Most vexing problem in pediatric fractures: Epiphyseal fractures

Abstract

Epiphyseal fracture is a significant etiology of limb deformity in children following fractures. However, unlike the rapid advancements in orthopedics, progress regarding the pathological changes, diagnosis, and treatment of epiphyseal fractures has been slow. This review provides an overview of the epidemiology and classification of epiphyseal fractures, as well as the post-fracture pathological changes occurring within the epiphysis and its surrounding areas. Furthermore, it reviews recent advancements in the treatment of epiphyseal fractures. By summarizing laboratory-to-clinical progress related to this type of fracture, this article aims to assist pediatric orthopedists in accurately recognizing, diagnosing, and treating such injuries.

Key Words: Epiphyseal fracture; Epidemiology; Pathological changes; Stem cells; Cartilage growth factors

Core Tip: Epiphyseal fracture is a significant etiology of limb deformity in children following fractures. However, unlike the rapid advancements in orthopedics, progress regarding the pathological changes, diagnosis, and treatment of epiphyseal fractures has been slow. This review provides an overview of the epidemiology and classification of epiphyseal fractures, as well as the post-fracture pathological changes occurring within the epiphysis and its surrounding areas. Furthermore, it reviews recent advancements in the treatment of epiphyseal fractures. By summarizing laboratory-to-clinical progress related to this type of fracture, this article aims to assist pediatric orthopedists in accurately recognizing, diagnosing, and treating such injuries.

INTRODUCTION

In contrast to bone, which can undergo complete regeneration, cartilage exhibits a limited regenerative capacity due to its avascular nature. Epiphyses, a specialized type of cartilage found in children and adolescents, play a crucial role in the growth and development of long bones by facilitating both longitudinal and transverse growth. Fractures in pediatric patients frequently involve epiphyseal injuries. Understanding the epidemiological data of epiphyseal fractures is essential for effective management. Moreover, examining the pathological changes in the epiphysis following fractures can provide insights into disease progression. Investigating the specific pathological mechanisms can assist clinicians in selecting appropriate treatment options and guide the development of novel therapeutic strategies to improve the management of epiphyseal injury.

EPIDEMIOLOGY AND CLASSIFICATION

Mizuta et al[1] reported that 18% of nearly 2000 bone injuries were epiphyseal injuries, while another study found that 18.5% of all fractures involved epiphysis[2]. Mann and Rajmaira[3] noted that growth plate injuries comprised 30% of fractures in their cohort. A recent study from Japan indicated that epiphyseal injuries accounted for 17.9% of fractures in children[4]. In this Japanese study, the authors highlighted that the most commonly injured epiphysis was the phalanx of the hand, which contrasts with findings from other studies as detailed in the epidemiology summary section. Based on these data, it is evident that epiphyseal injuries are relatively common. Consequently, neglecting such injuries following fractures can have a significant adverse impact on the growth and development of children and adolescents. Due to the limited visibility of the epiphysis on X-ray, there is a high risk of missed diagnosis in cases of epiphyseal injury. Magnetic resonance imaging (MRI) has emerged as a crucial complementary tool to X-ray examination for such injuries, capable of revealing soft tissue damage, including ligamentous injuries around the fracture site. For instance, in the study by Iwinska-Zelder et al[5], among 10 children diagnosed with epiphyseal injury via plain radiography, MRI reclassified and altered the treatment plan for four patients. Similarly, Carey et al[6] conducted a comparable study. Moreover, MRI demonstrates excellent diagnostic capability for occult epiphyseal fractures[7]. Consequently, for epiphyseal fractures, MRI provides more comprehensive information to guide treatment planning and prognosis assessment[8]. Additionally, it serves as an effective tool for the early diagnosis of epiphyseal diseases, such as Kaschin-Beck disease[9].

The Salter-Harris classification is the predominant system utilized for categorizing epiphyseal fractures in pediatric patients[10]. This classification encompasses five distinct types: (1) Type I, involving fractures that traverse the physis; (2) Type II, involving fractures through the physis and metaphysis; (3) Type III, involving fractures through the physis and epiphysis; (4) Type IV, involving fractures through the physis, epiphysis, and metaphysis; and (5) Type V, characterized by physeal compression or crush injuries[11]. Among these, Type II is the most frequently observed[12-15], a finding corroborated by subsequent studies. For instance, Sananta et al[16] reported the prevalence of each type as follows: Type II (75%), Type III (10%), Type IV (10%), Type I (5%), and the relatively rare Type V.

Deng et al's study[17] encompassed 1124 children with epiphyseal injuries, involving 1147 fracture sites, of which 789 were boys and 335 were girls. The authors concluded that the highest incidence of epiphyseal fractures occurred in the adolescent group (ages between 4015 and 6570 days). In all age groups, boys exhibited a higher incidence of epiphyseal fractures compared to girls. Falls were identified as the most common cause of injury, affecting 494 boys and 226 girls. The distal radius was the most frequent site of epiphyseal fractures (460 cases), followed by the phalanx (233 cases). Among the 1147 epiphyseal fractures, Salter-Harris type II fractures were the most prevalent, accounting for 1002 cases[17].

In another study[18], which included 1020 children (282 girls and 738 boys) with a mean age of 8.3 years, the incidence of fractures in boys was approximately three times higher than that in girls. A total of 59 cases were identified as epiphyseal fractures. The leading cause of fractures was outdoor falls (705 cases), followed by indoor falls (239 cases). In this study, fractures predominantly occurred in the upper limb (76.6%) and on the left side (56.0%). This finding is consistent with other literature indicating that upper limb fractures are more common than lower limb fractures in children[19-21]. The most frequent fracture site was the radius (304 cases), particularly the distal radius, aligning with the aforementioned data. For lower extremity fractures, the femur was the most commonly affected bone (92 cases).

In the study by Kaewpornsawan et al[22], a total of 716 patients with 718 fractures were included. The gender distribution was 68% male and 32% female. The peak age for fractures was between 10 and 16 years, with an epiphyseal fracture incidence of 12.4%. Salter-Harris type II fractures were the most common, accounting for 11.3% of all cases. Fractures occurred more frequently on the right side (53.8%) compared to the left side (46.2%). The distal forearm was the most common fracture site, representing 18.87% of all fractures. The leading causes of fractures were falls (34.6%), traffic accidents (28.4%), and falls from height (24.1%).

In a review of hand fractures in children[23], the authors reported the following data: The gender distribution of fractures was 24.6% (57 cases) in females and 75.4% (175 cases) in males, with an average age of 11.1 ± 3.3 years. The peak incidence occurred at approximately 12 years of age, and physical activity was identified as the most common cause. The fifth metacarpal bone was the most frequently affected bone (21.1%). Epiphyseal fractures accounted for 39.8% of all cases, with Salter-Harris type II being the predominant fracture type.

In a study on the epidemiology of sports-related epiphyseal injuries of the lower limbs[24], the authors reported the following findings: Among the 85 cases of epiphyseal fractures, 60 were males and 25 were females, with ages ranging from 4 to 17 years (mean age: 12.6 years). Soccer accounted for 28% of the injuries, while alpine skiing accounted for 26%. The most common site of injury was the distal tibia epiphysis (31 cases), followed by the distal fibula (17 cases) and the proximal tibia epiphysis (15 cases). There were 30 cases classified as Salter-Harris type I and 25 cases as type II, which showed a slight variation compared to other studies.

In conclusion, the incidence of epiphyseal injury following fractures is approximately 20%, predominantly observed in adolescents, with a higher prevalence among males. The majority of these injuries result from falls, which are closely associated with increased physical activity and sports participation during adolescence. Epiphyseal fractures most commonly occur in the upper limbs, particularly at the distal radius. The predominant type of epiphyseal fracture is Salter-Harris Type II.

PATHOLOGICAL CHANGES IN THE EPIPHYSEAL REGION AFTER FRACTURE

The epiphyseal plate (growth plate) is a cartilaginous structure located at the ends of long bones and consists of three distinct zones: The resting zone, the proliferative zone, and the hypertrophic zone[25]. Its primary function is to generate a mineralized cartilage scaffold that facilitates the formation of trabecular bone via endochondral ossification, which encompasses both chondrogenesis and osteogenesis[26]. The proliferative zone is the most frequently injured region among these three zones[27]. Chung et al[28] noted in their review of the injury response following epiphyseal fractures that the mechanisms governing growth plate injury response and bone repair appear to parallel those observed during fracture healing; however, the cellular and molecular processes underlying bone repair after growth plate injury remain incompletely understood. Previous animal studies have demonstrated that both intramembranous and endochondral osteogenesis mechanisms contribute to growth plate injury repair. Lee et al[29] reported no alterations in the expression of genes associated with endochondral ossification in a mouse model. In a rat model of burr-hole growth plate injury, Xian et al[30] observed the presence of Runx2 immunopositive osteoblasts during bone trabeculation at the site of growth plate injury, while the expression of genes related to chondrogenesis remained unchanged. However, a study using other rat growth plate injury models[31] have identified increased expression of cartilage-related genes (Sox9 and collagen 2). More significantly, a marked upregulation of collagen X, which is specifically expressed by hypertrophic chondrocytes during endochondral ossification, has been documented.

Previous studies have identified four distinct stages of injury response in the rat growth plate injury model: Inflammation (day 1-3), fibrosis (day 3-7), osteogenesis (day 7-14), and bone bridge maturation and remodeling (day 10-25). Comparable injury responses have been documented in growth plate injury models across various species, including mice, rabbits, pigs, and sheep[32-34].

As previously discussed, the initial response to growth plate injury is characterized by an inflammatory phase[35,36]. During this stage, a surge of inflammatory cells, primarily neutrophils along with macrophages/monocytes and lymphocytes, infiltrates the injured growth plate. Neutrophils actively remove bacteria and microdebris from the damaged area, facilitating soft tissue and bone healing[37,38]. Simultaneously, these cells secrete numerous growth factors and cytokines, which are crucial for regulating subsequent downstream reactions. The mRNA expression levels of these factors peak between 8 hours and 1 day post-injury. Notably, insulin-like growth factor-1 (IGF-I) and transforming growth factor (TGF)-beta exhibit upregulation in the early stages of injury repair. Bone morphogenetic protein (BMP), another key player during the inflammatory phase, promotes chondroblast and osteoblast differentiation while enhancing mesenchymal cell proliferation and migration[39,40]. Additionally, tumor necrosis factor-alpha (TNF-α) and interleukin-1alpha (IL-1α) show significant increases on day 1[41]. Birkl et al[42] have also emphasized TNF-α as a critical factor in healing and tissue repair. Collectively, the inflammatory phase is essential for repairing growth plate injuries as it orchestrates the downstream cascade of the healing response (Figure 1).

Figure 1 Pathological changes in the epiphyseal region after fracture. IGF: Insulin-like growth factor; TGF: Transforming growth factor; TNF: Tumor necrosis factor; IL: Interleukin; FGF: Fibroblast growth factor; PDGF: Platelet-derived growth factor; BMP: Bone morphogenetic protein.

In the rat growth plate injury model, the inflammatory phase transitions into the fibrotic phase 3-7 days post-injury. The fibrotic response is characterized by the infiltration of vimentin-immunoreactive mesenchymal cells into the injured site. This phenomenon was also observed in mice, where undifferentiated spindle-shaped cells were present near the upper and lower regions of the growth plate injury site approximately 7 days after injury. During this period, the mRNA levels of the growth factors fibroblast growth factor 2 (FGF-2) and platelet-derived growth factor (PDGF)-BB were significantly upregulated, indicating their potential involvement in regulating the fibrotic response[43]. FGF-2 plays a critical role in various biological processes, including cell proliferation, differentiation, and migration[44]. Specifically, it promotes mesenchymal cell migration and proliferation[45,46], inhibits chondrocyte differentiation[47], enhances alkaline phosphatase activity[48,49], and stimulates bone resorption in vitro[50,51]. Additionally, FGF-2 stimulates the proliferation and migration of osteoprogenitor cells[52]. In fracture repair, PDGFs are essential for initiating events that lead to the migration and proliferation of fibroblasts and osteoblasts[53]. A study by Chung et al[54] demonstrated that inhibiting PDGF-R signaling during the fibrotic stage reduced mesenchymal cell proliferation and infiltration at day 4 post-injury and decreased the amount of bony or cartilaginous tissue at the injury site by day 14, highlighting the crucial role of PDGF in the fibrotic phase of growth plate repair.

After the fibrotic phase, the subsequent stage of the osteogenic reaction involves osteocytic differentiation among infiltrating mesenchymal cells, as evidenced by positive immunohistochemical staining for Runx-2 and alkaline phosphatase. These markers respectively indicate osteoblast differentiation and maturation[55].

In the final stage, the remodeling and maturation of the bone bridge involve the separation of bone trabeculae by numerous bone marrow cells and their surrounding by quiescent, flat, spindle-shaped osteoblasts. Osteoclasts, which are absorptive cells, occasionally appear in certain areas of the newly formed trabeculae at the injury site[56]. Additionally, growth factors such as TNF-α, IGF-1, and BMP-7 increase, promoting osteoclast differentiation and recruitment, thereby facilitating bone remodeling[57,58]. There is limited research on the pathological changes around epiphyseal injuries. An early study observed that growth plate injury affects the periphery, with cartilage tissue invading the metaphyseal region, leading to the disruption of continuous bone growth in the surrounding tissue[59]. Micro-computed tomography (CT) imaging revealed significant damage in the remaining undamaged growth plates when the bone bridge formed, including cellular disarray and a substantial reduction in overall growth plate thickness and volume[60]. Interestingly, Coleman et al[61] noted that tethering typically forms with age as the growth plate begins to close, appearing earlier in adjacent growth plates after injury. Macsai et al[62] reported that by day 60, bone bridge formation was detected in 60% of adjacent uninjured areas in injured animals. Immunohistochemical analysis showed reduced chondrocyte proliferation (PCNA marker) and increased apoptosis (TUNEL marker) in these adjacent uninjured regions.

PROGRESS OF TREATMENT

The treatment of epiphyseal fractures encompasses both non-surgical methods, such as plaster immobilization, and surgical interventions. In addressing damaged growth cartilage, it is crucial to adhere to the principles of epiphyseal fracture management, which involve restoring and maintaining the continuity of the epiphysis[63]. Achieving good anatomical reduction, either through closed or open reduction with internal fixation, is a key factor in minimizing complications[64]. Cai et al[65] investigated the treatment strategies and surgical indications for distal tibial epiphyseal fractures in children. They recommended that treatment should be guided by the degree of fracture displacement. Specifically, for initial displacements less than 2 mm, long leg casts were applied following closed reduction. For displacements exceeding 2 mm, Kirschner wire or screw fixation was performed. Conservative management is appropriate for Salter-Harris type I and II fractures, while surgical intervention is preferred for types III and IV to reduce the risk of premature physeal closure[65]. Dahl et al[66] emphasized that the primary goal of epiphyseal fracture treatment is to minimize further damage to the epiphyseal plate. Experimental results demonstrated that the incidence of epiphyseal plate injury caused by smooth Kirschner wire cross-piercing is relatively low. In cases requiring open reduction and internal fixation, anatomical reduction should be achieved, with careful removal of entrapped periosteum and other soft tissues to prevent premature epiphyseal closure and malunion[67]. With the increasing participation of children and adolescents in group sports, anterior cruciate ligament (ACL) injuries have become a significant concern affecting the health of physically active young individuals. Treatment options for ACL injuries primarily consist of epiphyseal-sparing techniques, complete epiphyseal plate reconstruction, partial epiphyseal plate reconstruction, and trans-epiphyseal plate reconstruction. Based on prior studies, the first two approaches exhibit the least impact on the growth plate[68-70].

Due to the rapid growth characteristics of children, limb varus and valgus deformities may occur following epiphyseal injuries. For children with remaining growth potential and mild deformities, epiphyseal retardation is an appropriate choice due to its minimal invasiveness and high acceptability among patients and their families[71]. This technique is primarily suited for children who still possess growth potential and exhibit minor deformities. It is currently most frequently applied to coronal plane deformities around the knee joint; however, it is important to note that a rebound phenomenon of approximately 5° may occur after removal of the growth plate[72]. Nevertheless, there is limited research on the effects of this procedure on the growth plate, necessitating further fundamental studies to explore its implications. Conversely, for older children with severe deformities (involving multiple sites, limited growth potential, and deformities exceeding 20°), osteotomy has emerged as a corrective option[73].

For certain rare diseases, such as congenital spondyloepiphyseal dysplasia (SEDC), first described by Spranger and Wiedemann in 1966, it is an autosomal dominant genetic disorder characterized by asymmetric dwarfism, a short spine, a short neck, and varying degrees of coxa vara[74]. Orthopedic management in children should prioritize the cervical spine to prevent severe neurological deficits and/or mortality[74]. For coxa vara, proximal femoral valgus osteotomy has been demonstrated to be an effective treatment[75], while total hip and total knee arthroplasty can alleviate pain and enhance function[76,77]. However, due to the avascular nature of the epiphysis and limited cellular mobility, the regenerative capacity of articular cartilage after injury is severely constrained. Consequently, the effectiveness of these treatments diminishes significantly in patients with severe epiphyseal injuries, potentially impacting their growth and development. When the bone bridge occupies less than 50% of the growth plate area, surgical intervention is performed to remove the bone bridge and implant various interposition materials such as fat, bone wax, muscle, or polymer silicone. However, the clinical success rate of this procedure remains below 35%, primarily due to poor integration of the currently available interposition materials with host tissue, leading to subsequent complications. When the bone bridge exceeds 50% of the growth plate area, orthopedic surgery combined with limb lengthening becomes necessary; however, the outcomes in these cases are also unsatisfactory[78].

The application mechanism of skeletal stem cells (SSCs) in epiphyseal injury repair primarily relies on their self-renewal and multi-lineage differentiation capabilities. Following epiphyseal injury, SSCs can differentiate into osteoblasts via local or systemic signal transduction pathways, such as BMP and Wnt signaling, thereby facilitating bone damage repair[17,79]. Additionally, these stem cells can differentiate into chondrocytes, playing a critical role in the regeneration of epiphyseal cartilage[80]. During the repair process, SSCs also promote local angiogenesis by secreting vascular endothelial growth factor and other pro-angiogenic factors, enhancing blood supply to the injured area, providing essential nutrients and oxygen for tissue repair, and accelerating the regeneration process[81].

Currently, numerous researchers are dedicated to enhancing the regenerative potential of articular cartilage. Notably, significant efforts have been directed towards the research and development of mesenchymal stem cell (MSC) therapy, leveraging tissue engineering principles, as well as the introduction of cartilage growth factors. Cartilage tissue engineering employs a multifaceted approach that integrates various cell types and growth factors, such as bone marrow MSCs, chondrocytes, TGF-β, IGF-1, and FGF-2[82,83], along with diverse scaffolds fabricated from both natural and synthetic materials[84].

MSCs possess the capability to differentiate into various tissue cells, including cartilage, bone, and adipose tissue. Moreover, MSCs can be isolated from diverse sources such as periosteum, trabecular bone, adipose tissue, synovium, skeletal muscle, and bone marrow[85]. Notably, previous studies have demonstrated that synovial-derived MSCs exhibit enhanced chondrogenic differentiation potential compared to those derived from other mesenchymal tissues[86]. In a study by Yoshida et al[87], a 6-week-old rabbit growth arrest model was created by destroying the medial half of the proximal tibia. To evaluate the effect of synovial-derived MSCs, they were cultured in a scaffold-free structure, resulting in proliferation and differentiation into chondrocyte-like cells. This suggests that MSC-based therapy may offer a promising approach for treating growth plate injuries[87]. However, it has also been reported that bone marrow-derived MSCs (BM-MSCs) are particularly suitable for cartilage tissue engineering due to their superior proliferation rate and higher expression levels of cartilage-specific genes compared to MSCs from other tissues[88]. Additionally, BM-MSCs can be easily isolated and efficiently expanded[89]. Previous studies in rabbit models have indicated the feasibility and applicability of using MSCs to induce growth plate cartilage regeneration[90,91]. Nevertheless, the failure to achieve cartilage regeneration using autologous MSCs in a sheep growth plate injury model[92] underscores the need for further research to explore the potential of MSCs for growth plate regeneration in large animal models.

Given that chondrocytes are the predominant cell type in the growth plate, it is logical to implant chondrocytes within cartilage tissue engineering scaffolds for the treatment of growth plate injuries[93,94]. Both autologous chondrocyte studies[95] and allogeneic chondrocyte studies[96] have demonstrated that both types of chondrocytes can prevent bone bridge formation. However, the availability of autologous chondrocytes is limited and their harvest may cause additional damage[97]. Further experimental data are required to substantiate these findings.

Migration, proliferation, and differentiation of MSCs are significantly influenced by various signaling molecules, particularly growth factors. In the context of growth plate cartilage repair, an ideal approach involves the sequential application of multiple growth factors to first promote optimal MSC expansion and subsequently induce their differentiation into chondrocytes[98]. Previous studies have demonstrated that growth factors such as PDGF, IGF-1, FGF-2, and TGF alpha possess mitogenic properties for MSCs[99].

Additionally, growth factors with established chondrogenic effects include FGF-2, TGF-β1, TGF-β3, BMP-7, and IGF-1[100,101]. Wang et al[102] reviewed the critical roles of TGF-β, IGF-1, and FGF-2 in cartilage repair. According to reviews by Chen et al[103] and Dahlin et al[104], co-culture with chondrocytes and minimal exogenous TGF-β stimulation were found to be more effective for MSC differentiation or proliferation. IGF-1 not only stimulates the synthesis of matrix proteins such as type II collagen and aggrecan by chondrocytes but also inhibits chondrocyte degradation and apoptosis during cartilage injury by blocking the functions of IL-1 or TNF-α[105]. A clinical trial using IGF-1 to treat children with short stature for one year reported no adverse events, suggesting its potential for clinical applications[106].

Cartilage scaffolds must possess excellent biocompatibility, biodegradability, appropriate porosity, and suitable mechanical properties. Currently, both natural and synthetic materials are predominantly utilized for cartilage repair. Natural materials, such as extracellular matrix (ECM), alginate, agarose, and chitosan, exhibit superior biocompatibility and controlled biodegradability, making them ideal for initiating chondrocyte regeneration and promoting cartilage ECM secretion[107]. Synthetic materials, including poly (lactic-co-glycolic acid) (PLGA), polylactic acid, and polycaprolactone, are extensively employed in cartilage tissue engineering to fabricate scaffolds. These materials offer tunable mechanical properties and adjustable degradation rates by altering the degree of polymerization[108], providing greater mechanical strength and suitability for load-bearing applications and drug delivery compared to natural materials. Composite scaffolds have gained widespread use due to the limitations of individual materials. Combining materials with complementary advantages can address the shortcomings of single-material scaffolds[109,110]. For instance, Wang et al[111] developed a composite scaffold from PLGA, collagen, and silk fibroin for cartilage repair by optimizing the ratio of components. In vitro studies demonstrated that this composite scaffold promotes the proliferation and differentiation of MSCs without adverse effects. In vivo results indicated that this composite scaffold enhances articular cartilage regeneration and integration with surrounding cartilage. Consequently, this composite material holds significant promise for cartilage repair and regeneration.

In addition, several studies have demonstrated the potential of gene therapy in cartilage repair. For instance, chondrocytes cultured in vitro can sustain the expression of transgenic products such as TGF-β[112,113], BMP-7, and IGF-I[114] after modification with recombinant adenoviruses. However, Hu et al[115] noted that modifying MSCs may influence their differentiation into various tissue types. Palmer et al[116] found that only a specific subset of genes is necessary to induce chondrogenic differentiation of bone marrow-derived cells, and overexpression through gene-induced transduction could potentially hinder this process. Moreover, ex vivo gene therapy approaches present several challenges, including high costs, significant effort, and extended timeframes. Consequently, further investigation is required to determine the suitability of this type of cartilage engineering for growth plate cartilage regeneration[117].

CONCLUSION

Epiphyseal injuries are prevalent in adolescent fractures, significantly impacting patients' growth and development. Consequently, it is crucial to prioritize the identification of epiphyseal injuries during the treatment of adolescent fractures. Epidemiological studies on epiphyseal injuries in adolescents highlight the importance of fracture prevention and enhancing safety awareness among this population. Clinicians should focus on screening for epiphyseal injuries when treating fracture patients. Given the pathological changes associated with post-fracture epiphyseal injuries and current traditional treatment protocols, research into MSCs and cartilage growth factors should be intensified to improve therapeutic outcomes.