Vitamin D Dosing: Basic Principles and a Brief Algorithm (2021 Update)

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Abstract

Nowadays, in modern societies, many people can be at high risk to have low vitamin D levels. Therefore, testing of serum 25-hydroxy-vitamin D (25OH-D) levels should be performed before prescribing them vitamin D supplementation. However, in some cases the 25OH-D level assessment is not available at the right moment, e.g., due to mandatory quarantine of COVID-19 outpatients. Therefore, such patients could be advised to start taking moderate vitamin D doses (e.g., 4000 IU/day for adults), and their 25-OH-D levels could be checked later. The proposed algorithm also comprises vitamin D dosing principles when baseline 25OH-D levels are known.

1. Introduction

The numbers of new COVID-19 cases and deaths from COVID-19 are increasing in many countries, despite the availability of different vaccines, more or less strict lockdowns or other state-level infection control measures, and various treatment options. It seems that there is a need for other effective tools for combating the COVID-19 disaster. Vitamin D (Vit. D) was suggested as one such tool [1]. Is it well known that Vit. D, in the form of calcitriol, has a pleotropic activity in human organism [2]. There is some evidence from clinical trials regarding the benefits of Vit. D for COVID-19 patients [3,4,5,6,7], as it was also stated in two recent reviews [8,9]. In the previous paper, the main mechanisms of Vit. D action in regard to COVID-19 infection were already discussed, and some suggestions for Vit. D dosing in the COVID-19 era were proposed [10]. Recently it was suggested that Vit. D might also act as an important cofactor of strengthening the activity of COVID-19 vaccines [11].

It is still debatable if checking the 25-hydroxyvitamin D levels (25OH-D-a marker of Vit. D status) and supplementing with Vit. D should be included in the COVID-19 prevention and treatment guidelines. Nevertheless, diagnosing, preventing, and treating low Vit. D status is still an issue in regard to both COVID-19 patients and the whole population, particularly keeping in mind the reduced accessibility to health care services during the COVID-19 pandemic. The current paper discusses the main Vit. D dosing principles, outlines the most important low Vit. D risk groups, and suggests a brief Vit. dose selection algorithm for clinical practice.

2. Is There a Need for New Guidelines/Algorithms?

During the past 10–15 years, different international and regional guidelines for low Vit. D status prevention and treatment were published (e.g., [12,13,14,15,16]). However, for several reasons, physicians might currently need some new kinds of recommendations for clinical practice regarding Vit. D status evaluation and Vit. D dosing.

Despite the available evidence of vitamin’s D important role for the human organism, including extra-skeletal health and the high prevalence of low Vit. D status in different regions of the world [17,18,19,20,21], many countries still do not have national, up-to-date, approved Vit. D guidelines. The same applies also to Lithuania, which has only the Rickets’ diagnosis and treatment guidelines approved in 2015. Moreover, in most countries, the potential beneficial role of Vit. D for COVID-19 prevention and treatment (i.e., Vit. D as an adjuvant) is still not accepted; consequently, no specialized relevant recommendations are developed. Paradoxically, it is the COVID-19 pandemic that inspired the author of the present article to start developing national Vit. D guidelines for Lithuania. Hopefully, the basic principles of those guidelines presented in the current paper could be an additional source for more specialized future recommendations both for Lithuania and for other countries.

Traditionally, any well-prepared Vit. D guidelines should reflect clinical practice and therefore must include the following domains: definition of risk groups for low vitamin D; principles of evaluation of Vit. D status by using laboratory measurements; and Vit. D dosing for prevention and treatment. However, the COVID-19 pandemic brought some challenges that aggravated our routine clinical practice. Firstly, due to reduced accessibility to health care facilities, mandatory isolation of some patients (due to diagnosed COVID-19 disease or due to close contact with a confirmed COVID-19 case), or a patient’s fear of getting SARS-CoV-2 during visits to a clinic or laboratory, it is not possible to perform the measurements of serum 25OH-D levels at the desired time. Therefore, the recent Vit. D status of many outpatients could remain unknown. Secondly, with the absence of data on recent 25OH-D level measurements, it might be difficult for physicians to make decisions regarding Vit. D dosing, particularly for low Vit. D risk group patients. We need an extended list of risk factors that might suggest the clinician to presume that certain patients could be put into a Vit. D risk group and, consequently, to suggest him/her higher Vit. D doses for supplementation. Finally, even disregarding the potentially beneficial direct Vit. D role on COVID-19 prevention and treatment, it is wise to remember that the problem of low Vit. D in society has not disappeared during the pandemic. Moreover, some people, due to various reasons during lockdowns, may have even higher risk to newly develop Vit. D insufficiency, leading to poorer skeletal and extra-skeletal health [10]. Patients having low 25OH-D levels might be considered as high-risk group for getting severe illness from COVID-19 [22].

In older Vit. D guidelines, there is almost no talk about the causes that could result in failure to achieve the desired levels of 25OH-D by supplementing Vit. D, and the suggested actions for physicians. In the present article, the author also tried, in part, to fulfil those gaps.

It is the Vit. D supplementation that modern guidelines should be mostly oriented to. Production of vitamin D3 in the skin is not a reliable source for repletion of low Vit. D status. Firstly, human skin is able to produce only limited amount of vitamin D3 that can enter the circulation [23,24]. Secondly, it is difficult to predict the effect of solar radiation in regard to vitamin D3 production and its influence on 25OH-D levels, since a large number of factors might affect vitamin D3 synthesis in the skin, e.g., skin type, patient age, time of the day, altitude, etc. [23,25,26]. Finally, in some countries, e.g., Lithuania, that are located at the middle latitudes, the intensity of solar radiation decreases significantly during the cold season, and the synthesis of vitamin D3 in the skin is almost absent during the period from October till March [27,28]. Food, unless fortified with Vit. D, usually cannot serve as a valuable source of this vitamin, too [27,29,30]. Therefore, this paper does not discuss recommendations on exposure to sunlight or influence of certain types of food for prevention or treatment of low Vit. D status.

3. Risk Factors for Low Vitamin D Status

There are a number of diseases and conditions associated with low Vit. D status. Illnesses definitely caused by inadequate Vit. D status comprise only a small part of the group of all risk factors for low Vit. D status. Many diseases, conditions, or drugs per se can impair vitamin’s D metabolism and/or increase the needs for this vitamin, thus contributing to development of low Vit. D status.

In addition, there are a lot of diseases and conditions where low Vit. D status can be considered only as an epiphenomenon. In other words, low Vit. D status itself does not necessarily have cause−consequence relationships with certain diseases or conditions, but it frequently accompanies them and could have common causes. In many cases, an unhealthy lifestyle can act as such a common cause, and low Vit. D status might serve as an indicator of that lifestyle [31,32,33,34].

It is worth to try to identify those risk factors, since some of them can be corrected (or prevented) and this may help to prevent and treat low Vit. D. In addition, COVID-19 disease and low Vit. D status share many risk factors, e.g., older age and obesity [10]. Therefore, considering together those risk factors (including low Vit. D status) can help to correctly evaluate the risk of severe COVID-19 and, in some cases, also advocate vaccination. On the other hand, confirmed symptomatic COVID-19 disease might be considered as risk factor for suspecting low Vit. D status.

For simplicity, risk factors for low Vit. D status can be divided into several groups ( Table 1 ) [12,13,20,24,35,36,37,38,39,40,41]. Patients having one or several risk factors should be tested for their serum 25OH-D levels, since the analysis results helps in making better decisions regarding Vit. D supplementation [12,42,43].

Table 1

Risk factors for low Vit. D status.

4. Evaluation of Vitamin D Status

Vit. D status can be categorized by evaluating serum 25OH-D levels ( Table 2 ) [10,12,24,35,40,44]. For many years, it has been argued that levels of 25OH-D should be at least 50 nmol/L, since this is sufficient to maintain good skeletal health in almost all individuals [20]. However, many experts claim that levels of 75 nmol/L and above are those sufficient to ensure normal skeletal and muscular structure and function [12,24,45,46]. There is growing evidence that minimum 100 nmol/L of 25OH-D levels are needed to reduce the risk of some cancers (e.g., colorectal), cardiovascular disease, infectious diseases, pathological pregnancies (e.g., preeclampsia, gestational diabetes, preterm birth), systemic connective tissue diseases, diabetes, and also COVID-19 [9,14,16,22,41,44,47,48,49,50]. An optimal (at least 100 nmol/L) levels of 25OH-D mean that Vit. D is sufficient for all systems in the human body, not only for bones [16]. Some authors speculated that a laboratory-determined concentration of 100 nmol/L indicates that the true serum 25OH-D levels of the individual are greater than 75 nmol/L [12]. In summary, 25OH-D levels of 75–150 nmol/L should be considered as “normal”. The term “low vitamin D status” used in the present paper comprises both Vit. D deficiency and Vit. D insufficiency, as defined in Table 2 .

Table 2

Vit. D status categories by 25OH-D levels.

* Intoxication category also includes lower 25OH-D levels, if hypercalcemia is caused by vitamin D supplements. 25OH-D–serum 25-hydroxy-vitamin D levels.

5. Vitamin D Dosing Principles

In order to simplify and not to overload the final brief algorithm of Vit. D dose selection, it is reasonable to present both prophylactic Vit. D doses and Vit. D doses for treatment separately. The aim of this article is not to discuss various advices on Vit. D dosing from different guidelines in depth; therefore, only summarized recommendations are presented.

Table 3 presents recommended Vit. D doses for prevention of low Vit. D status in different age groups [12,13,24,51]. In cases of Vit. D deficiency or insufficiency, therapeutic Vit. D doses should be prescribed according to both baseline 25OH-D levels and patient age ( Table 4 ) [12,13,16,24,45,52,53,54,55].

Table 3

Vitamin D prophylactic doses.