Loading and unloading in the development and treatment of osteoarthritis

Osteoarthritis is a slowly degenerating joint disease with a high and still increasing incidence. The disease is characterized by pain, stiffness, and functional disabilities. Cartilage damage and subchondral bone changes, accompanied by synovial inflammation are causative. Current treatment aims at controlling pain and improving function, and will inevitably lead to surgical interventions, with finally replacement of the joint by an endoprosthesis. There are many factors involved in development and progression of OA,(over)loading playing a mayor role. Overloading can be caused e.g. by obesity, malalignment with a shift of the loading axis, joint instability in case of ligament and/or muscle dysfunction, and focal overloading due to impaired mechanical properties of surrounding cartilage or bone tissue. The first part of this thesis studies the role of loading in the development of OA with a focus on bone and cartilage interaction. Studying development and treatment of OA requires the use of animal models. The recently developed canine Groove model was compared to human OA. Despite species-specific differences, OA induced changes were similar, making the model suitable for evaluation of the disease. Using this and several other canine models of OA to study early changes in OA, in collaboration with the dept. of orthopedics Erasmus MC, revealed that early in the process of OA thinning of the subchondral plate coincides with cartilage degeneration whereas impairment of subchondral trabecular bone structure is related to unloading of the joint. Thinning of the subchondral plate is suggested to be dependent on soluble mediators originating from the cartilage which is damaged due to overloading. The second part of this thesis studies unloading as a treatment of OA. After an overview of possibilities to unload a joint, there is a focus on unloading joint in end stage OA by use of joint distraction. By placement of a external fixator bridging the joint, the joint is distracted for a few millimeters, avoiding the cartilage surfaces to contact. Biomechanical conditions were created that allow cartilage and bone to repair. By use of the aforementioned canine Groove model a beneficial effect on cartilage quality could be demonstrated. In collaboration with the veterinary department of the UU these structural changes appeared to be accompanied by improved loading (less pain) of the affect joint. A study in patients with severe ankle OA in collaboration with the University of Iowa showed clinical benefits which might be explained by bone repair activity. A final study in patients with severe knee OA in collaboration with the department of orthopedics showed clinical improvement but also cartilage repair, even in severely damaged areas, by use of X-ray, MRI and biomarker analyses. Joint distraction is the first treatment of OA that is able to induce cartilage and bone regeneration in severe end stage OA, accompanied by clear prolonged clinical benefit.