Osteoarthritis is the most common rheumatic disease encountered in small animal practice. No longer is osteoarthritis regarded as a simple consequence of aging and cartilage degeneration, but rather, the pathologic changes of osteoarthritis may result from active biochemical and biomechanical processes partly due to disturbances of the homeostatic mechanisms of anabolic and catabolic pathways. As to the cause of osteoarthritis, there is no one etiology and its cause may be multifactorial. While there are many initiating causes, osteoarthritis is an irreversible process that often results in an end-stage clinical syndrome of the joint. Osteoarthritis exhibits varying degrees of severity, ranging from a mild, intermittent condition that causes mild discomfort and minimal disability, to a clinical state characterized by constant pain and severe disability. Clinically, osteoarthritis can be a challenging diagnosis to make. The disease is typically a slowly progressive problem. Because of the wide range of presenting signs, osteoarthritis is likely one of the most underdiagnosed syndromes in dogs and, especially, in cats.1,2 It afflicts at least 20% of the canine population at any time.1,3 This translates to roughly 10 to 12 million dogs in the United States. There are no accurate estimates of the number of cats with osteoarthritis.
A single definition of osteoarthritis remains elusive. At a 1995 workshop, the American Academy of Orthopaedic Surgeons proposed the following consensus definition: Osteoarthritic diseases are a result of both mechanical and biologic events that destabilize the normal coupling of degradation and synthesis of articular cartilage chondrocytes, extracellular matrix, and subchondral bone. Although they may be initiated by multiple factors, including genetic, developmental, metabolic, and traumatic factors, osteoarthritic diseases involve all of the tissues of the diarthrodial joint. Ultimately, osteoarthritic diseases are manifested through morphologic, biochemical, molecular, and biomechanical changes in both cells and matrix that lead to softening, fibrillation, ulceration, articular cartilage loss, sclerosis and subchondral bone eburnation, and osteophyte production. When clinically evident, osteoarthritic diseases are characterized by joint pain, tenderness, movement limitation, crepitus, occasional effusion, and variable degrees of inflammation without systemic effects.4
Pathophysiology of osteoarthritis
For simplicity, think of osteoarthritis progression in three broad stages.5 Stage one is the proteolytic breakdown of cartilage matrix. Stage two involves fibrillation and erosion of the cartilage surface, accompanied by breakdown product release into the synovial fluid. Finally, during stage three, synovial inflammation begins when synovial cells ingest a breakdown product through phagocytosis and produce proteases and proinflammatory cytokines. However, these stages don't progress in a specific order. Morphologically, osteoarthritis is characterized by articular cartilage degeneration and changes in the periarticular soft tissues (synovium and joint capsule) and subchondral bone. Specifically, the pathologic changes of osteoarthritis involve articular cartilage degeneration, which includes matrix fibrillation, fissure appearance, gross ulceration, and full-thickness loss of the cartilage matrix. This pathology is accompanied by hypertrophic bone changes with osteophyte formation and subchondral bone plate thickening. Research also has shown some continuity between bone and cartilage changes in osteoarthritis, suggesting an interaction between these tissues.6
Normal articular cartilage is primarily composed of water (70% by weight in mature, healthy cartilage), a collagen fibril network, extracellular matrix, and chondrocytes. During normal weight bearing, several events occur in the joint. The different matrix components must share loads applied to the articular surface. Collagen fibrils dominate the tensile behavior of cartilage, while the osmotic properties of the proteoglycans provide resistance to volumetric compression. Two very desirable events occur during cartilage loading: cartilage deformation and increased joint conformity. Cartilage deformation increases overall contact area, which reduces tissue stress levels. And increased joint conformity provides additional joint stability. Furthermore, the ability to change the shape of the loaded cartilage may help form and retain a thin gel of concentrated lubricant between the articular surfaces; fluid is distributed away from the compressed regions of cartilage. These properties are controlled primarily by the cartilage's ability to maintain hydration under pressure, which is achieved through the low hydraulic permeability and the high osmotic pressure of the constituent proteoglycans.
An early event in osteoarthritis development is the increasing volume (swelling) of the collagen. This can only occur if the collagen network's tensile properties are altered. The level of aggrecan (a proteoglycan) also changes in the tissue early in osteoarthritis development.
Cytokines and growth factors appear to play a critical role in the induction and progression of osteoarthritis. Proinflammatory cytokines, including interleukin-1α and β and tumor necrosis factor α, induce articular cartilage depletion by increasing the synthesis of matrix-degrading enzymes and decreasing matrix protein synthesis in vitro.
The maintenance of normal cartilage homeostasis requires the coordinated synthesis and degradation of articular cartilage matrix macromolecules. If this balance in turnover is interrupted, matrix degradation is greater than chondrocyte replacement of lost matrix. Ongoing, repetitive injury seems to be important to cytokine synthesis, and a shift in the balance between proinflammatory and anti-inflammatory cytokines may contribute to the destructive process. Increased matrix synthesis in osteoarthritis, which occurs in response to injury, doesn't appear to counterbalance matrix loss. This is particularly noticeable in the content of proteoglycan, which decreases in osteoarthritic cartilage. As matrix metalloproteinases damage and deplete the collagen fibril network, the remaining proteoglycans accumulate additional water in an unconstrained fashion, leading to increased cartilage water content and cartilage swelling. Histopathologic changes characteristic of osteoarthritic articular cartilage include irreversible chondrocyte loss from necrosis or apoptosis and chondrocyte cloning (a hallmark of osteoarthritic cartilage), fragmentation of the cartilage surface, vertical clefts, bony remodeling at the joint periphery, and penetration of the tidemark by blood vessels. Multiple tidemarks are progressive changes suggesting increasing severity. Osteophytes or enthesiophytes seen on radiographs, at necropsy, and on histologic sections are often associated with osteoarthritis, but alone aren't sufficient for such a diagnosis. From a biomechanical point of view, the causes of cartilage degeneration can be simplified to normal loading on an abnormal surface or abnormal loading on a normal surface. Laxity or incongruity in the joint places the total load over a smaller area of articular cartilage, thereby increasing the focal stress. The final result is cartilage thinning caused by matrix loss, physical compression, fragmentation, and ulceration.5-9
Clinical presentation and risk factors
A diagnosis of osteoarthritis is made through clinical signs, physical examination findings, radiographic findings, and, occasionally, synovial fluid analysis. The most common clinical sign is joint pain and associated lameness that may be acute or chronic in dogs.10 Chronic pain resulting from osteoarthritis may be difficult to recognize, as it's frequently insidious in onset. This likely scenario of undetected chronic pain is especially true in cats. Cats often present with a history of reduced appetite, weight loss, reluctance to move, or failure to self-groom. Osteoarthritis should be on the list of differential diagnoses for cats with these nonspecific complaints.2,10,11 Occasionally in both dogs and cats, more specific signs, including the refusal to jump or an overt limp, signal the presence of pain. Regardless of historical findings, physical examination findings may include pain, crepitus, swelling, joint effusion, periarticular fibrosis, muscle atrophy, and a decreased range of motion in the affected joints.10,11 All forms of joint disease, including immune-mediated disease, may have similar physical findings; therefore, the cause of joint disease must be identified because the treatment varies accordingly. Radiographic osteoarthritic changes usually occur relatively late in the disease process. These signs may include sclerosis of subchondral bone, osteophyte formation, periarticular fibrosis, and joint effusion.12
The initial cause can be traumatic, mechanical, inflammatory, hereditary, or idiopathic. Identification and elimination or modification of risk factors is one of the areas where we make the most headway in controlling osteoarthritis. Regardless of the cause of injury, cartilage has a very limited ability for intrinsic repair, and current treatments for osteoarthritis, although continuously improving, have substantial limitations. Most pathways to the development of osteoarthritis involve developmental diseases with complex polygenic characteristics, rather than traumatic injury. And several other factors, such as lifestyle, husbandry, environment, and the severity of the genetic disease, play an important role in the clinical expression or outcome of each patient's condition.
Even when dogs are genotypically predisposed to osteoarthritis, evidence suggests that altering their environment can strongly affect the phenotypic expression of the gene. Weight is one of the most important factors in phenotypic expression of osteoarthritis. Seminal research reports describe the effects of limited food consumption on the incidence and severity of hip dysplasia in Labrador retrievers over their lifetime.13-17 The most dramatic finding was that dogs fed ad libitum had significantly worse hip dysplasia than dogs offered 25% less food. Similarly, research in cocker spaniels showed that dogs with cruciate disease and humeral condylar fractures were significantly heavier than controls.18 In practice, we need to explain to pet owners that an increase in body weight and body condition score increases the likelihood of dogs experiencing an injury or disease that predisposes them to osteoarthritis.18
Current osteoarthritis therapy is mainly palliative, aiming to reduce pain and maintain or improve joint function. Osteoarthritis management should be thought of as a multi-step approach with three equally important components: weight reduction, exercise and physical therapy, and pharmacologic management. Thus, initiating treatment requires a lengthy discussion with the client about all management aspects. The veterinarian must examine each case carefully, assessing the age, normal activity levels, and, most important, the owner's expectations for the animal's performance. Success largely depends on the accurate assessment of these expectations.10
Weight control is a must when dealing with osteoarthritis. The vast majority of our patients with clinical manifestations of osteoarthritis are obese. Owner education and proper dietary management must be considered in every case. In many cases, weight reduction with rest and exercise modification diminishes or completely alleviates the clinical signs of osteoarthritis.
Using the joint in a manner that consistently causes discomfort accelerates cartilage destruction. Most patients with osteoarthritis are comfortable with light to moderate exercise regimens that don't vary greatly. Enforced rest and exercise modification should be individualized for each animal, but exercise peaks and valleys tend to exacerbate clinical signs. A good reference documents physical therapy methods to help the osteoarthritis patient.19
Nonsteroidal anti-inflammatory drugs (NSAIDs) are used in treating osteoarthritis because of their ability to reduce pain—they are the mainstay of chronic analgesia therapy in small animal medicine. The major weakness of these drugs is toxicity. Unwanted side effects are especially problematic in cats. A wide variety of NSAIDs are now available; they decrease prostaglandin synthesis by inhibiting the cyclooxygenase (COX) enzyme.20 At least three different COX enzymes exist (COX-1, COX-2, and COX-3) that are active in arachidonic acid metabolism, and certain NSAIDs are selective in their actions against these isoenzymes.10 NSAIDs that selectively inhibit COX-2 and spare COX-1 will allow analgesia without the common side effects of COX-1 inhibition, which include altered gastrointestinal and thrombocyte function. These newer products are potentially safer and as effective in alleviating pain as older NSAIDs. In addition, extensive data show that many of the anti-inflammatory effects of NSAIDs are incremental to the inhibition of arachidonic acid metabolism. Additionally, there is strong evidence that NSAIDs act directly in the spinal cord and higher centers. The mechanisms of how the different COX isoenzymes are involved in generating painful sensations aren't completely understood.10
By critically evaluating the current state of our treatment outcomes, we see a need to improve our effectiveness in treating osteoarthritis pain. Clinical experience and experimental studies suggest that NSAIDs may not provide complete pain relief in canine osteoarthritis.21-24 Thus, a multimodal approach for treating chronic pain may be the best approach for the future. Studies reveal the importance of a constant input of noxious signals from the periphery in inducing changes in the central nervous system; such studies are beginning to redirect our treatment methods.25 The nervous system is plastic and inputs from the periphery can activate various receptors and change the way nociceptive signals are processed in the spinal cord.26,27 This cellular "windup" produces central sensitization through the activation of second messenger systems, the production of nitric oxide and eicosanoids, and the induction of immediate early genes. Current research is actively looking into these areas and may provide new treatment options in the near future.
Other than NSAIDs, there are few analgesics available that can be given chronically in the clinical setting. Compounds that will be discussed act more indirectly than NSAIDs, either early in the inflammatory cascade or directly on the tissues themselves, thus indirectly providing analgesic effects.10 Current research is directed toward compounds that are known as disease-modifying, or structure-modifying, previously called chondroprotective agents. These drugs can affect both the inflammatory cascade and release of mediators and also the target tissues (cartilage, bone, and synovium). The only disease-modifying drug licensed for veterinary use in the United States is polysulfated glycosaminoglycan solution (Adequan®-Luitpold). Other products such as pentosan polysulfate and diacerhein, which are approved in other countries, are currently undergoing additional testing to prove efficacy and safety in the United States. There are many other drug classes, such as bisphosphonates and anticytokine compounds that may provide additional options to help treat chronic osteoarthritis pain in the future.
Nutritional supplements of glucosamine and chondroitin sulfate are available. However, there is minimal scientific data available for these products to prove clinical efficacy in osteoarthritis pain relief in the dog or cat. Another nutritional approach that shows some promise is the use of long-chain omega-3 fatty acids. The most likely mode of action in the management of osteoarthritis appears to be the inhibition of cytokines, eicosanoids, and other mediators in the complex inflammatory cascade.
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