The ankle joint contains the shin- (tibia), calf- (fibula) and ankle bone (talus), stabilized in a mortise configuration by the syndesmotic ligaments. Their joint surfaces are covered by cartilage layers, providing shock absorption and smooth movements. Ankle fractures with disruption of the syndesmotic ligaments are prevalent and important injuries; inducing loss of joint integrity, aggravating peak joint stresses and altering cartilage load distribution. This results in cartilage breakdown and wearing of the joint - a disabling condition known as osteoarthritis. However, a profound understanding of this altered mechanics and its exact influence on the progression of ankle osteoarthritis is currently lacking, causing a diagnostic and therapeutic challenge. Therefore, the aim of this doctoral research is to clarify the role of syndesmotic injuries in the patho-mechanics of cartilage degeneration by means of advanced multidimensional statistics as well as personalized loading and stress analysis. Furthermore, the basic science of this thesis will gradually be translated into clinical practice by providing detailed diagnostic tools and a virtual pre-operative planning, implemented during surgery using custom-built navigation technology. In doing so, I strive to establish early detection of syndesmotic injuries and provide a patient-specific treatment plan to restore ankle load distribution and ultimately prevent progression towards end-stage ankle osteoarthritis.