Anti-NGF treatment worsens subchondral bone and cartilage measures while improving symptoms in floor-housed rabbits with osteoarthritis.

Osteoarthritis (OA) is a common joint disorder often affecting the knee. It is characterized by alterations of various joint tissues including subchondral bone and by chronic pain. Anti-nerve growth factor (NGF) antibodies have demonstrated improvement in pain associated with OA in phase 3 clinical trials but have not been approved due to an increased risk of developing rapidly progressive OA. The aim of this study was to investigate effects of systemic anti-NGF-treatment on structure and symptoms in rabbits with surgically induced joint instability. This was elicited by anterior cruciate ligament transection and partial resection of the medial meniscus in right knee of 63 female rabbits, housed altogether in a 56 m floor husbandry. Rabbits received either 0.1, 1 or 3 mg/kg anti-NGF antibody intra-venously at weeks 1, 5 and 14 after surgery or vehicle. During in-life phase, static incapacitance tests were performed and joint diameter was measured. Following necropsy, gross morphological scoring and micro-computed tomography analysis of subchondral bone and cartilage were performed. After surgery, rabbits unloaded operated joints, which was improved with 0.3 and 3 mg/kg anti-NGF compared to vehicle injection during the first half of the study. The diameter of operated knee joints increased over contralateral measures. This increase was bigger in anti-NGF treated rabbits beginning 2 weeks after the first IV injection and became dose-dependent and more pronounced with time. In the 3 mg/kg anti-NGF group, the bone volume fraction and trabecular thickness increased in the medio-femoral region of operated joints compared to contralateral and to vehicle-treated animals, while cartilage volume and to a lesser extent thickness decreased. Enlarged bony areas were found in right medio-femoral cartilage surfaces of animals receiving 1 and 3 mg/kg anti-NGF. Alterations of all structural parameters were particularly distinct in a subgroup of three rabbits, which also exhibited more prominent symptomatic improvement. This study showed that anti-NGF administration exerted negative impact on structure in destabilized joints of rabbits, while pain-induced unloading of joints was improved. Our findings open up the possibility to better understand the effects of systemic anti-NGF, particularly on subchondral bone, and thus the occurrence of rapidly progressive OA in patients.