisation study. BMJ 2018 362 arrest in a vitamin D-deficient infant. Global Pediatric Health
k3225. (https://doi.org/10.1136/bmj.k3225) 2018 5 2333794X18765064. (https://doi.org/10.1177/23337
163 Afzal S, Brøndum-Jacobsen P, Bojesen SE & Nordestgaard BG. 94X18765064)
Genetically low vitamin D concentrations and increased mortality: 176 Chehade H, Girardin E, Rosato L, Cachat F, Cotting J & Perez MH.
mendelian randomisation analysis in three large cohorts. BMJ 2014 Acute life-threatening presentation of vitamin D deficiency rickets.
349 g6330. (https://doi.org/10.1136/bmj.g6330) Journal of Clinical Endocrinology and Metabolism 2011 96 2681–2683.
164 Jassil NK, Sharma A, Bikle D & Wang X. Vitamin D binding protein and (https://doi.org/10.1210/jc.2011-1112)
25-hydroxyvitamin D levels: emerging clinical applications. Endocrine 177 Uday S & Högler W. Prevention of rickets and osteomalacia in the
Practice 2017 23 605–613. (https://doi.org/10.4158/EP161604.RA) UK: political action overdue. Archives of Disease in Childhood 2018
165 Kroll MH, Bi C, Garber CC, Kaufman HW, Liu D, Caston- 103 901–906. (https://doi.org/10.1136/archdischild-2018-314826)
Balderrama A, Zhang K, Clarke N, Xie M, Reitz RE, et al. Temporal 178 Zittermann A, Ernst JB, Prokop S, Fuchs U, Dreier J, Kuhn J,
relationship between vitamin D status and parathyroid hormone Knabbe C, Birschmann I, Schulz U, Berthold HK, et al. Effect of
in the United States. PLoS ONE 2015 10 e0118108. (https://doi. vitamin D on all-cause mortality in heart failure (EVITA): a 3-year
org/10.1371/journal.pone.0118108) randomized clinical trial with 4000 IU vitamin D daily. European
166 Sempos CT, Heijboer AC, Bikle DD, Bollerslev J, Bouillon R, Heart Journal 2017 38 2279–2286. (https://doi.org/10.1093/eurheartj/
Brannon PM, DeLuca HF, Jones G, Munns CF, Bilezikian JP, et al. ehx235)
Vitamin D assays and the definition of hypovitaminosis D: results 179 Bolland MJ, Grey A & Avenell A. Assessment of research waste part 2:
from the first International Conference on Controversies in Vitamin wrong study populations – an exemplar of baseline vitamin D status
D. British Journal of Clinical Pharmacology 2018 84 2194–2207. of participants in trials of vitamin D supplementation. BMC Medical
(https://doi.org/10.1111/bcp.13652) Research Methodology 2018 18 101. (https://doi.org/10.1186/s12874-
167 Zittermann A, Prokop S, Gummert JF & Börgermann J. 018-0555-1)
Safety issues of vitamin D supplementation. Anti-Cancer 180 EFSA NDA Panel, Turck D, Bresson J-L, Burlingame B, Dean T,
Agents in Medicinal Chemistry 2013 13 4–10. (https://doi. Fairweather‐Tait S, Heinonen M, Hirsch-Ernst KI, Mangelsdorf I,
org/10.2174/187152013804487290) McArdle HJ, et al. Update of the tolerable upper intake level for
168 Rooney MR, Harnack L, Michos ED, Ogilvie RP, Sempos CT & vitamin D for infants. EFSA Journal 2018 16 e05365. (https://doi.
Lutsey PL. Trends in use of high-dose vitamin D supplements org/10.2903/j.efsa.2018.5365)

Received in final form 18 December 2018

Accepted 16 January 2019
Accepted Preprint published online 16 January 2019

Mastery in Coaching A Complete Psychological Toolkit For Advanced Coaching (Jonathan Passmore) (Z-Lib.-6
100% (1)
Mastery in Coaching A Complete Psychological Toolkit For Advanced Coaching (Jonathan Passmore) (Z-Lib.-6
345 pages
CHAPTER 73 Investment in Education-Inputs and Incentives 4883
No ratings yet
CHAPTER 73 Investment in Education-Inputs and Incentives 4883
1 page
NGT
100% (4)
NGT
53 pages
Bronchial Asthma Case Write Up
No ratings yet
Bronchial Asthma Case Write Up
5 pages
Surakshit Matritva Aashwasan (Suman) : An Initiative For Zero Preventable Maternal and Newborn Deaths
100% (1)
Surakshit Matritva Aashwasan (Suman) : An Initiative For Zero Preventable Maternal and Newborn Deaths
8 pages
CIPPC Body of Knowledge
No ratings yet
CIPPC Body of Knowledge
7 pages
EMG Study Review
No ratings yet
EMG Study Review
4 pages
Kriya Yoga
100% (1)
Kriya Yoga
24 pages
Skeletal and Extraskeletal Actions of Vitamin D: Current Evidence and Outstanding Questions
No ratings yet
Skeletal and Extraskeletal Actions of Vitamin D: Current Evidence and Outstanding Questions
43 pages
APA Manual - Extract
No ratings yet
APA Manual - Extract
15 pages
Dental Elevators
No ratings yet
Dental Elevators
28 pages
Plasma Enzyme Diagnosis
No ratings yet
Plasma Enzyme Diagnosis
30 pages
Vitamin D
No ratings yet
Vitamin D
72 pages
Vitamin D and Multiple Sclerosis A Comprehensive
No ratings yet
Vitamin D and Multiple Sclerosis A Comprehensive
27 pages
504: Ty Mawr Farm, Newport. Building Survey Record. APAC. LTD
No ratings yet
504: Ty Mawr Farm, Newport. Building Survey Record. APAC. LTD
35 pages
Kobayashi2015 PDF
No ratings yet
Kobayashi2015 PDF
10 pages
Skeletal and Extraskeletal Actions of Vitamin D - Current Evidence and Outstanding Questions - PMC
No ratings yet
Skeletal and Extraskeletal Actions of Vitamin D - Current Evidence and Outstanding Questions - PMC
76 pages
Vitamin D: Modulator of The Immune System
No ratings yet
Vitamin D: Modulator of The Immune System
15 pages
Vitamin D From Photosynthesis
No ratings yet
Vitamin D From Photosynthesis
27 pages
Plasmodium Malaria
No ratings yet
Plasmodium Malaria
21 pages
Nutrients 12 01471 2
No ratings yet
Nutrients 12 01471 2
16 pages
Review Article: The Pleiotropic Effect of Vitamin D
No ratings yet
Review Article: The Pleiotropic Effect of Vitamin D
7 pages
Vitamin D - Disease and Drug Interactions
No ratings yet
Vitamin D - Disease and Drug Interactions
20 pages
Vitamin D and The Athlete: Current Perspectives and New Challenges
No ratings yet
Vitamin D and The Athlete: Current Perspectives and New Challenges
14 pages
Povidone Iodine Based Antimicrobial Foam Soap Scrub Formulation and Manufacturing Process
No ratings yet
Povidone Iodine Based Antimicrobial Foam Soap Scrub Formulation and Manufacturing Process
7 pages
Pharma - CCR
No ratings yet
Pharma - CCR
24 pages
Articullo Vitamina D Osteop, Obes y Diab
No ratings yet
Articullo Vitamina D Osteop, Obes y Diab
24 pages
Vitamin D Deficiency and Its Repletion A Review 2167 7921.1000105
No ratings yet
Vitamin D Deficiency and Its Repletion A Review 2167 7921.1000105
11 pages
Nutrients 15 02290
No ratings yet
Nutrients 15 02290
4 pages
Zitterman - Vitamin D in Preventive Medicine
No ratings yet
Zitterman - Vitamin D in Preventive Medicine
21 pages
Vitamin D
No ratings yet
Vitamin D
36 pages
670104915eec8pmi Saincidentinvelo4 05october2024
No ratings yet
670104915eec8pmi Saincidentinvelo4 05october2024
121 pages
Controversies in Vitamin D: Summary Statement From An International Conference
No ratings yet
Controversies in Vitamin D: Summary Statement From An International Conference
7 pages
Vitamin D Deficiency DR Ag Ko Ko SCS Endocrinology 29.8.2020
No ratings yet
Vitamin D Deficiency DR Ag Ko Ko SCS Endocrinology 29.8.2020
78 pages
Artículo - Assessment of Vitamin D Status - A Changing Landscape
No ratings yet
Artículo - Assessment of Vitamin D Status - A Changing Landscape
24 pages
Vitamin D in Health and Disease: Current Perspectives: Review Open Access
No ratings yet
Vitamin D in Health and Disease: Current Perspectives: Review Open Access
13 pages
Phri Ad-Hoc Data Entry Clerk Advert
No ratings yet
Phri Ad-Hoc Data Entry Clerk Advert
2 pages
Vitamin+D+Lecture 1
No ratings yet
Vitamin+D+Lecture 1
35 pages
Edoardo Zollo Bridging The Gap For Italians in London Through Psychotherapy
No ratings yet
Edoardo Zollo Bridging The Gap For Italians in London Through Psychotherapy
2 pages
Vitamina D y Fertilidad Femenina
No ratings yet
Vitamina D y Fertilidad Femenina
21 pages
Natural Vitamin D Content in Animal Products - Adv Nutr-2013-Schmid-453-62
No ratings yet
Natural Vitamin D Content in Animal Products - Adv Nutr-2013-Schmid-453-62
10 pages
JPNR - 2022 - S08 - 19
No ratings yet
JPNR - 2022 - S08 - 19
12 pages
Overview of Vitamin D
No ratings yet
Overview of Vitamin D
17 pages
Nutrients: The Potential Role of Vitamin D Enhanced Foods in Improving Vitamin D Status
No ratings yet
Nutrients: The Potential Role of Vitamin D Enhanced Foods in Improving Vitamin D Status
19 pages
Vitamin D Literature Review
100% (3)
Vitamin D Literature Review
8 pages
Ryan Park - Media Release - Minns Labor Government Halves Overdue Planned Surgery List - Thursday, 26 October 2023
No ratings yet
Ryan Park - Media Release - Minns Labor Government Halves Overdue Planned Surgery List - Thursday, 26 October 2023
2 pages
Refusal of Treatment Certificate Competent Person 071010
No ratings yet
Refusal of Treatment Certificate Competent Person 071010
2 pages
Vitamin D
No ratings yet
Vitamin D
9 pages
Vitamin D and Human Health: Molecular Sciences
No ratings yet
Vitamin D and Human Health: Molecular Sciences
6 pages
Vitamin D Calcium
No ratings yet
Vitamin D Calcium
6 pages
Overview of Vitamin D Uptodate2015
No ratings yet
Overview of Vitamin D Uptodate2015
5 pages
Fact Sheet Vitamin D Final
No ratings yet
Fact Sheet Vitamin D Final
3 pages
Vitamin D
No ratings yet
Vitamin D
6 pages
Biomedicines 11 01542 v3
No ratings yet
Biomedicines 11 01542 v3
26 pages
Vitamin D (Calcitriol)
100% (1)
Vitamin D (Calcitriol)
4 pages
Vitamin D: Fat-Soluble Vitamins & Micronutrients
No ratings yet
Vitamin D: Fat-Soluble Vitamins & Micronutrients
9 pages
Vitamin D: Vitamin D (Disambiguation) Ergocalciferol Cholecalciferol Vitamin D4 Vitamin D5
No ratings yet
Vitamin D: Vitamin D (Disambiguation) Ergocalciferol Cholecalciferol Vitamin D4 Vitamin D5
6 pages
Vitamin D For Postmenopausal Women
No ratings yet
Vitamin D For Postmenopausal Women
2 pages
Brochure - Active Member Summary of Benefits
No ratings yet
Brochure - Active Member Summary of Benefits
7 pages
English Insert Paper 1 2022
No ratings yet
English Insert Paper 1 2022
4 pages
Summary
No ratings yet
Summary
3 pages
Presentation 5
No ratings yet
Presentation 5
19 pages
Lesson 8 - Vitamin D and Health - The Missing Vitamin in Humans - pp.1-3
No ratings yet
Lesson 8 - Vitamin D and Health - The Missing Vitamin in Humans - pp.1-3
3 pages
CASE OF J.B. AND OTHERS v. MALTA
No ratings yet
CASE OF J.B. AND OTHERS v. MALTA
53 pages
Hypervitaminosis D or Vitamin D Toxicity: Volume 2, Issue 5, May 2024 ISSN (E)
No ratings yet
Hypervitaminosis D or Vitamin D Toxicity: Volume 2, Issue 5, May 2024 ISSN (E)
9 pages
Sources of Vitamin D
No ratings yet
Sources of Vitamin D
5 pages
2 Vitamin D Deficiency in Childhood Old Lessons and Current Challenges
No ratings yet
2 Vitamin D Deficiency in Childhood Old Lessons and Current Challenges
14 pages
Vitamin - D
No ratings yet
Vitamin - D
39 pages
Nutrients 16 00416
No ratings yet
Nutrients 16 00416
15 pages
Artwork Correction - Asafoetida Powder
No ratings yet
Artwork Correction - Asafoetida Powder
2 pages
Getein Product Introduction - 25-OH-VD
No ratings yet
Getein Product Introduction - 25-OH-VD
28 pages
Excli 21 967
No ratings yet
Excli 21 967
24 pages
Vitamin D: Continuing Education Activity
No ratings yet
Vitamin D: Continuing Education Activity
5 pages
Vitamin D - Health Professional Fact Sheet
No ratings yet
Vitamin D - Health Professional Fact Sheet
37 pages
Vitamin Basics 06 Vitamin-D
No ratings yet
Vitamin Basics 06 Vitamin-D
6 pages
The Role of Vitamin D in Health and Dise
No ratings yet
The Role of Vitamin D in Health and Dise
21 pages
5 Vitamin D and Cardiovascular Disease
No ratings yet
5 Vitamin D and Cardiovascular Disease
17 pages
Nair Maseeh 2012 Vitamin D The Sunshine Vitamin
No ratings yet
Nair Maseeh 2012 Vitamin D The Sunshine Vitamin
9 pages
Beneficios Vitamina D
No ratings yet
Beneficios Vitamina D
32 pages
Grade 7 Pre Technical Studies Schemes of Work Term 1 KLB Top Scholar 2025
No ratings yet
Grade 7 Pre Technical Studies Schemes of Work Term 1 KLB Top Scholar 2025
11 pages
Prospectus Part-A Ini-Cet July 2025 Session
No ratings yet
Prospectus Part-A Ini-Cet July 2025 Session
31 pages
Physiological Basis For Using Vitamin D To Improve
No ratings yet
Physiological Basis For Using Vitamin D To Improve
26 pages
Bouillon 2011
No ratings yet
Bouillon 2011
10 pages
A Review of Vitamin D and Its Precursors in Plants
No ratings yet
A Review of Vitamin D and Its Precursors in Plants
29 pages
Pediatric Success Nclexstyle Qa Review Third Edition Beth Richardson Download
No ratings yet
Pediatric Success Nclexstyle Qa Review Third Edition Beth Richardson Download
83 pages
Vitamin D, A Steroid Hormone, From Theory To Practice: This Paper Is Dedicated To The Memory of Prof. Luboslav Stárka
No ratings yet
Vitamin D, A Steroid Hormone, From Theory To Practice: This Paper Is Dedicated To The Memory of Prof. Luboslav Stárka
6 pages
Articulo SCALA MAS
No ratings yet
Articulo SCALA MAS
6 pages
Ros Vitamin D and Bone Health in Adults February 2020
No ratings yet
Ros Vitamin D and Bone Health in Adults February 2020
25 pages
Students and Social Service Essay in Tamil Language
100% (4)
Students and Social Service Essay in Tamil Language
8 pages

Ec 18 0432

Uploaded by

Ec 18 0432

Uploaded by

S Pilz et al.

Vitamin D testing and 8:2 R27–R43

Vitamin D testing and treatment: a narrative

Correspondence should be addressed to S Pilz: [email protected]

mortality, but they do not confirm the reductions in

Germany, Austria Nordic European

DRV/DRI EAR RDA AI AI RNI RI

0–6 months 10 (400) 10 (400) 8.5–10 (300–400)

Age group Vitamin D in µg (international units, IU) per day (1 µg = 40 IU)

Received in final form 18 December 2018

You might also like