Post-traumatic joint osteoarthritis usually occurs with fractures that involve the joint. The current literature reports a more than 75% incidence of osteoarthritis following joint injury; and if an intra-articular fracture occurs, the patient’s risk of knee osteoarthritis can increase more than 20-fold.
Despite current improvements in treatment techniques and methods, the incidence of post-traumatic osteoarthritis has not improved significantly over the past few decades. The occurrence of PTOA after intra-articular fracture may be associated with multiple factors, such as articular cartilage damage in the early stages of injury, joint instability in the later stages, and excessive weight bearing on the joint due to unevenness of the joint surface or changes in the axis, which can trigger PTOA.
The understanding of the pathogenesis of PTOA and the development of a reasonable treatment plan are the most practical studies for clinical purposes. In this paper, we review the pathogenesis and treatment of PTOA to guide daily clinical work.
PTOA usually occurs after joint injury and is the most common complication of intra-articular fracture or joint instability. It has been reported in the literature that approximately 12% of medical expenditures after hip, knee, and ankle fractures are directly related to late PTOA, and in the United States, the annual medical costs spent on PTOA approach $3 billion.
The literature reports a 75% risk of postoperative osteoarthritis in patients with severe joint trauma, and a 20-fold increased risk in patients with intra-articular fractures. Despite significant advances in surgical treatment techniques and instrumentation for periarticular joints over the decades, the incidence of PTOA has not been radically reduced.
The mechanisms by which PTOA occurs after joint injury remain unclear, so early clinical intervention and prevention of PTOA remains difficult. Available research evidence suggests that the development of PTOA is related to multiple factors, including early trauma, damage to articular cartilage, biological stress (hemorrhage, inflammation), and later chronic joint overload due to joint instability, unevenness of the joint surface, and disturbed joint axis alignment; other relevant factors include patient age and injury severity. In this paper, the mechanisms related to the occurrence of PTOA are described, and measures to prevent and reduce the occurrence of PTOA are proposed.
Structure, function and response of articular cartilage to mechanical injury
The intra-articular cartilage structure contains approximately 60-85% water, while the solid matrix portion contains a series of extracellular collagen fibers (mainly type II, but also type VI, IX, XI), proteoglycans (mainly aggregated proteoglycans, but also core proteoglycans, dimeric glycans, and fibrinoglycans).
The composition, structure, and remodeling of intra-articular cartilage are usually compatible with the normal function of the joint, which is relatively unresponsive to injury. Mechanical stimuli to articular cartilage, such as injury, can result in a biological response at the macro (tissue) or micro (cellular) level, which activates intracellular signaling pathways and triggers a series of cascade responses. Depending on the nature of the mechanical injury and the local environment within the joint after the injury, articular cartilage cells may repair or degenerate, with the latter persisting leading to PTOA.
PTOA pathogenesis
1.Acute intra-articular injury
Acute intra-articular injury is currently considered to be a pathogenesis of PTOA. Intra-articular cartilage injury can induce chondrocyte death or dysfunction to cartilage dysfunction, which can lead to cartilage degeneration throughout the joint at a later stage. Studies have shown that cartilage blocks with intra-articular fractures in the heel bone contain significantly lower levels of chondrocytes than normal controls (73% vs. 95%, p=0.005).
In a recent study by Tochigi et al. in which a model of tibial ankle cavity apex fracture was created by direct vertical longitudinal violent impact on a fresh human cadaveric ankle specimen, it was found that the number of chondrocytes surviving in the area of the ankle joint closer to the fracture line was significantly less than in the area distant from the fracture line (25.9% vs. 8.6%), and the number of cartilage deaths continued to increase after 48 hours post-injury.
In animal models, chondrocyte death was usually found in the vicinity of the fracture line, and the number of chondrocytes surviving in joints damaged by violence without fracture was higher than in areas where fracture occurred, suggesting that exposure of the joint to forces exceeding physiological load levels can lead to severe acute intra-articular cell damage.
Several in vitro experiments have investigated the pathways to chondrocyte death after external impact on the joint cavity to determine whether the chondrocyte death is apoptotic or necrotic. In vitro mechanomechanical experimental studies have found a correlation between cell death and the duration and degree of external force loading. In in vitro experiments, some studies have identified signs of early chondrocyte necrosis, while others have identified signaling molecules for apoptosis, and how the aforementioned cell necrosis or apoptosis leads to a cascade of PTOA responses is currently unknown.
One possible mechanism that induces the cascade of chondrocyte death is the local release of proinflammatory mediators regulators or oxygen radicals within the injured joint, and the persistence of these substances within the joint can lead to progressive chondrocyte damage and matrix degeneration. Some in vitro studies suggest that external impact on the joint leads to mitochondrial damage within the articular chondrocytes and release of oxygen radicals, which induces articular chondrocyte death and cartilage matrix degeneration.
More severe external impacts can lead to more severe local tissue damage and a higher percentage of articular cartilage death and matrix destruction. Intra-articular fractures can lead to increased inflammatory cytokine precursors and mediators in the synovial membrane (e.g., tumor necrosis factor-a, interleukin-1, NO, matrix metalloproteinases, fibronectin.
A recent study in an animal model showed a correlation between cellular damage events and the development of PTOA after joint injury. borrelli et al. found a decrease in chondrocyte metabolic markers (procollagen II, BMP-2) in the knee joint in a rabbit model of external knee injury with damage to the cartilage extracellular matrix. Other related studies suggest that the viscoelasticity of intra-articular cartilage changes over time, while intra-articular subchondral bone formation increases.
In a study by Furman et al. in a mouse tibial plateau fracture model, degenerative intra-articular lesions including reduced bone density and increased subchondral bone thickness occurred within 8 weeks of injury without treatment, while severe intra-articular cartilage loss occurred 50 weeks after injury, in addition to intra-articular changes including proliferation of inflammatory factors and altered serum and synovial fluid biomarkers.
The results of this study suggest that the inflammatory response after intra-articular injury plays a very important role in the development of PTOA, and that reducing the degree of intra-articular inflammatory response early in the injury reduces the severity of postoperative PTOA in patients.
2. Long-term joint overload
Early surgical treatment is recommended for patients with intra-articular fractures to restore the joint surface flatness and securely fix the joint surface fracture block. Joint surface unevenness, joint instability, and joint axis disturbance all play a role in the development of PTOA; however, the exact mechanism of these factors in the development of PTOA is unclear. Although the current requirement for joint surface unevenness is limited to 2 mm, for some joints, joint surface unevenness beyond 2 mm is still within the tolerable range.
Some animal and finite element studies have found that unevenness within the articular surface can lead to a sustained increase in contact pressure within the articular surface, and one ankle cadaver study reported that the presence of articular step-like changes within the articular surface can lead to an increase in intra-articular contact pressure of more than 300%.
Post-injury joint instability and unevenness of the joint surface can lead to increased contact stresses at localized sites, altering the weight-bearing pattern within the joint, resulting in a shift of the joint stress contact area to unconventional sites, leading to joint wear and tear, and a failure of the repair mechanism of the articular cartilage to compensate, leading to arthritis.
However, many intra-articular fracture models have found that the contact stress increase in intra-articular fractures, even when the joint surface is uneven, is not as great as one might expect. A dog study found that creating a 7-mm-thick cartilage defect in the medial femoral condyle increased contact stresses during weight-bearing by only 10-30% in dogs.
However, the results of these studies were obtained with other joints fixed and the study joint active, and may not mimic the daily life environment of humans, so the conclusions of such studies need to be accepted with caution. In addition, such experiments do not take joint instability into account during the study. At this stage, methods for assessing dynamic contact loading stresses in vitro and in vivo have been improved. More studies are needed at a later stage to assess the ultimate impact of joint surface flattening and joint stability on the development of PTOA after internal fixation of intra-articular fractures.
Recently, Giannoudis et al. performed a systematic review to analyze the correlation between step-like changes in the articular surface and the risk of developing PTOA of the joint. It was found that the risk of PTOA appears to be related to the joint involved. In a PTOA on intra-articular fractures of the distal radius, intra-articular step-like changes and joint gap size were found to be associated with a high incidence of imaging PTOA, but there was no clinical evidence that poorer intra-articular fracture reduction or imaging degenerative changes were associated with a poorer long-term prognosis for wrist function.
In a meta-analysis of PTOA after surgical treatment of acetabular fractures, anatomic repositioning of the top weight-bearing region of the acetabulum was found to reduce the incidence of postoperative PTOA and improve the clinical functional prognosis; such unstable fractures of the posterior acetabular rim were an independent risk factor for PTOA prognosis and were independent of the degree of intra-articular fracture repositioning.
In addition, two studies of tibial plateau fractures found a better functional prognosis for severe bicondylar fractures with good intra-articular reduction. Other factors, such as joint stability, preservation of the meniscus, and axial alignment of the knee, may be more important for the development of PTOA, and it has been suggested that the better tolerance of unevenness in the knee may be related to the thicker articular cartilage within the knee surface. There is no uniform understanding of the acceptable range of the maximum value of step-like changes in the articular surface.
The specific mechanisms of step-like changes in the articular surface, joint instability, and joint axis disturbance in the development of PTOA are not yet clear. According to earlier reports in the literature, there may be different mechanisms for the occurrence of PTOA in different joints; the occurrence of PTOA in the knee joint may be related to the alignment of the knee axis and the preservation of the ligament/meniscus. In most patients with intra-articular fractures, restoration of articular surface flatness, joint stability, and joint axis alignment are the three aspects that are needed to reduce the incidence of PTOA.
Evaluation of articular surface fracture repositioning
Pre-, intra-, and post-operative assessment of articular surface repositioning can be performed by radiographs, CT, and angiography. Some studies have reported poor intergroup agreement among trauma surgeons in assessing the flatness of the articular surface on radiographs.
The use of CT can improve the accuracy of preoperative articular surface fracture assessment and the accuracy of postoperative articular surface repositioning; CT has better sensitivity for preoperative articular surface fracture assessment than X-rays; in some patients, CT findings can even be decisive in determining the surgical treatment plan. In a study of the accuracy of 2D and 3D CT assessment of distal radius fractures, it was found that 3D CT could change the surgical decision in 48% of patients.
Moed et al. compared the accuracy of radiographic and CT evaluation of 67 posterior acetabular wall fracture reductions. anatomic repositioning was seen in all patients on radiographs, but on CT, 11 patients had repositioned articular surface irregularities of more than 2 mm and 52 patients had fracture repositioning gaps of more than 2 mm. these studies The results suggest that the accuracy of radiographic examination to assess intra-articular fractures is not high and that preoperative and postoperative CT examinations are necessary to accurately assess intra-articular fracture repositioning.
Intraoperative 3D CT reconstruction and intra-articular angiography can provide a valid assessment of intra-articular repositioning and guide the accurate placement of intra-articular plates. The use of intraoperative 3D CT or imaging can reduce the chance of patients requiring reoperation due to poor plate placement, screw penetration, and uneven articular surface repositioning; however, the clinical use of intraoperative CT to guide articular surface fracture repositioning is still uncommon.
Intra-articular fracture treatment and its impact on PTOA
The current focus of treatment for intra-articular fractures is to restore articular surface flatness, reshape joint stability and axial alignment of the knee, and thereby reduce the incidence of long-term PTOA. There have been many studies focused on reducing or alleviating the occurrence of PTOA in intra-articular fractures.
Improving intra-articular fracture repositioning
Because intraoperative imaging assessment of intra-articular step-like changes is inaccurate, clinical scientists are currently searching for a method to improve the accurate assessment of intra-articular fracture block repositioning. More published literature describes techniques to improve intra-articular repositioning through arthroscopic-assisted repositioning.
A systematic analysis of arthroscopic-assisted resurfacing techniques published by Atesok et al. found that arthroscopically assisted resurfacing techniques are now widely used in various fracture sites such as tibial plateau, intercondylar tibial ridge, ankle, pilon, heel, femoral head, articular glenoid, greater tuberosity, distal clavicle, radial head, coronoid process, distal radius, and scaphoid.
Potential advantages of arthroscopic-assisted resurfacing techniques include direct visualization of the joint surface, reduced intra-articular trauma, intraoperative diagnosis or treatment of cartilage and ligament injuries, and intra-articular debridement and lavage. However, it is important to note that arthroscopic assisted resurfacing techniques are more demanding on the operator and have an increased rate of associated medical costs and risks such as osteofascial compartment syndrome due to the addition of additional procedures.
More literature has compared the differences in clinical function and imaging prognosis after arthroscopic-assisted fracture reduction and standard open surgery. Two studies compared postoperative outcomes for intra-articular fractures of the distal radius: one compared the prognostic differences between arthroscopically assisted and fluoroscopically assisted resetting techniques, and the other compared the prognostic differences between the arthroscopically assisted technique and the conventional open resetting technique. In both studies, there was a significant improvement in imaging performance and joint motion in the arthroscopically assisted resurfacing group compared to the other group, but the comparison of patient joint function between the groups did not lead to a definitive conclusion.
Two studies comparing the clinical prognosis of arthroscopically assisted and open reduction for tibial plateau fractures found that the arthroscopically assisted reduction group had a shorter hospital stay, shorter time to full weight bearing of the lower extremity, and better early functional joint motion and joint surface repositioning, but long postoperative follow-up did not lead to a definitive conclusion on the functional prognosis of the two groups. More clinical studies are needed to determine whether the arthroscopic-assisted fracture reduction technique can fundamentally improve the functional prognosis of the joint and reduce the late occurrence of PTOA.
Biological interventions and long-term studies
Biointerventional treatment of osteoarthritis is currently a hot topic in continuing medical research. Most studies have focused on the treatment of intermediate and late stage osteoarthritis. Staging of acute joint injury and biological response to injury provide excellent therapeutic targets for early biologic interventions (Table 2). Biologic treatment of intra-articular fractures can act at any of the stages of joint injury staging, early, intermediate (catabolic and anabolic homeostasis), and late (limited repair, remodeling, matrix formation).
Early stages of joint injury include cell death and inflammatory response (apoptosis/necrosis) with elevated inflammatory factors, enzymes, oxygen free radicals, etc. Appealing changes can lead to joint damage in the distant future. An in vitro study has demonstrated that intra-articular application of intra-articular apoptosis inhibitory factor reduces mechanically induced articular chondrocyte death in the early stages of joint injury.
Topical application of P188 surface active factor (a cell membrane stabilizing factor that inhibits stress-related P38 cytokinin-activating protein) reduces the occurrence of apoptosis. Blocking the fibronectin pathway is effective in reducing cellular injury and mechanistic degeneration. Topical application of antioxidants within hours after injury reduces chondrocyte death and matrix degeneration in vitro.
Topical application of dexamethasone injections may also improve the onset of intra-articular cartilage degeneration to some extent. Despite the positive findings of all these studies, there are still more obstacles to their practical application in humans.
Two of the more established biologic factors used in clinical practice are hyaluronic acid derivatives and BMP-7, which have been shown to delay or prevent the progression of PTOA. Researchers believe that HA reduces the development of osteoarthritis by decreasing the rate of substance breakdown and reducing the release of inflammatory factors and enzymes in the joint during the early stages of joint injury.
A study of synovial tissue obtained after tibial plateau fractures found HA to have anti-inflammatory and chondroprotective effects. However, some studies have also reported no significant effect of HA in the treatment of PTOA of the elbow joint. Topical application of BMP-7 in the injured joint within 3-4 weeks after surgery has a chondroprotective function.
Given the paucity of literature on the use of biotherapeutic factors in clinical practice, it is not yet possible to make an accurate judgment on the specific efficacy of such drugs. In addition, tissue engineering is also becoming a hot topic of research in the treatment of joint injuries, but such therapeutic measures are not the target of this thesis for the time being.
Summary
The development of PTOA after intra-articular fracture is the result of multiple factors. Early cartilage damage, chondrocyte death, cellular matrix destruction, release of inflammatory factors and oxygen free radicals, late joint instability, uneven articular surfaces, and joint alignment disorders may all have an impact on the eventual development of PTOA. More studies are needed later to demonstrate the ultimate impact of the above influencing factors on the occurrence and development of PTOA, and to develop reasonable treatment strategies to prevent the development of PTOA accordingly. Based on the current clinical evidence, the future prevention and treatment of PTOA may be a multifaceted combination of bio-interventional therapy combined with surgical treatment.