Osteoarthritis is a major disabling factor. In the past, the main focus has been on the treatment of advanced osteoarthritis without effective disease-modifying treatment options. Recently, however, there has been a clinical focus on the remission of joint symptoms until joint replacement is required. A forum is presented to observe the latest clinical shifts in treatment that have emerged, from symptom relief to prevention of osteoarthritis. The central idea of this discussion is to clarify the prediagnosis and treatment of osteoarthritis, that is, those joint states that increase can exacerbate the progression of osteoarthritis.
This study summarizes 3 clinically significant orthopedic disease transformation studies, anterior cruciate ligament injury, intra-articular fracture, and hip dysplasia to explain these ideas. Emerging MRI is able to detect articular cartilage damage. These data suggest that improved diagnostic techniques can not only clarify the factors of cartilage damage but also assess the effectiveness of early treatment. The use of new mouse models to observe intra-articular fractures has shown that inflammation is related to the severity of the injury and that super mice can avoid early osteoarthritis due to their ability to block inflammation. These studies show that treatment of acute and persistent inflammation can prevent the development of osteoarthritis.
In terms of long-term therapeutic efficacy, temporary gene therapy may sustain stable control of intra-articular inflammation or other biologically active substances to maintain joint homeostasis. The excellent medium- to long-term results of periprosthetic osteotomies suggest that mechanical stress abnormalities play an important role in hip osteoarthritis. If orthopaedic surgeons need to treat all joint problems, from joint trauma to pre-arthritic states to advanced arthritis, then recognizing a shift in treatment options to prevent osteoarthritis can improve clinical care and participation in research for new clinical treatment options. Osteoarthritis is a major cause of pain and disability.
OA is the leading cause of pain and disability [1]. Conventional treatment has focused on advanced OA without effective protocols that can alter the course of the disease. The result is that clinicians have focused on relieving pain until joint replacement. Although OA is multifactorial, joint injury and excessive weight bearing are considered to be factors that exacerbate joint degeneration. Given the increasing cost of medical and disability treatment due to OA, there is an increasingly urgent need to find new options that can prolong joint health.
From 2013 AAOS began to focus on the clinical discussion of changing from symptom relief to prevention of disease progression in patients with OA. The central idea of this discussion is the early diagnosis and treatment of preexisting OA, which means improving the state of the joint and eliminating pathological states that would accelerate OA progression [2]. Three orthopedic states: anterior cruciate ligament injury, intra-articular fracture, and hip dysplasia, are associated with preexisting OA states, and here again we discuss their relationship to OA and long-term clinical outcomes.
Early diagnosis of ACL can reduce the risk of OA with early treatment
ACL injuries are common, affecting young people [3,4], accelerating joint degeneration, and half of patients develop symptomatic OA imaging changes 10-20 years after injury [5]. ACL reconstruction stabilizes the preoperative joint and does not reduce the early changes in knee OA [6,7]. With the increase in ACL reconstruction, there are progressively more reports of temporary treatments such as ACL augmentation and the use of non-radiolucent sterilized allograft ligament dissection that would show a reduction in OA incidence. Another school of thought is that ACL reconstruction does not reduce joint degeneration because of the minor but irreversible cartilage damage present at the time of trauma. Improving the understanding of early changes in ACL injury and reconstruction may lead to more effective disease course changes.
Quantitative MRI techniques for the assessment of cartilage damage (such as delayed iodine-enhanced MRI of cartilage) may improve early confirmation of whether articular cartilage damage is reversible [2,8,9]. It is currently believed that full and partial cartilage injuries do not heal, and it is unclear whether self-repair after cartilage injury affects the articular surface. Recent studies have shown that matrix repair occurs at cartilage floaters after ACL injury if there is no mechanical stress.
Recently, T2 ultrashort echo-enhanced images can assess the matrix of articular cartilage [10,11]. This new quantitative technique is able to determine the extent of cartilage and meniscal damage and the therapeutic efficacy of treatment measures. If the intra-articular situation is evaluated after ACL injury, the T2 technique of deep tissue can reveal the integrity of the articular cartilage and the condition of the meniscus can be compared with the contralateral side without injury, which can reveal damage to the subchondral matrix [11,12]. More importantly, long-term follow-up data showed that the morphology of the cartilage remained normal 2 years after ACL reconstruction, suggesting that the subchondral damage was healed [12].
This study presents new quantitative MRI data supporting that pre-OA changes are preventable: articular cartilage is capable of self-repair if pathological irritants such as inflammation or mechanical loading precede the rupture of the articular surface in the early stages of the disease.The AOA forum audience also prompted acceptance of this idea when asked about this question. When the audience was asked to summarize the presentation, the response was “Articular cartilage is intact, after articular surface damage.” This was 35%, compared to 7% before the forum began. Also, 92% of the audience felt that mechanical loading of the articular cartilage had an effect on the healing of the articular cartilage.
The ability to observe early and reversible cartilage damage supports the need for disease-modifying treatments. Molecular biological targets such as cartilage growth promoters growth factors, anti-apoptotic agents, free radical scavenging and anti-inflammatory treatments [13,14]. In vitro studies have shown that progressive cartilage death and apoptosis occur in the following minutes and days after mechanical injury to articular cartilage, and therefore, these treatments are effective [13,15]. In particular, short-term oxygen radical scavenging was shown to significantly reduce oxidative stress and prevent chondrocyte death within 2 hours after mechanical injury [13].
Lymphocytic infiltration is present within the synovial membrane in OA joints, a common feature in chronic inflammation [16]. Anti-inflammatory drugs provide symptomatic relief. the development of OA is long-term, and there are some problems with long-term use of anti-inflammatory drugs. Studies of systemic toxicities of drugs have shown the effect of anti-inflammatory drugs on polymeric hyaluronic acid [17]. Glucocorticoid injections have anti-inflammatory effects, but many studies are also focusing on their chondrotoxic effects, especially when glucocorticoids and local anesthetics are mixed [18,19]. Topical injection therapy reduces the systemic toxic effects, and if the injections are not repeated then the long term and stable effects are not available.
Gene therapy for stable and long-term biologically active substances. More than a decade ago, much of the literature was published on the issue of viral vectors now renewed attention to safety issues. The current strategy is to use non-toxic viral vectors, non-viral vectors for topical treatment, and to add other methods to control gene expression. Recent work is using small non-replicating or non-enveloped viruses that are thought to cause any disease that results in sustained transgene expression after a single intra-articular injection [20]. These viruses also bind to specific sites in their own gene family and should therefore theoretically reduce the occurrence of associated diseases, including tumors.The safety of AAV can be controlled by extrinsic control of the shutdown or opening of certain genes in vivo such as tobramycin [20]. Subsequently, AAV has been approved in clinical studies in sites such as the brain, eye, and knee.
With public understanding of the bacterial and viral gene families contained in the human body, this viral vector gene therapy is accepted in the future. In response to the question that gene therapy using non-pathogenic vectors for pre-treatment of knee OA changes can protect the joint, about half of the respondents thought it was acceptable and 29% thought maybe. These responses call for a focus on effective and multiple approaches to the evaluation of disease and treatment effects on articular cartilage in order to have new treatment options to prevent or delay the onset of disabling osteoarthritis in the clinical setting.
From mice to humans: reducing the incidence of traumatic osteoarthritis after intra-articular fractures
Approximately 12% of patients with intra-articular fractures require surgery to treat traumatic symptomatic osteoarthritis [21]. Although post-traumatic osteoarthritis develops rapidly [22,23], the different fracture types, sites and severity make it difficult to determine the etiology. It is important to evaluate and identify new treatment options in valid animal model studies in controlled locations [24]. In the forum, small animal modeling, application and treatment received attention.
It is important to make models of intra-articular fractures to keep the joint cavity closed, as surgery may alter the physiological response to the injury. Mouse models facilitate biomechanical studies. Therefore, tibial plateau fractures were produced in wild or adult C57BL/6 mice [25]. This was performed by computer-controlled, localized strikes. Progressive joint degeneration could be detected by means of histological observations performed at 8 and 15 weeks after injury by means of a modified Mankin score.
The decrease in articular chondrocyte activity was the earliest change compared to healthy joints and was significantly much lower. However, no significant differences were found between low- and high-energy injuries. In addition, the work of Krenn etal found that in a mouse model, inflammatory changes in the joint were significantly worse after 7 days of injury compared to normal joints [26]. Synovitis in low-energy fractures was predominantly lateral to the joint cavity, whereas synovitis in high-energy fractures was total joint cavity.
These data suggest that, similar to the consequences of intra-articular fractures in humans, closed intra-articular fracture mice accelerate articular cartilage damage and degeneration. In addition, there is a clear inflammatory response. Also, the weight-bearing requirements, life extension, and disease course are different in mice and humans. Mouse models, including transgenic, knockout mice, and special species of mice allow for a more economical study of the biological mechanisms involved in the development of osteoarthritis after tibial plateau fracture surgery.
This model uses superhealing mice for studying the response to closed intra-articular fractures. In this mouse, although the intra-articular fractures healed in a poor location, there was no significant change in modified Mankin histology to assess articular cartilage degeneration at any time point. In contrast, in the case of C57BL/6 mice, traumatic osteoarthritis was evident in the injured lower extremity compared to the contralateral healthy one. There was no significant difference between the control joint without fracture and the contralateral healthy joint of the experimental animals.
There was also a significant difference in gene expression between the Super Rat and the C57BL/6 tibial plateau with closed fractures [27]. In this study, the C57BL/6 mouse model showed osteoarthritic alterations at 8 weeks post-injury, while the super mice did not. Gene expression analysis of inflammatory factors and chemokines from the synovial membrane of injured mice revealed a significant increase in the expression of proinflammatory factor genes, such as TNF-a, IL-1a, and IL-1b. TNF-a expression was increased early in C57BL/6 mice and persisted until 7 days post-injury. IL-1a expression was increased in both mice. the greatest difference in IL-1b expression was 720-fold in C57BL/6 mice and 74-fold in super mice on the first day and continued to rise until 7 days in C57BL/6 mice, while super mice returned to normal levels after 3 days.
Synovial fluid analysis showed the same levels of TNF-a and IL-1a in the fractured joint as in the normal contralateral joint. tNF-a was largely undetectable in the synovial fluid. il-1b was the same in the synovial fluid in C57BL/6 and super mice but not in the contralateral healthy joint. il-1b remained consistently elevated in C57BL/6 until 7 days, whereas super mice returned to normal at 3 days post-injury. Serum IL-1a and IL-b expression in the second-line mice corresponded to the levels in the synovial fluid. Serum levels were slightly increased in C57BL/6 mice at all time points.
Synovial inflammation was evident in C57BL/6 mice at day 7, and disappeared in both lines at days 28 and 56. ImmunoM assay showed more pronounced macrophage activation in the local synovial membrane in C57BL/6. Macrophage staining was more pronounced at day 7. Although synovial inflammation subsided, macrophage infiltration still persisted for 28 days in C57BL/6 mice.
Analysis of the super mice revealed that elimination of inflammation in the joint cavity prevented the development of traumatic arthritis. Super mice also developed synovitis in the early post-injury period, but they were able to limit the progression of inflammation. These data suggest that early elevation of IL-1 may be the mechanism by which osteoarthritis occurs in wild mice. Similarly, activation of intra-articular fracture macrophages may also be responsible for joint metaplasia.
These studies suggest that post-traumatic intra-articular inflammation plays a partial role in the development of arthritis. Treatments targeting DNA transcription or blocking specific inflammatory pathways are frequently used in oncology and cardiovascular disease [28,29]. From audience returns, it was found that 97% of the audience understood that fracture severity and inflammation were related, and 86% knew that super mice were able to limit inflammation after fracture. Studying animal models for the development of post-traumatic osteoarthritis can allow us to focus on new potential options for delaying the onset of osteoarthritis in patients with human joint injuries.
30 years of experience in joint preservation surgery
In the hip joint, joint preservation surgery has a long history of improving joint function and delaying the onset of osteoarthritis by correcting force lines, and new arthroscopic techniques have been developed to address soft tissue injuries and femoroiliac impingement syndrome well. However, many surgical options are used to treat DDH, and it is now increasingly recognized that many cases can be femoroiliac impingement syndrome, a common cause of hip osteoarthritis. The field audience chose either DDH or femoroiliac impingement syndrome as a common cause of osteoarthritis in Europe and the Americas in half each. Any discussion of new hip preservation surgery options is driven by new ideas, related diagnostic techniques, and the treatments themselves.
The conceptual framework for the prevention and treatment of osteoarthritis of the hip assumes that osteoarthritis is caused by mechanical factors rarely by articular cartilage disease, although there are differences in the genetic diversity of cartilage resistance. Thus, there are anatomical abnormalities that cause abnormal force line mechanisms and activities that lead to damage to articular cartilage.Felson summarized the risk factors for osteoarthritis, including damage to joint protective mechanisms, excessive loading, and a combination of both. [30].
Worldwide, osteoarthritis of the hip is associated with developmental status, particularly DDH, Legg-Calve-Perthes disease, slipped femoral head, and anatomical abnormalities such as posterior tilt of the femur and acetabulum, pelvic coalescence, and reduced cervical stem angle. The most recent focus has been on the mechanical basis of hip disease, including instability and femoroiliac impingement. The malleolar rim is the earliest site of impingement injury [31]. Instability is due to excessive forces of the femoral head acting on the acetabular rim, specifically hip extension, abduction or external rotation. Acetabular dysplasia can lead to an outward shift of the weight-bearing region of the acetabulum forming a typical mechanical instability that is evident in children and less evident but problematic in adults.
Ganz et al. first described acetabular impingement, which is an impingement of the proximal femur and acetabular rim, resulting in cartilage damage [32]. Hip impingement may occur in the joint capsule or outside the joint. Intra-articular acetabular impingement may be internal, in which case the rounded femoral head and neck bulge during hip motion cause soft tissue injury between the acetabular rim and glenoid labrum, or the type of impingement such as posterior tilt of the neck or acetabulum, acetabular over-deepening or ligamentous laxity at the femoral neck impinging on the glenoid labrum during flexion, abduction, or internal rotation. Recent studies have suggested that cam-type rather than involute deformity leading to joint tissue damage is a risk factor for early osteoarthritis. Also, acetabular impingement and instability increase the risk of hip OA.
A detailed history of a patient with hip osteoarthritis can suggest signs and symptoms that are compatible with biomechanics. Physical examination includes compression of the hip joint. Static imaging is the gold standard for diagnosing orthopedic conditions, and several recent publications have highlighted the role of X-ray imaging in the evaluation of most conditions [33]. Orthopantomographs of the pelvis including the proximal femur are useful, and Dunn lateral films
and true lateral films can provide a comprehensive view of pelvic morphology.
Important advances in static imaging include CT, where imaging from the distal femur allows visualization of the femoral angles, and recently low-dose radiography has been used. MRI without or with contrast enhancement can also be done. MRI techniques can also assess glycoprotein damage within the articular cartilage [34].
Another variation in imaging to assess hip mechanics is the use of dynamic methods for assessment. While CT reconstruction techniques are able to show impingement, real-time ultrasound is able to show intra- and extra-articular impingement between different structures of the hip joint [35,36]. Ultrasound requires special equipment and specialized training but is relatively inexpensive, more comfortable for patients, safer, faster, and more suitable for screening.
Although, from published data it is possible to prolong hip function in patients with DDH to support early treatment. ddh remains a worldwide disease with a high correlation between pelvic osteotomy force lines and outcome. steppacher etal reported Ganz osteotomy at 20 years follow-up and 61% of patients remained well [40]. matheney
etal and soballe and Troelsen reported similar mid-term outcomes to Bern for periacetabular osteotomies [39-41]. Risk factors for poor mid- to long-term outcomes include having osteoarthritis, different heart, severe dysplasia, glenoid labral tears, older age at the time of surgery, and inadequate or excessive correction.
New protocols for the prevention and treatment of hip osteoarthritis should recognize the importance and interplay of anatomy, dynamics, and biology. Instability and impingement are common causes of joint injury, but the degree of cartilage damage at the time of treatment remains a key determinant of outcome. Arthroscopy is able to diagnose and treat damage to the articular cartilage structure caused by mechanical stressors, thus reducing the risk of osteoarthritis.
DDH treatment has yielded good long-term results, and prospective multicenter evaluation of hip arthroscopy for acetabular impingement is a hot topic of current research.
Summary
Orthopaedic surgeons treat all joint diseases, from joint trauma to pre-osteoarthritic disease and advanced osteoarthritis. Information on the healing of subchondral mechanical stress injuries, the role of inflammation in osteoarthritis, and the long-term outcomes after surgical correction of joint force lines are presented in this article. This information supports early intervention to delay the onset of osteoarthritis. This forum focuses on the frontier of orthopaedic research: the treatment of clinical osteoarthritis should shift from symptom relief to prevention of osteoarthritis.