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"Child`s Health" 6 (49) 2013

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The bone tissue, metabolic and immunological disorders in the pathogenesis of osteoarthritis in adolescence

Authors: Shevchenko N.S. - SI «Institute for Children and Adolescents Health Care of the NAMS of Ukraine, Kharkiv, Ukraine

Categories: Family medicine/Therapy, Pediatrics/Neonatology

Sections: Clinical researches

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In order to prevent the progression of pathological changes in the joints of adolescents with osteoarthritis the researchers have studied the bone tissue state at the initial manifestations of the disease and analyzed the relationships with biochemical, immunological and genetic parameters. Structural and functional indices of bone were investigated in 51 adolescents with the diagnosed initial stage of knee osteoarthritis (31 girls and 20 boys), aged 12-14 years (33.3%) and 15-18 years (67.7%), using ultrasound densitometry. Тhere were studied the results of the immunological (cellular and humoral immunity, cytokines content), biochemical (blood glycosaminoglycans and chondroitin sulphates and urinary uronic acids levels, urinary hydroxyproline, activity of acid and alkaline phosphatases, collagenase, elastase, elastase inhibitors, content of calcium, phosphorus, magnesium) and genetic (frequency of spontaneous chromosomal aberrations) parameters.
The study of structural and functional states of the bone tissue in adolescents with OA revealed a significant (60.7%) osteopenia incidence. Significantly more often it was present in females, aged 14 years, the formation of osteoarthritis against reactive arthritis, while reducing the height of the articular cartilage and the presence of synovitis. Analysis of the relationship of the indicator Z-scorе with biochemical and immunological parameters as well as the level of chromosomal aberrations showed a significant effect of various homeostasis systems changes on bone state in adolescents with osteoarthritis.


osteoarthritis, teens, osteopeniа syndrome.

Introduction. There is considerable evidence that one of the most common disorders in the structure of lesions in the joints is osteoarthritis (OA) which is at present a serious medical problem. At the end of the twentieth century, taking into consideration the results of numerous studies of the disease complicated pathogenesis, both researchers and clinicians began to regard OA not only as a degenerative, but also as a dystrophic process [1, 2]. The study has established that OA formation occurs in adolescence and development of the pathology in most cases is secondary [3, 4]. By no means unimportant in the development of the disease is the bone tissue status as a structure that provides cartilage nourishing and macroanatomic comparability of joints. The process of the bone tissue  rearrangement continues under the control of a number of systemic (hormones, vitamin D) and local (cytokines, growth factors, a variety of biologically active proteins, etc.) factors which on the whole compound a complicated system of interactions [5 - 8]. Moreover, regulation of bone remodeling processes is affected by the occurrence of pathological states in the human body, including rheumatic diseases (RD). Over the previous decades the authors have studied the bone tissue in children and adolescents together with systemic diseases of the connective tissue (systemic lupus erythematosus, dermatomyositis, scleroderma) and juvenile rheumatoid arthritis. The results obtained enabled them to make a conclusion that osteopenia is not only a complication of anti-inflammatory and immunosuppressive therapy with glucocorticoids, but is also a part of the systemic inflammatory process [9 - 13]. At present there is a convincing evidence that the disorders in the structural and functional state of bones in childhood are a component of the whole connective tissue pathology in dysplastic lesions [14, 15]. However, in the available literature  our authors have found no evidence of the osteopenic syndrome in children with atropathies of noninflammatory nature. Therefore, in order to prevent OA development in such patients the researchers have studied the bone tissue state at the initial manifestations of the disease and analysed the relationships with biochemical, immunological and genetic parameters.

Materials and methods. Structural and functional characters of the bone tisue were investigated in 51 adolescents with the diagnosed initial stage of OA of the knee joints: in girls (n=31; 60.8%) and in boys (n=20;39.2%), aged 12-14 (33.3% ) and 15 - 18 years (67.7%). For the diagnosis of OA the authors used the сurrent version of the International Classification of Diseases (ICD) and protocols for diagnosis and treatment of RD, approved by the Association of Rheumatologists of Ukraine. Clinical symptoms with a detailed assessment of the locomotor system, which included examination and palpation of the joints, X-ray and ultrasound (US) investigations, were defined in all patients, included in the study. The risk factors for OA development were also taken into account: 22 (43.1%) patients manifested the joint hypermobility syndrome (JHS), 17 patients (33.3%) had the signs of reactive arthritis (RA) of various etiology which had occurred 3 years before our study. The bone tissue study was performed using ultrasound densitometry of the heel bone (calcanel) by "Sonos-2000". Diagnosis of osteopenia was carried out according to the WHO international standards considering the Z-score parameters: a decrease in Z-score parameters at the fist stage was 1,0 - 1,5 SD (sygmal deviation);1,5 - 2,0 SD at the second stage, and 2,0 - 2,5 SD at the third stage of the disease. Evaluation of structural and functional states of the bone tissue was conducted basing on the nomograms of indices for children in Kharkiv region. To clarify the role of some links of OA pathogenesis there were studied the results of the unified investigatory methods: immunological (immunoregulatory subpopulations of lymphocytes: CD3 +, CD4 +, CD8 +, CD22 +;  circulating immune complexes (CIC), A,M, and G immunoglobulins (Ig), the complement, and IL-1, IL- 6, TNF-α cytokine levels); biochemical (blood glycosaminoglycans (GAG)  and urinary uronic acids (UA) levels, chondroitin sulphates (CS), oxyproline (OP), acid (AP) and alkaline (AlP) phosphatases, collagenase (Col), elastase (El), elastase inhibitors (ElI), calcium, phosphorus, and magnesium content); and genetic (frequency of spontaneous chromosomal aberrations (ChA)).

Results and discussion. Analysis of OA clinical symptoms in adolescents made it possible to determine the signs, characteristic of this age [16]. The principal manifestation sign was pain syndrome, characterized by daily (47.1%) arthralgia, mainly in the evening (64.7%), which increased after exercise (94.1%) and at the first movements after rest (88.2 %). Meteoropathy (64.7%) and seasonal dependence (39.2%) were among the major features of the disease. Assessing pain intensity according to Huskisson’s visual-analog scale, the authors found clear sex-related differences with their higher values in girls (p <0,05). Rigidity after rest was established in 50.9% of adolescents. The majority of patients had pronounced crunching sounds of various degree in their joints (96.1%). In the examined adolescents typical radiologic changes of OA were revealed, the most common of them being pointing and stretching of intercondylar eminences of the tibia (80.4%), and joint space narrowing (68.6%). Objective assessment of the articular structures state was obtained by ultrasound investigations. Insufficient ultrasonic thickness  of the articular cartilage (64.7%) was found most often in adolescents with HMS (78.4% vs. 47.1% in children with  ReA in their medical history, p <0.01), and certain changes in the cartilage structure, its transparency and integrity (41.2%) were revealed mainly in patients after ReA in anamnesis (52.9% vs. 31.4%, p <0.05), as well as joint space narrowing and its unevenness (58.8%). Ultrasound reflection of the involvement of the bone tissue in the pathological process were an increase in subchondral layer echogenicity and its uneven thickening (47.1%). Signs of synovitis at the time of examination were found in 29.4% of adolescents, indicating the development of inflammatory response and confirming its role in the pathogenesis of the disease. When comparing ultrasound and clinical OA features  it was revealed that the pain syndrome was not always accompanied by the presence of synovitis, mainly it took place due to the disorders in the cartilage integrity, occurrence of  hyperechoic inclusions in its structure, and changes in the bone subchondral layer.

The study of structural and functional states of the bone tissue in adolescents with OA revealed a significant (60.7%) osteopenia incidence. Significantly more often it was present in females (74.2% vs. 40.0% in boys, p <0.01), at the age of 14 (76.5% vs. 52.9% in patients over 15, p <0.01), mainly in  the cases, where OA was developed against the background of ReA in medical history than against HMS (82.3% vs. 45.4%, p <0,05). Osteopenia in most patients corresponded to stage 1 according to the WHO data (62.7%). In some patients (n = 4, 7.8%) osteopenic syndrome was significantly more pronounced and reached the third stage. These values were found only in the patients who suffered from ReA in the past.

When comparing the results of instrumental examinations the authors have not established any relationship between radiologic evidence of the disease and character of the bone state. In the ultrasonic OA parameters the researchers have found certain correlation between the decreased height of the articular cartilage and the presence of osteopenia. Significantly higher rate of this ultrasonic parameter occurs in patients with low bone mass (64.5 vs. 50.0%, p <0,05). In the group of adolescents with the confirmed by ultrasound investigations development of secondary synovitis osteopenia is registered 1.5 times more often (35.5% vs. 20%, p <0,05).

Identified changes in the bone tissue, depending on clinical and instrumental features of the articular syndrome, have provided the basis for analyzing the relationships of the Z-score parameters,  obtained during densitometry, with the findings  of biochemical and immunological homeostasis, as well as the level of chromosomal aberrations in the examined adolescents with OA. Table 1 shows the results of measuring these parameters in patients with OA compared with healthy age-matched persons. It has been found that in the disease development there are observed abnormalities in the metabolism of proteoglycans and collagen, which are manifested in redistribution  of GAG fractions with their content deficiency in blood serum, a decreased UA excretion and  an increased OP  levels with a simultaneous rise in the collagenase activity levels.  A decreased elastase activity and an increased phosphorus content with its reduced daily excretion are characteristic of our patients. Formation of OA occurs in adolescents with participation of immunoinflammatory component (Table 2). Depression of T-and activation of B- links together with decreased CD3+ and CD8+ and an increased CD22+ levels, CIC content, IgA and IgG , which takes place against the background of proinflammatory cytokines (IL-1β, IL-6, TNF-α) overproduction have also been revealed in our study.

On the basis of stepwise multiple linear regression it has been established that the Z-score parameters depend on a number of variables ( Table 3). The greatest impact on their decrease have levels of total GAG concentrations, their first and second fractions (regression coefficients are 3.64, -3.18 and -2.75, respectively). Other factors have rather low coefficients, but their common systemic influence is highly significant reliability index p is 0.0002). The above conclusion proves that the bone tissue under conditions of the disease of degenerative nature development against the background of both dysplastic and inflammatory states is an active participant of the process, and its structural and functional status reflects a set of pathological shifts in various systems of homeostasis. Such combination of disorders in the connective tissue metabolism, immune status and chromosomal stability becomes a pathogenetic chain, which affects the bone tissue, creating in its turn one more link in the general pathological process.

Conclusions. In adolescence OA is formed against the background of changes of the connective tissue, including the bone tissue, the immune system and genetic apparatus, characterizing the failure of compensatory abilities and contributing to the further development of the disease. Therefore, therapeutic measures should include not only drugs chondroprotective and anti-inflammatory action, but also osteotropic (magnesium, calcium, and vitamin D3 containing drugs) and stabilization of the genome (folic acid drugs) agents.

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