A clinico-molecular classification scheme for ossification of ligamentum flavum: Based on 1034 cases.

Introduction: Thoracic ossification of the ligamentum flavum (TOLF) is characterized by ectopic bone formation within the ligamentum flavum. It progresses gradually over an extended period, often leading to severe spinal cord damage, resulting in significant myelopathy that typically necessitates surgical intervention. While various factors have been suggested to contribute to its development, the exact cause of TOLF remains unclear. Objective: To develop a novel classification system for TOLF by integrating clinical, radiological, and molecular characteristics to better understand and explore its pathogenesis. Methods: We conducted a retrospective analysis of 1034 surgically treated TOLF patients at our institution from January 2010 to December 2023. The study incorporated four clinical dimensions: consensus clustering (n = 76), epidemiological distribution (n = 1034), imaging characteristics (n = 399), and clinical feature assessment (n = 586). Molecular analysis was performed on surgical specimens from 11 representative cases. Results: Our analysis revealed two distinct TOLF subtypes with characteristic profiles: (1) The degenerative type (75 % of cases) primarily affected elderly patients (mean age 60 years) with normal body mass index(BMI), with localized involvement (≤3 levels) in the upper/lower thoracic spine. This subtype demonstrated significant biomechanical alterations, including changes in C2-7 SVA and LL, as supported by finite element analysis showing stress changes in the ligamentum flavum. Molecular analysis revealed the activation of wound-healing, ossification, and inflammatory pathways. (2) The metabotropic type (25 %) predominantly affected younger patients with abdominal obesity and metabolic syndrome, who exhibited multilevel involvement with preserved spinal curvature but elevated blood lipid levels and distinct dysregulation of lipid/energy metabolism pathways. Conclusion: A novel TOLF classification system consisting of two subtypes, namely, degenerative and metabotropic, each with distinct clinical, biomechanical, and molecular profiles, was developed. The degenerative subtype is primarily associated with mechanical stress and the ageing process, whereas the metabotropic subtype is linked to systemic metabolic dysfunction. Translational potential statement: The translational potential of this article lies in its innovative TOLF classification system, which offers a comprehensive approach to understanding the disease from clinical, biomechanical, and molecular perspectives. By identifying two distinct TOLF subtypes-degenerative and metabotropic-this study provides valuable insights into their unique pathophysiological mechanisms. This classification can facilitate more accurate diagnosis and enable the development of targeted, personalized treatment strategies tailored to the specific subtype, whether through biomechanical interventions for the degenerative form or metabolic therapies for the metabotropic type. Additionally, the identified molecular pathways could lead to novel therapeutic targets for TOLF, improving patient outcomes and reducing the need for invasive procedures.