Managing osteoarthritis (Proceedings)

Osteoarthritis can result from direct trauma to the joint or cartilage, injury to ligaments or soft tissues resulting in joint instability, obesity or developmental disease. The effect of osteoarthritis varies, with a wide range of severity and associated radiographic and clinical signs; however, resultant discomfort and activity restrictions can have a profound effect on quality of life. Because osteoarthritis progresses slowly, and veterinary patients are often able to compensate and mask clinical signs, the diagnosis and clinical significance is often overlooked.

Clinical signs

Osteoarthritis (OA) is diagnosed by means of historical behavior changes, clinical signs, physical examination and radiographic evaluation. Arthrotomy and arthroscopy can also be used to determine the severity of damage to the articular cartilage. Behavioral changes often associated with OA include; sore when touched or reluctant/avoiding being touched in certain areas, reluctance to walk, run, climb stairs, jump or play, difficulty rising from rest or slow to sit, crying, cowering, or whimpering, changes in temperament, aggressiveness, stiffness, especially early in the day. The clinical signs of OA include; discomfort, lameness and abnormal posture (hunched back, abnormal tail carriage, etc), decreased joint range of motion, loss of muscle mass and tone, joint thickening, crepitus and decreased overall limb use.

Additionally, chronic discomfort and nociceptive input can lead to modulation of the central nervous system, referred to as "spinal windup" amplifying the primary disease and systemic response while impairing the response to therapy. Though OA is considered a chronic progressive disease, the clinical picture may be quite dynamic with intermittent periods of acute signs or "flare ups" with periods of clinical quiescence. In addition, there also appears to be variation in the clinical impact between individual dogs.

Though radiographs are the simplest least invasive way to confirm the diagnosis of OA, because of the individual nature of the disease, radiographic changes correlate poorly with the severity of clinical signs. Owner assessment of behavior and activity and physical examination are the best estimators of disease severity and response to treatment.

The objectives for the management of OA are to minimize signs associated with OA, maintain or improve limb use and quality of life, and if possible, slow the progression of disease. A multimodal approach provides treatment aimed at different aspects of the disease process working synergistically and non-competitively for a more effective response in the treatment of OA. This allows for the administration of collectively lower doses of medication, decreasing the potential side effects of any one treatment prescribed. There is no specific recipe for the management of OA. In addition to Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), multimodal therapy for the treatment of OA also incorporates weight loss, exercise modification and rehabilitation, and diet changes. Additionally, adjunctive analgesics, chondromodulating agents, nutraceuticals and other dietary supplements may be utilized.

Nonsteroidal Anti-inflammatory Medications (NSAIDs). NSAIDs are the most commonly prescribed class of medications to alleviate the clinical signs of OA. NSAIDs reduce the formation of inflammatory prostaglandins and thromboxane production by inhibiting cyclo-oxygenase (COX) enzymes in the arachadonic acid pathway decreasing synovitis and limiting cartilage matrix degradation associated with OA. With the inhibition of COX isoenzymes, NSAIDs have a local effect at the site of injury as well as a central effect minimizing spinal nociception and central sensitization. There are many NSAIDs available on the veterinary market. The selection of an NSAID is primarily based on individual response (analgesic and adverse), veterinarian and owner preference, availability, cost, and ease of administration. Despite similar efficacies between different NSAIDs, there can be a dramatic difference in individual response. It is common to try different NSAIDs until an acceptable response is achieved or the patient experiences an adverse reaction. Similar to humans, an individual may become refractory to chronic administration to a certain NSAID at which point another should be selected. Interestingly this lack of response to a certain NSAID does not last indefinitely and may be used again, effectively, in the future. Presently there is extensive debate regarding the length of washout between different NSAIDs. This only appears to be an issue when switching from aspirin and the formation of a protective aspirin triggered lipoxin (ATL) to a COX-2 selective or COX-1 sparing NSAID, which will block those gastric mucosa protective lipoxins. This is also a concern since COX-2 selective NSAIDs have been shown to impede gastric healing once ulceration is present.

Additional Analgesics. Though NSAIDs are the initial drugs of choice for the treatment of OA, they do not completely suppress the inflammatory process and do not completely obviate the clinical signs of OA. The addition of other analgesics (Tramadol, Amantadine, Gabapentin) can improve pain control while lowering the effective dose of NSAIDs thereby minimizing the potential adverse effects of NSAIDs. Tramadol (2-4mg/kg PO q8-12hr) is a mixed opioid exerting effects at the µ receptor while inhibiting serotonin uptake and norepinephrine reuptake. There is some indication that NSAIDs may sensitize µ receptors to the effects of opioids, explaining the synergism between these two medications. Amantadine (3-5mg/kg PO q24hr) first recognized as an anti-viral agent has also been shown to be a NMDA receptor antagonist and is used to prevent central sensitization and spinal wind up in chronic pain cases. One report comparing the effects of Meloxicam with or without the addition of amantadine demonstrated that amantadine in addition to Meloxicam, improved comfort and activity in dogs with OA. It is important to note that the duration of action may be prolonged in animals with renal insufficiency. Gabapentin (1-4mg/kg PO q24hr) has also been shown to be effective for the treatment of neuropathic pain and central sensitization/ wind up. Gabapentin was initially thought to be a GABA agonist, being structurally similar to this excitatory transmitter, however, presently the mode of action is considered to be through the alpha2 subunit of voltage-gated calcium channels. Amitriptyline (Dogs 1-2mg/kg POq12-24hr, Cats 5-10mg total PO q24hr) inhibits the reuptake of norepinephrine and serotonin similar to tramadol. Amitriptyline is contraindicated in patients with cardiovascular disease and patients concurrently taking MAO Inhibitors.

Adjunctive Therapies/ Chondromodulating Agents

Recently there has been increased interest in alternative therapies for the management of OA not only to alleviate the clinical signs associated with disease, but also to slow the process of cartilage degradation and promote cartilage synthesis. Such therapies include Polysulfated glycosaminoglycan, Hyaluronan, Adipose derived stem cells, Glucosamine/Chondroitin sulfate, and Omega-3 fatty acids. Polysulfated glycosaminoglycans (PSGAGs) is a intramuscularly injected synthetic mixture of glycosaminoglycans derived from bovine lung and tracheal cartilage. PSGAGs are beneficial in the treatment of OA by inhibiting cartilage degradative enzymes while stimulating cartilage repair processes promoting protein synthesis, collagen formation, and increasing GAG and hyaluronan concentration. PSGAGs also maintain chondrocyte viability and stimulate chondrocyte division; thereby, slowing the process of ECM degradation. Hyaluronan (hyaluronic acid) is a nonsulfated glucosaminoglycan that is the primary constituent of synovial fluid, which interacts with the aggrecan monomer producing the large aggregating polyglycosaminoglycans of articular cartilage. The intra-articular administration of HA is speculated to increase synovial fluid viscosity via viscosupplementation as well as attenuate the inflammatory process within the joint. Glucosamine/Chondroitin sulfate formulations encompass the majority of nutritional supplements available for the management of OA. Both constituents are building blocks of the large proteoglycans of articular cartilage and hyaluronan of synovial fluid and exert their effects by inhibiting the synthesis of cartilage degradative enzymes while improving or maintaining synovial fluid viscosity. In the literature there are conflicting results regarding the amelioration of clinical disease progression giving this supplementation. Adipose-derived stem cells. Recently there has been interest in the application of intra-articular and intravenous administration of adipose derived stem cells to alleviate clinical signs of OA and delaying its progression. Stem cells can differentiate into chondrocytes and osteocytes in areas in need of repair, but also have been shown to alter intra-articular cytokines promoting cartilage regeneration, inducing angiogenesis and replacing damaged tissues. Stem cells have also been found to have a immunomodulatory response, suppressing the inflammatory response and homing to sites of injury. Omega-3 polyunsatured fatty acid (PUFAs) supplementation attempts to modulate the inflammatory component of OA through nutrition. N-3 PUFAs incorporated into the cell membrane as apposed to n-6 PUFAs will result in a decrease in the arachadonic acid pathway producing 2- and 4- series prostaglandins both of which are pro-inflammatory and instead promote the eicosapentaenoic pathway and 3-and 5- series prostagladins, thromboxanes and leukotrienes which are much less inflammatory thereby modifying the inflammation associated with OA and resulting clinical signs. The most common n-3 fatty acids used for supplementation include eicosapentaenoic acid (EPA), docosahexainoid acid (DHA) and alpha-linolenic acid (ALA). EPA is the only n-3 PUFA with selectivity for the chondrocyte cell membrane, decreasing inflammation and aggrecan degradation and muting signal mRNA that prompts production of degradative enzymes. Current interest in n-3 dietary supplementation has spurred the advent of several commercial diets including Hill's J/D diet, CNM Joint Mobility JM diet, and the Royal Canin JS diet.

Weight control/Diet. The importance of weight control in the management of OA cannot be understated. Obesity results in excessive forces being placed on joints and articular cartilage, which is exacerbated by inactivity and muscle loss. There is some speculation that Leptin, a fat derived hormone, elevated in obese patients, may have play a role in the development of cranial cruciate ligament tears by modifying ligamentocytes and collagenase activity. In extensive research of obese dogs with hip dysplasia, it has been shown that the loss of excessive weight can significantly improve clinical signs associated with OA.

It is important when creating, maintaining and adjusting multimodal regimes to remember that no individual responds the same and no individual disease progresses the same. Treatment varies with patient tolerance, severity of disease, clinical signs, expectations of the owner, patient's quality of life and disease stage. OA is a dynamic process, so the patient's response to therapy must be reassessed, both during disease flare-ups as well as in maintenance. If subtle changes occur, a change in the treatment plan can be immediately altered. Various objective and subject measures including thigh circumference, joint range of motion, or visual/numerical rating scales assessing willingness to perform certain activites can be helpful to monitor the patient's response to treatment.