1. Introduction

The world is experiencing an unwavering aging of its population, making the health of the elderly, reducing their mortality rates, increasing life expectancy, and improving their quality of life a priority.

Osteoarthritis (OA) is a heterogeneous group of diseases with various etiologies, sharing similar bio-morphological and clinico-laboratory parameters. In elderly and senile individuals, the severity of these changes increases, leading to irreversible processes. According to WHO data, the rates of disability and mortality due to OA vary by patient gender: 65% in women in menopause, while in men it does not exceed 30%.

Previously, osteoarthritis (OA) was generally considered a condition primarily affecting the elderly. Unfortunately, the issues of preventing, diagnosing, and treating deforming osteoarthritis (DOA) of the knee joints (KJ) have recently gained significant importance due to the disease's emergence in adolescence. The prevalence of DOA has increased by 35% in recent years. Among all forms of DOA, knee joint involvement holds a particularly prominent place. OA of the knee joint is noteworthy because of its progressive course and the pain syndrome that impairs patients' motor activity [2].

Gonarthrosis (OA of the knee) occurs with equal frequency in men and women after 40 years of age, but severe forms are observed in women at an earlier age. The main clinical and biomechanical signs of damage to the musculoligamentous apparatus of the knee joint in gonarthrosis include:

* Pain in the anterior lower third of the thigh

* Rapid fatigue of the lower limbs

* A feeling of instability in the knee joint

* Development of lateral deformities of the knee joint

* Patellar displacement

* Thigh muscle hypotrophy

* Reduced range of motion in the knee joint

* Decreased muscle strength, reduced thigh muscle tone, and bioelectrical activity of muscles

* Knee joint hypermobility [38]

Tschon M. et al. [48] note that the causes of OA onset are multifactorial, and the rapid progression of the disease can be attributed to structural and anatomical features of the musculoskeletal system, genetic determinants, traumatic joint injuries, and an imbalance in sex hormone production in patients.

Normally, a significant role in maintaining the biochemical homeostasis and structural integrity of bone and and cartilage tissues, along with other factors, belongs to the regulatory influence of steroid sex hormones. An imbalance in hormonal regulation affects the nature of reparative processes in skeletal connective tissues during degenerative-inflammatory diseases of the musculoskeletal system [26].

Considering the peculiarities of the clinical presentation and diagnosis of osteoarthritis in elderly individuals, a comprehensive management plan for patients with knee osteoarthritis (OA) in old age has been proposed. It involved the implementation of several key points:

* Conducting a comprehensive geriatric assessment

* Patient education in an OA school

* Involving social services in the management of elderly patients

* Diet regulation, with increased control from relatives and the immediate environment regarding medication adherence

* Psychological and psychotherapeutic consultation for all patients, followed by the development of special treatment and rehabilitation programs.

The authors concluded that for knee OA in old age, it is advisable to conduct a comprehensive geriatric assessment focused on identifying age-related conditions [30,31].

Data from some researchers indicate that in men with OA, anabolic effects on the extracellular matrix of subchondral bone (SCB) are linked to the activation of growth factor production and elevated testosterone levels [36].

In women, the impact of estrogen and progesterone deficiency on bone tissue homeostasis has been studied, specifically concerning the ligand-receptor system: osteoprotegerin (OPG), receptor activator of nuclear factor kappa-beta (RANK), and its ligand (RANKL). These play a role in regulating osteoclast differentiation and influencing resorptive processes [29,47].

One of the reasons for the formation of functional joint insufficiency and the reduction in quality of life for female patients with OA and menopause is pronounced musculoskeletal pain, indirectly associated with the deprivation of female sex hormones [44].

The multifactorial influence of estrogen on the biology of joint tissues in both sexes in OA is due to the presence of two main estrogen receptors (ER-α and ER-ß), as well as an ER-ß-like receptor. These receptors differ in their transcriptional activity and are expressed by synoviocytes, chondrocytes, fibroblasts, myocytes, and subchondral bone cells [45].

It has been established that estrogen also plays a dominant role in regulating bone resorption processes in elderly men, while the significance of testosterone shows a tendency to gradually decrease [46]. Furthermore, men's articular cartilage initially contains a greater number of mRNA transcripts for estrogen receptors, which makes the structural and metabolic processes in joint tissues dependent on sex hormone levels.

A clinical and laboratory examination was conducted on 131 patients with manifestations of post-traumatic gonarthrosis. In female patients with this condition who were in natural menopause, an increased concentration of type I collagen telopeptides in blood serum, an increase in bone isoenzyme alkaline phosphatase activity, and an imbalance in the expression of vitamin K-dependent non-collagenous protein osteocalcin were found, compared to women of reproductive age. The authors concluded that sex hormone deficiency in menopause is a disease-modifying factor that exacerbates the imbalance of bone tissue metabolism processes in gonarthrosis [10].

The aim of the work by Ilnitsky A.N. et al. [15] was to determine the influence of comorbid pathology, specifically sarcopenia combined with malnutrition, on the course of gonarthrosis in 345 elderly patients. The results indicate more pronounced clinical complaints, local status changes, and a reduced quality of life in patients with comorbid sarcopenia and malnutrition compared to patients with only sarcopenia or only malnutrition.

Panikar V.I. et al. [30,31] studied the characteristics of knee osteoarthritis (OA) progression in 123 elderly patients and 126 older adults based on a comprehensive geriatric assessment. The authors found that knee OA in old age is accompanied by a 24.5% decrease in quality of life. Age-related conditions in people over 75 years old can be identified through the use of a comprehensive geriatric assessment, which allows for timely initiation of treatment.

According to Poryadin G.V. et al. [34], in hyperlipidemic states, free fatty acids abnormally accumulate in joint tissues, exerting a lipotoxic effect. The authors believe that factors of systemic inflammatory response produced by adipose tissue act as a link in the pathogenesis of metabolic knee OA.

The aim of the study by Sinyachenko O.V. et al. [39] was to assess the influence of cobalt (Co), chromium (Cr), molybdenum (Mo), nickel (Ni), thallium (Ti), and vanadium (V) in the soil of the regions where 87 patients with gonarthrosis (aged 32-76 years) resided, on the nature of gonarthrosis progression. It was found that trace element imbalance of metals in the blood of gonarthrosis patients was observed in 41% of cases, and in hair in 23% of cases. The authors concluded that regions of residence for gonarthrosis patients with high soil content of Co, Ni, and V are risk factors for trace element imbalances of Mo, Ti, and V.

Russian researchers Kuznik B.I. et al. [22] investigated microcirculatory hemodynamic disturbances in the area of arthritic joints in 136 patients. The data indicated that microhemodynamic impairments developed in the affected joint area, which undeniably impacts the course of the pathological process.

The study aimed to create a comprehensive treatment system for elderly and senile patients with gonarthrosis, incorporating sanitation arthroscopy and intra-articular injection therapy. For some patients with relevant indications, the authors performed sanitation arthroscopy as the first stage of treatment. The best results were achieved by combining sanitation arthroscopy with a subsequent course of intra-articular therapy using platelet-rich autoplasma [7].

In their literature review, Novakov V.B. et al. [29] analyzed publications on the molecular mechanisms of knee OA etiology and pathogenesis, as well as disease risk factors. The analysis revealed that significant roles in disease development are played by mechanisms based on cartilage metabolism disruption, inflammation, subchondral bone changes, and pathological processes occurring in the synovial membrane.

Another review by Kashevarova N.G. and Alekseeva L.I. [17] highlighted the problem of knee OA progression. They showed that the most significant predictors of disease progression are: female sex, intense knee pain, presence of synovitis, joint deformity, increased body mass index, history of trauma, high values of bone mineral density in the axial skeleton and subchondral areas of the femur and tibia, and the presence of bone marrow edema.

Even though X-ray and symptomatic signs of knee joint (KJ) disorders are common in most people over 60, women face an increased risk of degenerative changes in their knee joints as early as 35.

X-ray diagnostics plays a leading role in diagnosing KJ diseases. Radiographically, several stages of deforming osteoarthritis (DOA) development are identified using the Kellgren J.H. and Lawrence J.S. classification. For earlier DOA diagnosis, methods that can detect initial changes in articular cartilage pathology are employed. Arthroscopy is one such method, allowing visual recognition of cartilage changes at a pre-radiographic stage of DOA manifestation [1].

Dyakchkova G.V. et al. [12] studied the radiographic manifestations of deforming arthrosis of the hip and knee joints in 48 patients aged 60-70. Their results showed that X-ray anatomical changes were accompanied by alterations in the density of the femoral head and characteristic restructuring of the femoral and tibial condyles and patella. The authors found that a typical sign of quantitative change in bone tissue density in patients with deforming arthrosis was a decrease in bone density in the condylar region with a relative increase in the density of the subchondral layer, especially in cases of varus deformity of the knee joint.

In recent years, Magnetic Resonance Imaging (MRI) has become widely used. It allows for the diagnosis of DOA at the stage of pathological changes in the articular cartilage matrix, as well as the visualization of meniscal and ligamentous apparatus injuries of the knee joint. Based on examinations of 968 patients, Babaev M.V. et al. [2] presented an analysis of radiography, sonography, and MRI results in recognizing the severity stages of deforming knee arthrosis, offering a differentiated approach to classifying the stages of this pathology. They examined the diagnostic significance in recognizing the dominant manifestations of the degenerative-dystrophic process in the compensation, subcompensation, and decompensation stages.

Similar studies were conducted by Yakubov D.J. and Gaybullaev Sh.O. [43]. Based on the examination of 96 patients, they presented results of a comparative analysis of radiography, sonography, and MRI methods. They considered the contribution of each method used at various stages of disease development.

The diagnostic value of determining the biochemical marker cartilage glycoprotein-39 was studied in the diagnosis of knee OA in 120 osteoarthritis patients aged 60 and older. The authors found that the content of cartilage glycoprotein-39 in patients with knee OA is closely correlated with the severity of pain syndrome and functional insufficiency, reflecting the severity of gonarthrosis progression and potentially serving as a tissue marker of the disease [23].

In a study involving 103 patients with gonarthrosis aged 36-50 years, researchers measured blood serum concentrations of osteocalcin, pyridinoline, type I collagen telopeptides, vitamin D metabolites, oligomeric matrix cartilage protein, and bone alkaline phosphatase activity. They also assessed the diagnostic significance of these markers using ROC analysis. The results highlighted the role of subchondral remodeling in the pathogenesis of primary gonarthrosis. Pyridinoline and type I collagen telopeptides in blood serum were identified as promising markers for bone tissue metabolism in the initial stages of gonarthrosis [10,11].

Kravchenko A.I. et al. [20] developed a scoring system for the clinical and radiographic signs of gonarthrosis and correlated the total score with the severity of the patients' condition. Their findings showed that a score of 20 to 50 indicates Grade I severity, 51 to 90 indicates Grade II, and a score above 90 indicates Grade III gonarthrosis severity.

Role of Oxidative Stress in Post-Traumatic Gonarthrosis

The role of the pro-oxidant-antioxidant system in the molecular mechanisms of post-traumatic gonarthrosis (PTGA) was investigated in 95 patients diagnosed with PTGA. Indicators of oxidative stress were examined in plasma, blood cells, and synovial fluid (SF). It was found that PTGA development was accompanied by dysfunction of antioxidant system components and a decrease in the antioxidant potential of plasma and SF in patient groups compared to controls. The authors concluded that local and systemic oxidative stress, developing in joint tissues and blood, plays a crucial role in the molecular mechanisms of PTGA pathogenesis [6].

A retrospective analysis of 80 medical records of patients aged 65 years and older who were receiving inpatient treatment was conducted. Prescription sheets were analyzed to identify potentially inappropriate medications according to STOPP/START (2014) and Beers (2015) criteria. It was found that 90% of elderly and senile patients hospitalized for musculoskeletal diseases had comorbidity (an average of 5.9 diseases per patient). On average, each patient was prescribed 6.8 medications, with polypharmacy detected in 50% of cases. It was established that in 53.8% and 70.0% of cases, patients were taking medications that should be avoided. The authors concluded that to combat polypharmacy and reduce the frequency of adverse drug reactions, it is necessary to optimize pharmacotherapy and adhere to STOPP/START and Beers criteria [21].

Bragina S.V. and Matveev R.P. [3] presented the results of treating 42 outpatients with knee OA using local injection therapy. They found that the best results were achieved in Stage I OA (94.7% of patients), followed by Stage II (83.3%), and Stage III (60.0%). Local injection therapy is indicated for Stage I and II gonarthrosis.

The possibility of thermographically assessing the effectiveness of magnetotherapy using the "ALMAG-01" device was studied in 57 patients with knee osteoarthritis. The authors concluded that the recommended method of infrared thermography can be used as a diagnostic technique reflecting the degree of inflammatory activity in arthritic joints [8].

Based on the results of intra-articular treatment of gonarthrosis with platelet-rich plasma (PRP), the authors concluded that the method is safe, helping to reduce pain and improve knee joint functionality in the short term and for 3-6 months, with improvements across all parameters. The treatment allowed for rapid elimination of pain syndrome, improved joint function, shortened the duration of pain, and increased the length of remission. According to the authors, the accessibility and effectiveness of the method open prospects for its widespread use in traumatology and orthopedics [24,41].

Malanin D.A. et al. [28] aimed to determine the effectiveness of using platelet-rich autologous plasma (PRP) in treating 81 patients with Stage III gonarthrosis. This treatment helped to reduce the severity of pain syndrome and improve the knee joint function of patients for 9 weeks during their preparation for surgical treatment.

For physiotherapy, Levin A.V. and Tyrnov P.V. [25] used a method of introducing medicinal substances via stimulating bipolar pulsed currents employed for electroanalgesia. Transdermal electropharmastimulation with the non-steroidal anti-inflammatory drug "Meloxicam", combined with acupuncture in micro-acupuncture zones of the hand and foot, showed high effectiveness in treating patients with knee osteoarthritis.

The impact of a complex of physical exercises using static voluntary stretching along the axis was studied for the rehabilitation of 20 elderly women with Stage I-II gonarthrosis. A positive effect on locomotor function and physical performance was noted in patients compared to traditional methods. The indicator of lower limb function improvement and the Lequesne index exceeded by 50%, and physical performance increased by 32.6% compared to the control group [42].

Several studies have explored the effectiveness of backward walking (BW) for gonarthrosis in elderly and senile individuals. BW places less load on the knee joint and is a natural way to strengthen the quadriceps femoris. Research has shown that adding BW to traditional physical therapy contributes to reduced pain, improved knee joint function, and increased quadriceps strength [18].

Ginoyan A.O. et al. [9] analyzed the treatment outcomes of 124 patients with gonarthrosis using arthroplasty. Results were assessed using the KSS scale and radiography. In the first month post-surgery, functional activity recovered due to pain relief, restoration of muscle tone, and regional hemodynamics in the knee joint area. However, functional recovery between the first and third months was less intense in patients with bilateral gonarthrosis due to decompensation of the contralateral joint.

An analysis of surgical treatment outcomes in 45 patients with Stage II-III gonarthrosis (under 70 years old) using tantalum oxide electrets was presented. Treatment results were evaluated by the WOMAC index dynamics and clinical-radiological studies. The use of electret stimulators contributes to improved joint function, which reduces the risk of progressive degenerative changes in patients with Stage II disease. For Stage III gonarthrosis, electret application can improve joint function for over 2 years and delay endoprosthesis surgery [4].

The impact of physical rehabilitation on the functional state and kinematic characteristics of knee joints was assessed in 33 women aged 60-65 with Stage I and II gonarthrosis. It was found that in women of this age, in addition to symptoms, biomechanical disturbances in the knee joint also manifest as kinematic changes in angular positions across sagittal, frontal, and transverse planes of motion. After correction, a leveling of angular asymmetry between the knee joints of the dominant and non-dominant limbs was observed [40].

Povazhnaya E.S. et al. [33] studied the effectiveness of the combined action of magnetotherapy and "Zhivokost" balm (based on the Comfrey plant) for knee arthrosis. Treatment resulted in improved patient condition with reduced pain symptoms and increased range of motion in the knee joint.

A meeting of the Expert Council on September 9, 2023, aimed to discuss the prospects of using a combination of undenatured (native) type II collagen, methylsulfonylmethane, boswellic acids, and vitamins C and D3 (Artneo) as part of complex OA therapy. Experts concluded that Artneo in patients with Stage I-III knee OA is comparable in effectiveness to the combination of chondroitin sulfate and glucosamine hydrochloride. It even surpasses it in reducing signs of synovitis according to MRI data and in the dynamics of reducing gonarthrosis severity based on the Lequesne index [27].

A review of clinical and experimental studies over the past 20 years, focusing on the effectiveness and safety of intra-articular hyaluronic acid (HA) in OA, found that in vitro studies confirmed its positive effect on articular cartilage. However, in vivo clinical studies of intra-articular HA preparations have not been performed. Nevertheless, some works indicate that HA therapy achieves a clinical effect in early-stage OA, but yields unsatisfactory results in terminal gonarthrosis [32].

Vvedensky B.P. et al. [5] evaluated morphological changes in knee joint tissues in rats with modeled arthrosis and therapy using cryopreserved human cord blood serum (CHCBS). They found that untreated animals showed progressive signs of gonarthrosis at all observation times. Intramuscular administration of CHCBS was associated with positive dynamics of reparative processes, but complete restoration of articular cartilage did not occur. The authors suggest that CHCBS treatment helped to slow down the degeneration of the articular surface, prevented pannus formation, and reduced the activity of the pathological process in the joint capsule.

Mazurov V.I. et al. [27] investigated the influence of various drug groups (NSAIDs, SYSADOAs, etc.) on the clinical course of gonarthrosis. The authors concluded that the use of polyenzyme preparations enhances treatment effectiveness. Patients with gonarthrosis who received a combination of chondroitin sulfate, glucosamine sulfate, and Phlogenzym showed a significant reduction in synovitis severity, more frequent reductions in daily selective NSAID doses, or their complete discontinuation, compared to controls who received symptomatic slow-acting drugs in combination with NSAIDs.

The effectiveness of the "Bi-Luron" dietary supplement was evaluated in 70 patients with Stage I-II deforming osteoarthritis (DOA). A statistically significant reduction in knee pain levels, improved joint function compared to baseline, and positive dynamics in ultrasound and MRI signs of knee inflammation were observed. Patients also reported reduced need for analgesics over 12 weeks and a decreased requirement for NSAIDs [49].

Zagorodny N.V. et al. [13] aimed to assess the efficacy and safety of Aertal® in treating 80 early-stage gonarthrosis patients (average age 58 years). Patients received either Aertal® 100 mg twice daily or diclofenac 75 mg twice daily for 6 weeks. The average Visual Analogue Scale (VAS) score for pain intensity was 7.4-7.6 initially. After 6 weeks of conservative treatment, the VAS index decreased to 3.8-5.4, indicating a reduction in pain intensity.

A high-level evidence review of 148 published scientific papers on the use of arthroscopic lavage, debridement, and meniscectomy in gonarthrosis patients was conducted. A total of 1614 gonarthrosis patients aged 49-63 years were analyzed, and meta-analyses included 20770 patients aged 42-62.4 years. Based on evidence-based medicine principles, the authors concluded that arthroscopy in gonarthrosis patients is largely ineffective and has limited indications. If conservative treatment fails, periarticular osteotomies and knee arthroplasty should be preferred [37].

Irismatov M.E. et al. [16] analyzed the results of arthroscopic debridement with proximal fibular osteotomy (PFO) in treating deforming osteoarthritis of the knee joint in 152 patients with Stage I-II-III deforming osteoarthritis and varus knee deformity. The authors concluded that the KSS scale is optimal for evaluating long-term outcomes in patients with deforming knee osteoarthritis. The combined use of arthroscopic debridement and PFO significantly increased the proportion of good results to 89% (vs. 69% in patients who received arthroscopy without PFO) and reduced the proportion of unsatisfactory results to "0".

Zubavlenko R.A. et al. [14] presented a retrospective review of the study of post-traumatic knee arthrosis pathogenesis, including their own experimental findings from laboratory animals.

Klementyeva V.I. et al. [19] studied the features of subchondral bone tissue remodeling and synovitis severity in the knee joint of 60 patients in the early stages of gonarthrosis. They found that in patients with Stage II gonarthrosis, levels of Beta-Cross Laps and C-reactive protein were significantly higher, osteophyte sizes were larger, and articular cartilage thickness was less than in the Stage I group.

Kazakhstani researchers Raimagambetov E.K. et al. [35] presented the results of treating knee OA patients using the stromal vascular fraction of adipose tissue and mesenchymal stem cells from the synovial membrane in 60 patients with knee OA. The study results showed that the functional state of patients' knee joints improved after treatment with these methods.

The aim of the research by Zagorodniy N.V. et al. [13] was to evaluate the effectiveness and safety of Aertal® in treating patients with early-stage gonarthrosis. This study involved 80 patients with an average age of 58 years. Patients either received Aertal® 100 mg twice daily or diclofenac 75 mg twice daily for 6 weeks. The mean visual analog scale (VAS) score for pain intensity was 7.4-7.6. After 6 weeks of conservative treatment, the VAS index decreased to 3.8-5.4, indicating a reduction in pain intensity.

Klementyeva V.I. et al. [19] studied the features of subchondral bone remodeling and the severity of synovitis of the knee joint in 60 patients with early-stage gonarthrosis. It was established that in patients with Stage II gonarthrosis, levels of Beta-Cross Laps and C-reactive protein were significantly higher, osteophyte sizes were larger, and articular cartilage thickness was less than in the group with Stage I.