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Consensus on the Prevention of Vitamin D Deficiency
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This entry is adapted from the peer-reviewed paper 10.3390/nu14071483

Vitamin D is crucial for musculoskeletal health, as it plays an important role in the regulation of bone and mineral metabolism, and it can prevent and cure nutritional rickets and osteomalacia. In addition, vitamin D receptor (VDR) expression in almost all human cells suggests, or even documents, a more widespread role of vitamin D for overall health, a notion that is supported by several experimental and epidemiological studies. While there still exist knowledge gaps and controversy regarding potential extra-skeletal effects of vitamin D, there is a wide consensus that the high worldwide prevalence of vitamin D deficiency is of concern and requires actions to improve this situation.

vitamin D recommendations guidelines osteoporosis

1. Introduction

Vitamin D is crucial for musculoskeletal health, as it plays an important role in the regulation of bone and mineral metabolism, and it can prevent and cure nutritional rickets and osteomalacia [1][2]. In addition, vitamin D receptor (VDR) expression in almost all human cells suggests, or even documents, a more widespread role of vitamin D for overall health, a notion that is supported by several experimental and epidemiological studies [1][3][4][5][6][7][8]. While there still exist knowledge gaps and controversy regarding potential extra-skeletal effects of vitamin D, there is a wide consensus that the high worldwide prevalence of vitamin D deficiency is of concern and requires actions to improve this situation [2][7][9]. Addressing this issue has to consider the unique metabolism of vitamin D, which is mainly synthesized in the skin stimulated by ultraviolet-B (UV-B) exposure, whereas nutrition is usually only a minor source of vitamin D [10]. Vitamin D from all different sources is metabolized to 25-hydroxyvitamin D (25(OH)D, calcifediol) in the liver, which is the main circulating vitamin D metabolite that is determined to assess vitamin D status. Further hydroxylation of 25(OH)D in the kidneys or certain extra-renal tissues results in the formation of 1,25-dihydroxyvitamin D (1,25(OH)2D, also called calcitriol), which exerts endocrine, autocrine, and paracrine effects as a steroid hormone [10]. Heterogeneous recommendations, regarding several issues in the practical management of vitamin D deficiency, represent a challenge for clinicians and health authorities on how to deal with this public health problem [11][12][13][14][15][16][17][18][19][20][21][22]. In this context, systematic evaluations of current vitamin D guidelines did, not only, observe a great heterogeneity of the recommendations, but it also reported a low quality score regarding the methodological processes for the majority of these vitamin D guidelines [17][18]. Table 1 and Table 2 provide an overview of selected guideline recommendations, with a focus on Central and Eastern European countries, for prevention and treatment of vitamin D deficiency, respectively.
Table 1. Selected guideline recommendations for prevention of vitamin D deficiency in adults with a focus on Central and Eastern European countries, published since 2010.
Table
Authority and/or Country or
Region (Year)		 Target Population Age (Years) Oral Vitamin D (IU) Reference
Endocrine
Society (2011)
USA		 General population 19–70 600–2000/day Holick et al. [14]
>70 800–2000/day
Pregnant and lactating women   600–2000/day
Obese individuals/Patients on anticonvulsants, glucocorticoids, antifungals, AIDS medications   2–3 times more
DACH (2012)
Germany/Austria/Switzerland		 General population >18 800/day DGE [23]
EVIDAS (2013)
Central Europe		 General population >18 800–2000/day Płudowski et al. [21]
Obese individuals and elderly   1600–4000/day
Prevention of pregnancy and fetal
development complications		 >16 1500–2000/day
Night workers and dark skin pigmentation   1000–2000/day
EFSA (2016)
Europe		 General population >18 600/day EFSA [24]
Russia (2016) General population >18 800–1000/day Pigarova et al. [25]
Pregnant women   800–2000/day
Poland (2018) General population 19–75 800–2000/day Rusińska, Płudowski et al.
[26]
Obese individuals 19–75 1600–4000/day
General population >75 2000–4000/day
Obese individuals >75 4000–8000/day
Pregnant and lactating women   2000/day
Belarus (2013) General population >18 800–2000/day Rudenko [27]
Hungary (2012) General population >18 1500–2000/day Takács et al. [22]
Pregnant and lactating women   1500–2000/day
Bulgaria (2019) General population >19 600–2000/day Borisova et al.
[28]
Pregnant and lactating women   600–2000/day
Patients on anticonvulsants, glucocorticoids, antifungals   2–3 times more
Slovakia (2018) Postmenopausal osteoporosis patients >50 800–1000/day Payer et al. [29]
Table 2. Selected guideline recommendations for treatment of vitamin D deficiency in adults with a focus on Central and Eastern European countries, published since 2010.
Table
Authority and/or Country or
Region (Year)		 Target Population Oral Vitamin D for Treatment (IU) Treatment
Duration		 25(OH)D
Target
Concentration
nmol/L (ng/mL)		 Oral Vitamin D for
Maintenance (IU)		 Reference
Endocrine
Society (2011)
USA		 General
population		 50,000/week or
6000/day		 8 weeks 75
(30)		 1500–2000/day Holick et al. [14]
Obese individuals/Patients on anticonvulsants, glucocorticoids, antifungals, AIDS medications 2–3 times more; at least 6000–10,000/day 3000–6000/day
EVIDAS (2013)
Central Europe		 General
population		 50,000/week or
7000–10,000/day		 4–12 weeks 75–125
(30–50)		 a maintenance dose may be instituted Płudowski et al. [21]
Italy (2018) General
population		 50,000/week or
5000/day		 8 weeks >75
(>30)		 50,000 IU twice per month or
1500–2000 IU/day		 Cesareo et al. [30]
Russia (2016) General
population		 25(OH)D < 50 nmol/L (<20 ng/mL):   >75
(>30)		 1000–2000/day or
6000–14,000/week		 Pigarova et al. [25]
50,000/week or 8 weeks
200,000/month or 2 months
150,000/month or 3 months
6000–8000/day 8 weeks
25(OH)D < 75 nmol/L
(30 ng/mL):		  
50,000/week or 4 weeks
200,000 or single dose
150,000 or single dose
6000–8000/day 4 weeks
Poland (2018) General
population		 6000/day 12 weeks or
until a 25(OH)D concentration of 75 nmol/L (30 ng/mL) is reached		 >75–125
(>30–50)		 maintenance dose i.e., a prophylactic dose recommended for the general population (see Table 1) Rusińska, Płudowski et al. [26]
Belarus (2013) General
population		 25(OH)D < 25 nmol/L (<10 ng/mL):
2000 to 10,000/day		 4–12 weeks 75–200
(30–80)		 800–2000 IU/day Rudenko [27]
25(OH)D 25–50 nmol/L (10–20 ng/mL):
800 to 4000/day		 1 year
Hungary (2012) General
population		 50,000/week or 4–8 weeks 75
(30)		 1500–2000/day Takács et al. [22]
30,000/week or 6–12 weeks
2000/day 12 weeks
Bulgaria (2019) General
population		 To maintain bone health:
1000–2000/day		 - 50
(20)		 maintenance dose i.e., a prophylactic dose recommended for the general population (see Table 1) Borisova et al. [28]
For extra–skeletal
effects:
2000–4000/day		 - 75–110
(30–44)

2. Current Situation of Vitamin D Deficiency Diagnosis, Prevention and Treatment

Epidemiological studies have documented a high prevalence of vitamin D deficiency worldwide [31]. Data from Europe showed that 25(OH)D concentrations below 20 ng/mL (50 nmol/L) and below 12 ng/mL (30 nmol/L) are observed in 40.4% and 13.0% of the general population, respectively [9]. Therefore, a huge gap exists between the recommendations of nutritional societies regarding dietary reference intakes, as well as target 25(OH)D concentrations, and the actual situation, as documented in large population surveys [32]. Public health actions are, therefore, required to improve the vitamin D status in the general population, but regional differences in vitamin D status, related to factors such as latitude, genetics, lifestyle, body composition, or dietary intake have to be considered [9][32][33][34][35]. A major issue to achieve this task is to harmonize the current heterogeneous efforts and guideline recommendations.

3. Screening of Vitamin D Deficiency in Adults

No published study evaluated the effects of a screening program for vitamin D deficiency in the general population, so the evidence is insufficient to balance the benefits and harms of such a screening [36][37]. Accordingly, it can be stressed that it is currently not justified to recommend a general screening for vitamin D deficiency by measuring 25(OH)D concentrations in the whole general population. Nevertheless, considering that certain groups of individuals or patients are particularly prone to vitamin D deficiency and/or may particularly benefit from vitamin D treatment, it can be suggested, in line with the Endocrine Society, that 25(OH)D measurements should be considered in these groups [14].
Total serum 25(OH)D concentration, i.e., the sum of 25(OH)D3 and 25(OH)D2, is the accepted marker for the assessment of vitamin D status, as it best reflects vitamin D supply by all different sources, i.e., endogenous vitamin D synthesis in the skin, diet, supplements, and mobilization from tissue stores. Previous reports on a relatively high inter-assay and inter-laboratory variability of 25(OH)D measurements underscore the need for assay standardization and laboratory quality assurance [38][39]. In patients with vitamin D deficiency and certain related health issues, e.g., bone diseases, it should be considered to measure additional laboratory parameters, including serum calcium, phosphate, alkaline phosphatase, parathyroid hormone (PTH), creatinine (to calculate the estimated glomerular filtration rate), and magnesium, as these laboratory markers may be useful to guide further diagnostics and treatment of these patients. Measurements of, e.g., serum calcium and creatinine are, however, also advised in patients with 25(OH)D concentrations above 100 ng/mL (250 nmol/L), as vitamin D oversupply/toxicity may lead to hypercalciuria, followed by hypercalcemia, potential acute kidney disease, and vascular calcification. Hypercalcemia does, however, usually not occur at 25(OH)D concentrations below 150 ng/mL (375 nmol/L) [40]. There are hardly any contraindications to correct vitamin D deficiency by vitamin D supplementation (e.g., kidney stones are per se no contraindication) except of rare conditions with an increased sensitivity to vitamin D treatment, such as inherited 24-hydroxylase-deficiency [41]. This is a rare genetic disorder in which catabolism of vitamin D metabolites is impaired, leading to hypercalcemia, low PTH concentrations, and relatively high serum 25(OH)D concentrations along with an increased risk of nephrolithiasis [41]. If such a disease is suspected, the measurement of 24,25-dihydroxyvitamin D, in a specialized laboratory, aids in the diagnosis as a high ratio of 25(OH)D to 24,25-dihydroxyvitamin D suggests this disease that is further confirmed by genetic analyses [41].
Classification of vitamin D status and its terminology, according to 25(OH)D concentration, remains a controversial issue in the scientific literature [7][16][21]. Being aware that it is an individual continuum from vitamin D deficiency to a sufficient and optimal vitamin D status, as well as to vitamin D toxicity, it can be suggested that a classification system. It should be kept in mind that such a general classification of vitamin D status cannot take into account variations in the individual sensitivity to vitamin D effects that may be due to genetic polymorphisms, epigenetic or nutritional factors (e.g., magnesium status), as well as co-morbidities or medications [42][43][44][45][46].

4. Prevention of Vitamin D Deficiency in Adults

Most nutritional vitamin D guidelines conclude that vitamin D requirements are met for the vast majority (i.e., 97.5%) of the population when achieving a target 25(OH)D concentration of at least 20 ng/mL (50 nmol/L) [11][12]. Recommended dietary reference intakes for vitamin D usually range from 600 to 800 international units (IU) (40 IU are equal to 1 µg) per day and should ensure a sufficient vitamin D status under conditions of minimal-to-no sunlight exposure [11][12][13][16][47][48]. These vitamin D intake doses were calculated according to meta-regression analyses of so called “winter RCTs” to estimate the dose-response curve of vitamin D intakes and achieved serum 25(OH)D concentrations without relevant endogenous vitamin D synthesis in the skin [11]. It is a major limitation of most nutritional vitamin D guidelines that they performed meta-regression analyses based on aggregate data because such an approach does not adequately capture between person variability in the treatment response [47][48]. Using individual participant data instead of aggregate data for meta-regression analyses, as a superior methodological approach, results in significantly higher vitamin D intakes to achieve certain target 25(OH)D concentrations [47][48]. Individual participant data meta-regression analyses and single RCTs suggest that an overall vitamin D intake of about 1000 IU of vitamin D per day is required to maintain 25(OH)D concentrations of, at least, 20 ng/mL (50 nmol/L) in 97.5% of the population [48][49]. Therefore, a vitamin D supplement dose of at least 800 IU per day is recommended when targeting a sufficient vitamin D status, i.e., a 25(OH)D concentration of at least 20 ng/mL (50 nmol/L). Of course, it can be improved and maintained vitamin D status by consuming natural or fortified food sources, but vitamin D intake by diet is usually in the range of about 100 to 200 IU per day in the general population [31][50].
In detail, a vitamin D supplementation dose of 800 to 2000 IU per day is recommend for adults who want to ensure a sufficient vitamin D status, with up to 4000 IU per day for certain groups, particularly for patients with obesity and malabsorption syndromes, as well as for individuals with a dark skin pigmentation (see Table 3). The relatively wide dose ranges for vitamin D account for various differences in the dose-response relationship for a given supplemental vitamin D dose and the achieved 25(OH)D concentration with higher dose requirements with increasing body weight and vice versa [51][52][53][54][55][56][57][58]. If a clinician is asked by a random individual which vitamin D dose is safe and very likely avoids vitamin D deficiency, a dose of 800 to 1000 IU per day should fulfill these criteria for the vast majority, even if individual characteristics, including the 25(OH)D status, is unknown. It should, however, also be noted that a few health authorities and experts consider a 25(OH)D concentration, of at least 10–12 ng/mL (25 to 30 nmol/L), as a reasonable treatment target that can be achieved by supplementation of 400 IU of vitamin D per day [11][13][16][47].
Daily, weekly, or monthly vitamin D supplementation, at equivalent doses, lead to similar increases in 25(OH)D serum concentrations, when measured after 2 to 3 months [59][60][61]. Adherence may be better with intermittent vitamin D dosing, but there are also concerns that high intermittent vitamin D doses may be less beneficial or might even be harmful in certain settings [61][62][63]. In view of the available evidence from clinical vitamin D trials and some pathophysiological considerations (e.g., altered vitamin D metabolism with high intermittent vitamin D doses), a daily vitamin D dosing schedule should rather be preferred, but when exceedingly high intermittent vitamin D doses are avoided, a weekly or monthly dosing schedule can also be applied [60][61]. The panel members could not reach a clear consensus on a clear cut-off for exceedingly high vitamin D doses, but single doses above about 50,000 IU of vitamin D should rather be avoided. Due to superior evidence regarding clinical benefits and dose-response, the vitamin D3 (cholecalciferol) is preferred over vitamin D2 (ergocalciferol) for the prevention of vitamin D deficiency [45][64].
Table 3. Statement regarding prevention of vitamin D deficiency in adults.
Table
Consensus Statement Consensus Voting Scale Level of Agreement
In healthy adults without other risk factors, a supplementation of 800–2000 IU/day, for those who want to achieve a targeted/measured 25(OH)D concentration, should be considered during wintertime (mainly November-April) due to insufficient endogenous dermal vitamin D synthesis and depending on the body weight.
Due to decreased skin synthesis in elderly (>65 years), a supplementation of 800–2000 IU/day is recommended throughout the year.
In hospitalized/institutionalized individuals, a supplementation of 800–2000 IU/day is recommended throughout the year.
Women planning a pregnancy should start or maintain the vitamin D supplementation as recommended for healthy adults without other risk factors (800–2000 IU/day). The vitamin D supplementation should be continued throughout pregnancy and lactation.
In certain patients/individuals or conditions 2–3 times higher vitamin D dosages, without using vitamin D doses above the UL of 4000 IU/day, are recommended for prevention compared to healthy adults without other risk factors:
Malabsorption (e.g., cystic fibrosis, inflammatory bowel diseases, bariatric surgery, radiation enteritis)
Obesity (BMI ≥ 30 kg/m2)
Dark skin pigmentation
As vitamin D metabolites are stored in fat and other tissues and gradually released into the blood circulation, a daily or weekly or monthly supplementation regimen is equally effective and safe, if monthly doses are not exceedingly high, for the prevention of vitamin D deficiency.
A tailored approach for vitamin D administration, involving the patients’ preferences of the supplementation regimen (daily, weekly, monthly) might enhance the adherence to preventive vitamin D supplementation.
For the prevention of vitamin D deficiency, the supplementation of oral cholecalciferol (vitamin D3) is recommended.		 9 (strongly agree) 30%
8 20%
7 (agree) 50%
6 0%
5 (neutral) 0%
4 0%
3 (disagree) 0%
2 0%
1 (strongly disagree) 0%
   
Overall agreement 100%, consensus endorsed

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Subjects: Nutrition & Dietetics
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INGVARS RASA
,
Pawel Pludowski
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Mihail Boyanov
,
Zhanna Belaya
,
Camelia Diaconu
,
Tatiana Mokhort
,
Nadiia Zherdova
,
Stefan Pilz
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Update Date: 22 Apr 2022
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