Osteoarthritis and osteoporosis

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

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

Osteoporosis is a systemic skeletal disease characterized by decreased bone mass and microarchitectural changes in bone tissue, leading to increased bone fragility and the risk of fractures (Conference on Osteoporosis, Copenhagen, 1990).

According to WHO experts, osteoporosis ranks third among the main medical and social problems of our time after cardiovascular diseases and diabetes mellitus and, according to some researchers, is the most common and serious metabolic disease of the human skeleton. 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 forearm bones, femoral neck, 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 aged 50 is 15.6% and is higher than the risk of breast cancer (9%). At the same time, the risk of death is approximately the same (2.8%). According to WHO, almost 25% of women under 65 already have compression fractures of the vertebrae, and 20% have fractures of the forearm bones. In addition, patients with osteoporosis have an increased risk of non-traumatic (spontaneous) fractures of the spine and radius (32 and 15.6%, respectively). In recent decades, the problem of osteoporosis has acquired particular medical and social significance due to the significant aging of the population of highly developed countries and the corresponding increase in the number of women in the climacteric period.

The problem of osteoporosis is also relevant in Ukraine due to the significant aging of the population - 13.2 million (25.6%) are people aged 55 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 (CBT) decreases in women by 27%, in men - by 22%, and spongy CBT - 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 the risk of fractures exists in 4.4 million women and 235 thousand men; a total of 4.7 million, or 10.7% of the total population.

Abroad, the problem of osteoporosis has been actively developed since the 60s of the 20th century and is one of the most expensive medical programs: treatment of patients with osteoporosis and its complications is a long process, not always effective and requiring significant material costs. If in 1994, funding for such a program in the United States amounted to 10 billion dollars, then in 2020, according to experts, its cost may increase to 62 billion. Thus, the need for prevention and treatment of osteoporosis and its complications is beyond doubt, and the success of prevention depends on the timing of osteoporosis diagnosis.

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Disturbances in the bone tissue 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 are determined by the functions for which the macroscopic and microscopic structure is adapted. Bone consists of cortical (compact) and spongy substance (in the skeleton, respectively, making up 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 substance is about 20%, and spongy - about 80%.

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

During a person's life, there is a constant renewal of bone, which consists of resorption of individual sections of the skeleton with almost simultaneous formation of new bone tissue (remodeling). Every year, 2 to 10% of the skeletal mass is rebuilt, and this internal remodeling is local and does not change the geometry or size of the bones. It is typical for an adult organism, while a growing bone is characterized by morphogenesis - growth in length and width.

Remodeling occurs in discretely located bone areas - the so-called remodeling units, the number of which reaches 1 million at any one time. About 30 days are required for the resorption of 100 µm of bone, the replacement of this bone mass with new bone occurs within 90 days, i.e. the 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 - the ratio of the amount of resorbed and newly formed bone in each unit. The process of bone tissue remodeling occurs much more actively in trabecular bones than in cortical bones.

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

Osteoporosis is thus considered to be the result of a disturbance in bone tissue remodeling processes and usually occurs first in the metabolically more active trabecular tissue, where the number and thickness of the plates decreases and the cavities between them increase due to perforation of the trabeculae. These changes are due to disturbances in the balance between the depth of the resorbed cavities and the thickness of the newly formed plates.

The process of bone tissue remodeling is controlled by a number of systemic and local factors, which together constitute a system of interaction that is repeatedly duplicated at different levels. Systemic factors influence the release and activation of local factors, which in turn have an autocortex or paracortex effect on bone tissue.

Factors Affecting Bone Tissue Remodeling

Systemic factors	Local factors
1. Hormones: Parathyroid hormone (PTH) Calcitonin Thyroid hormones Estrogens Androgens Glucocorticosteroids (GCS) Somatotropic hormone (growth hormone?) 2. Other factors: Vitamin D ???	Mnterleukins TNF (-alpha, -beta) TFR (-alpha, -beta) IFR Platelet-derived growth factors FRF A2-Microglobulin Macrophage CSF Granulocyte-macrophage CSF Associated with parathyroid hormones Peptides U-Interferon Prostaglandins Bone morphogenesis proteins Vasoactive intestinal peptide Calcitonin gene-mediated peptide Large bone matrix protein Other factors?

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Alimentary causes of osteoporosis

Many alimentary factors are known to cause osteoporosis. Here are the most important of them.

Some dietary factors that increase the risk of developing osteoporosis include:

• Various dietary violations
• Insufficient calcium intake from food
• Insufficient intake of vitamin D
• High protein or high phosphate diet
• Caffeine
• High sodium diet
• Alcohol
• Low fluoride intake
• Scurvy
• Deficiency of vitamins _B6, B2 _, K
• Deficiency of microelements (boron, zinc, etc.).

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Disturbances in calcium homeostasis or its deficiency

Most scientists now recognize that osteoporosis is a calcium-dependent disease. Of the 1-1.7 kg of calcium contained in the body of an adult, 99% is part of the skeleton and 1% circulates in the intercellular 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 fluid.

Calcium deficiency occurs due to its nutritional insufficiency, impaired intestinal absorption or increased excretion. Important factors are decreased calcium absorption, low concentrations of calcitriol and resistance of target tissues to it. As a result, bone resorption increases to equalize the calcium balance. However, differences in calcium intake in different regions of the world cannot explain the difference in fracture risk between populations. Thus, femur fractures are very common in countries with high calcium intake, such as Scandinavia and the Netherlands, and vice versa, their number is lower in countries with low calcium intake. This fact confirms the complex pathogenesis of osteoporosis, which includes a calcium-dependent mechanism. Accelerated bone loss may occur due to increased sensitivity of bone tissue to PTH and, in some cases, due to decreased sensitivity of renal a-hydroxylase to it. As a result of accelerated bone remodeling, the 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 in target organs may be due to estrogen deficiency, especially in the postmenopausal period.

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Age aspects in osteoarthritis

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

Abroad, the study of the indices of mineral saturation and mineral density of the bone marrow in individuals of various age groups in order to establish patterns of bone tissue formation and resorption has been conducted for over 20 years. In Ukraine, similar studies are conducted at the Institute of Gerontology of the Academy of Medical Sciences of Ukraine, the Ukrainian Rheumatology Center (URC), and the Institute of Spine and Joint Pathology of the Academy of Medical Sciences of Ukraine. Data obtained using single-photon absorptiometry (SPA) at the URC and the Institute of Spine and Joint Pathology of the Academy of Medical Sciences of Ukraine (Kharkiv).

The literature data available today on the relationship between osteoporosis and osteoarthrosis are contradictory. According to some researchers, osteoporosis and osteoarthrosis rarely occur in the same patients.

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

Sign	Osteoporosis	Osteoarthritis
Definition	Metabolic bone disease	Metabolic (degenerative) disease of cartilage
The main pathogenetic mechanism	Disruption of remodeling (balance of osteoclast-mediated resorption and osteoblast-mediated formation) of bone tissue	Disruption of anabolism and catabolism (the balance between chondrocyte-mediated synthesis and degradation) of cartilage tissue
Floor	Female	Female
Frequency in population	About 30% (>50 years)	About 10-30% (>65 years)
Complications	Fractures	Dysfunction of joints
Impact on life expectancy	++ (hip fractures); 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
IPC	Reduced	Elevated or normal
BM bone resorption (Pir, D-Pir)	Increased	Increased
Risk of skeletal fractures	Increased	?

Note: Pyr is pyridinoline, D-Pyr is deoxypyridinoline.

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Hormonal mechanisms of osteoporosis development

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

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The effect of estrogens on bone tissue

• Promotes calcium absorption in the intestines, increasing sensitivity to vitamin D;
• stimulate cellular and humoral links of immunity;
• have an antiresorptive effect (affect the processes of osteoclast activation);
• stimulate endochondral ossification of cartilage tissue by acting directly on chondrocyte receptors;
• stimulate the release of osteoclast-suppressing factors by osteoblasts;
• reduce the activity of PTH and the sensitivity of bone tissue 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.

The detection of specific high-affinity receptors on osteoblast-like cells indicates a direct effect of estrogens on the skeleton. Secretion of growth factors by osteoblasts and regulation of IL-6 and calcitonin production by estrogens indicate the possibility of paracrine effects of estrogens on bone tissue.

The indirect effects of estrogens, in particular their influence on hemostasis, are also important. Thus, it is known that high doses of these drugs reduce the activity of antithrombin III, and low doses (especially transdermal forms) accelerate the launch of the fibrinolytic system by approximately 8 times. This is important in a number of RZS, when the hemostasis system is prone to hypercoagulation. In addition, estrogens reduce the risk of ischemic heart disease and the risk of recurrent myocardial infarction (by 50-80%), climacteric disorders (in 90-95% of women), improve muscle tone, skin, reduce the likelihood of hyperplastic processes in the uterus and mammary glands, urogenital disorders, etc.

Evidence of the Effect of Estrogen on Bone Tissue

• More significant bone loss in postmenopausal women.
• The production of anabolic steroids in postmenopausal women decreases by 80% (in men - by 50%), while the production of corticosteroids - only by 10%.
• Among patients with presenile osteoporosis, there are 6-7 times more women 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 frequently noted signs of hypogonadism.
• Estrogen replacement therapy has resulted in a reduction in postmenopausal CKD loss and, as a consequence, a reduction in the incidence of fractures over the past 10 years.

Because estrogen deficiency results in a local imbalance in remodeling units, metabolic changes that increase the rate of bone remodeling will contribute to the acceleration of bone loss in the future.

Considering that one of the main pathogenetic mechanisms of development of primary osteoporosis is estrogen deficiency, one of the most effective methods of prevention and treatment of the disease is hormone replacement therapy (HRT).

Back in the early 20s, R. Cecil and B. Archer (1926) discovered that during the first 2 years after menopause, 25% of women develop symptoms of degenerative arthritis. It was later established that if osteoarthrosis (like osteoporosis) is registered in men and women with approximately the same frequency before the age of 50, then after 50 the incidence of osteoarthrosis (the so-called menopausal arthritis) increases sharply 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 osteoarthrosis, HRT has a beneficial effect on the progression of both diseases.

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

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The effect of glucocorticosteroids on bone tissue

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

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

By separating the processes of bone formation and resorption, GCS cause rapid bone loss, directly inhibiting bone formation and thereby reducing the synthesis of the main components of the matrix, including collagen and proteoglycans. Disturbances in calcium and phosphorus homeostasis are among the most common consequences of GCS therapy. The latter-induced disturbance of phosphorus-calcium metabolism is associated both with the direct action of drugs on tissues and organs, and with a disorder of the functions of calcium-regulating hormones. The leading link in this pathological process is the inhibition of calcium and phosphorus absorption in the intestine, associated with a violation of metabolism or physiological action of vitamin D. A 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 calcium excretion with urine, a negative calcium balance and an increase in bone resorption.

Secondary calcium deficiency contributes to the development of hyperparathyroidism, which aggravates skeletal demineralization and leads to changes in the organic matrix of the CT and increased losses 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 a direct negative effect on the production of estrogens 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 the drug use (exposure), and specificity. Thus, it has been shown that after intra-articular administration of GCS, a decrease in the level of pyridinoline and deoxypyridinoline is noted.

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Vitamin D metabolism

Metabolites of vitamin D bind specifically to receptors with high affinity in receptor sites and appear in the nuclei of target tissue cells and organs (bone, intestine, endocrine glands, etc.). In vivo experiments have shown 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 resorption of bone tissue, so it is currently considered a systemic steroid hormone in its effect on bone. In addition, vitamin D has been proven to influence the synthesis of collagen and proteoglycans, which determines 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, therefore hypovitaminosis D is accompanied by significant demineralization of bone tissue. In biopsies, wide osteoid layers are found due to insufficient calcification. Chronic vitamin D deficiency leads to osteomalacia, which can complicate the course of osteoporosis. Progressive hypomineralization of bone worsens the biomechanical properties of the latter and increases the risk of fractures. Excess vitamin D leads to increased bone resorption. It is known that vitamin D poisoning is accompanied by hypercalcemia, hyperphosphatemia, hypercalciuria and hyperphosphaturia.

Vitamin D acts on bone resorption together with PTH, and animal experiments and clinical observations have revealed the existence of a reciprocal relationship between them: 1,25-(OH) ₂ D ₃ controls the secretion and synthesis of PTH (the stimulus for increased secretion is a decrease in 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 involutional influence due to the following factors:

• Estrogen deficiency (due to a decrease in the level of calcitonin, which has the ability to indirectly stimulate the formation of 1,25-(OH), D3 _, as well as the level of 1-a-hydroxylase activity in the kidneys).
• A decrease in the skin's ability to produce vitamin D with age (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.
• Age-related decrease in the number of calcitriol receptors in the intestine.

An age-related decrease in calcitriol formation by the feedback principle leads to an increase in PTH synthesis. In turn, the excess of the latter increases 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, data have emerged that vitamin D is involved in the metabolism of not only bone but also cartilage tissue. It stimulates proteoglycan synthesis by chondrocytes and modulates the activity of metalloproteinases involved in cartilage destruction. For example, decreased levels of 24,25- and 1,25-vitamin D are associated with increased activity of metalloproteinases, while normal levels reduce the activity of these enzymes in vitro. Thus, decreased levels 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 at an early stage of osteoarthritis, vitamin D-dependent cartilage metabolism disorder can be accompanied by remodeling and thickening of subchondral bone tissue. This causes a decrease in the cushioning capacity of the subchondral bone and acceleration of degenerative changes in the cartilage.

Recent studies have shown that in patients with gonarthrosis, decreased dietary vitamin D intake and low serum 25-vitamin D levels are associated with a 3-fold increased risk of progression of radiographic changes in the knee joints, a 3-fold increased risk of osteoarthritis, and a 2-fold increased risk of cartilage loss (as measured by joint space narrowing). Elderly women with low serum 25-vitamin D levels have a 3-fold increased incidence of coxarthrosis (as measured by joint space narrowing, but not osteoarthritis) compared with women with normal vitamin D levels. Moreover, it has recently been suggested that bone loss and degenerative changes in the spine are pathogenetically interrelated processes that have a common tendency to progress with age. It is believed that calcium and vitamin D deficiency leads to increased PTH synthesis, which in turn causes excess calcium deposition in articular cartilage.

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

Recommended Intake of Vitamin D (Holick MF, 1998)

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

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

Calcitriol binds directly to intestinal vitamin D receptors and therefore has a more local effect, promoting intestinal calcium absorption, and does not significantly affect PTH synthesis.

Unlike calcitriol, alphacalpidol is initially transformed in the liver to form the active metabolite 1,25 (OH) ₂ D, so its effects on PTH synthesis and calcium absorption are comparable, indicating its more physiological action. Daily doses of the drug are 0.25-0.5 mcg for the prevention of GCS-induced osteoporosis and 0.75-1 mcg in cases of reliably established osteoporosis.

An effective combination drug is calcium-D3 Nycomed, which 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) completely covers the recommended daily requirement for these substances and is absolutely safe even with long-term use.

Immunological aspects in osteoarthritis

Currently, the significant role of immune system mediators (cytokines and growth factors) in local regulation of the processes of KTK remodeling is beyond doubt. It is believed that disturbances in the immune mediator system play an important role in the pathogenesis of secondary osteoporosis against the background of RZS.

Having similar morphological properties with some bone marrow stromal cell lines, osteoblasts are able to synthesize cytokines (CSF, interleukins). The latter suggests 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, which simultaneously play a leading role in the regulation of local and systemic inflammatory reactions in various human diseases, take part in the development of osteoclasts - IL-1, IL-3, IL-6, IL-11, FIO, granulocyte-macrophage colony-stimulating factors (GM-CSF). It is also important 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), which is involved in the transmission of cytokine-mediated activation signal to target cells. It is noteworthy that estrogens suppress, while 1,25 (OH) ₂ D ₃ and PTH enhance the expression of GP-130 in bone marrow cells. Therefore, changes in hormone levels (including those against the background of the acute phase response associated with autoimmune inflammation in RD) can affect the sensitivity of osteoclast and osteoblast precursors to the effects of cytokines involved in the process of bone tissue remodeling.

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