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Purpose: To assess the diagnostic performance of three-dimensional (3D) CT-based texture features (TFs) using a convolutional neural network (CNN)-based framework to differentiate benign (osteoporotic) and malignant vertebral fractures (VFs). Methods: A total of 409 patients who underwent routine thoracolumbar spine CT at two institutions were included. VFs were categorized as benign or malignant using either biopsy or imaging follow-up of at least three months as standard of reference. Automated detection, labelling, and segmentation of the vertebrae were performed using a CNN-based framework (https://anduin.bonescreen.de). Eight TFs were extracted: Varianceglobal, Skewnessglobal, energy, entropy, short-run emphasis (SRE), long-run emphasis (LRE), run-length non-uniformity (RLN), and run percentage (RP). Multivariate regression models adjusted for age and sex were used to compare TFs between benign and malignant VFs. Results: Skewnessglobal showed a significant difference between the two groups when analyzing fractured vertebrae from T1 to L6 (benign fracture group: 0.70 [0.64–0.76]; malignant fracture group: 0.59 [0.56–0.63]; and p = 0.017), suggesting a higher skewness in benign VFs compared to malignant VFs. Conclusion: Three-dimensional CT-based global TF skewness assessed using a CNN-based framework showed significant difference between benign and malignant thoracolumbar VFs and may therefore contribute to the clinical diagnostic work-up of patients with VFs. [ABSTRACT FROM AUTHOR]