European Journal of Clinical Nutrition (2020) 74:1498–1513

https://doi.org/10.1038/s41430-020-0558-y

REVIEW ARTICLE

Vitamin D deficiency 2.0: an update on the current status worldwide

Karin Amrein 1,2 Mario Scherkl1 Magdalena Hoffmann 1,3,4 Stefan Neuwersch-Sommeregger5,6
● ● ● ●

Markus Köstenberger5,6 Adelina Tmava Berisha7 Gennaro Martucci 8 Stefan Pilz1 Oliver Malle1
● ● ● ●

Received: 6 October 2019 / Revised: 17 December 2019 / Accepted: 6 January 2020 / Published online: 20 January 2020
© The Author(s), under exclusive licence to Springer Nature Limited 2020

Abstract
Vitamin D testing and the use of vitamin D supplements have increased substantially in recent years. Currently, the role of
vitamin D supplementation, and the optimal vitamin D dose and status, is a subject of debate, because large interventional
studies have been unable to show a clear benefit (in mostly vitamin D replete populations). This may be attributed to
limitations in trial design, as most studies did not meet the basic requirements of a nutrient intervention study, including
vitamin D-replete populations, too small sample sizes, and inconsistent intervention methods regarding dose and
metabolites. Vitamin D deficiency (serum 25-hydroxyvitamin D [25(OH)D] < 50 nmol/L or 20 ng/ml) is associated with
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unfavorable skeletal outcomes, including fractures and bone loss. A 25(OH)D level of >50 nmol/L or 20 ng/ml is, therefore,
the primary treatment goal, although some data suggest a benefit for a higher threshold. Severe vitamin D deficiency with a
25(OH)D concentration below <30 nmol/L (or 12 ng/ml) dramatically increases the risk of excess mortality, infections, and
many other diseases, and should be avoided whenever possible. The data on a benefit for mortality and prevention of
infections, at least in severely deficient individuals, appear convincing. Vitamin D is clearly not a panacea, and is most likely
efficient only in deficiency. Given its rare side effects and its relatively wide safety margin, it may be an important,
inexpensive, and safe adjuvant therapy for many diseases, but future large and well-designed studies should evaluate this
further. A worldwide public health intervention that includes vitamin D supplementation in certain risk groups, and
systematic vitamin D food fortification to avoid severe vitamin D deficiency, would appear to be important. In this narrative
review, the current international literature on vitamin D deficiency, its relevance, and therapeutic options is discussed.

Introduction of this widespread deficiency and necessity for supple-

mentation has been questioned [3]. Certainly, vitamin D is
Vitamin D testing has exponentially increased in recent not a panacea. Because more often than not, trials have
years [1]. The definition and relevance of vitamin D defi- included non-deficient individuals, it is not surprising that
ciency are still under debate. Recent large observational interventional trials have usually not been able to find a
data have suggested that ~40% of Europeans are vitamin D benefit of vitamin D supplementation on clinical outcomes.
deficient, and 13% are severely deficient [2]. The relevance This was also reflected in meta-analyses on the topic that

* Karin Amrein 5
Department of Anaesthesiology and Intensive Care Medicine,
karin.amrein@medunigraz.at
Klinikum Klagenfurt am Wörthersee, Klagenfurt am Wörthersee,
1 Austria
Department of Internal Medicine, Division of Endocrinology and
6
Diabetology, Medical University of Graz, Graz, Austria Immunology and Pathophysiology, Otto Loewi Research Center,
2 Medical University of Graz, Heinrichstrasse 31a, A-8010
Thyroid Endocrinology Osteoporosis Institute Dobnig,
Graz, Austria
Graz, Austria
7
3 Department of Psychiatry and Psychotherapeutic Medicine,
Executive Department for Quality and Risk Management,
Medical University of Graz, Graz, Austria
University Hospital Graz, Graz, Austria
8
4 Department of Anesthesia and Intensive Care, IRCCS-ISMETT
Research Unit for Safety in Health, Division of Plastic, Aesthetic
(Istituto Mediterraneo per i Trapianti e Terapie ad Alta
and Reconstructive Surgery, Department of Surgery, Medical
Specializzazione), Palermo, Italy
University of Graz, Graz, Austria
Vitamin D deficiency 2.0: an update on the current status worldwide 1499

were carried out with poor methodological standards [4]. Table 1 Risk groups for vitamin D deficiency including high-risk
medications.
Consequently, many authors have dismissed a role of
vitamin D on important clinical outcomes, and suggested Risk group Medication
that vitamin D may be more an associative than a causal
Chronic disease, particularly kidney, heart, Several antiretroviral
factor in acute and chronic disease. and liver failure, in particular transplant medications
On the other hand, a low vitamin D status is emerging as a candidates and recipients
very common condition worldwide, and several studies from Gastrointestinal diseases including Crohn’s Antifungals, e.g.,
basic science to clinical applications have highlighted a strong disease, inflammatory bowel disease, and ketoconazole
association with chronic diseases, as well as acute conditions. malabsorption syndromes
Moreover, the large amount of observational data currently Granuloma-forming disorders including Several antiseizure
sarcoidosis and tuberculosis medications
available are also accompanied by pathophysiological asso-
Hospitalized individuals, especially ICU Cholestyramine
ciations of vitamin D with energy homeostasis, and regulation patients
of the immune and endocrine systems [5]. Hyper- and hypoparathyroidism Glucocorticoids
Recent negative interventional trials may be biased by
Obese children and adults, particularly after Rifampicin
substantial methodological and study design errors, making bariatric surgery
it impossible to show the potential contributing role of Older adults with a history of falls and/or
vitamin D supplementation in a deficient population. fractures, osteoporosis
Typically, most studies have missed important prerequisites Oncologic patients
for a nutrient intervention trial: the absence of the problem Pregnant and lactating women, preparing for
to be solved—vitamin D deficiency, often ridiculously pregnancy
small sample sizes, and varying interventional regimes Reduced UV-B exposure or effectiveness
regarding dose and metabolite. Even the recent very large (shift workers, immobilized patients, chronic
neuropsychiatric disease, dressing habits, burn
trials did not exclusively include deficient populations and skin cancer survivors, and nonwhite
[6–8]. Moreover, interventional regimes have used a one- persons)
size-fits-all approach without taking into account individual Respiratory diseases including COPD, asthma,
differences in BMI and vitamin D metabolism. and cystic fibrosis

Methods deficiency [13–16]. The clinical practice guidelines of the

Endocrine Society Task Force on Vitamin D [12] have
Articles were individually retrieved up to October 2019 by defined a cutoff level of 50 nmol/L as vitamin D deficient.
search in PubMed (MEDLINE). Studies were excluded if Furthermore, different societies and expert bodies have
they were not in English. Across the last few decades, defined 50 nmol/L as “vitamin D requirement of nearly all
vitamin D-related research/publications have dramatically normal healthy persons,” by using bone health as the main
increased. Therefore, we decided to focus on the largest, basis. For example, a cutoff level of 50 nmol/L is recom-
most relevant, and most recent studies that are now in this mended by the Institute of Medicine (IOM, USA) in their
version of the review. “Dietary Reference Intakes”. Vitamin D levels of <30 nmol/
All authors supplied a first draft paper on a specific topic. L (or 12 ng/ml) should likely be prevented with a public
All papers were then exchanged and discussed among health approach [17]. There are many large and relevant risk
authors by e-mail. groups for vitamin D deficiency (Table 1).

Definition of vitamin D deficiency Prevalence of vitamin D deficiency worldwide

Serum 25(OH)D is considered to be the best marker for Prevalence rates of severe vitamin D deficiency, defined as
assessing vitamin D status, and reliably reflects the free 25(OH)D <30 nmol/L (or 12 ng/ml), of 5.9% (US) [18],
fractions of the vitamin D metabolites, despite the fact that, 7.4% (Canada) [19], and 13% (Europe) [2] have been
in theory, the bioavailable fractions may be more clinically reported. Estimates of the prevalence of 25(OH)D levels
informative [9, 10]. A range of below 75 nmol/L (or <50 nmol/L (or 20 ng/ml) have been reported as 24% (US),
30 ng/ml) of serum/plasma 25(OH)D concentration is con- 37% (Canada), and 40% (Europe) [2, 17–19]. This may
sidered vitamin D deficiency by most authors [11, 12]. A vary by age, with lower levels in childhood and the elderly
cutoff of <25 or <30 nmol/L (or 10/12 ng/ml) increases the [17], and also ethnicity in different regions, for example,
risk of osteomalacia and nutritional rickets dramatically, European Caucasians show lower rates of vitamin D defi-
and therefore is considered to determine severe vitamin D ciency compared with nonwhite individuals [2, 17].
1500 K. Amrein et al.

Worldwide, many countries report very high prevalences of exception of critical care, bolus doses with long dosing
low vitamin D status. 25(OH)D levels <30 nmol/L (or intervals are not used. They are no longer recommended
12 ng/ml) in >20% of the population are common in India, because of the higher risk of adverse effects (falls and
Tunisia, Pakistan, and Afghanistan. For example, it has fractures) associated with them [26]. Moreover, the 2017
been estimated that 490 million individuals are vitamin D individual patient data meta-analysis by Martineau et al.
deficient in India [2, 17]. showed a clear benefit for vitamin D on acute respiratory
Specific categories of patients have a very high prevalence infection when daily or weekly dosing was used, but not
of vitamin D deficiency. Often, they are characterized by an with longer dosing intervals [16]. In the intensive care,
insufficiency or failure of organs involved in vitamin D however, a typical daily dose is inefficient, and an upfront
metabolism. Patients with chronic renal failure and on loading dose (followed by a daily dose) is necessary to
hemodialysis, renal transplant recipients affected with liver improve vitamin D levels rapidly [27].
disease or after liver transplantation may have a prevalence of It is also important to note that different dosing regimes
vitamin D deficiency ranging from 85 to 99% [20–22]. may have different effects on clinical outcomes. Because a
daily dose leads to stable availability of various vitamin D
Vitamin D deficiency in critical illness metabolites, this could be an important explanation for
many of the negative vitamin D intervention trials [28].
Similarly, critically ill patients have a very high prevalence To maintain optimal vitamin D status, use of vitamin D
of vitamin D deficiency, and low vitamin D levels are supplementation is often required, as sunlight exposure and
clearly associated with greater illness severity, morbidity, dietary intake alone is usually insufficient in most indivi-
and mortality in both adult and pediatric intensive care unit duals [29–31]. Currently, there is no international consensus
(ICU) patients, as well as medical and surgical ICUs [23]. on the optimal level for vitamin D supplementation.
However, as in most other populations, the most important Recommendations differ in many countries, and range from
question remains unanswered: whether low vitamin D is an 400 to 2000 IU daily [11]. A safe and commonly available
innocent bystander, simply reflecting greater disease dose of 25 μg of vitamin D3 (1000 IU) raises 25-
severity, or represents an independent and modifiable risk hydroxyvitamin D [25(OH)D] serum level by 15–25 nmol/
factor amenable to rapid normalization through loading L on average (over weeks/months) [32, 33]; it should be
dose supplementation [24, 25]. noted that there is a nonlinear response of serum 25(OH)D,
The question is meaningful, since in this subgroup of with a steeper rise with <1 IU/day of vitamin D, and a more
patients, many factors contribute to low levels: hemodilu- flattened response with >1 IU/day. This is evidenced by
tion, reduced production and conversion by the liver, several studies in all age groups [11, 34].
reduced synthesis of vitamin D-binding protein, higher By using the above-mentioned recommended vitamin D
consumption during the acute phase of disease and systemic supplementation levels, there is no need to monitor serum or
inflammation, and increased tissue demand and enhanced urinary calcium or renal function [35, 36]. There is no
catabolism of metabolites. More data are emerging from international consensus on the safe upper level for vitamin
basic science about the immediate and late effects of vita- D supplementation. While the upper daily limit given by the
min D supplementation on endocrine, autocrine, and para- Endocrine Society is 10,000 IU [12], the IOM and The
crine and genomic targets. European Food and Safety Authority recommend staying
below 4000 IU/day (100 µg) [37, 38]. Most countries have
prudently set the safe upper level at 50 μg daily (2000 IU)
Vitamin D replacement for adults [35]. However, this level was set despite the
availability of adequate studies of dose–response relation-
Metabolites ships or toxicity. There is no convincing evidence that daily
intakes of up to 125 μg (5000 IU) elicit severe adverse
It cannot be emphasized enough that various vitamin D effects [39]. It has been reported that an intake of 1250 µg
metabolites with a very different efficacy, half-life, and risk (50,000 IU) once every 2 weeks for several years, equiva-
of toxicity exist. This is discussed in detail in “Vitamin D lent to 89.3 µg (3571 IU) daily, did not cause hypercalcemia
supplementation: cholecalciferol, calcifediol and calcitriol” or other evidence of hypervitaminosis D [40]. Small studies
by Reinold Vieth et al. in this special issue. showed that even a daily consumption of up to 250 μg
(10,000 IU) of vitamin D over long periods did not cause
Interval, target level, and dose adverse effects in healthy adults [32, 33], though
some studies revealed a negative impact on bone mineral
For some time, bolus dosing was en vogue because it was density by using high-dose vitamin D supplementation
thought to be interesting for practical reasons. With the of 10,000 IU/day [11]. Nevertheless, supplementation of
Vitamin D deficiency 2.0: an update on the current status worldwide 1501

>10,000 IU of vitamin D is rarely necessary in clinical example, consumption of vitamin D-enriched eggs from
practice. hens fed with additional vitamin D3 resulted in a zero
As there is no evidence that increasing the recommended prevalence <25 nmol/L, while the control group showed
daily dose of vitamin D supplementation up to 50 μg an usual seasonal decline in winter with 22% being
(2000 IU) would cause severe side effects in the general <25 nmol/L [52]. The rationale and guidance for sys-
population, and considering that 20 μg (800 IU) is the tematic vitamin D food fortification, including a call for
lowest dose consistently associated with a bone benefit, it action, has recently been published by an expert group of
seems reasonable to recommend a daily dose of 20–50 μg vitamin D scientists.
(800–2000 IU) (levels 2–4 evidence, grades B–D recom-
mendation) [39]. In general, a daily vitamin D of 800 IU
appears to be sufficient to achieve a target 25(OH)D level of Selected RCTs in recent years
at least 50 nmol/L (or 20 ng/mL) in most healthy indivi-
duals, whereas 2000 IU is sufficient to achieve a level of at Several very large randomized controlled trials have been or
least 75 nmol/L (or 30 ng/mL). are being performed in recent years. They are summarized
Some data suggest that a higher 25(OH)D level than in Table 2 [53–63].
50 nmol/L (or 20 ng/mL) may be required for optimal risk
reduction for various endpoints [41–44].
Effect size and basic statistical principles
Toxicity
Though it appears attractive to dismiss any relevant effect of
The use of vitamin D supplementation has increased sub- vitamin D on all the conditions that have been studied in
stantially. Growing awareness of vitamin D in the general those partly very large trials in recent years, it must be
population, and over-the-counter vitamin D with partially considered that often the basic principles for optimal design
very high doses, include the risk for uncontrolled use and of a nutrient intervention study were not fulfilled [64], e.g.,
exogenous hypervitaminosis D, resulting in high con- measurement of vitamin D at baseline and choosing
centrations of serum 25(OH)D or free 1,25-dihydrox- vitamin D deficiency as an inclusion criterion, using a
yvitamin D [1,25(OH)2D], leading to hypercalciuria and meaningful intervention able to change vitamin D status,
finally hypercalcemia [45]. Reports of vitamin D overdose and verification of vitamin D status improvement by repeat
are rare in the literature. Serum 25(OH)D usually exceeds measurement.
375 nmol/l (or 150 ng/ml), and factors such as high-calcium Moreover, even in the largest trials including thousands
intake contribute to the risk of hypercalcemia [46]. How- of individuals, the sample size was still too small when
ever, there are also endogenous causes of hypervitaminosis mostly individuals without vitamin D deficiency and a low
D, such as increased production of 1,25(OH)2D as part of baseline risk were included. By modeling future interven-
granulomatous disorders or lymphomas [47]. Having a long tion trials, Brenner et al. reported that several hundreds of
half-life in the tissues, vitamin D accumulation due to thousands of participants would be necessary to be able to
excessive intake lasts up to 18 months [48], and may cause show an effect on mortality [65].
chronic toxic effects such as nephrocalcinosis following On the other hand, even a very small effect may be useful
hypercalcemia and hypercalciuria [47]. for a substance with such an excellent safety profile and low
Since the 1930s, public health officials in the United cost, especially when considering a public health approach.
States and the United Kingdom have recommended routine However, to show a small, but meaningful benefit on
fortification of foods like milk to prevent vitamin D defi- important outcomes like mortality or infections, very large
ciency and low vitamin D status, which was expected to be population samples are needed, but such trials are very
an effective public health strategy [46]. However, there costly and will likely be scant.
was an increased incidence of hypercalcemia due to mas-
sive intakes of vitamin D from various food fortifications.
In some cases, hypercalcemia was associated with drink- Important systematic reviews and meta-
ing vitamin D-fortified milk, revealing a fortification of up analyses
to 232,565 IU instead of standard 400 IU/quart, and con-
sequently, prohibition of milk fortification [49]. However, The association of vitamin D supplementation on a number
current evidence suggests that vitamin D fortification of endpoints including mortality has been explored in more
prevents deficiency safely and effectively [50, 51]. Feed- detail in the last few years. Selected relevant systematic
ing animals might represent an additional source of vita- reviews and meta-analyses are summarized in Table 3
min D without compromising product quality. For [16, 66, 67].
Table 2 Recent important vitamin D intervention trials (ongoing and finished).
1502

Title Meth- Intervention Objectives/primary endpoint Results Comment

ods

VITAL Vitamin D RCT, Vitamin D3 (cholecalciferol) at Composite endpoint of incidence During a median follow-up of 5.3 years, cancer was diagnosed in 1617 participants Only 1 in 8 had
Supplements and two- a dose of 2000 IU/day and of invasive cancer or (793 in the vitamin D group and 824 in the placebo group; hazard ratio, 0.96; 95% 25OHD <20 ng/ml!
Prevention of Cancer by- marine n−3 (also called omega- cardiovascular events among men confidence interval [CI], 0.88–1.06; P = 0.47). A major cardiovascular event Placebo group was
and Cardiovascular two 3) fatty acids at a dose of 1 g/ 50 years of age or older and occurred in 805 participants (396 in the vitamin D group and 409 in the placebo allowed to take
Disease. By Manson factor- day. women 55 years of age or older. group; hazard ratio, 0.97; 95% CI, 0.85–1.12; P = 0.69) 800 IU/day.
et al. [7, 53] ialdes- Supplementation with vitamin D did not result in a lower incidence of invasive
ign cancer or cardiovascular events than placebo (n = 25871).
VIDA overview of RCT Vitamin D3 (2.5 mg or Evaluate the efficacy of monthly No effect of vitamin D on the cumulative incidence of CVD which occurred in beneficial effects
results from the 100,000 IU) or placebo softgel vitamin D supplementation in 11.8% of the vitamin D group and 11.5% of placebo, yielding a hazard ratio of 1.02 from vitamin D
Vitamin D Assessment oral capsules, mailed monthly reducing the incidence of a range (95% CI 0.87–1.20). No effect of vitamin D on the incidence of falls, with 51.7% in supplementation for
(ViDA) study. By to participants' homes, with two of acute and chronic diseases and the vitamin D group and 52.7% in the placebo group reporting at least one fall, lung function
Scragg [54, 55] capsules sent in the first mail- intermediate outcomes. giving an adjusted hazard ratio for falls of 0.98 (95% CI 0.92–1.06). No effect of among ever
out post-randomization (i.e., vitamin D on the incidence of fractures, which were observed in 6% of participants smokers (especially
200,000 IU bolus, or placebo), in the vitamin D arm and 5% in the placebo arm. The adjusted hazard ratio of if vitamin D
followed 1 month later (and fracture was 1.15 (95% CI 0.92–1.45) for vitamin D compared with placebo. In 328 deficient).
thereafter monthly) with incident cancer cases were identified, with the cumulative incidence being 6.5% in
100,000 IU vitamin D3 or the vitamin D group and 6.4% in the placebo group. The adjusted hazard ratio was
placebo capsules. 1.01 (95% CI 0.81–1.25). No significant lung function improvements (vitamin D vs.
placebo) in the total sample, vitamin D-deficient participants or asthma/COPD
participants. no beneficial effects on arterial function were seen for any of the
parameters of arterial function.No beneficial effect of vitamin D supplementation on
incidence of cardiovascular disease, falls, non-vertebral fractures and all cancer (n =
5110).
DO-HEALTH Vitamin Interv- Simple home exercise program Fracture risk, cognitive function, Instead of the planned 3000 patients, 1078 patients were included with a baseline 25- No results
D3-Omega-3-Home entio- three times a week and to take blood pressure, lower extremity hydroxyvitamin D level <20 ng/ml or 50 nmol/l. The 90-day mortality was 23.5% in available.
Exercise-Healthy nalstu- regular supplements of vitamin function, and rate of infection. the vitamin D group (125 of 531 patients) and 20.6% in the placebo group (109 of
Ageing and Longevity dy D and/or Omega-3 fatty acids Further key endpoints include rate 528 patients) (difference, 2.9 percentage points; 95% CI, −2.1 to 7.9; P = 0.26).
Trial. By Bischoff- and/or placebo. of falls, joint health There were no clinically important differences between the groups with respect to
Ferrari [56] (osteoarthritis), sarcopenia, frailty, secondary clinical, physiological, or safety end points.
oral and dental health, glucose
metabolism and diabetes, major
cardiovascular events,
maintenance of autonomy, and
quality of life.
FIND Finnish Vitamin RCT 3 groups with 6000 in each, Cardiovascular disease [Time Recruitment completed. (n = 2495). Last update on https://clinicaltrials.gov, No results
D Trial. By Tuomainen with daily supplementation of Frame: 5 years] CVD incidence in October 2018 available.
et al. [57] either: (1) 40 µg/day (1600 IU) Vitamin D arms vs. placebo arm. Blood samples were collected for assessment of effect modification by baseline 25-
of vitamin D3, (2) 80 µg/day Cancer [Time Frame: 5 years] hydroxyvitamin D, as well as for future ancillary studies of genetic/biochemical
(3200 IU) of vitamin D3, or (3) Cancer incidence in Vitamin D hypotheses.
placebo. arms vs.placebo arm.
AMATERASU Effect RCT Oral supplemental capsules of Relapse or death in patients with Relapse or death occurred in 50 patients (20%) randomized to vitamin D and 43
of Vitamin D vitamin D (2000 IU/day); or digestive tract cancers overall and patients (26%) randomized to placebo. Death occurred in 37 (15%) in the vitamin D
Supplementation on placebo. in subgroups stratified by 25- group and 25 (15%) in the placebo group. The 5-year relapse-free survival was 77%
Relapse-Free Survival hydroxyvitamin D (25[OH]D) with vitamin D vs. 69% with placebo (hazard ratio [HR] for relapse or death, 0.76;
Among Patients With levels. 95% CI, 0.50–1.14; P = 0.18). The 5-year overall survival in the vitamin D vs.
Digestive Tract placebo groups was 82% vs. 81% (HR for death, 0.95; 95% CI, 0.57–1.57; P = 0.83)
Cancers: The Among patients with digestive tract cancer, vitamin D supplementation, compared
AMATERASU with placebo, did not result in significant improvement in relapse-free survival at 5
Randomized Clinical years (n = 166).
Trial. By Urashima
et al. (2019)
K. Amrein et al.
Table 2 (continued)
Title Meth- Intervention Objectives/primary endpoint Results Comment
ods

VIDAL Vitamin D and RCT 100,000 IU monthly (average Overall mortality in men and Results not available (planned n = 375) (n = 1615). Bolus dose has
Longevity (VIDAL) 3300 IU/day) of oral vitamin women aged 65–84. been shown to be
Trial: Randomized D3 or double-blind placebo problematic,
Feasibility Study. By control or 100,000 IU monthly especially at
Peto et al. [58] (average 3300 IU/day) of oral intervals longer
vitamin D3 or open control. than 1 week.
VDOP The Vitamin D RCT Monthly oral dosing with Plasma 25OHD concentration Results not available (planned n = 375). None.
in Older People. By 12,000 IU, 24,000 IU or required to maintain bone health
Schoenmakers et al. 48,000 IU of vitamin D3. and to develop a set of
(2013) [59] biochemical markers that reflects
the effect of vitamin D on bone.
D2D Vitamin D RCT 4000 IU/day of vitamin D3 or New-onset diabetes trial design After a median follow-up of 2.5 years, the primary outcome of diabetes occurred in Inclusion regardless
Supplementation and placebo. was event-driven, with a target 293 participants in the vitamin D group and 323 in the placebo group (9.39 and of the baseline
Prevention of Type 2 number of diabetes events of 508. 10.66 events per 100 person-years, respectively). The hazard ratio for vitamin D as serum 25-
Diabetes. Pittas et al. compared with placebo was 0.88 (95% confidence interval, 0.75–1.04; P = 0.12). hydroxyvitamin D
[6] Among persons at high risk for type 2 diabetes not selected for vitamin D level! (27.7 ng/ml
insufficiency, vitamin D3 supplementation at a dose of 4000 IU per day did not at baseline in the
result in a significantly lower risk of diabetes than placebo (n = 2423). vitamin D and
28.2 ng/ml in the
placebo group!).
SUNSHINE Effect of RCT mFOLFOX6 plus bevacizumab Progression-free survival (PFS) in The median progression-free survival for high-dose vitamin D3 was 13.0 months
Vitamin D deficiency 2.0: an update on the current status worldwide

High-Dose vs. chemotherapy every 2 weeks patients with advanced or (95% CI, 10.1–14.7; 49 PFS events) vs. 11.0 months (95% CI, 9.5–14.0; 62 PFS
Standard-Dose and either high-dose vitamin D3 metastatic colorectal cancer. events) for standard-dose vitamin D3 (log-rank P = 0.07); multivariable hazard ratio
Vitamin D3 (n = 69) or standard-dose for PFS or death was 0.64 (1-sided 95% CI, 0–0.90; P = 0.02). There were no
Supplementation on vitamin D3 (n = 70) daily until significant differences between high-dose and standard-dose vitamin D3 for tumor
Progression-Free disease progression, intolerable ORR (58% vs. 63%, respectively).
Survival Among toxicity, or withdrawal of Among patients with metastatic CRC, addition of high-dose vitamin D3, vs.
Patients With consent. standard-dose vitamin D3, to standard chemotherapy resulted in a difference in
Advanced or median PFS that was not statistically significant, but with a significantly improved
Metastatic Colorectal supportive hazard ratio.
Cancer. By Kimmie (n = 139).
et al. [60]
Effect of Higher vs. RCT 400 or 1200 IU of vitamin D3 Bone strength and incidence of We found no differences between groups in bone strength measures, including bone These findings
Standard Dosage of daily from age 2 weeks to parent-reported infections at mineral content (mean difference, 0.4 mg/mm; 95% CI, −0.8 to 1.6), mineral density imply that a daily
Vitamin D3 24 months. 24 months. (mean difference, 2.9 mg/cm3; 95% CI, −8.3 to 14.2), cross-sectional area (mean dose of 1200 IU of
Supplementation on difference, –0.9 mm2; 95% CI, −5.0 to 3.2), or polar moment of inertia (mean vitamin D3 in this
Bone Strength and difference, –66.0 mm4, 95% CI, −274.3 to 142.3). Bone strength measurements for age group is safe,
Infection in Healthy total bone and cortical bone did not differ between groups. No differences of but even 400 IU
Infants infection between groups (incidence rate ratio [IRR], 1.00; 95% CI, 0.93–1.06) A will maintain
A Randomized vitamin D3 supplemental dose of up to 1200 IU in infants did not lead to increased vitamin D
Clinical Trial. By bone strength or to decreased infection incidence. Daily supplementation with sufficiency in most
Rosendahl et al. [61] 400 IU vitamin D3 seems adequate in maintaining vitamin D sufficiency in children children.
younger than 2 years (n = 975).
Effect of Monthly, RCT Vitamin D3 200,000 IU (initial Effects of monthly, high-dose, Mean depersonalized 25-hydroxyvitamin D increased from 66 nmol/L (SD: 24) at Benefit of vitamin
High-Dose, Long- sub- dose) followed 1 month later by long-term (≥1-year) vitamin D baseline to 122 nmol/L (SD: 42) at follow-up in the vitamin D group, with no change D only among
Term Vitamin D study monthly 100,000-IU doses supplementation on central blood in the placebo group. Monthly, high-dose, 1-year vitamin D supplementation adults with vitamin
Supplementation on (n = 256) or (2) placebo pressure (BP). lowered central BP parameters among adults with vitamin D deficiency but not in the D deficiency but
Central Blood Pressure monthly (n = 261). total sample (n = 517). not in the total
Parameters: A sample.
Randomized Largely replete
Controlled Trial population
Substudy. By Sluyter Bolus dose.
et al. [62]
1503
Table 2 (continued)
1504

Title Meth- Intervention Objectives/primary endpoint Results Comment

ods

VITDAL-ICU Effect RCT Patients with vitamin D Vitamin D3 or placebo was given Length of hospital stay was not significantly different between groups (20.1 days
of high-dose vitamin deficiency (≤20 ng/mL) orally or via nasogastric tube once [IQR, 11.1–33.3] for vitamin D3 vs. 19.3 days [IQR, 11.1–34.9] for placebo; P =
D3 on hospital length assigned to receive either at a dose of 540,000 IU followed 0.98). Hospital mortality and 6-month mortality were also not significantly different
of stay in critically ill vitamin D3 or a placebo. by monthly maintenance doses of (hospital mortality: 28.3% [95% CI, 22.6–34.5%] for vitamin D3 vs. 35.3% [95%
patients with vitamin D 90,000 IU for 5 months. CI, 29.2–41.7%] for placebo; hazard ratio [HR], 0.81 [95% CI, 0.58–1.11]; P =
deficiency: the 0.18; 6-month mortality: 35.0% [95% CI, 29.0–41.5%] for vitamin D3 vs. 42.9%
VITdAL-ICU [95% CI, 36.5–49.4%] for placebo; HR, 0.78 [95% CI, 0.58–1.04]; P = 0.09). (n =
randomized clinical 475).
trial. By Amrein et al.
[112]
VIOLET Vitamin D to RCT Single dose of 540,000 IU of Patients with vitamin D deficiency Results not available (planned n = 3000, actual ca. 1400). Stopped
Improve Outcomes by vitamin D3 vs. Placebo. (levels <20 ng/mL) and at high Last update on https://clinicaltrials.gov September 2019. prematurely at the
Leveraging Early risk for ARDS and 90-day first interim
Treatment. By PETAL mortality. analysis (ca.
Network [111] n = 1400)
One loading dose
only, no follow-up
medication, and
primary endpoint
90-day mortality
Substantially less
severely ill
population
compared with
previous ICU
studies.
VITDALIZE Effect of RCT Oral dose of vitamin D3 28-day mortality in adult critically Recruitment ongoing (planned=2400). Including only
High-dose Vitamin D3 (540,000 IU loading followed ill patients with severe vitamin D patients with severe
on 28-day Mortality in by 4000 IU daily for 3 months) deficiency (≤12 ng/ml or vitamin D
Adult Critically Ill or placebo. undetectable). deficiency (≤12 ng/
Patients ml or undetectable).
(VITDALIZE). By
Amrein et al. (Protocol
in BMJ Open NOV
2019) [113]

NA not applicable, RCT randomized controlled trial, IU International units, CVD cardiovascular disease
K. Amrein et al.
Table 3 Selected important systematic reviews and meta-analyses.
Title Methode Intervention Objectives/primary endpoint Results Conclusion Comment

Association between vitamin D Systematic review Randomized controlled trials To investigate whether vitamin 52 trials with a total of 75,454 Vitamin D supplementation alone
supplementation and mortality: comparing vitamin D D supplementation is associated participants were identified. Vitamin D was not associated with all-cause
systematic review and meta- supplementation with a placebo or with lower mortality in adults. supplementation was not associated mortality in adults compared with
analysis. By Zhang et al. [3] no treatment for mortality were with all-cause mortality (RR 0.98, placebo or no treatment. Vitamin
included. 95% CI 0.95–1.02), cardiovascular D supplementation reduced the
mortality (RR 0.98, 95%CI 0.88 to risk of cancer death by 16%.
1.08), or non- cancer, non- Additional large clinical studies
cardiovascular mortality (RR 1.05, are needed to determine whether
95% CI 0.93 to 1.18). Vitamin D vitamin D3 supplementation is
supplementation statistically associated with lower all-cause
significantly reduced the risk of cancer mortality.
death (RR 0.84, 95% CI 0.74 to 0.95).
In subgroup analyses, all-cause
mortality was significantly lower in
trials with vitamin
D3 supplementation than in trials with
vitamin D2 supplementation (P for
interaction = 0.04).
Vitamin D supplementation to Systematic review Randomized, double-blind, To assess the overall effect of 25 eligible randomized controlled Vitamin D supplementation was Patients who were severely
prevent acute respiratory tract placebo-controlled trials of vitamin D supplementation on trials (total 11,321 participants, aged safe and it protected against acute vitamin D deficient and those
infections: systematic review and supplementation with vitamin D3 risk of acute respiratory tract 0–95 years) were identified. Vitamin respiratory tract infection overall. not receiving bolus doses
meta-analysis of individual or vitamin D2 of any duration infection. D supplementation reduced the risk of Patients who were very vitamin D experienced the most benefit.
participant data. By Martineau were eligible for inclusion if they acute respiratory tract infection among deficient and those not receiving
et al. [16] had been approved by a research all participants (OR 0.88, 95% CI bolus doses experienced the most
ethics committee, and if data on 0.81–0.96; P for heterogeneity benefit.
Vitamin D deficiency 2.0: an update on the current status worldwide

the incidence of acute respiratory <0.001). The best effects coulb be

tract infection were collected shown at daily or weekly vitamin D
prospectively and prespecified as without additional bolus doses (OR
an efficacy outcome. 0.81, 95% CI 0.72 to 0.91), but not in
those receiving one or more bolus
doses (OR 0.97, 95% CI 0.86 to 1.10).
The protective effects were stronger in
those with baseline 25-
hydroxyvitamin D levels <25 nmol/L
(OR 0.30, 95% CI 0.17– 0.53) than in
those with baseline 25-
hydroxyvitamin D levels ≥25 nmol/L
(OR 0.75, 95% CI 0.60–0.95).
Vitamin D and vitamin D analogs Systematic review Randomized or quasi-randomized To determine the effects of In total, 53 trials with a total of 91,791 Vitamin D alone is unlikely to In high-risk populations
for preventing fractures in post- trials that compared vitamin D or vitamin D or related compounds, participants were included. A high- prevent fractures in the doses and (residents in institutions with
menopausal women and older men. related compounds, alone or with with or without calcium, for quality evidence was found that formulations tested so far in older an estimated 54 hip fractures
By Avenell et al. [66] calcium, against placebo, no preventing fractures in post- vitamin D alone is unlikely to be people. Supplements of vitamin D per 1000 per year), this
intervention or calcium alone, and menopausal women and effective in preventing hip fracture (11 and calcium may prevent hip or equates to nine fewer hip
that reported fracture outcomes in older men. trials, 27,693 participants; RR 1.12, any type of fracture. There was a fractures per 1000 older
older people. The primary 95% CI 0.98–1.29) or any new small but significant increase in adults per year (95% CI
outcome was hip fracture. fracture (15 trials, 28,271 participants; gastrointestinal symptoms and 2– 14).
RR 1.03, 95% CI 0.96–1.11). Also a renal disease associated with
high-quality evidence was shown that vitamin D and calcium. This
vitamin D plus calcium results in a review found that there was no
small reduction in hip fracture risk (9 increased risk of death from
trials, 49,853 participants; RR 0.84, taking calcium and vitamin D.
95% CI 0.74–0.96; p = 0.01). Also a
high- quality evidence was found that
vitamin D plus calcium reduces the
risk of any type of fracture (10 trials,
49,976 participants; RR 0.95, 95% CI
0.90– 0.99). Mortality was not
adversely affected by either vitamin D
or vitamin D plus calcium.
1505
1506 K. Amrein et al.

Selected target organs, conditions, and

participants, high risk of bias

endpoints

with significant intertrial

Only few trials with an
insufficient number of
Mortality

heterogeneity.
Comment

Vitamin D deficiency has been strongly associated with

various health outcomes, including all-cause mortality [68].
A 2014 Cochrane meta-analysis showed a relevant and
whether vitamin D supplements in

adverse events because the results

evidence on the effect of vitamin

D2, 1,25-dihydroxyvitamin D, or

mortality, liver-related mortality,

the form of vitamin D3, vitamin

significant lower all-cause mortality of ~7% and cancer

related morbidity and health-

25-dihydroxyvitamin D have
important effect on all-cause

or on serious or non-serious

D supplementation on liver-
were imprecise. There is no
Authors are uncertain as to

mortality of ~13% in patients who received vitamin D3

related quality of life.

[69]. The results of a meta-analysis by using individual
participant data conducted by Gaksch et al., analyzing
almost 17,000 individuals, showed a strong association
Conclusion

between low 25(OH)D and increased risk of all-cause

mortality [70]. Using a Mendelian randomization with
genetic variants in the vitamin D synthesis pathway, the
vitamin D on all-cause mortality at the
insufficient (<20 ng/mL). The effect of

0.70, 95% CI 0.09–5.38). The effect of

and on serious adverse events such as

end of follow-up is uncertain because
with 1034 participants were included.

hypercalcemia, myocardial infarction,

In total, 15 randomized clinical trials

remaining nine trials were vitamin D

Participants in six trials had baseline

vitamin D on liver-related mortality,

the results were imprecise (Peto OR

and thyroiditis, is uncertain because

above vitamin D adequacy (20 ng/

analysis of Aspelund et al. supports a causal relationship

supplementation (29 trials, 71,032

25-hydroxyvitamin D levels at or
participants, RR 0.97, 95% CI

between vitamin D deficiency and increased all-cause

mL), while participants in the

the results were imprecise.

mortality. However, despite a cohort of >10,000 partici-

pants, it was still too underpowered to confirm a causal
relationship [71].
0.93–1.01).

Lung
Results

The effect of vitamin D on the lungs has a strong rationale,

supplementation in people with

demonstrated by basic science, due to its immunomodulant,

harmful effects of vitamin D
Objectives/primary endpoint

Assess the beneficial and

anti-inflammatory, and anti-infective role that has been

chronic liver diseases.

highlighted in patients with community-acquired infections,

acute respiratory failure, as well as in lung transplantation
recipients (this is a very specific model for severe infective
and inflammatory lung disease) [21].
Vitamin D supplementation reveals direct anti-
inflammatory properties in the lungs. This is due to local
intervention in adults with chronic
compared vitamin D at any dose,

administration vs. placebo or no

Systematic review Randomized clinical trials that

inhibition of nuclear factor-κB and mitogen-activated pro-

tein kinase activity, reducing the secretion of inflammatory
duration, and route of

cytokines and chemokines involved in the lung inflamma-

tory process and extravascular leaking, such as interleukin
liver diseases.

(IL)-1β, IL-6, and IL-8. This, in turn, also influences the

Intervention

number of inflammatory cells infiltrating the interstitial

space [72]. Moreover, 1,25(OH)2D is also implicated in the
reduction of oxidative stress by inhibiting anti-protease
activity, and acting on the nuclear factor erythroid-related
factor 2, a transcriptional regulator of most antioxidant
Methode

genes. Moreover, vitamin D acts with well-known anti-

infectious properties by increasing proliferation of mono-
chronic liver diseases in adults. By

cytes to macrophages (acting as a fine-tuner of the innate

Vitamin D supplementation for

and adaptive immunity), and determining a transcriptional

upregulation of cathelicidin also in the airway epithelial
Table 3 (continued)

Bjelakovic et al. [67]

cells. Finally, 1,25(OH)2D inhibits the expression of several

metalloproteinases in airway smooth-muscle cells and
alveolar macrophages, thus being involved in the tissue
remodeling pathway by regulating the process of bronchial
Title

airway muscle activation and extracellular matrix deposition

Vitamin D deficiency 2.0: an update on the current status worldwide 1507

by fibroblasts. All these complex pathways, partially mod- trials on vitamin D supplementation in lung and kidney
ified by vitamin D, warrant supplementation in patients with recipients are ongoing under the hypothesis that vitamin D
respiratory disease. Significant benefits have already been supplementation may contribute to reducing the occurrence
shown in adults and children with asthma, and for the of rejection by it immunomodulating action.
prevention of respiratory tract infections, particularly in
severe vitamin D deficiency. Pregnancy

Sepsis In 2019, two Cochrane analyses on vitamin D and preg-

nancy were published. They suggested that vitamin D
Sepsis, a complication of severe infection, is characterized supplementation may reduce gestational diabetes, low
by signs of systemic inflammation expressed with failure of birthweight, and preeclampsia, but a higher than currently
organs often remote from the site of the initial infection. recommended dose appeared to have no additional benefit
Septic patients have high mortality and lower circulating except for possible further reduction of gestational diabetes
levels of vitamin D. The interest in vitamin D for infection [74, 75]. However, several studies in recent years have
has risen after the recognition of the expression of the highlighted that women are at high risk for vitamin D
vitamin D receptor, ubiquitous in cells of the innate and deficiency, and this is associated with adverse pregnancy
adaptive immune system. Vitamin D is an important link outcomes, including preeclampsia and gestational diabetes
between Toll-like receptor activation and antibacterial [76–80]. It has been demonstrated that vitamin D supple-
responses. The in vivo supplementation of a high dose of mentation is able to reduce adverse pregnancy outcomes
cholecalciferol (400.000 IU as a single bolus) in the early when a higher level is achieved, with an increasing efficacy
stage of sepsis and septic shock has been shown able to when the target level is raised from 20 to 40 ng/mL or
safely and rapidly increase the level of vitamin D, as well as 50 ng/mL. Interestingly, the maximum change is achieved
the circulating level of cathelicidin, a vitamin D-dependent 6–8 weeks after initiating the treatment, likely exerting the
endogenous anti-microbial and endotoxin-binding peptide genomic actions of vitamin D [81–83]. Three major adverse
largely found in human neutrophils [73]. These findings pregnancy outcomes appear to improve with vitamin D
were corroborated by the significant reduction of IL-1β and supplementation: a 60% reduction in preeclampsia, a 50%
IL-6, which play important roles in the early inflammatory reduction in gestational diabetes, and a 40% reduction in
response. preterm delivery [84]. These data are consistent with pre-
vious work on the topic [82]. Moreover, following the
Organ transplantation recipients genomic and epigenetic effects of vitamin D supplementa-
tion, vitamin D deficiency during pregnancy also seems able
Several studies have highlighted that lower 25(OH)D levels to induce specific genomic pathways relevant to auto-
are associated with prolonged hospitalization and mortality, immune disease in childhood and later in life [85, 86]. The
also in the postsurgical setting. Given its wide immuno- placenta can convert 25(OH)D to the active form 1,25(OH)
biological effects, vitamin D has been frequently considered 2D, similarly to the kidneys; therefore, more basic research
a potential modulating factor after solid organ (and stem should shed light in the future on the specific vitamin D
cell) transplantation (mainly liver, kidney, and lung). The metabolism during pregnancy [85]. The FDA has recently
transplantation recipient population is particularly prone to approved the statement “Pregnant women who have higher
infections, mainly in the early stage after transplantation, serum vitamin D levels have a decreased risk of preterm
due to immunomodulation/chronic immunosuppressive birth.”
therapy and to long-term bone dysfunction. The recipients Taking into account the recent literature, vitamin D
of solid organ transplantation are, by definition, vitamin D deficiency is associated with worse outcomes during preg-
insufficient for manifold reasons, including limited sunlight nancy, and at least 400–600 IU of daily vitamin D supple-
exposure, limited physical activity, reduced dietary intake mentation is reasonable for women with a vitamin D level
of vitamin D in food, as well as liver and kidney dysfunc- <40 ng/mL, with higher required doses in more severe
tion according to their main disease. As an example, in liver deficiency.
transplantation recipients (a group of patients with very low
vitamin D levels), osteoporosis has a high prevalence, with Cancer
a large decline in bone mineral density in the first year after
transplantation. Moreover, a negative association between Vitamin D supplementation as a strategy for preventing
low vitamin D levels and graft function, as well as a role of cancer was considered, as results from several observational
vitamin D in reducing the recurrence of hepatitis C virus studies suggested an association between vitamin D defi-
infection, has been demonstrated. Several interventional ciency and risk for several types of cancer [87]. It was
1508 K. Amrein et al.

already assumed in 1980 that calcitriol could inhibit the and-effect relationship is inconclusive. On the other hand,
growth of malignant melanoma cells [88]. Ecologic studies diabetes per se results in physiological changes too, such as
revealed a decreased cancer mortality in areas with greater increased renal elimination of vitamin D-binding protein
sun exposure [11]. Over the decades, vitamin D and its compared with healthy individuals [106]. Therefore, the
anticancer action was investigated for various malignancies value of hypovitaminosis D as a trigger for developing
resulting in mixed findings [89]. Hence, the cancer- T1DM remains unclear. Vitamin D deficiency was also
protective effect of vitamin D remained unclear. In 2014, shown to have a negative impact on insulin resistance [107].
two meta-analyses revealed no significant decrease in the Hence, a higher risk of developing type 2 diabetes mellitus
incidence of cancer in association with vitamin D supple- (T2DM) in individuals with low 25(OH)D levels was
mentation, but a significant reduction in the rate of death assumed. However, vitamin D supplementation did overall
from cancer [90, 91]. However, as most of the data derive not result in a lower risk of developing T2DM [6, 108]. In
from observational studies, correlation does not imply the recent D2D study by Pittas et al., vitamin D did not
causation. Investigating cancer incidence following vitamin significantly reduce new onset of diabetes, but vitamin D
D plus calcium supplementation, Lappe et al. revealed a deficiency was no inclusion criterion, and only a minority of
non-, but nearly significant (hazard ratio 0.70; 95% CI included patients had a 25(OH)D level <50 nmol//L (or
0.47–1.02) 30% risk reduction compared with placebo [92]. 20 ng/mL). Moreover, the hypothesized treatment effect
A recent large RCT using a daily dose of 2000 IU vitamin used for the sample size calculation was relatively large
D3 conducted by Manson et al. [7], analyzing the incidence (hazard ratio 0.75 for the vitamin D group). The actual
of cancer following vitamin D supplementation in over hazard ratio for vitamin D as compared with placebo was
25,000 participants, did not reveal a significant reduction 0.88 (95% confidence interval, 0.75–1.04; P = 0.12).
neither of invasive cancer of any type nor in the rate of Interestingly, the effect appeared to be stronger in patients
death from any cause. However, subgroup analyses with a BMI <30. However, a post hoc subgroup analysis of
revealed a significant lower cancer incidence in normal- individuals with a 25(OH)D level below 12 ng/ml (30 nmol/
weight individuals. Considering that the study was not l) revealed a significantly reduced risk of developing T2DM
adjusted for this comparison, this finding should be con- (hazard ratio 0.38; 95% CI, 0.18–0.80).
sidered hypothesis-generating. An ongoing long-term RCT
[93], investigating vitamin D supplementation and the Musculoskeletal effects of vitamin D
incidence of cancer and precancerous lesions in a high-risk
population (overweight adults with prediabetes), will pro- The detrimental effects of vitamin D deficiency on the
vide further and important data on the causality. musculoskeletal system were the first visible mode of action
that was attributed to vitamin D (i.e., rickets in children).
Diabetes The necessity of an adequate vitamin D status for muscle
and bone health is undebated, and therefore not discussed in
Several studies demonstrated a link between 25(OH)D detail in this review.
levels and diabetes, and revealed a higher frequency of
vitamin D deficiency in patients with type 1 diabetes mel-
litus (T1DM) compared with healthy individuals [94–97]. Vitamin D intoxication and hypersensitivity
Investigating prenatal vitamin D exposure of the fetus, a
lower gestational 25(OH)D level [98] or avoiding vitamin Vitamin D intoxication is rare and usually only occurs at
D-fortified food [99] was significantly associated with very high supplementation doses [109]. However, various
higher risk of developing T1DM. In infancy, vitamin D mutations in vitamin D metabolizing enzymes that may lead
supplementation [100] or vitamin D-fortified margarine [99] to increased sensitivity to standard vitamin D supple-
was shown to reduce the risk of developing type 1 diabetes mentation or even endogenous vitamin D intoxication with
mellitus. The effect of vitamin D supplementation on hypercalcemia, hypercalciuria, and nephrocalcinosis/
T1DM onset seems to be dependent on life stage. Supple- chronic renal insufficiency have been described [110].
mentation between 7 and 12 months of age resulted in an Typically, these mutations affect CYP24A1, the enzyme
almost twofold lower risk of developing T1DM compared that catabolizes 1,25OHD2 to the inactive metabolite
with earlier supplementation [101]. In adolescents, many 24,25OHD2. Therefore, a diagnosis can be made by using
studies revealed no association between 25(OH)D level and the ratio of 24,25:25 D and does not necessarily require
onset of T1DM [102–104]. However, there is a clear effect genetic testing.
of vitamin D in young adults, as low 25(OH)D levels were This condition has been termed idiopathic infantile
significantly associated with developing T1DM [105]. hypercalcemia, but due to the greatly varying clinical phe-
However, according to the available literature, the cause- notypes, patients may well become symptomatic only in
Vitamin D deficiency 2.0: an update on the current status worldwide 1509

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