Targeting pain and degeneration in osteoarthritis and intervertebral disc disease

Abstract

Degenerative joint diseases including osteoarthritis (OA) and low back pain due to intervertebral disc (IVD) degeneration are common clinical entities in both humans and companion dogs, posing a large psychosocial and economic burden on society. In this dissertation, a novel treatment strategy based on local and controlled release of locally delivered anti-inflammatory drugs for OA and disc disease was investigated and translated towards the veterinary bedside. In this respect, the inflammatory character of OA and low back pain was investigated, and it appeared that in dogs, as in humans, degeneration of the IVD is driven by pro-inflammatory mediators such as PGE2. Moreover, there seemed to be a striking difference in OA susceptibility and inflammatory response in cartilage and synovial tissue of normal and short-legged (chondrodystrophic) dogs; on a joint level the former seems to be more sensitive to inflammatory-driven degenerative processes than chondrodystrophic dogs. To investigate the disease-modifying effects of the sustained release of the anti-inflammatory drug celecoxib, preclinical animal models were employed first. Herein, we demonstrated that intra-articular application of biodegradable celecoxib-loaded microspheres was able to inhibit subchondral bone changes and synovial inflammation associated with OA. In line with this, in canine patients suffering from OA, a single treatment with celecoxib-loaded microspheres led to improved pain-related behaviour and synovial inflammation for over two months. A pilot study assessing the clinical effect of the controlled release of the corticosteroid triamcinolone acetonide showed similar favourable results in companion dogs suffering from OA. Furthermore, local sustained celecoxib release inhibited inflammation and prevented progression of IVD degeneration both in vitro and in vivo. Intradiscal celecoxib was subsequently applied in canine patients suffering from low back pain. Preliminary results showed favourable effects for this application as well. For dogs suffering from low back pain due to end-stage intervertebral disc disease not amenable to the aforementioned therapeutic strategy, surgical stabilisation of the lumbosacral spine with pedicle-screw rod fixation demonstrated good to excellent results in medium to long-term follow-up of a cohort of canine patients. Altogether these results provide a proof-of-concept that serves as a basis for further translation of local injection of controlled release platforms loaded with anti-inflammatory drugs from bench to the (veterinary) bed side for the treatment of early and medium stage osteoarthritis and low back pain.