La force de réaction au sol verticale maximale comme témoin d'effets fonctionnels et structuraux chez des modèles canins d'arthrose : potentiel  envers le développement thérapeutique
Animal models of osteoarthritis are useful to evaluate the potential of osteoarthritis therapeutics at the preclinical stage of development. In this thesis, the dog is used as a model of naturally-occurring (i.e. companion animal) and experimentally induced (i.e. by surgical transection of the cranial cruciate ligament) osteoarthritis. The peak of the vertically-oriented ground reaction force, which is measured during kinetic gait analysis, is proposed to be an indicator of structural and functional benefits in these models of osteoarthritis.  In a canine model of naturally-occurring osteoarthritis, the threshold of the minimal detectable change in peak vertical force was determined. An improvement in the locomotor disability can now be identified according to the measurement error (noise) of the peak vertical force. This allows the identification of responders when the peak vertical force is used as an outcome measure of functional benefits. A retrospective analysis later determined that current therapeutic approaches provided a responder rate of 62.8% with an effect size of 0.7 in dogs with naturally-occurring osteoarthritis. This analysis also determined that the therapeutic response is favored in cases of severe locomotor disability.   In a canine model of osteoarthritis induced by surgical transection of the cranial cruciate ligament, the peak vertical force demonstrated an inverse relationship with different types of structural changes, as evaluated upon magnetic resonance imaging. The sensitivity of the peak vertical force to detect structural benefits on the subchondral bone was also shown in this model using an antiresorptive agent (i.e. tiludronate).  The experiments conducted in dogs with naturally-occurring osteoarthritis further validate findings from clinical trials in which the peak vertical force is used as an outcome measure of functional benefits. The practice of an evidence-based medicine is then expected. The experiments conducted in dogs with surgically-induced osteoarthritis support the recording of the locomotor disability, being in line with the level of the structural changes. By performing gait analysis in addition to structural evaluations, it is expected to establish the impact of structural benefits on joint discomfort   This thesis suggests that a platform for preclinical investigations, which combines the canine model of osteoarthritis induced by surgical transection of the cranial cruciate ligament and a clinical trial in dogs with naturally-occurring osteoarthritis, offers the opportunity to discern structural benefits having functional impacts. A better prediction of outcomes for human clinical trials is expected by using the peak vertical force.
Kinetic gait analysis Cinical trials Drugs Preclinical research Pain Lameness