Osteoarthritis and osteoporosis

The study of the relationship between osteoporosis and rheumatic diseases of the joints is of great interest not only among rheumatologists, but also among specialists in other fields of medicine. Along with inflammation and therapy with glucocorticosteroids, which are the most universal factors leading to the development of secondary osteoporosis in rheumatic diseases of the joints, there are plenty of other factors that influence the formation of osteopenic syndrome in this group of patients - immobilization, concomitant pathology, especially endocrine, etc.

There are a number of common factors predisposing to development as osteoarthritis and osteoporosis - female gender, old age, genetic predisposition (family aggregation of type I collagen gene, etc.), estrogen deficiency and vitamin D, etc. Osteoporosis is diagnosed in every 5th woman aged 75 years, and osteoarthrosis It is noted in 1 out of 10 people over the age of 50 years and every second person over the age of 75 years. Both diseases play a significant role in the violation of public health, leading to early disability and reduced life expectancy.

Osteoporosis is a systemic skeletal disease characterized by a decrease in bone mass, impaired bone microarchitecture, leading to increased bone fragility and fracture risk (Conference on Osteoporosis, Copenhagen, 1990).

According to WHO experts, osteoporosis ranks third after and cardiovascular disease (cardiology) of diseases of the cardiovascular system and diabetes, and, according to some researchers, is the most common and serious diseases (endocrinology) of human skeletal metabolic disease. First of all, this is due to the frequent development and severity of its complications, among which the most important are pathological bone fractures, including compression fractures of the vertebral bodies, fractures of the distal portion of the forearm bones, neck of the femur, etc. These complications lead to disability and often to premature death of patients from concomitant disorders of the cardiovascular and respiratory systems. For example, the risk of femoral neck fracture in women at the age of 50 years old is 15.6% and it is higher than the risk of developing breast cancer (9%). At the same time, the risk of death is about the same (2.8%). According to the WHO, almost 25% of women under the age of 65 already have vertebral compression fractures, and 20% have forearm bone fractures. In addition, patients with osteoporosis increase the risk of non-traumatic (spontaneous) fractures of the spine and radial bone (32 and 15.6%, respectively). In recent decades, the problem of osteoporosis has acquired a special medico-social significance due to the significant aging of the population of highly developed countries of the world and the corresponding increase in the number of women in menopause.

The problem of osteoporosis is also relevant in Ukraine due to the significant population aging - 13.2 million (25.6%) are people aged 55 years and older, as well as a high percentage of people living in radioactively contaminated areas and having an unbalanced diet. The results of studies conducted at the Institute of Gerontology of the Academy of Medical Sciences of Ukraine showed that from 30 to 80 years the mineral density of compact bone tissue (CTC) decreases in women by 27%, in men - by 22%, and spongy CTC - by 33 and 25%, respectively.. This leads to a significant increase in the risk of fractures and a real increase in their number. Taking into account the data of epidemiological and demographic studies in Ukraine, it can be predicted that 4.4 million women and 235 thousand men have a risk of fractures; only 4.7 million, or 10.7% of the total population.

Abroad, the problem of osteoporosis has been actively developed since the 1960s. And belongs to one of the most expensive medical programs: the treatment of patients with osteoporosis and its complications is a long process, not always effective and requiring significant material costs. If in 1994 the funding of such a program in the United States amounted to $ 10 billion, then in 2020, according to specialists, its cost could increase to 62 billion. Thus, the need for prevention and treatment of osteoporosis and its complications is beyond doubt, and the success prevention depends on the timing of diagnosis of osteoporosis.

[1], [2], [3], [4], [5]

Disorders in the bone remodeling system as a cause of osteoporosis

From the standpoint of modern osteology, bone is studied as an organ of the musculoskeletal system, the shape and structure of which is determined by the functions for which the macroscopic and microscopic structure is adapted. The bone contains cortical (compact) and spongy substance (in the skeleton, respectively, 80 and 20% of the mass), the content of which depends on the shape of the bones. Bone tissue is a mobile reserve of mineral salts, and in the metabolism of bone tissue, the share of compact matter is about 20%, and spongy - about 80%.

The bone cell elements involved in the constant exchange of mineral and organic components between the bone matrix and tissue fluid with pericellular resorption of the bone substance as an essential component of such an exchange are osteoblasts (form bone), osteoclasts (destroy bone) and osteocytes.

During the life of a person, there is a constant renewal of the bone, which consists in resorption of separate parts of the skeleton with the almost simultaneous formation of new bone tissue (remodeling). Each year, from 2 to 10% of the skeleton mass is rebuilt, and this internal restructuring is local and does not change the geometry or size of the bones. It is characteristic of an adult organism, while a growing bone is characterized by morphogenesis — an increase in length and width.

Remodeling occurs in discretely located parts of the bone - the so-called remodeling units, the number of which simultaneously reaches 1 million. Resorption of 100 microns of bone takes about 30 days, the replacement of this bone mass with a new bone occurs within 90 days, i.e. Full remodeling cycle is 120 days. At the tissue level, metabolic processes in the skeleton are determined by the total number of active remodeling units (normally about 1 million) and the remodeling balance - by the ratio of the amount of resorbed and newly formed bone in each unit. The process of bone remodeling is much more active in the trabecular bones than in the cortical.

In practically healthy young people, the rate of bone remodeling in terms of remodeling remains constant: the amount of bone tissue resorbed by osteoclasts practically corresponds to the number formed by osteoblasts. Disturbance of remodeling in the direction of the predominance of resorption processes over the processes of bone formation leads to a decrease in mass and disruption of the structure of bone tissue. Involutive osteoporosis is characterized by reduced bone formation, while in a number of diseases that cause secondary osteopenia, increased bone resorption is observed.

Thus, osteoporosis is considered as a result of impaired bone remodeling processes and usually occurs first in the metabolically more active trabecular tissue, where the number and thickness of the plates and the cavities between them decrease due to perforation of trabeculae. These changes are due to imbalances between the depth of resorbed cavities and the thickness of the newly formed plates.

The process of bone remodeling is controlled by a number of systemic and local factors, all of which together form a system of interaction that is repeatedly duplicated at different levels. Factors of systemic action affect the release and activation of factors of local action, which, in turn, have an autocorporeal or parascopic effect on bone tissue.

Factors affecting bone remodeling

Systemic factors	Local factors
1. Hormones: Parathyroid hormone (PTH) Calcitonin Thyroid Hormones Estrogen Androgens Glucocorticosteroids (GCS) Growth Hormone (growth hormone?) 2. Other factors: Vitamin D ???	Interleukins TNF (-alpha, -beta) TFR (-alpha, -beta) IFR Platelet Growth Factors FRF ? 2 -Microglobulin CSF macrophages Granulocyte macrophage CSF Associated with parathyroid hormone Peptides U-interferon Prostaglandins Bone morphogenesis proteins Vasoactive intestinal peptide Calcitonin gene mediated peptide Large Bone Matrix Protein Other factors?

[6], [7], [8], [9], [10], [11]

Nutritional causes of osteoporosis

There are many nutritional factors that cause osteoporosis. We give the most important of them.

Some nutritional factors causing an increased risk of osteoporosis:

• Various diet disorders
• Insufficient calcium intake with food
• Insufficient intake of vitamin D
• High Protein or Phosphate Diet
• Caffeine
• High Sodium Diet
• Alcohol
• Low intake of fluorides
• scurvy
• Vitamin B ₆, B, ₂, K deficiency
• Deficiency of trace elements (boron, zinc, etc.).

[12], [13], [14], [15], [16], [17], [18]

Disorders of calcium homeostasis or its deficiency

Most scientists now recognize that osteoporosis is a calcium-dependent disease. From 1-1.7 kg of calcium contained in the body of an adult, 99% is part of the skeleton and 1% circulates in the extracellular fluid. The daily requirement for elemental calcium is at least 1100–1500 mg, which is necessary for the normal functioning of organs and systems involved in the metabolism of bone minerals: the digestive tract, liver, kidneys, blood serum and interstitial tissue.

Calcium deficiency occurs due to its nutritional deficiency, impaired intestinal absorption or increased secretion. Important factors are reduced calcium absorption, low concentrations of calcitriol, and target tissue resistance to it. As a result, bone resorption increases to equalize calcium balance. However, differences in calcium intake in different regions of the world cannot explain the difference in the risk of fractures between populations. Thus, femur fractures are very frequent in countries with high calcium intake, for example in the Scandinavian countries and the Netherlands, and vice versa, their number is lower in countries with low calcium intake. This fact confirms the complex pathogenesis of osteoporosis, of which the calcium-dependent mechanism is a component. Perhaps the accelerated loss of bone mass occurs due to increased sensitivity of bone tissue to PTH and, in some cases, due to the reduced sensitivity of renal a-hydroxylase to it. As a result of accelerated bone remodeling, skeletal balance becomes negative; in addition, due to insufficient formation of 1,25- (OH) ₂ D _3, calcium absorption in the intestine is reduced.

Changes in sensitivity to PTH of target organs may be due to estrogen deficiency, especially in the postmenopausal period.

[19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29]

Age aspects of osteoarthritis

Currently, most researchers point to the importance of bone mass laid down during the active formation of the skeleton and the achievement of the so-called peak of bone mass - PCM (in foreign literature - peak bone mass). An analysis of the structural and functional state of bone tissue in children and adolescents of Ukraine, conducted on the basis of ultrasound densitometry and OFA, showed that the main increase in bone mass occurs in children of both sexes aged from 10 to 14 years. PCM, which depends on many factors, is an important determinant of the structural and functional state of the skeletal system in people of older age groups, the development of involutional osteoporosis (postmenopausal and senile) and its complications. According to PI Meunier et al. (1997), a small initial bone mass causes osteoporosis in 57% of cases. This theory is supported by the rarer occurrence of osteoporosis in populations with a large bone mass, for example, in representatives of the Negroid race.

Abroad, the study of indicators of mineral saturation and mineral density of CTC in individuals of different age groups in order to establish patterns of formation and resorption of bone tissue has been carried out for more than 20 years. In Ukraine, such studies are carried out at the Institute of Gerontology, Academy of Medical Sciences of Ukraine, Ukrainian Rheumatology Center (URC), Institute of Spinal and Joint Pathology, Academy of Medical Sciences of Ukraine. Data obtained using single-photon absorptiometry (OFA) based on the URC and the Institute of Spinal and Joint Pathology, Academy of Medical Sciences of Ukraine (Kharkiv).

The currently available literature data on the relationship between osteoporosis and osteoarthritis are contradictory. According to some researchers, osteoporosis and osteoarthritis are rare in the same patients.

Primary osteoarthritis and osteoporosis: similarities and differences (according to Nasonov EL, 2000)

Sign of	Osteoporosis	Osteoarthritis
Definition	Metabolic Bone Disease	Metabolic (degenerative) cartilage disease
The main pathogenetic mechanism	Impaired remodeling (balance of osteoclast-mediated resorption and osteoblast-mediated formation) of bone tissue	Violation of anabolism and catabolism (balance between chondrocyto-mediated synthesis and degradation) of cartilage tissue
Floor	Female	Female
Population frequency	About 30% (> 50 years old)	About 10-30% (> 65 years old)
Complications	Fractures	Dysfunction of the joints
Impact on life expectancy	++ (fractures of the femoral neck); increased risk of myocardial infarction and stroke	+ (decrease by 8-10 years in women, but not in men, as the number of affected joints increases); diseases of the lungs and digestive tract
IGC	Reduced	Elevated or normal
BM bone resorption (Feast, D-Feast)	Elevated	Elevated
The risk of skeletal bone fractures	Elevated	?

Note. Pir - pyridinoline, D-Pir - deoxypyridinoline.

[30], [31], [32], [33], [34], [35], [36], [37], [38]

Hormonal mechanisms of osteoporosis

Most researchers recognize the role of hormones in the control of metabolism and bone tissue homeostasis. It is known that anabolic hormones (estrogens, androgens) stimulate bone formation, and anti-anabolic hormones (for example, GCS) increase bone resorption. According to some researchers, hormones such as PTH, calcitonin and vitamin D are more involved in the regulation of calcium homeostasis than directly affect the functional activity of osteoblasts and osteoclasts.

[39], [40], [41], [42], [43], [44], [45]

The effect of estrogen on bone tissue

• Promote calcium absorption in the intestines, increasing sensitivity to vitamin D;
• stimulate cellular and humoral immunity;
• have antiresorptive effect (affect the processes of activation of osteoclasts);
• stimulate endochondral ossification of cartilage tissue, acting directly on the receptors of chondrocytes;
• stimulate osteoblast secretion by osteoclast suppressors;
• reduce the activity of PTH and the sensitivity of bone cells to it;
• stimulate the synthesis and secretion of calcitonin;
• modulate the activity and synthesis of cytokines (especially IL-6), stimulate the synthesis of IGF and TGF-beta.

Detection of specific high-affinity receptors on osteoblast-like cells indicates the direct effect of estrogens on the skeleton. Osteoblasts secretion of growth factors and estrogen regulation of IL-6 and calcitonin production indicate the possibility of paracrine effects of estrogen on bone tissue.

Also important are the mediated effects of estrogens, in particular their effect on hemostasis. So, it is known that high doses of these drugs reduce the activity of antithrombin III, and low doses (especially of the transdermal forms) speed up the launch of the fibrinolytic system approximately 8 times. This is important in a number of RZS, when the hemostasis system is prone to jugipercoagulation. In addition, estrogen reduces the risk of coronary heart disease and the risk of recurrence of myocardial infarction (50-80%), menopausal disorders (90-95% of women), improve the condition of muscle tone, skin, reduce the likelihood of hyperplastic processes in the uterus and mammary glands, urogenital disorders, etc.

Facts about the effect of estrogen on bone tissue

• More significant bone loss in postmenopausal women.
• The production of anabolic steroids in postmenopausal women is reduced by 80% (for men by 50%), while the production of corticosteroids is only 10%.
• Among patients with presenile osteoporosis, women are 6-7 times more than men.
• Women with early (including artificially induced) menopause lose bone mass faster than women of the same age with physiological menopause.
• Osteoporosis or hypostosis are often marked signs of hypogonadism.
• Estrogen replacement therapy over the past 10 years has led to a decrease in postmenopausal loss of CTC and, as a result, to a reduction in the number of fractures.

Since estrogen deficiency leads to a local imbalance in units of remodeling, metabolic changes that increase the rate of bone remodeling will accelerate bone loss in the future.

Considering that one of the main pathogenetic mechanisms for the development of primary osteoporosis is estrogen deficiency, hormone replacement therapy, HRT, is among the most effective methods of preventing and treating the disease.

Back in the early 20s, R. Cecil and V. Archer (1926) found that in the first 2 years after menopause, in 25% of cases, women develop symptoms of degenerative arthritis. Later it was found that if up to 50 years, osteoarthritis (like osteoporosis) is recorded in men and women with approximately the same frequency, then after 50 years the incidence of osteoarthrosis (the so-called menopausal arthritis) increases dramatically in women but not in men. Moreover, according to the latest data, HRT helps reduce the incidence of coxarthrosis and gonarthrosis, and long-term HRT affects the progression of degenerative changes in the joints to a greater extent than a short course of HRT. All of the above indicates that estrogen deficiency plays an important role in the development of not only osteoporosis, but also osteoarthritis, HRT has a beneficial effect on the progression of both diseases.

The hormones that have a positive effect on bone tissue include androgens, especially in women immediately after menopause, when there is a sharp (by an average of 80%) decrease in the production of anabolic steroids (in men of the same age groups, on average, by 50%). They increase the mineral mass of the bone, acting directly on bone cell receptors, and stimulate protein biosynthesis in osteoblasts, promote the inclusion of calcium, phosphorus. A similar effect on bone tissue and progestogens. Considering the fact that bone tissue contains receptors only for estradiol, the effect of gestagens on bone tissue is more powerful than estrogens.

An important property of the above hormones is their effect on corticosteroid receptors in bone tissue, which competes with exogenous corticosteroids (see below). They also stimulate protein synthesis in osteoblasts and intramembrane ossification.

[46], [47], [48], [49]

Effect of glucocorticosteroids on the state of bone tissue

GCS, being currently the most powerful of the available anti-inflammatory drugs, has been used to treat a wide range of diseases for over 40 years. In osteoarthritis, it is primarily about the local (intra-articular or periarticular) use of these hormones. However, one should not detract from the systemic effect of GCS on the body, which manifests itself even when used locally, and in some cases is quite pronounced.

The skeleton, being a target organ for the GCS, is most often affected. Clinically, GCS-induced calcium metabolism is manifested by osteopenia, OP, aseptic bone necrosis, hyperparathyroidism, myopathy, tissue calcification, and other disorders.

Separating the processes of bone formation and resorption, GCS cause rapid loss of bone mass, directly inhibiting the formation of bone and thereby reducing the synthesis of the main components of the matrix, including collagen and proteoglycans. Disorders of calcium and phosphorus homeostasis are among the most common consequences of GCS therapy. The latter-induced disturbance of calcium-phosphorus metabolism is associated both with the direct effect of drugs on tissues and organs, and with the disorder of the functions of calcium-regulating hormones. The leading element in this pathological process is the suppression of calcium and phosphorus absorption in the intestine, associated with impaired metabolism or physiological action of vitamin D. The decrease in calcium absorption in the intestine as a result of inhibition of the synthesis of calcium-binding protein responsible for the active transport of calcium into the intestinal wall, leads to an increase in excretion calcium in urine, negative calcium balance and increased bone resorption.

Secondary calcium deficiency contributes to the development of hyperparathyroidism, which aggravates skeletal demineralization and leads to changes in the organic matrix KTK and an increase in the loss of calcium and phosphorus in the urine. In addition, GCS reduce the secretion of sex hormones by inhibiting the secretion of pituitary gonadotropin, as well as by direct negative effects on the production of estrogen and testosterone.

According to S. Benvenuti, ML Brandi (1999), the effect of GCS on the processes of differentiation of bone tissue cells depends on the doses used, the type of GCS, the duration of use of the drug (exposure), specificity. Thus, it was shown that after intra-articular administration of GCS, a decrease in the level of pyridinoline and deoxypyridinoline was noted.

[50], [51], [52], [53]

Vitamin D metabolism

Vitamin D metabolites specifically bind to receptors with high affinity in receptor sites and appear in the cell nuclei of tissues and target organs (bone, intestine, endocrine glands, etc.). In vivo experiments showed that l, 25- (OH) ₂ D and 25- (OH) D bind to isolated bone cells and bone homogenates. Studies using radiolabeled vitamin D have shown that the latter is localized in osteoblasts, osteocytes and chondrocytes. Vitamin D induces both mineralization and bone resorption, therefore at the present time, by its effect on bone, it is considered as a steroid hormone of systemic action. In addition, the effect of vitamin D on the synthesis of collagen and proteoglycans has been proven, which leads to its additional effect on the bone formation process. The mechanism of action of vitamin D is also associated with increased transport of calcium and phosphorus in the intestine, reabsorption of calcium in the kidneys, so hypovitaminosis D is accompanied by significant demineralization of bone tissue. At the same time, wide osteoid layers are found in biopsy specimens due to insufficient calcification. Chronic vitamin D deficiency leads to osteomalacia, which can complicate osteoporosis. Progressive hypomineralization of the bone impairs the biomechanical properties of the bone and increases the risk of fractures. An excess of vitamin D leads to increased bone resorption. Vitamin D poisoning is known to be accompanied by hypercalcemia, hyperphosphatemia, hypercalciuria and hyperphosphateuria.

Vitamin D acts on bone resorption in conjunction with PTH, and in experiments on animals and in clinical observations, the existence of a reciprocal connection between them was revealed: 1.25 (OH) ₂ D ₃ controls the secretion and synthesis of PTH (stimulus to enhance its secretion serves to reduce the level of calcium in the blood), and PTH is the main hormonal factor regulating the synthesis of renal I-a-hydroxylase. The occurrence of secondary hyperparathyroidism in the presence of vitamin D deficiency can be explained by this interaction.

The synthesis and metabolism of vitamin D in the body is subject to the involutionary effects due to the following factors:

• Estrogen deficiency (by reducing the level of calcitonin, which has the ability to indirectly stimulate the formation of 1,25- (OH), D ₃, as well as the level of activity of 1-a-hydroxylase in the kidneys).
• Decrease with age of the skin's ability to form vitamin D (by the age of 70 - more than 2 times).
• Involutional changes in the kidneys (nephrosclerosis) lead to a decrease in the activity of enzyme systems involved in the metabolism of vitamin D.
• The decrease in the number of receptors for calcitriol in the intestine with age.

An age-related decrease in the formation of calcitriol on the basis of feedback leads to an increase in the synthesis of PTH. In turn, the excess of the latter enhances bone resorption and leads to its rarefaction.

Thus, vitamin D deficiency is one of the leading factors in the development of almost all forms of osteoporosis.

In recent years, there is evidence that vitamin D is involved in the metabolism of not only bone but cartilage. It stimulates the synthesis of proteoglycan chondrocytes, modulates the activity of metalloproteinases involved in the destruction of cartilage. For example, a decrease in 24,25- and 1,25-vitamin D levels is associated with an increase in the activity of metalloproteinases, and a normal level reduces the activity of these enzymes in vitro. Thus, a decrease in the level of vitamin D can enhance the production of destructive enzymes and reduce the synthesis of matrix proteoglycans, which in turn leads to the loss of cartilage tissue. It should also be emphasized that in the early stage of osteoarthritis, vitamin D-dependent metabolic disorders of cartilage may be accompanied by remodeling and thickening of the subchondral bone tissue. This causes a decrease in the depreciation capacity of the subchondral bone and the acceleration of degenerative changes in cartilage.

In recent studies it has been shown that in patients with gonarthrosis, a decrease in vitamin D intake with food and a low serum 25-vitamin D level is associated with a 3-fold increase in the risk of progression of radiological changes in the knee joints, a 3-fold increase in the risk of formation of PF and 2 - multiple - loss of cartilage tissue (judging by the narrowing of the inter-articular gap). Elderly women with a low level of 25-vitamin D in the serum there is a 3-fold increase in the incidence of coxarthrosis (judging by the narrowing of the inter-articular space, but not the formation of OP) compared with women with normal levels of vitamin D. Moreover, recently it has been suggested that bone loss and degenerative changes in the spine are pathogenetically interrelated processes that have a general tendency to progression with age. It is believed that calcium and vitamin D deficiency leads to an increase in the synthesis of PTH, which in turn causes excessive calcium deposition in the articular cartilage.

The recommendations of the American Academy of Sciences concerning the rate of adequate intake of vitamin D in different age groups, the need to increase daily intake of vitamin D to 400 IU (for men) and 600 IU (for women) in age groups 51 years old - 70 years and older are important for prevention not only osteoporosis, but also osteoarthritis.

Recommendations for vitamin D intake (Holick MF, 1998)

Age	1997 Recommendation ME (mcg / day)	Maximum dose of ME (µg / day)
0-6 months	200 (5)	1000 (25)
6-12 months	200 (5)	1000 (25)
1 year-18 years old	200 (5)	2000 (50)
19 years-50 years	200 (5)	2000 (50)
51 years old - 70 years old	400 (10)	2000 (50)
> 71 years	600 (15)	2000 (50)
Pregnancy	200 (5)	2000 (50)
Lactation	200 (5)	2000 (50)

In clinical practice, predominantly synthetic derivatives of vitamin D are used - calcitriol and alfacalcidol, which appeared on the Ukrainian market, the latter being considered the most promising drug in this group (well tolerated by patients, cases of hypercalcemia and hypercalciuria are rare).

Calcitriol binds directly to the receptors of the intestine to vitamin D, therefore, has a more local effect, contributing to the absorption of calcium in the intestine, and does not significantly affect the synthesis of PTH.

Alfacalpidol, unlike calcitriol, first undergoes transformation in the liver to form the active metabolite 1,25 (OH) ₂ D, therefore its effects on PTH synthesis and calcium absorption are comparable, indicating a more physiological effect. Daily doses of the drug are 0.25-0.5 μg for the prevention of GCS-induced osteoporosis and 0.75-1 μg for reliably established osteoporosis.

Calcium-D3 Nycomed, an effective combination drug, contains 500 mg of elemental calcium and 200 IU of vitamin D in one tablet. Taking 1 or 2 tablets of this drug (depending on dietary habits, age and level of physical activity) fully covers the recommended daily requirement for these drugs. Substances and absolutely safe, even with prolonged use.

Immunological aspects of osteoarthritis

Currently, the essential role of mediators of the immune system (cytokines and growth factors) in the local regulation of the remodeling of CTCs is beyond doubt. It is believed that disorders in the system of immune mediators play an important role in the pathogenesis of secondary osteoporosis on the background of OCR.

Possessing similar morphological properties with some lines of bone marrow stromal cells, osteoblasts are able to synthesize cytokines (CSF, interleukins). The latter implies the participation of osteoblasts both in the process of bone tissue remodeling and in myelopoiesis. Since osteoclasts originate from hematopoietic granulocyte-macrophage colony-forming units (CFU), which are precursors of monocytes / macrophages, the early stages of hematopoiesis and osteoclastogenesis are regulated in a similar way. Cytokines take part in the development of osteoclasts, which simultaneously play a leading role in the regulation of local and systemic inflammatory reactions in various human diseases - IL-1, IL-3, IL-6, IL-11, full name, granulocyte-macrophage colony-stimulating factors (GM -KSF). Also important is the fact that the action of cytokines with osteoclastogenic (IL-6 and IL-11) and osteoblastogenic (LIF) properties is mediated by similar molecular mechanisms, namely modulation of glycoprotein 130 (GP-130) involved in the transmission of cytokine-mediated activation signal target cells. It is noteworthy that estrogens suppress, and 1,25 (OH) ₂ D ₃ and PTH enhance the expression of GP-130 in bone marrow cells. Consequently, changes in hormone levels (including on the background of an acute-phase response associated with autoimmune inflammation in OCR) can affect the sensitivity of osteoclast and osteoblast precursors to the effects of cytokines involved in bone remodeling.

[54], [55], [56], [57], [58], [59], [60], [61], [62], [63], [64]