Etiopathogenesis of Knee Osteoarthritis
Osteoarthritis (OA) is the most common disease of peripheral joints. The risk of developing this disease increases with age, and therefore its prevalence is rising as life expectancy increases. The etiopathogenesis of OA is complex; it usually involves a combination of degenerative, inflammatory, and reparative processes affecting articular cartilage, in which there is a reduction in proteoglycan content and impaired collagen synthesis in chondrocytes. Changes also occur in other joint structures, such as the synovium and subchondral bone. The fundamental degenerative process consists of changes in cartilage, which alters its structure, softens, and loses surface integrity; fissures develop, its resistance decreases, and cartilage mass is lost. Clusters of chondrocytes form, producing inflammatory cytokines and proteolytic enzymes. In later stages, the number of chondrocytes decreases, and their activity in collagen production also declines, contributing to disease progression. It is currently assumed that the initial process triggering cartilage degeneration is reduced production of proteoglycans in the extracellular cartilage matrix. As a consequence of their loss, the matrix becomes less resistant to proteolytic enzymes, resulting in accelerated OA progression. Another change is increased water content in cartilage, thinning of the type II collagen fiber network, and increased type I collagen content, characteristic of scarring. The activity of catabolic enzymes such as metalloproteinases increases. The dynamic balance of cartilage anabolism and catabolism shifts toward catabolism. Degraded matrix fragments have pro-inflammatory effects, and an inflammatory process develops in the cartilage. In addition to cartilage, other joint components—including the synovium, ligaments, bone, and muscle insertions—also contribute to disease progression.1,2
Regarding OA localization, the most common form is involvement of the knee joint—gonarthrosis (knee osteoarthritis). In most cases it is a primary type of disease, but a number of risk factors may contribute to its development. One of the main factors is older age. In older individuals, chondrocyte mitotic and metabolic activity is reduced, which has negative consequences for cartilage properties. Another risk factor is female sex: women are affected more often, and symptoms are also more pronounced in women. Genetic factors also play an important role in the development of knee OA; they are assumed to contribute to approximately one-third of cases. This may involve mutations, for example, in genes for the production of various collagen types. Obesity is a significant risk factor for the development of knee OA. Injuries affecting the integrity of certain parts of the knee joint, as well as long-term overloading, also contribute to the disease. In most patients, knee OA is a slowly progressing process. The first stage consists of clinically silent processes such as disturbed cartilage metabolism. Clinical manifestations usually appear only with the development of reactive changes in surrounding joint tissues (e.g., joint capsule, synovial fluid, or subchondral bone). Typical radiographic changes, on which current diagnosis of knee OA is based (especially narrowing of the joint space), develop only after biochemical and clinical changes, as the final stage. Diagnosis of knee OA can be refined by magnetic resonance imaging (MRI), indicated when lesions of soft intra-articular structures, such as cartilage defects, are suspected.1,2
Treatment of Knee Osteoarthritis: General Rules and Oral Therapy
Despite relatively advanced knowledge of the etiopathogenesis of knee OA, no truly causal treatment is yet available that would completely prevent disease progression. Some commonly used medications act symptomatically, while others are aimed at partial influence on certain components of the pathogenetic process. Treatment of knee OA should be comprehensive and individualized. Treatment options can be divided into non-pharmacological (education, lifestyle measures), pharmacological (oral and intra-articular), and surgical in advanced cases.
The ESCEO working group (European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases) recommends managing knee OA in several defined steps: in the mildest stage, in addition to non-pharmacological approaches, paracetamol and chondroprotectives are recommended; in the second step (more severe conditions), oral nonsteroidal anti-inflammatory drugs (NSAIDs) are recommended; if symptoms persist, intra-articular corticosteroids and hyaluronic acid are recommended (see below for details). In the third step, weak opioids and duloxetine (a selective serotonin and norepinephrine reuptake inhibitor, SNRI) are recommended; in the fourth step, surgical procedures are indicated, and if contraindicated, opioids.3 However, there are considerable discrepancies between the guidelines of individual rheumatology societies, whether national or international, such as EULAR,4 ESCEO,5 ACR,6 and OARSI.7
We briefly mention commonly used oral medications. These include strong and weak analgesics (paracetamol is the most commonly used), NSAIDs, and a group of slow-acting chondroprotective agents, so-called SYSADOA (symptomatic slow acting drugs in osteoarthritis). It should be noted that these oral drugs are associated with certain risks and problems. For example, with otherwise commonly used paracetamol, higher doses may pose a risk of hepatorenal toxicity. With oral NSAIDs, the risks are well known, including gastrointestinal, cardiovascular, renal, and musculoskeletal adverse effects (intermittent local NSAID application is considered safer). Drugs in the SYSADOA group, such as glucosamine sulfate, chondroitin sulfate, diacerein, and avocado/soybean unsaponifiables (ASU), are not associated with significant adverse effects when used at recommended doses; however, criticism concerns the variable quality of commercially manufactured products and their problematic bioavailability. The prevailing view is that glucosamine sulfate and chondroitin sulfate may improve pain and function in some cases of knee OA.3 If non-pharmacological and oral therapy are ineffective, the next step in treating knee OA is the option of intra-articular therapy, which is discussed in more detail below.
Intra-Articular Therapy: The Role of Pharmacokinetics and the Placebo Effect
Intra-articular drug administration offers a number of advantages for OA patients compared with oral treatment. These advantages include higher bioavailability at the target site, reduced systemic exposure, and therefore greater safety. However, the efficacy of individual agents used remains controversial. For these reasons, recommendations from expert societies often differ regarding intra-articular OA treatment.8,9 One issue is also the pharmacokinetics of the drugs, especially how long the administered substance remains in the joint.10 This parameter is influenced primarily by molecular size.11 For example, the half-life of soluble corticosteroids in the joint is only 1–4 hours.12 Long-term experience with intra-articular treatment shows that this route of administration is accompanied by a significant placebo effect, both in pain and in function of the affected joint.13 It is now generally accepted that the placebo effect accompanying intra-articular administration can be substantial.14 Results of placebo-controlled studies show that differences between the administration of, for example, corticosteroids and placebo are sometimes minimal; the magnitude of the placebo effect could explain the frequently small differences between groups.15 The intra-articular needle insertion itself provides a certain effect, and as one meta-analysis showed, even the injection of saline alone can improve parameters such as the visual analog scale (VAS) for pain or the WOMAC index.10,16
Commonly Used Intra-Articular Agents
The most commonly used agents administered intra-articularly in knee OA are corticosteroids and hyaluronic acid. These agents are usually indicated in patients whose condition has not improved after oral treatment (paracetamol, NSAIDs). However, the efficacy and safety of these intra-articularly administered agents are sometimes questioned17 and expert opinion is not uniform in this regard. It is also important to note that patients with knee OA respond to treatment individually. Different patient subgroups may therefore differ in their responses. Since knee OA is not a uniform disease and the contribution of individual etiopathogenetic factors and the course of the disease are not uniform, different individual response patterns to treatment exist.18 Treatment should also be considered in terms of cost and potential risk of harm, especially if the effectiveness of the given therapy is uncertain.
Corticosteroids
Intra-articular corticosteroid injections in patients with knee OA have a long history, being used for more than 50 years. Their use is based on the anti-inflammatory effect of these drugs, which leads to a temporary analgesic effect. However, this effect is short-term and is usually not accompanied by improved function. With repeated corticosteroid administration, efficacy gradually declines, and for example, with injections once every 3 months, after two years the effect was comparable to placebo; their chondrotoxicity is also non-negligible.3
The American Academy of Orthopaedic Surgeons (AAOS), in its guidelines, noted a lack of convincing evidence supporting the use of corticosteroids in OA treatment and also a questionable balance between benefits and possible harmful effects.19 The AAOS recommendation was based on six key studies, four of which were placebo-controlled and assessed pain for at least 4 weeks. The results of these studies were inconsistent and the studies had design flaws. Therefore, the AAOS concluded that there is no convincing evidence supporting the use of corticosteroids in knee OA.19 OARSI guidelines are more favorable toward the use of intra-articular corticosteroids in knee OA,20 but criticism has also been published pointing to the ambiguity of the available studies.21 A Cochrane meta-analysis showed that some studies may suggest a certain benefit of intra-articular corticosteroids, but the effect is relatively short-lived.22 Nevertheless, some guidelines recommend their use (e.g., NICE in the UK), but according to some authors these recommendations are not sufficiently supported.23
Since publication of the above recommendations, concerns have increased about the harmful catabolic effects of corticosteroids on cartilage.24 For example, one study suggests that glucocorticoid injections before knee arthroplasty may increase the risk of postoperative infection.25 Another study showed that patients with knee OA treated with intra-articular corticosteroids had significantly greater cartilage volume loss than those receiving intra-articular saline over 2 years.26 This finding is concerning because it suggests that corticosteroid chondrotoxicity may increase the risk of requiring surgical intervention.27,28
Hyaluronic Acid
Hyaluronic acid (HA) is a natural body substance that is part of both the synovium and articular cartilage. It enables smooth and painless joint movement and acts primarily as a lubricant. One component of OA pathogenesis is a reduction of HA content in the affected joint and a change in its quality caused by depolymerization, leading to impaired lubricating ability. Injecting HA in patients with osteoarthritis is based primarily on a mechanical effect, i.e., replenishing the content of this substance in the joint (viscosupplementation). It is assumed that this not only facilitates movement of joint surfaces (thus improving function), but also creates a protective layer around joint nociceptors and thereby reduces pain during movement. Intra-articular administration of HA with different molecular weights has traditionally been used in general orthopedic practice. As shown by meta-analyses, a number of clinical studies have demonstrated that intra-articular HA administration (often in the form of a series of several injections) can reduce pain and improve function of the affected joint in patients with knee OA.29 Meta-analyses report that HA is generally more effective and safer than NSAIDs or injectable corticosteroids.30 A 2020 systematic review and meta-analysis of randomized trials comparing intra-articular HA with oral NSAIDs31 brought interesting findings. The results showed that HA injections provided greater pain relief and improved knee function compared with oral NSAIDs. The difference was statistically significant; HA had a lower risk of adverse effects than NSAIDs. The duration of HA effect is usually up to 6 months after the last injection.29 Among professional societies that recommend HA application in patients with knee OA in their guidelines are OARSI and EULAR.32 The position of some societies (e.g., AAOS) differs,33 but meta-analyses of studies are mostly positive; for example, a 2018 systematic review concluded that intra-articular HA may be beneficial in patients with knee OA.34
Newer Types of Therapy: Platelet-Rich Plasma and Stem Cells
Platelet-Rich Plasma
Platelet-rich plasma (PRP) is an autologous plasma product (ACP, autologous conditioned plasma) containing four to five times more platelets than unprocessed blood plasma. PRP is obtained by centrifugation of several milliliters of the patient’s blood (erythrocytes are removed). Platelets in PRP produce various substances, such as cytokines and growth factors. It is assumed that after intra-articular application into an OA-affected joint, these substances may initiate an anti-inflammatory and possibly healing process in the joint. In general, the lack of high-quality studies and confusion arising from both biological complexity and lack of standardization among different PRP protocols make it difficult to draw conclusions about the effectiveness of this treatment.35
In patients with knee OA, PRP has usually been compared with HA monotherapy or placebo. In some studies, the effectiveness of PRP and HA monotherapy was comparable; in others, PRP was more effective in reducing pain and improving joint function. Meta-analyses have shown similar results.36 For other efficacy criteria, such as the patient-reported IKDC scale (Subjective International Knee Documentation Committee scale), which comprehensively evaluates knee function, higher PRP efficacy was seen in only half of studies. Regarding adverse effects, a 2021 meta-analysis states that these may include pain (most often temporary mild to moderate arthralgia), allergic reaction, or an exaggerated inflammatory reaction at the injection site.36 Another meta-analysis examined duration of effect and structural effects of PRP in knee OA patients.37 The authors concluded that PRP may in some cases slow progression of knee OA, but the effect is temporary. Most studies on PRP efficacy are case studies and preclinical studies. One issue is that several different PRP preparation protocols exist; there is currently no consensus that would define a gold standard. PRP dosing regimens also vary across studies. Before more definitive conclusions about PRP efficacy can be drawn, further standardized, high-quality studies are needed.21
Mesenchymal Stem Cells
Intra-articular administration of mesenchymal stem cells (MSCs), which can be obtained for example from bone marrow or adipose tissue, may represent a promising OA treatment method due to their potential to differentiate into various cell lineages, including chondrocytes. It is assumed that the mechanism of action of MSCs is mediator production. Their ability to directly influence cartilage damage and support regeneration is not yet sufficiently substantiated.38 MSCs from adipose tissue are obtained by liposuction as part of the stromal vascular fraction (SVF). Various treatment protocols exist, which often makes studies difficult to compare or evaluate collectively.
Several systematic reviews have been published attempting to critically assess intra-articular MSC application in knee OA. Their conclusions were inconsistent, with some being more skeptical, noting that study quality is not always sufficient.41 Some meta-analyses were more optimistic. A 2020 meta-analysis of clinical studies on MSC efficacy and safety40 included 19 studies related to knee OA. It showed encouraging results with significant improvements in VAS and WOMAC scores and a relatively low rate of adverse effects. Authors of another 2020 meta-analysis41 state that MSC application in studies led to reduced knee pain, but did not substantially affect joint function. MRI examination did not confirm a significant effect of MSCs on cartilage regeneration. Another 2020 meta-analysis42 included 10 randomized controlled trials in patients with knee OA. In this meta-analysis, MSCs were effective in reducing pain and improving knee function, and some studies showed a protective effect of MSCs on articular cartilage. Authors of the meta-analyses note that the included studies were of unequal methodological quality, mostly with small numbers of patients. They state that safety and efficacy of this method must be evaluated in larger randomized trials before it is introduced into routine clinical practice. Malignant transformation remains a potential risk for any cell therapy. Part of the MSC literature has questionable safety assessment methodology.43
Experimental Types of Treatment
Experience with the efficacy of biological agents in some connective tissue diseases led to the idea of using these agents in OA, but results of clinical studies have so far mostly failed to convincingly confirm efficacy. Another aspect is cost and the issue of adverse effects of this type of treatment. Several studied concepts are mentioned here. The antagonist of the pro-inflammatory cytokine IL-1beta, anakinra, was well tolerated in one study, but efficacy in OA was not confirmed. Another approach tested is blockade of TNF (tumor necrosis factor), which is associated with cartilage degradation in the knee joint. The TNF antagonist infliximab has been investigated as a potential OA drug, but evidence is not yet convincing. Other studied options for intra-articular biological treatment of knee OA include growth factors, such as recombinant fibroblast growth factor 18 (FGF-18), sprifermin.21
Innovative Biological Approach: Intra-Articular Application of Biogenic Substances
Injectable Collagen
Collagen fibers are the main component of articular cartilage and other intra-articular structures. During osteoarthritis, articular cartilage is affected by progressively predominant degradation caused by the combined action of matrix metalloproteinases and metalloendopeptidases.44 The finding that the degradative process in OA affects collagen as the main component of cartilage and other joint structures45 formed the basis for the concept of collagen application as part of intra-articular OA treatment. In in vitro studies, when synovial or cartilage cells were directly exposed to collagen, hyaluronic acid production increased and release of pro-inflammatory mediators decreased.46 Studies also showed that collagen reduces cartilage degradation in OA and significantly increases type II collagen production in chondrocytes.47 Preparations for oral collagen supplementation are debated due to variability in composition, digestion in the gastrointestinal tract and absorption of fragments into circulation, as well as the issue of biological availability of these fragments and their effect in the affected joint. These problems are eliminated with intra-articular application. Injectable preparations with different collagen types are available, for example the so-called MD products (Guna, Italy), available locally, containing porcine tropocollagen with a molecular weight of 300 kDa, and CHondroGrid (Bioteck, Italy), containing lyophilized hydrolyzed bovine collagen with a molecular weight below 3 kDa.
The beneficial effect of intra-articular collagen in patients with knee OA has been confirmed in randomized controlled trials that showed marked clinical improvement in all evaluated parameters.48,49 For example, in one of these studies49 collagen administration provided statistically highly significant clinical improvement compared with placebo in all assessed parameters (VAS, WOMAC index, Lequesne index). The effect of collagen was sustained; at 6-month follow-up it persisted, and the difference versus placebo remained significant. In another study50 the long-term effect of intra-articularly administered collagen (a total of 6 injections at weekly intervals) in patients with grade 2–3 knee OA was evaluated with respect to prevention and/or postponement of total knee replacement. Patients were followed for 60 months and the condition of the affected joint improved sufficiently after treatment that they did not require surgery during the observation period. In another study51 lyophilized hydrolyzed collagen (CHondroGrid) was used. The study had two parts: in the laboratory part, chondrocytes obtained from OA patients were cultured with this preparation. Results showed that after contact with collagen peptides, chondrocytes produced increased amounts of type II collagen, characteristic of cartilage. In the clinical part, the effect of intra-articular hydrolyzed collagen administration was evaluated in patients with grade 1–4 knee OA. Patients were treated with three intra-articular injections into the affected knee (interval between the 1st and 2nd injection was 15 days, between the 2nd and 3rd injection 30 days). The results showed that after only one dose, average pain in the affected joint significantly decreased and mobility and function improved; VAS and Lequesne index values remained stable after the second injection and 6 months after the third injection, while WOMAC scores continued to improve significantly after the second injection. All parameter values remained improved even more than 7 months from study start: WOMAC and its individual components decreased by more than 70% vs. baseline; pain on movement (VAS) was reduced by 55%, and pain at rest was reduced by 100% at the end of follow-up. The beneficial and long-term effects of intra-articularly administered lyophilized hydrolyzed collagen in patients with knee OA were also confirmed in a retrospective study52 including 70 patients aged 22 to 80 years with grade 1–4 knee OA. Patients were again treated with three intra-articular collagen injections. Median VAS values at rest and during movement, Lequesne index, and WOMAC scores decreased significantly after the first injection and declined further after the second injection. Even more than 7 months after treatment initiation, all monitored parameters remained significantly lower than baseline (by 50–80%). The preparation was well tolerated. Results of available studies on intra-articular collagen in osteoarthritis are summarized in a published review from 2023.53
Combination of Hyaluronic Acid with Amino Acids and a Chondroprotective Agent
Intra-articular application of hyaluronic acid can currently be considered an established part of knee OA treatment thanks to relatively long clinical experience. New knowledge about the multifactorial etiology of this disease has led to the concept of combining hyaluronic acid with other substances that would directly affect multiple etiopathogenetic factors in the joint simultaneously and complement or deepen the effects of HA. Such an innovative concept is represented by the combination product Algyl GGP, which in addition to HA contains other biogenic (endogenous) substances that broaden the spectrum of beneficial effects on the affected joint: the chondroprotective agent N-acetylglucosamine and the amino acids glycine and proline. The main effects of the components of this product are summarized below.
Hyaluronic acid is one of the main components of synovial fluid and cartilage. It contributes to lubrication of joint surfaces, organization of proteoglycans in the extracellular matrix of cartilage and other joint structures, and maintenance of a non-inflammatory joint environment. It improves elasticity and viscosity of the intra-articular environment and, by “coating” nociceptors, reduces joint pain. It stimulates chondrocyte activity to increase endogenous synthesis of glycosaminoglycans and their deposition in the extracellular matrix. N-acetylglucosamine (NAG), as a chondroprotective agent in OA treatment, has advantages over other glucosamine forms. It is more effective and does not affect glucose metabolism, and is therefore safer. After intra-articular administration it remains in the joint relatively long and contributes to cartilage restoration. It inhibits matrix metalloproteinases, activates chondrocytes to synthesize physiological ECM components, and reduces production of pro-inflammatory cytokines.54
During OA progression, connective tissue levels of amino acids decrease, especially glycine and proline, which are collagen components. Glycine is an essential part of collagen and is important for proper folding and stability. It is a component of proteoglycan-4 (lubricin), produced in synovial fibroblasts, and is important for joint lubrication. It has anti-inflammatory and antioxidant effects. Proline is also an amino acid essential for collagen synthesis. In patients with OA, proline production is reduced. Proline has anti-inflammatory and immunomodulatory effects and acts against OA progression. It supports proliferation and differentiation of chondrocytes, facilitates articular cartilage regeneration, and contributes to regulation of bone metabolism balance.55
The efficacy of Algyl GGP, containing a patented gel with a combination of HA, NAG, glycine, and proline,56 was verified both in a study comparing its efficacy with mono-component HA57 and in clinical practice, which confirmed not only efficacy but also safety.58 The complex composition of Algyl GGP offers several advantages. Unlike short-acting drugs (such as corticosteroids), the product not only provides a viscosupplementation effect mediated by hyaluronic acid, but—thanks to its ability to support cartilage regeneration and modulation of inflammatory processes—also acts long-term. As shown by orthopedic clinical experience, it is well tolerated by most patients, making it a safe alternative to some other treatment approaches. Thanks to its rational composition, the product enables a combination of several mechanisms of action of the individual components, which complement each other. Algyl GGP represents a comprehensive, effective, safe, and long-acting therapy without significant side effects. It thus offers hope for improving quality of life in patients with chronic degenerative joint disease such as OA.
Regarding combination with other agents used in osteoarthritis treatment, Algyl GGP allows synergistic or complementary effects with preparations having other mechanisms of action. For a comprehensive approach to osteoarthritis treatment, it can be effectively combined, for example, with injectable collagen preparations. Combinations of this type offer a synergistic effect, supporting not only cartilage regeneration but also protection and improvement of the viscoelastic properties of synovial fluid.
Conclusion
Knee osteoarthritis is the most common clinical form of osteoarthritis. This disease significantly worsens patients’ quality of life and is associated with major social and healthcare costs.
Current treatment options are very limited. If non-pharmacological approaches and oral pharmacotherapy are ineffective (with NSAIDs associated with significant adverse effects), intra-articular treatment is recommended, and if that fails, surgical intervention. At present, intra-articular therapy is limited mainly to corticosteroids or hyaluronic acid monotherapy. Based on the role of chondrocyte failure and changes in the extracellular cartilage matrix in etiopathogenesis, the concept of intra-articular application of collagen (MD products, CHondroGrid) and the combination of hyaluronic acid with other biogenic substances (a chondroprotective agent and amino acids) in a single intra-articular preparation (Algyl GGP) has emerged. These methods represent a promising and safe therapeutic strategy for treating patients with osteoarthritis.
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