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UDC 615.356:577.161.2:577.161.5
EFFICIENCY OF USE OF COMBINED VITAMIN COMPLEX: VITAMIN D AND VITAMIN K (LITERATURE REVIEW)
Altai State Medical University, Barnaul
L.A. Kostyuchenko, N.S. Kharitonova, V.M. Vdovin
In the present literature review, the data on the role of two vitamins D and K involved in the regulation of calcium metabolism, as well as other physiological and pathophysiological processes in the human body is provided. Taking into account the modern data, the relationship between the level and effects of vitamin K and vitamin D on calcium metabolism in bone tissue is discussed.
Key words: vitamin D, vitamin K, osteoporosis, extraosseous effects of vitamin D.
Role of vitamin D in the regulation of bone structure
The amount of calcium contained in human bone tissue is in a state of direct dynamic equilibrium with the concentration of this ion in human plasma. Thus, a stable level of its circulation in the blood is maintained. At the same time, 99% of calcium is contained in bone tissue, and the remaining 1% is accounted for by blood plasma, muscles, brain cells and also skin. Despite such a small percentage of calcium in these organs, its biological activity is very high - it acts as a regulator of muscle contraction, including the heart muscle, participates in the mechanisms of synoptic transmission of impulses, changes nervous excitability, affects the permeability of cell membranes, participates in blood coagulation processes, etc.
By themselves, the bones of the skeleton are not an inert place of calcium deposition. Old calcium deposits in them are destroyed, the new ones are formed in their place. The speed of this process, called the turnover rate, varies significantly with age.
In infants, up to 100% of the calcium in the bones can be replaced during the first year of life. In older children, the calcium turnover is about 10% per year, while in adults, the figure does not exceed 2-3%. The increase in bone mass occurs mainly in childhood and adolescence, while the trabec-ular (spongy) bone reaches its peak (maximum) mass at 12-16 years, and cortical - at 20-24 years. The peak of bone mass is reached by 25-30 years, and in 40-50-year-old people, bone mass usually begins to decrease (up to about 1% per year), since bone resorption may begin to predominate over its formation. Bone mass loss accelerates during menopause - during the first 5 years of menopause, the bone mineral density (BMD) index may decrease to 5% per year. Peak bone mass is an important predictor of risk of fractures in the period of maturity and aging of the body. The magnitude of the peak of bone mass is influenced by genetic (60-85%) and hormonal, as well as environmental factors (in particular, physical activity and nutrition) [1]. A huge role in maintaining the desired 30
bone density is played by hormones, including exogenous hormones: vitamins D and K.
Calcium is a hardly digestible element that enters the body with food through the small intestine, being absorbed mainly in the duodenum. Here, fatty acids form complex compounds with calcium salts, which are then absorbed by the villi of the intestines. Calcium absorption in the intestine occurs in two ways: transcellularly (transcellu-larly) and intercellularly (paracellularly). The first mechanism is mediated by the action of the active form of vitamin D (calcitriol) and its intestinal receptors. It plays an important role in low and moderate intake of calcium from food. With an increase in the calcium content in food, the intercellular transport of ion begins to play a leading role due to the significant gradient of its concentration.
For effective absorption of calcium, fat-soluble vitamin D is necessary. Without it, and also without fatty acids, calcium cannot overcome the barrier between the gastrointestinal tract and blood. Vitamin D enhances calcium absorption in the small intestine by inducing the synthesis of calcium-binding protein by enterocytes, and also increases calcium reabsorption in the renal tubules.
Vitamin D increases the permeability of the cy-toplasmic membrane of cells of the intestinal epithelium for calcium, as a result of which it enters the enterocytes along an electrochemical gradient. This process of calcium transport can be mediated through the nuclei of target cells by stimulating of transcription of DNA and RNA by vitamin D [2], which is accompanied by an increase in the synthesis of specific transport proteins, for example, calcium binding protein [3], including calcium transport from enterocytes to the blood.
Influencing the kidneys, vitamin D enhances the reabsorption of calcium in them. In addition, vitamin D stimulates the absorption of phosphates and magnesium from the intestines, and also participates in the final differentiation and maturation of osteoblasts, without which normal bone tissue formation is impossible [4, 5].
Thus, maintaining a normal concentration of this vitamin in the body is of paramount impor-
tance for mineral metabolism. Thus, by hypocalcemia, vitamin D affects the bone architecture like parathyroid hormone (PTH), i.e. increases bone resorption and at the same time calcium absorption in the intestine. When vitamin D is deficient, only 10-15% of calcium and 60% of phosphorus from food are adsorbed in the intestine [6].
Extraosseous effects of Vitamin D
All of the above effects of vitamin D in the body is not limited. Recent studies have shown the effect of vitamin D on the immune system [7]: in particular, by stimulating transforming growth factor TGFbeta-1 and the production of interleukin 4 (IL-4), vitamin D suppresses the inflammatory activity of T-lymphocytes, allergic and autoimmune disorders, for example, such as juvenile diabetes, rheumatoid arthritis, etc. [8-14]. Vitamin D and calcium prevent the development of muscle weakness, is necessary for the functioning of the thyroid gland and normal blood clotting. A number of studies show that by improving the absorption of calcium and magnesium, vitamin D helps to restore the myelin sheaths of neurons [15-16], so it is included in complex therapy for multiple sclerosis and participates in the regulation of blood pressure and heart rate (in particular, by hypertension in pregnant women) ). Its deficiency is associated with common diseases such as Alzheimer's disease and schizophrenia [17]. Vitamin D affects cell proliferation, differentiation and apoptosis, and also modulates the activity of the immune system. Apoptosis is important for the elimination of tumor cells. So, vitamin D through the immu-nomodulating activity of its own receptor causes the death of cancer cells. In this process, vitamin D affects the transcription of genes involved in the regulation of cell growth, division and apop-tosis [18]. These effects make it effective in the prevention and treatment of cancers of the breast, ovaries, prostate, brain and leukemia [19-26].
Vitamin D realizes its biological effects through genomic and extragenomic mechanisms. Extrag-enomic mechanisms involve the effect of vitamin D on signaling pathways in cells of the immune and nervous systems. The mechanism mediated through the genetic material of the cell is the most important mechanism for the effects of vitamin D. The vitamin D receptor regulates the expression of several thousand genes in the human genome [27]. Thus, vitamin D is one of the key factors for maintaining genome stability.
Recent studies have shown that children with vitamin D deficiency are more likely to be obese [27]. It has been established, that in the development of obesity, the violation of the activity of insulin-like growth factor-1 (IGF-1) is significant. This regulatory peptide is one of the most important factors supporting the balance between adipose and muscle tissue. By the deficiency of IGF-1 ac-
tivity, adipose tissue begins to predominate over the muscle one [28]. As a result, atherosclerosis and vascular calcification are accelerated. Vitamin D stimulates the synthesis of IGF-binding proteins, which prolongs the half-life of IGF-1, thereby enhancing anti-atherosclerotic effects. Consequently, vitamin D deficiency can be associated with obesity [29], high BMI [30], insulin resistance [31] and an adverse effect on insulin secretion [27].
There is a fairly large amount of data on the effects of vitamin D on the regeneration of skin and body tissues. It is known that diabetes mellitus occurs with characteristic changes in the skin: hyperpig-mentation and dryness of the elbows, dull appearance of the skin of the face, itchy skin, a tendency to form pustular elements. Such changes are associated with impaired insulin receptor activity (insulin resistance). Active forms of vitamin D alter the expression of the insulin receptor gene, increasing their density and activity in the kidneys, liver and adipose tissue. At the same time, vitamin D regulates the transcription of fibroblast growth factor necessary for the implementation of the healing process of wounds [32], which is very important in the treatment and prevention of diabetic foot in patients with diabetes mellitus. The vitamin D receptor regulates the expression of interleukins, tumor necrosis factor, affects the production of antimicrobial peptides, which are endogenous "antibiotics", synthesized to maintain the immunity of the skin and other epithelial surfaces. Vitamin D contributes to wound healing, skin recovery by psoriasis and atopic dermatitis [27].
Vitamin D enters the human body in two ways: with food rich in this vitamin (fatty fish, fish oil, dairy products with normal fat) [4], and from the skin, where vitamin D is formed from a cholesterol-like substance under the influence of sunlight. If the body receives a sufficient amount of ultraviolet radiation on the open surface of the skin, the need for vitamin D is fully compensated [33, 34]. However, having considered this process in more detail, it is easy to see that it is quite difficult for a modern city dweller to avoid hypovitamino-sis, because the amount of vitamin D synthesized in the malpighian and basal layers of the epidermis under the action of sunlight depends on factors such as:
- wavelength of visible light - the most effective is the average spectrum of UV-B waves, the wavelength is 290-315 nm;
- intensity of UV-B radiation. The sufficiency of UV-B radiation for the synthesis of vitamin D is observed only at certain times of the day: from about 11 to 14 hours [35]. Most of the territory of Russia is located in a zone of low insolation (north of 40 ° latitude), and most of the settlements are characterized by a small number of sunny days per year (from 40 to 70 days) [36]. At the same time, UV-B radiation, necessary for the synthesis of vi-
tamin D, does not reach the Earth's surface in all regions of the country [37];
- the level of the atmosphere pollution. Industrial emissions and dust do not transmit the spectrum of ultraviolet rays that potentiate the synthesis of vitamin D. This explains, in particular, the high prevalence of rickets in children living in industrial cities [38];
- initial pigmentation of the skin. The activity of the synthesis of vitamin D is inversely related to the degree of skin pigmentation [39, 40], the synthesis of vitamin D gradually decreases with increasing tanning [7];
- age. Aging skin loses its ability to synthesize vitamin D [41];
- physical activity. A rather active transition of the synthesized vitamin D from the epidermis into the bloodstream occurs during active exercise. Hypodynamia significantly reduces the content of cholecalciferol synthesized in the skin into the bloodstream [42].
In addition, it is known that calcitriol can be synthesized not only in the kidneys, but also in the cells of the pancreas, stomach, large intestine, epidermis, vascular endothelium, as well as in macrophages and placenta, which indicates para- and autocrine function.
Currently, there are many works proving the presence of vitamin D deficiency in the modern inhabitant of northern latitudes [43-52,37], as well as the deficit of Ca and osteoporosis. Low levels of vitamin D are associated with an increased risk of bone fractures. Vitamin D deficiency can contribute to weakness in the muscles of the proximal limbs, slowing down the walking speed, difficulty getting up from a sitting or squatting position, as well as lifting heavy objects [27].
Vitamin D with calcium supplements is used for the prevention and complex treatment of osteoporosis in a number of developed countries [53]. Vitamin D preparations are prescribed individually to patients, based on laboratory data on the concentration of this vitamin in the blood plasma [37]. In cases of improperly selected dosage or prescription of drugs without laboratory control, an overdose effect is possible. And at the same time, applied therapy does not always achieve the desired effect. Hypervitaminosis D is fraught with various consequences, the most important of which is abnormal calcification (deposits in vessels, kidneys and other tissues: deposits in the mammary glands, heel spurs) [54].
Depositing in the vessels and giving them rigidity, precious calcium seriously harms the body. In addition, calcium is often deposited in cholesterol plaques, making them very dense. As a result, the lumen of the vessel narrows, and its wall collapses. All this leads to thrombosis or rupture of blood vessels, and therefore to heart attacks, strokes and internal hemorrhages. Calcium
in the arteries is now more dangerous than diabetes, elevated cholesterol and hypertension [55]. In such cases, calcium, having overcome with such difficulty the barrier of the gastrointestinal tract, can have an adverse effect on the body.
Exactly the disturbances in the distribution of calcium in the body (arising primarily due to calcium deficiency), and not some kind of imaginary "excess consumption" of calcium, can be the cause of both atherosclerosis and osteoporosis. Osteoporosis and vascular diseases are comorbid conditions (results of 25-year observations of the Framingham cohort) [56]. A large-scale study of intima wall thickness and density of lumbar bones showed that intimal wall thickness (an indicator of atherosclerosis progression) is inversely proportional to bone density (reflecting the state of the body's calcium depot) [57]. Calcium supplementation leads to an improvement in vasodilation of vessels and significantly reduces cardiovascular risk [58]. It should be noted that the intake of calcium preparations in doses that meet the recommended daily intake is completely safe [27].
The value of vitamin K
It is known that, having entered the blood, calcium should reach its destination - bone, muscle and other tissues, and not circulate infinitely in too large quantities in the bloodstream.
However, calcium alone cannot do this. It needs a carrier, which is a vitamin K-dependent protein. It delivers calcium to the bone tissue and organs -muscles, heart, brain. For a long time, vitamin K has not been given such great importance, since it was believed that there is no hypovitaminosis K, and the only purpose of vitamin K is to regulate the formation of vitamin K-dependent coagulation factors (II, VII, IX, X, proteins C and S), affecting blood clotting [59, 60].
In fact, the physiological function of vitamin K is much broader. Vitamin K is a fat-soluble vitamin that, in addition to hemostatic, plays a significant role in the metabolism in bone and connective tissues. To begin with, vitamin K consists of a mixture of several similar substances, the main of which are K1 (phylloquinone) and K2 (menaqui-none) [61]. Phylloquinone is close to chlorophyll, is located in the green part of plants of vegetable greens (parsley, dill, spinach, sorrel, carrots, beets, turnips, as well as in all kinds of cabbage, zucchini, cucumbers, tomatoes, legumes, apples, nuts) and comes from the duodenum into the blood, where it presents for short, 2-3 hours, in contrast to K2 (6-8 hours). Vitamin K2 (menaquinone) is synthesized by the normal microflora (E. coli) of the large intestine, and also comes from fatty foods (fermented cheeses and soy products, beef liver, egg yolks, butter are rich in them). Both forms of vitamin K affect calcium metabolism, but K2 has a more powerful effect than K1 [62].
Vitamin K is involved in the synthesis of 16 proteins (ten in the liver and six other tissues). These proteins undergo carboxylation with the participation of the corresponding enzyme (vitamin K is a cofactor of this enzyme) [63-68], and only after that does the protein bind calcium. It is assumed that the form of vitamin K2 has a greater affinity for these proteins compared to the form of vitamin K1, which explains its greater efficiency [62].
Bone tissue is represented by cellular elements, an organic matrix and minerals. The organic matrix of 90% consists of collagen fibrils, and the remaining 10% are various non-collagen proteins. Osteo-calcin (matrix Gla protein) is the main non-collagen protein synthesized predominantly by osteoblasts. At the same time, osteocalcin belongs to vitamin K-dependent proteins [69]. This protein, important in the formation of bone tissue, promotes the deposition of calcium salts in them. Vitamin K2 provides carboxylation of osteocalcin. Slowing the carboxylation of this protein adversely affects its ability to bind to bone tissue and reduces bone mineralization. It is important that by the lack of vitamin K, less carboxylated forms of osteocal-cin are formed. By a pronounced vitamin K deficiency, part of the osteocalcin remains completely non-carboxylated. These forms have a lower affinity for bone tissue. Thus, the more non-carboxyl-ated osteocalcin in the blood, the lower the bone mineral density [70].
Another important protein is MGP, which, produced by chondrocytes and vascular smooth muscle cells, prevents the deposition of calcium in the vessels [71]. In the presence of a sufficient amount of vitamin K in the body, the process of bone calcification proceeds normally and calcium is distributed in the body correctly [72]. Therefore, vitamin K deficiency is a direct route to osteoporosis and atherosclerosis [73, 74].
It should be noted that not only the prescription of vitamin K2, but simply the prescription of vitamin D reduces the level of non-carboxylated os-teocalcin. In addition, this indicator is considered a risk factor for osteoporotic fractures.
Another mechanism of action of vitamin K on the bone system is the effect on osteoclasts: maintaining programmed death of osteoclasts (apopto-sis) [75], vitamin K maintains a balance between the formation and death of these cells, thereby preventing excessive demineralization of bone tissue. Vitamin K also has other functions: it prevents the oxidative processes in the cells [76] (this effect is especially marked in the cells of the nervous tissue), participates in the synthesis of sphingolipids necessary for the myelin sheaths of the nerves [77], and also helps in regulating the body's inflammatory response (decreases release of some inflammatory mediators, for example, interleukin-6) [78].
Recent studies have shown the positive role of vitamin K in the prevention and treatment of a num-
ber of diseases: viral hepatitis, liver cancer, diabetes, Alzheimer's disease, rheumatoid arthritis [79].
Today we can note the presence of a deficiency of this essential vitamin [80, 81]. Vitamin K1 is found in green leafy vegetables - cabbages, salads, as well as in wheat and other cereals. However, vitamin K2 is not sufficient in them, it is synthesized from vitamin K1 in the body of animals and birds that eat herbs and grains, namely in fatty tissues, and also gets into the milk and all the dairy products. The modern concept of healthy eating says that all foods must be low fatty, i.e. devoid of vitamin K. Animals and birds are almost not fed on green grass and cereals, transferring to forage, deprived of vitamin K1. As a result, they also stopped synthesizing K2 for us. Butter and other dairy products are mostly not useful.
In the low-fat cottage cheese and milk, vitamin K is completely absent. It turns out that healthy food, which we have been strongly promoting in recent years, only harms us. Low-fat cottage cheese has a high calcium content, but a substance that correctly distributes it throughout the body lacks in it. So, lovers of low-fat products who are afraid of the accumulation of cholesterol in the body, are going to suffer from the imbalance of substances in the body. Cholesterol participates in the creation of plaques on the walls of blood vessels, but together with calcium. However, since vitamin K prevents the deposition of calcium on the walls of blood vessels, by sufficient content of this vitamin, cholesterol does not accumulate there. It turns out that truly healthy food, although it contains cholesterol, also includes countering the harmful work of cholesterol.
Another source of vitamin K, which is the normal intestinal flora, also suffers. After all, any problems with digestion can contribute to vitamin K deficiency [82], the main of which today is dysbac-teriosis.
Intake of a large number of different drugs, presence of preservatives, antibiotics in food, increased radiation background - all this leads to the fact that almost everyone is susceptible to disruption of the normal intestinal flora, and therefore, vitamin C deficiency. In addition, hypovitaminosis can cause: ulcerative colitis, celiac disease, shortened small bowel syndrome, gastrointestinal surgery, problems with the function of the pancreas, liver, gallbladder. Drugs, which not only cause dysbac-teriosis, but also many others: anticoagulants, sa-licylates, promote hypovitaminosis [83]. Vitamin K deficiency often develops endogenously, caused by a violation of its formation in the intestine or a violation of absorption. There is some evidence that the aging process itself can contribute to vitamin K deficiency.
So, we can conclude that for most people today there is not only a deficiency of such an important and difficult to digest trace element as calcium, but
also a lack of substances that make its work effective, which creates conditions for the development of osteoporosis and atherosclerosis. Therefore, the prevention of these diseases is necessary, using calcium only in combination with them, i.e. with vitamins D and K [84-86].
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Contacts
Corresponding author: Vdovin Vyacheslav Mikhai-lovich, Candidate of Medical Sciences, Associate Professor, Head of the Department of Pathological Physiology of ASMU, Barnaul. 656038, Barnaul, Lenina Prospekt, 40. Tel.: (3852) 241962. E-mail: [email protected]
Author information
Kostyuchenko Liliya Albertovna, Candidate of Medical Sciences, Associate Professor of the Department of Pathological Physiology of ASMU, Barnaul.
656038, Barnaul, Lenina Prospekt, 40.
Tel.: (3852) 241962.
E-mail: [email protected]
Kharitonova Natalia Sergeevna, endocrinologist of the "Isida" medical center, Barnaul. 656049, Barnaul, ul. Partizanskaya, 132. Tel.: (3852) 622020. Email: [email protected]
