A Novel Insight into the Pathological and Clinical Heterogeneity of Intravertebral Cleft in Osteoporotic Vertebral Fractures Through Multilevel Analysis

Background: Intravertebral cleft (IVC) is a characteristic imaging feature of impaired healing after osteoporotic vertebral compression fracture (OVCF) and is associated with unfavorable outcomes. However, the mechanisms underlying cleft formation and the pathological significance of different IVC phenotypes remain unclear. This study aimed to investigate factors associated with the presence of IVC and to characterize the clinical, metabolic, histopathological, and immunohistochemical heterogeneity among different IVC subtypes.<br><br>Methods: A total of 328 surgically treated OVCF patients were retrospectively enrolled between January 2022 and December 2024. Based on preoperative imaging, patients were categorized into two groups: Non-IVC and IVC. The latter group was further classified into two subgroups: Gas-IVC and Fluid-IVC. Clinical, radiological, and biochemical parameters were compared among groups. Histopathological and immunohistochemical analyses were performed to assess differences in bone remodeling and inflammatory microenvironments among IVC phenotypes.<br><br>Results: Of 328 patients, 115 had IVC and 213 did not. Symptom duration, β-CTX, and vertebral compression ratio were independently associated with the presence of IVC. Among IVC patients, Gas-IVC was associated with longer symptom duration, whereas Fluid-IVC showed higher β-CTX and P1NP levels. Histologically, Gas-IVC contained more necrotic bone, while Fluid-IVC exhibited greater woven and lamellar bone formation. Immunohistochemistry demonstrated increased IL-6 expression in Fluid-IVC and higher IL-10 expression in Non-IVC specimens, with no significant differences in IL-1β or TNF-α among groups.<br><br>Conclusions: IVC in OVCF was associated with prolonged disease duration, increased bone resorption, and vertebral collapse, suggesting that cleft formation represents a dynamic impaired-healing process involving remodeling imbalance and mechanical instability. Different IVC subtypes exhibited distinct metabolic and pathological features, supporting the concept that IVC is a heterogeneous clinicopathological phenotype rather than a simple static imaging sign.