Without this group of biologically active substances (including cholecalciferol and ergocalciferol), the functioning of many organs is impossible. With a vitamin deficiency, bones become brittle and brittle - this is the first sign of vitamin deficiency.
Residents of countries where there is a lot of sunshine are practically not threatened by shortages. Their body synthesizes the vitamin thanks to the rays of the sun. In countries where there is little sun, vitamin D deficiency is often diagnosed.
Vitamin D Metabolism
Vitamin D has a unique metabolism; unlike other vitamins, it is primarily produced in the skin, where exposure to ultraviolet B rays from sunlight causes skin-produced 7-dehydrocholesterol to be converted to vitamin D3 (colecalciferol/cholecalciferol) [1]. Vitamin D intake from food has traditionally played only a minor role, with few natural sources available. Animal sources such as fatty fish, cod liver oil or egg yolks contain vitamin D3, and plant sources such as mushrooms and yeast exposed to sunlight or UV radiation contain vitamin D2 (ergocalciferol) [1–3]. The metabolic pathways and functional activities of vitamins D3 and D2 are generally the same, with the exception of the faster degradation of D2, which allows us in this work to combine them with the term “vitamin D” (by vitamin D we mean vitamin D3 and/or vitamin D2). Despite the high degree of heritability of serum 25-hydroxyvitamin D levels, 25(OH)D found in twin studies, work using genomic wide sequencing (GWAS) shows that serum 25(OH)D concentrations have only a modest (7.5% ) heritability in the form of common single nucleotide polymorphisms. This highlights the major influence of non-genetic factors on the variability of serum 25(OH)D concentrations [4, 5].
Vitamin D itself does not have a biological effect; for this, it must be activated by going through the process of hydroxylation twice [1]. The general metabolism of vitamin D from any source involves, as a first step, hydroxylation to 25(OH)D, which is mediated by various enzymes with hydroxylase activity [1]. Serum 25(OH)D is the major circulating metabolite of vitamin D and is generally considered to best indicate overall vitamin D status because it reflects vitamin D intake from multiple sources. 25(OH)D has a traceable half-life of approximately 2-3 weeks, while vitamin D itself has a half-life of only 1 day, before being converted to 25(OH)D or other metabolites. In the bloodstream, approximately 85 to 90% of 25(OH)D is bound to vitamin D binding protein (DBP) and 10 to 15% is bound to albumin, so less than 1% of serum 25(OH)D is unbound. , free state [6].
Classification of vitamin D status is currently based on total blood 25(OH)D concentrations, i.e. the sum of bound and free fractions 25(OH)D2 and 25(OH)D3. However, it should be recognized that there is ongoing debate about whether measuring free 25(OH)D concentrations may also be useful [6, 7]. Such considerations are based on the fact that free 25(OH)D can cross the plasma membrane due to its inherent lipophilic properties, whereas only a few organs that are critical for vitamin D action, such as the kidneys, parathyroid glands and placenta, are able to take up DBP-associated vitamin D metabolites via endocytosis by the megalin/cubilin complex [6, 7]. The special properties of the free form of vitamin D are currently only the subject of active scientific discussion, since it has been reliably established that 25(OH)D itself is biologically inactive and must undergo an additional, second, stage of hydroxylation at position 1, which mainly occurs in kidneys. Renal 1-alpha-hydroxylase (CYP27B1) converts 25(OH)D to 1,25-dihydroxyvitamin D, or 1,25(OH)2D, which is also called calcitriol or D-hormone. If the rate of 25-hydroxylation in the liver mainly depends on the amount of substrate and reaching a plateau at high concentrations of 25(OH)D in the serum, then 1-alpha-hydroxylation in the kidneys is under strict control of the metabolism of calcium, inorganic phosphorus, and parathyroid hormone (PTH). ) (which stimulates 1-alpha-hydroxylation) and fibroblast growth factor-23 (which inhibits this process) [7].
From a physiological point of view, 1,25(OH)2D functions as a classical steroid hormone, similar to sex or thyroid hormones. After binding of 1,25(OH)2D to the vitamin D receptor (VDR) and dimerization with the retinoid X receptor, this complex translocates into the cell nucleus and regulates the expression of hundreds of genes by interacting with vitamin D-responsive elements in the DNA structure. Because serum 1,25(OH)2D levels are primarily dependent on renal processes and have classical endocrine functions, there is also widespread tissue expression of extrarenal 1-alpha-hydroxylase, which converts 25(OH)D to 1,25(OH)2D at the local (tissue) level, thereby promoting the autocrine and paracrine functions of 1,25(OH)2D. It is important to note that the expression of VDR in almost all human tissues provides a strong scientific basis for postulating that vitamin D is important for overall human health. Further metabolism and degradation of vitamin D metabolites is initiated by 24-hydroxylase (CYP24A1), and after additional steps of hydroxylation and oxidation, the resulting water-soluble metabolites, one of which is calcitroic acid, are excreted in bile and urine [1, 8].
Epidemiology of vitamin D deficiency and insufficiency
Studies of the last decade, when it became possible to accurately and quickly determine vitamin D in the blood, signal a global pandemic of vitamin D deficiency and insufficiency, including on the territory of the Russian Federation [9, 10]. 50–92% of the population around the world have vitamin D levels less than 30 ng/ml, which is considered insufficient. In Europe, serum 25(OH)D concentrations of <12.5 ng/ml and <20 ng/ml, reflecting severe vitamin deficiency and deficiency, respectively, were reported in 13.0 and 40.4% of the general population, and in the USA , where there is a program for adding vitamin D to foods and it is widely accepted as a food supplement - in 6.7 and 26.0% of residents, respectively [11–13].
The explanation for this widespread occurrence of low vitamin D levels is that only 20% of the body's supply comes from food. The remaining 80% is expected to be formed in our skin under the influence of ultraviolet radiation from the sun. In the 1960s To prevent rickets, dosages of vitamin D from 4000 to 5000 IU/day were prescribed. Our diet today is low in wild fish (which is 10 times richer in vitamin D than farmed fish), wild eggs and fresh milk. Nowadays, both children and adults are predominantly indoors, and powerful sunscreen cosmetics are used to prevent melanoma—all of which contribute to the high prevalence of vitamin D deficiency, even in sunny countries [14].
Definition and features of the pathogenesis of osteoporosis
An imminent health problem in a society with a large proportion of elderly people is osteoporosis, which is defined as a systemic skeletal disease characterized by low bone mass and microarchitectural destruction of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture [15]. The WHO study group has proposed common criteria for the diagnosis of osteoporosis based on dual-energy X-ray absorptiometry, which is considered the standard tool for assessing osteoporosis. According to these criteria, osteoporosis is diagnosed if bone mineral density (BMD) is 2.5 or more standard deviations below the mean for young adults [16]. The incidence of osteoporosis increases with age, and the population aged 60 years and over is constantly increasing in many countries due to increasing life expectancy. It is estimated that osteoporotic fractures affect 9 million people annually worldwide [17, 18]. Therefore, the prevention and treatment of osteoporosis is receiving increasing attention throughout the world.
Bone is a dynamic organ that during childhood and adolescence goes through the stage of modeling and accumulation of peak bone mass, with its further maintenance due to bone tissue remodeling throughout the life of the body. Bone remodeling is achieved through coordinated synergy between three different types of bone cells: osteoclasts (bone-dissolving cells), osteoblasts (bone-forming cells), and osteocytes (bone storage and resorption cells). Osteoblasts are derived from mesenchymal stem cells in the bone marrow, which can also differentiate into chondrocytes, myocytes, and adipocytes. Osteoporosis is caused by an imbalance of remodeling, which is a continuous process where mature bone tissue is removed by osteoclasts (bone resorption) and new bone tissue is formed by osteoblasts (bone formation). Excessive bone resorption or inadequate new bone formation during bone remodeling can lead to osteoporosis [19]. For the growth of bone tissue, the accumulation of its peak density, and the maintenance of bone homeostasis, the functions of osteoblasts and osteoclasts are coordinated by a wide range of molecules, and vitamin D plays an important role in this process [20].
Contraindications
There are several contraindications to the use of pharmaceuticals:
- Kidney failure
- Hypercalcemia
- Hypervitaminosis D
- Sarcoidosis
- Urolithiasis disease
- Less than 1 month old
- Kidney diseases
- Urolithiasis disease
- Hypersensitivity to the constituent drugs
- Tuberculosis
The drug is prescribed with caution:
- Bedridden patients
- During pregnancy and breastfeeding
- If a person uses cardiac glycosides
- Children who were born with a small crown size
Vitamin D in the prevention of osteoporosis
Vitamin D deficiency is associated with diseases affecting the skeletal system: rickets, osteomalacia and osteoporosis. Rickets is characterized by impaired mineralization of developing bone tissue and decreased or absent endochondral ossification of the growth plate with subsequent deformation. Symptoms of rickets include bone deformities, swelling of the wrist with an enlarged growth plate, delayed closure of fontanelles, and musculoskeletal pain. Rickets usually develops towards the end of the first year and during the second year of life. Subsequently, clinical signs of vitamin D deficiency become less obvious. In particular, adolescents may develop nonspecific symptoms, such as pain in the lower extremities or difficulty climbing stairs, due to proximal myopathy secondary to vitamin D deficiency [21].
Peak bone mass acquisition during adolescence and young adulthood (before 22–25 years) is influenced by both genetic and lifestyle factors such as vitamin D status, physical activity, and calcium intake [22, 23]. Vitamin D makes a significant contribution to bone mineralization by promoting the absorption of calcium and phosphorus in the intestines, the reabsorption of calcium in the kidneys, and the supply of calcium and phosphorus to the mineralized area of bone tissue. In addition to directly regulating calcium-phosphorus metabolism, vitamin D also indirectly promotes the accumulation of bone mass by stimulating the development of muscle tissue [24]. Bone mass accumulation begins during fetal development and continues throughout childhood and adolescence until the end of the growth period when peak bone mass is reached [25]. A lack of vitamin D in childhood and adolescence leads to decreased bone mass, which can no longer be recovered in the future.
Osteomalacia is a metabolic bone disease that leads to decreased bone mineralization in adults and develops mainly due to impaired vitamin D metabolism [26]. In a study of iliac crest biopsies from 675 women and men from Northern Europe, mineralization defects were present in 25.6% of patients with 25(OH)D levels >30 ng/ml [27]. Thus, vitamin D deficiency in adulthood also leads to decreased bone mass.
Reduced levels of vitamin D in the blood may be associated with the risk of fractures due to osteoporosis. A 7.1-year case-control study compared baseline serum 25(OH)D levels in 400 patients with hip fracture and 400 controls. Lower serum 25(OH)D concentrations were associated with an increased risk of hip fracture: the adjusted odds ratio (OR) for each decrease of 12.5 ng/mL was 1.33, indicating a 33% increased risk of fracture. Thus, serum 25(OH)D concentrations around 20 ng/mL are associated with a higher risk of hip fracture [28]. In another study (involving 1311 elderly Dutch men and women followed for 6 years), low serum 25(OH)D levels (<12 ng/mL) increased the risk of fractures in those aged 65–75 years (relative risk ( RR) 3.1; 95% confidence interval 1.4–6.9), but not in older people (75–89 years), which may be explained by the initially high age-related risk of fractures in these individuals [29].
The effectiveness of oral vitamin D supplementation as a means of preventing fractures in women and men aged 65 years and older was assessed in a meta-analysis of 12 double-blind randomized controlled trials (RCTs) of vertebral fractures (n=42,279) and 8 RCTs of hip fractures (n= 40 886). The pooled RRs were 0.86 (95% CI 0.77–0.96) and 0.91 (95% CI 0.78–1.05) for preventing vertebral fractures or hip fractures, respectively. However, significant heterogeneity was observed for both endpoints. Factors explaining this heterogeneity were different daily doses of vitamin D and correspondingly achieved serum 25(OH)D concentrations. When assessing cases with high dose vitamin D (482–770 IU/day), the risk of vertebral fractures was reduced by 20% and hip fractures by 18%, whereas doses <400 IU/day did not show such an effect [30].
Pooled participant data from 11 double-blind RCTs using oral vitamin D supplements (daily, weekly, or every 4 months) with or without calcium were compared with data from a placebo group or data from a calcium-only group (in those aged 65 years or older). . A total of 31,022 people (mean age 76 years; 91% women) with 1111 hip fractures and 3770 vertebral fractures were included in the study. Participants who were randomly assigned to receive vitamin D, compared with those in the control group, had a 10% reduced risk of hip fracture and a 7% reduced risk of vertebral fracture. A reduction in fracture risk was only shown at the highest level of vitamin D intake in these studies (median 800 IU per day), with a 30% reduction in the risk of hip fracture and a 14% reduction in the risk of any vertebral fracture. The benefits of vitamin D intake were consistent and independent of age, location, baseline 25(OH)D levels, and supplemental calcium intake. A dose of vitamin D of 800 IU/day had a beneficial effect on the prevention of hip fractures and all vertebral fractures in people under 65 years of age [31].
Thus, vitamin D deficiency is one of the main risk factors influencing the development of osteoporosis. Decreased calcium absorption due to insufficient blood levels of vitamin D leads to an increase in PTH with secondary activation of bone remodeling and mobilization of calcium from bone, which is a mechanism of bone loss at any age.
Side effects
With an excess of vitamin D, the following negative manifestations are observed:
- Loss of appetite
- Nausea
- Constipation
- Dry mouth
- Polyuria
- Sleep problems
- Weight loss
- Renal or vascular calcification
- Increase in body temperature
- Weakness
- Polyuria
- Mental disorders
If any of the signs of hypervitaminosis D appear, you should stop taking the medication. Try to reduce the intake of calcium in the body and start taking vitamins A, C, and B.
In some people, taking vitamin D3 leads to allergic reactions.
Vitamin D in the treatment of osteoporosis
In the modern arsenal of a doctor for the treatment of osteoporosis, there are many drugs that increase BMD and reduce the risk of fracture. Almost all drugs are antiresorptive in their mechanism of action (bisphosphonates, denosumab) and only one drug has a bone-anabolic effect - teriparatide. All treatment regimens should include adequate intake of calcium and vitamin D, and the absence of underlying vitamin D deficiency is also essential for the use of parenteral bisphosphonates, which have significant hypocalcemic effects.
Studies have shown that the level of 25(OH)D in the blood is closely related to the effectiveness of antiresorptive therapy [32]. Patients with a mean 25(OH)D value ≥33 ng/mL were 4.5 times more likely to have a favorable response to bisphosphonate therapy and maintain it during treatment. The odds of an inadequate response to bisphosphonate therapy were 4 times higher in patients with 25(OH)D <30 ng/mL (OR 4.42; 95% CI 1.22–15.97) [33]. In patients with vitamin D deficiency during treatment with bisphosphonates, a less pronounced decrease in the resorption marker beta crosslapse is observed, which may reflect less effectiveness of treatment [34].
A group of researchers led by F. Bertoldo [35] showed that 25(OH)D levels can modulate the acute-phase response associated with the first administration of nitrogen-containing bisphosphonates. When vitamin D status normalized, body temperature and C-reactive protein levels decreased.
In a longitudinal clinical study of 40 people with severe chronic periodontitis, patients with baseline vitamin D deficiency (25(OH)D 16–19 ng/mL) had significantly worse periodontal treatment outcomes than patients with sufficient vitamin D deficiency. amount of vitamin D [36]. These data are supported by the work of A. Hokugo et al., who described a 4.7-fold increased risk of bisphosphonate-associated osteonecrosis of the jaw in vitamin D-deficient rats. Oral bone necrosis has been described as a rare complication in patients treated with nitrogen-containing bisphosphonates or denosumab. In rats, increased time of open necrotic bone sequestration was clearly associated with pseudoepitheliomatous hyperplasia in the experiment. The authors suggested that the pathophysiological mechanism underlying osteonecrosis of the mandible may involve an interaction between antiresorptive drugs and impaired functions of vitamin D in skeletal homeostasis and innate immunity [37].
Thus, adequate levels of vitamin D in the treatment of osteoporosis are important not only from the point of view of preventing decompensation of calcium-phosphorus metabolism and increasing the effectiveness of antiresorptive treatment, but can also reduce the likelihood of treatment complications - influenza-like syndrome and osteonecrosis of the mandible.
Treatment and prevention of vitamin D deficiency/insufficiency
Current scientific knowledge suggests that serum 25(OH)D levels should be between 30 and 100 ng/mL to avoid long-term negative health effects. A 25(OH)D concentration of 40 to 60 ng/ml is the target [10, 38, 39]. A 25(OH)D level below 20 ng/ml is considered severe vitamin D deficiency, and a level between 21–29 ng/ml is considered vitamin D deficiency.
To achieve a blood level of 25(OH)D >30 ng/ml in most cases in modern conditions, additional vitamin D intake is required. The recommended drug for the treatment of vitamin D deficiency is colecalciferol (D3), which is explained by the relatively greater effectiveness of colecalciferol compared to ergocalciferol (D2) in achieving and maintaining target serum 25(OH)D levels [40].
According to the clinical guidelines of the Russian Association of Endocrinologists for the diagnosis, treatment and prevention of vitamin D deficiency in adults [39], treatment of vitamin D deficiency (<20 ng/ml) in adults is recommended to begin with a total saturating dose of colecalciferol of 400,000 IU, and for vitamin D deficiency ( 20–29 ng/ml) - from 200,000 IU, with further transition to maintenance doses.
Saturation can be achieved using various treatment regimens.
For vitamin D deficiency (<20 ng/ml), the saturating dose is 400,000 IU:
daily intake of 7000 IU for 8 weeks.
For vitamin D deficiency (20–29 ng/ml), the saturation dose is 200,000 IU:
daily intake of 7000 IU for 4 weeks.
Preventing deficiency/insufficiency and maintaining target vitamin D levels (30–60 ng/ml):
daily intake of 1000–2000 IU continuously.
Vitamin D3 is available in various forms (aqueous and oily solution, capsules, tablets) and dosages. One of the products containing cholecalciferol is the tableted product Detrimax® vitamin D3, which contains the optimal form of vitamin D in a dosage of 1000 IU, which allows for precise dosing in various treatment regimens. Vitamin D3 in the form of an oil solution is presented by the new product Detrimax® Active with a unique pump dosing device that allows you to accurately and quickly measure the required dose of vitamin D in both the range of therapeutic and preventive doses. 1 drop of Detrimax® Active for adults contains 500 IU of cholecalciferol. When dosing, there is no need to turn the bottle over, which makes it easy to use. The dispenser pump will prevent accidental overdose, which is also an advantage over a standard plastic dropper.
Overdose
When consuming large doses of the vitamin, the following occurs:
- Diarrhea
- Nausea
- Polyuria
- Intestinal colic
- Constant desire to drink and constipation
- Vomit
- Depression
- Muscle and joint pain
- Increased potassium loss
- Increased pressure
In special situations, overdose leads to:
- Stone formation
- Visual impairment
- Papilledema
- Calcification of tissues and organs
In case of overdose:
- You should stop taking the drug immediately
- Drink plenty of fluids
- If necessary, do not refuse hospitalization