Prevalence of vitamin D level disorders in therapeutic patients and features of their correction

Introduction

Vitamin D belongs to a group of vital elements that have a wide safe dosage range in acute administration but cause severe injuries to the internal organs and the musculoskeletal system under prolonged hypo- and hyper-states. Particular interest in this vitamin over the COVID-19 infection period was associated with the available data on its significant protective effect under therapeutic doses in cases of bacterial and viral infections, which determined recommendations for its monitoring during the COVID-19 pandemic [1][2][3]. Determination of vitamin D status in a particular individual is based on the proposed gradation of 25 (OH)D concentration in the blood serum. In this context, six value ranges of 25 (OH)D are distinguished depending on its level in the serum from severe deficiency (with values less than 10 ng/ml) through moderate deficiency (values more than 10 ng/ml but less than 20 ng/ml) and insufficiency (concentration vitamin D level ≥20–<30 ng/ml) to possible toxic effects (vitamin D levels greater than 100 ng/ml). Adequate concentrations of 25 (OH)D are considered to be 30–60 ng/ml as reflected in Russian [4] (Russian Osteoporosis Association) and international recommendations (International Osteoporosis Association).

Investigation of the vitamin D place in the human body has shown that in addition to well-known tissues whose functions depend on this vitamin level (intestines, bone tissue, calcium metabolism), the mandatory participation of the local regulatory mechanisms in maintaining vitamin D concentration was evidenced in almost all tissues [5]. Patients of rheumatological and cardiological profiles have factors a priori leading to a decrease in bone tissue density such as rheumatoid arthritis, limitation of physical activity, certain drug administration, and decreased glomerular filtration rate, which cannot be corrected in the majority of patients of this cohort. However, the vitamin D level is a correctable factor, which not only is considered one of the indicators of osteoporosis risk but also affects the calcium metabolism in the body, the immune defense state in general, and the prevention of respiratory infections [6].

Of particular interest are the works by Amado Diago et al. (2016), which showed the ability of native forms of vitamin D to activate the transcription of antimicrobial proteins cathelicidin and β-defensins through cellular receptors in monocytes, neutrophils, epithelial cells, and keratinocytes, which explained the vitamin D participation in the prevention and treatment of infectious diseases [7].

According to the draft clinical guidelines “Diagnosis, treatment and prevention of vitamin D deficiency in the adults”, designed by the public organization “Russian Association of Endocrinologists” [4], the following effective and safe regimens for correction of vitamin D deficiency in adults have been demonstrated: 50,000 IU weekly for 8 weeks orally; or 200,000 IU monthly for 2 months orally; or 150,000 IU monthly for 3 months orally; or from 6,000 to 8,000 IU daily for 8 weeks orally. The choice of the regimen is determined by patient compliance. For adults with achieved the target vitamin D level, the durations of maintenance therapy and effective maintenance therapy have not been determined. According to a number of studies, a daily dose of 2000 IU may not be enough to achieve such indicators [8][9], while lower doses (900–1800 IU per day) were revealed effective in some studies [10], which is confirmed by the experience of domestic experts [11][12] and requires dynamic determination of vitamin D concentration in clinical practice.

In view of the above, it was of interest to investigate the regional peculiarities of vitamin D level alterations, as well as its dependence on concomitant pathology that generally determined the purpose of the study.

The purpose of the study is to investigate the prevalence of vitamin D level alterations among therapeutic patients and their correction features.

Materials and methods

The study was conducted in accordance with international GCP standards between January 2021 and April 2022. The laboratory data of 322 patients who applied for consultation with a rheumatologist and cardiologist were analyzed. The determination of 25(OH)D in the blood was carried out using chemiluminescent immunoassay in the laboratory SMLab (Krasnodar), CLLAB (Krasnodar), and the clinical diagnostic laboratory of the regional clinical hospital No. 2 (Krasnodar). According to the interpretation of the Russian Association of Endocrinologists 2021, the level of 25(OH)D was regarded as adequate at a level of 30–100 ng/ml (75–250 nmol/l); vitamin D insufficiency was determined at values of ≥20–<30 ng/ml ( ≥50–<75 nmol/l); deficiency was estimated at its concentrations <20 ng/ml (<50 nmol/l), and severe deficiency was set in cases of vitamin D values <10 ng/ml (<25 nmol/l); target vitamin D levels were 30–60 ng/mL (75–150 nmol/L); levels with possible vitamin D toxicity were ˃100 ng/mL (˃250 nmol/L). The array of information on drug therapy for identified vitamin D disorders was also analyzed. After creating the research matrix in the Excel software, the statistical processing of the data was carried out using the Attestat software. The normality of distribution was assessed using the Kolmogorov and Smirnov tests. The mean, standard deviation, median, and quartiles (25th, 75th) were used to describe quantitative data. Shares and percentages were calculated to describe qualitative parameters. When testing statistical hypotheses, the critical level of significance was taken equal to 0.05.

Results

The age of the examined individuals ranged from 19 to 85 years with an average of 53.6±14.3 years. The study population was predominantly female (81%). The structure of diagnoses in descending order was as follows: osteoarthritis (32.0%), rheumatoid arthritis (19.9%), hypertension (17.4%), osteoporosis (8.1%), and hyperuricemia (4.0%). In 9.9%, the diagnosis was not established at the first visit. All patients referred to a rheumatologist and cardiologist had their vitamin D levels determined. The average vitamin D level in patients was 27.8±14.4 ng/ml, and its range was from 5.1 to 119.1 ng/ml. The results on the frequency of occurrence of individual levels of vitamin D retrieved from the present investigation and data from a multicenter non-interventional study conducted in different regions of the Russian Federation in 2020 [13], as well as the reliability of the differences obtained, are presented in Table 1:

In the previous screening studies conducted in 2013 among 38 general medical patients, the proportion of individuals with vitamin D deficiency was 36.8% and those with insufficiency was 44.74% [14]; under the examination of 300 rheumatology patients conducted in 2021, the target values for vitamin D were not revealed although individuals with vitamin D deficiency and insufficiency were identified in equal proportions (50.0%) [15].

In this examination, a quarter of individuals (25.6%) had target levels of vitamin D (30–60 ng/ml), which we are inclined to explain by the emphasis on this supplement against the backdrop of the COVID-19 infection pandemic.

Analysis of the characteristics of drug therapy in the examined cohort of patients with impaired vitamin D levels (severe deficiency, deficiency, insufficiency) revealed a high frequency of administration of glucocorticoid with various regimens (prednisolone, methylprednisolone in short courses or continuously) in 21.4% of the examined individuals, while 50% of patients have been taking proton pump inhibitors for a long time mode. Systematic administration of vitamin D in any dose was not revealed among these patients. Among individuals with normal concentrations of 25(OH)D (30–100 ng/ml), 17% of them regularly took vitamin D at a dose of 1000 to 10,000 IU per day, on average 2000 [ 1250; 4750] IU per day, the remaining patients of this group used irregular medications although doses were indicated from 5000 to 20,000 IU.

Discussion

Vitamin D enters the body in two ways: it goes with food and is synthesized in the skin under the effect of ultraviolet radiation. Solar ultraviolet radiation is more significant as a source of vitamin D for humans. The main climatic factors predisposing to vitamin D deficiency in Russia are the setting in northern latitudes above the 40th parallel, few sunny days, and low average annual temperature [4]. Thus, according to a multicenter noninterventional study conducted in different regions of the Russian Federation in 2020, the proportion of individuals with impaired vitamin D levels was 84.01% [13], and according to the present investigation, it was 72.7% (p<0.00001), which is consistent with the results of other domestic studies [16] and may reflect the regional peculiarity of the “sunny Kuban”. In a multicenter noninterventional study, the proportion of individuals with vitamin D deficiency [13] was 56.4%, and 27.9% with its insufficiency. Meanwhile, in the present investigation, the proportion of individuals with vitamin D deficiency (less than 20 ng/ml) was 28.4% (p < 0.00001) and with its insufficiency (20–30 ng/ml) was 44.3% (p < 0.00001)). The obtained discrepancies can be explained by the fact of uncontrolled administration of vitamin D preparations in recent times by the population, which is fraught with the development of overdose [17]. Thus, in the present investigation, individuals with normal vitamin D levels (30–100 ng/ml) consumed vitamin D daily at a dose of 2000 IU, although the Russian Association of Endocrinologists recommends taking 800–1000 IU of vitamin D per day to maintain adequate vitamin D level. However, vitamin D toxicity is rare but some literature reports describe cases of hypercalcemia and hypercalciuria when taking high doses of vitamin D (8000–12,000 IU per day) [17][18][19][20].

Vitamin D has skeletal and extraskeletal effects in the body. The skeletal effects of vitamin D include preventing the development of rickets in children and osteomalacia in adults; it is also used for the prevention and complex treatment of osteoporosis along with calcium supplements [21][22]. The present investigation shows that among patients of therapeutic and rheumatological profiles, risk factors for osteoporosis were found with high frequency and included female gender (81%), years old (average age 53.6±14.3 years), and drug administration (proton pump inhibitors and glucocorticoids were taken in 50% and in 21.4% of cases, correspondently). Among the extraskeletal effects of vitamin D, its impact on the cardiovascular system deserves special attention as an inverse relationship between the 25 (OH)D level and hypertension has been revealed [23][24]. Animal studies strongly support the 1,25(OH)D-mediated reduction of renin expression and RAAS (renin-angiotensin-aldosterone system) activity through its interaction with the vitamin D receptor [25]. The recent discovery of vitamin D functioning as a potent negative endocrine regulator of renin gene expression provides some insight into the development of hypertension [26]. However, data on the relationship between vitamin D and incident arterial hypertension are conflicting [27][28][29].

Thus, patients of a rheumatologic profile require repeated laboratory tests to monitor the vitamin D level and preventive interventions in the case of its deficiency [30][31]. For patients of a cardiac profile, additional research should be carried out for further determination of the 25(OH)D role in the prevention and treatment of arterial hypertension.

Conclusion

The present investigation showed that among patients of the therapeutic profile, who applied for consultation with a rheumatologist and cardiologist, there was a high prevalence of vitamin D deficiency and insufficiency in combination with risk factors for the development of osteoporosis, which justifies the need to monitor vitamin D concentrations in this cohort of patients. However, it should be noted that recently there has been a tendency toward a decrease in the proportion of individuals with vitamin D deficiency and a simultaneous increase in the proportion of individuals with less severe forms of its insufficiency. There remains a need for various forms of public information regarding the recommended adequate serum level of vitamin D and safe dosages of vitamin D supplements for daily administration. “Patient schools” and newsletters may be used for this purpose. The authors believe that such interventions will not only increase patient devotion to active monitoring of treatment results but also prevent emerging cases of hypervitaminosis D.