This review examines the molecular mechanisms driving structural damage in Spondyloarthritis (SpA), a chronic inflammatory condition characterized by new bone formation that can lead to partial or complete spinal ankylosis. We explore the complex interplay between inflammation, mechanical stress, and bone metabolism in SpA, focusing on key signaling pathways and cytokines that contribute to disease progression. The review analyzes both structural and inflammatory aspects, particularly the role of enthesis biology and the impact of mechanical factors. Additionally, we assess how current therapeutic approaches, including biologic treatments targeting specific inflammatory pathways such as tumor necrosis factor inhibitors, affect disease progression. While these treatments can reduce inflammation and manage clinical symptoms, their limited ability to completely prevent new bone formation highlights the complexity of the underlying pathological processes. We also evaluate emerging therapeutic strategies targeting specific molecular pathways involved in bone formation. Understanding these intricate molecular mechanisms and their interactions is crucial for developing more effective targeted therapies that could potentially not only manage symptoms but also prevent or reverse structural damage in SpA patients.