A mulitmodal approach to treating canine osteoarthritis beyond NSAIDs (Sponsored by Nestlé Purina)

Osteoarthritis, the most common orthopedic disease we see in dogs today, is an insidiously progressive disease of diarthrodial joints that can profoundly impact a dog's quality of life. It has been reported that one in five adult dogs experience osteoarthritis.1

The disease is characterized clinically by pain, limitation of movement, effusion, and variable degrees of inflammation of the affected joints. Clinical signs may initially be limited to occasional stiffness, difficulty rising, or reluctance to exercise, but as osteoarthritis progresses, the clinical signs of stiffness, lameness, loss of range of motion, and muscle atrophy in the region of the affected joint(s) become easily identifiable. Osteoarthritis causes pain and discomfort to the dog and can be an emotional and financial burden to the owner.

Because there is no cure for osteoarthritis, managing it is crucial and should involve a multimodal process in which practitioners seek to manage pain; maintain or improve range of motion of affected joints; maintain or improve muscle mass; return working and performance dogs to their previous levels; and control the progression of the disease process.

Several factors can complicate the successful management of osteoarthritis and assessment of treatment, including:

• owner compliance

• affordability of treatment plans

• recognition of the location of the affected joints and cause of lameness

• method of assessing success (subjective vs. objective measurements)

• owner perceptions and expectations for the pet.

The initial treatment plan needs to be safe, noninvasive, easy for the owner to manage, and produce visible results. Fortunately, most osteoarthritis patients can be managed with one or more of the following: weight management, physical activity, disease-modifying osteoarthritis drugs (DMOADs), and nonsteroidal anti-inflammatory drugs (NSAIDs). Physical therapy, a developing modality in veterinary medicine, can also be beneficial. This multimodal approach to the osteoarthritis patient will ideally increase pain-free movement, decrease inflammation, decrease stress on joints, and have some chondroprotective attributes.

The normal joint

To understand the effects of osteoarthritis on a pet's mobility and well-being, it is helpful to review the anatomy of a normal joint. Diarthrodial joints are composed of a joint capsule, synovial fluid, articular cartilage, and subchondral bone. The synovial joint has two functions—to facilitate predictable, energy efficient, and pain-free movement, and to support the musculoskeletal system and transmit load. Synovial fluid is an ultrafiltrate of plasma containing the glycosaminoglycan (GAG) hyaluronic acid. The fluid serves as lubrication, has viscoelastic properties, and provides nutrients to the cartilage, as well as removing metabolic waste products from cartilage.

Chondrocytes are the cellular component of articular cartilage and are responsible for the synthesis and maintenance of the extracellular matrix (ECM). Chondrocytes are imbedded in the ECM, which is a hydrated proteoglycan gel and fibrous collagen framework. The ECM is composed of primarily type II collagen and proteoglycans with a small percentage of other glycoproteins.2,3

Proteoglycans consist of a central protein core to which one or more GAG side chains are attached. Proteoglycans provide the articular cartilage with selective permeability and compressive stiffness, while collagen fibers provide tensile strength. Destruction of proteoglycans or collagen framework inhibits the stress-absorbing capacity of the articular cartilage and contributes to inflammation and further damage of the cartilage.2

Osteoarthritis

Understanding the pathophysiology of osteoarthritis is important for selecting appropriate treatment regimes. Osteoarthritis affects not only the cartilage, but also the entire joint structure, including the synovial membrane, subchondral bone, ligaments, and periarticular muscles. In osteoarthritis, the synovium undergoes inflammatory changes that include synovial hypertrophy and hyperplasia with an increased number of lining cells, and also an infiltration of the sublining tissue with a mixed population of inflammatory cells.4 Most specialists agree that the synovial inflammation frequently associated with osteoarthritis is secondary to the destruction of cartilage and the release of cartilage breakdown products into the synovial fluid.4

Osteoarthritis is biochemically characterized by a reduction of proteoglycan concentration in cartilage, alterations in the size and aggregation of proteoglycans, increased water content of the cartilage, collagen fibril disruption, and an imbalance in synthesis and degradation of matrix macromolecules. The affected cartilage has increased production and concentrations of inflammatory mediators such as: interleukins (IL-1, IL-6 and IL-8), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), nitric oxide (NO), and matrix metalloproteinases (MMP-2, MMP-3, MMP-9 and MMP-13). The major catabolic cytokines involved in the destruction of articular cartilage are IL-1 and TNF-α. Both are produced by synovial cells and chondrocytes. These inflammatory mediators stimulate an increase in MMPs, which degrade GAGs and collagen, thus damaging articular cartilage. They also reduce hyaluronic acid concentrations in synovial fluid leading to less viscous synovial fluid.2, 3

Cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) enzymes produce eicosanoids, which include: PGE2, thromboxane A2 (TXA2), and leukotriene B4 (LTB4). The activity of these enzymes, and resulting eicosanoids, are increased in osteoarthri-tis and osteoarthritis cartilage spontaneously releases 50 times more PGE2 compared with normal cartilage.4, 5

Multimodal treatment

Multimodal treatment objectives are designed to affect the multiple pathways that cause an osteoarthritic dog to have pain and limited function.

Weight management: Obesity is the most common form of nutritional disorder in dogs with an estimated prevalence of 28 percent.6 International studies have estimated the incidence of obesity in dogs to be 21 to 40 percent.7,8

Excess body weight increases stress on weight-bearing joints in which excessive cyclic stress contributes to degradation of articular cartilage and remodeling of subchondral bone. Studies have noted excessive body weight to be a risk factor for osteoarthritis development in people, guinea pigs, mice, and dogs.9-5

In one study of dogs with hip osteoarthritis, a weight reduction of 11 percent showed significant improvement in severity of hind limb lameness.11 Another study reported body weight to be a predisposing factor in humeral condylar fractures, cranial cruciate ligament rupture, and intervertebral disc disease in cocker spaniels.16

A study looking at 48 Labrador retrievers over their lifetime showed that restricted feeding had a profound effect on radiographic signs of hip osteoarthritis.17 This study showed that clinical signs of osteoarthritis were seen in dogs that did not have their diet restricted, on average, almost two years earlier than in their diet-restricted counterparts.10

Being overweight increases the load placed on joints, which increases stress and could possibly hasten the breakdown of cartilage. For example, it is estimated that a force of nearly three to six times one's body weight is exerted across the human knee while walking; therefore, an increase in body weight increases the force placed on the joint by three to six times the amount of weight gained.18

Of the nonpharmaceutical, non-nutritional therapies for osteoarthritis, weight reduction is probably the single most efficacious. The weight reduction protocol needs to be tailored toward the individual patient. Total calorie restriction can successfully lead to weight loss, but has the potential, depending on the diet, to cause excessive protein (and thus lean body mass) loss.12 One study compared high-protein and low-fiber diet to a commercial weight reduction diet that was lower in protein and higher in fiber.19 Both diets worked in reducing the overall weight of the dog but the diet with a higher protein minimized the amount of lean tissue lost.19 Therefore, I recommend using purpose-formulated diets or weight-reduction diets that, when overall calories are decreased, still provide appropriate protein levels and micronutrients.

Weight-loss programs that encourage the owner and the dog to visit the clinic need to be established. Veterinarians need to scrutinize the dog's weight frequently and follow through with the owner to help ensure that the pet reaches its ideal weight.

Physical activity and physical Therapy: Exercise is an effective intervention in osteoarthritis and important in its prevention. Dogs need muscular balance and well-conditioned muscles to attenuate impact loads, provide joint stability, and to support overall function of the body. Several human studies have shown the benefits of exercise for people with osteoarthritis.20 Regular activity replenishes lubrication to the cartilage of the joint and reduces stiffness and pain. The goals of an exercise program for the canine patient with arthritis are to:

• preserve or restore range of motion and flexibility of the muscles around affected joints

• increase muscle strength and endurance; and

• increase overall conditioning to decrease health risks associated with a sedentary lifestyle.

In veterinary medicine today we have Certified Canine Rehabilitation Therapists who design and perform exercises that are specifically designed for the particular dog and orthopedic problem(s). Modalities used such as underwater treadmills, hydrotherapy, and electrical stimulation are just a few modalities that will improve muscle range of motion and stability.

Disease-modifying osteoarthritis drugs: DMOADs have become an appealing primary or adjunct treatment for osteoarthritis in both people and dogs. These substances modify the course of osteoarthritis by improving the health of articular cartilage or synovial fluid.

Many studies have explored the effects of DMOADs in people.22,23 In these types of studies, a significant difference compared to placebo needs to be demonstrated and benefits are measured by three co-primary end-points—joint space narrowing (JSN), pain, and function.

In canine patients, these parameters are difficult to ascertain. We can't evaluate joint space accurately in dogs because our patients are not weight-bearing during radiographs. Owners usually provide us with our patients' relative pain and function scores. Objective measurements such as force plate analysis and kinematics would be ideal; however, subjective assessments by owners and veterinarians are the most common method for evaluating treatment modalities for osteoarthritis. Therefore, when choosing a DMOAD, it is important to rely on evidence-based medicine as a guide to efficacy.

Some common DMOADs used in veterinary medicine include polysulfated GAGs (glucosamine, chondroitin sulfate, or a combination of the two) omega-3 fatty acids, and methyl-sulfonyl-methane (MSM). For this article we will discuss glucosamine, chondroitin sulfate and fatty acid DMOADs.

Glucosamine:

Glucosamine is an amino sugar that is a precursor to GAGs that are present in the ECM of articular cartilage. Osteoarthritic cartilage appears to have a decreased ability to synthesize glucosamine compared to healthy cartilage. Glucosamine salt supplements are readily available and are most commonly found as glucosamine hydrochloride or glucosamine sulfate. The hydrochloride form is most commonly used in published studies and was used in one of the largest studies in people.21

Chondroitin sulfate (CS): CS is the predominant GAG found within the ECM. CS has been found to decrease IL-1 production, inhibit MMPs, and stimulate GAG and collagen synthesis.24 However, the form and source of chondroitin sulfate influences its pharmacokinetic profile.3 Chondroitin-4-sulfate, which is sulfated on the fourth carbon of the N-acetylgalactosamine residue, is derived primarily from mammalian tissue. Chondroitin-6-sulfate, which is sulfated on the sixth carbon, is derived primarily from shark cartilage. These two types of chondroitin sulfate may vary greatly in molecular weight, which can potentially influence their bioavailability and purity.25 Pure low-molecular weight chondroitin sulfate displays significant accumulation upon multiple dosing in beagle dogs.26

When used together, the effects of glucosamine and chondroitin sulfate combine to:

• stimulate the metabolism of chondrocytes and synoviocytes

• inhibit degradative enzymes

• reduce fibrin thrombi in periarticular microvasculature.

Extrapolation from some animal and human trials suggests that there can be some benefit from these compounds.3 ,25 ,27 Because they are relatively harmless and potentially hold a promise of protecting articular cartilage and relieving clinical signs, they can be a valuable additional treatment modality for dogs with osteoarthritis.

Figure 1

Omega fatty acids: Polyunsaturated fatty acids (PUFAs) are classified as omega-3, omega-6, or omega-9, depending on the position of the last double bond along the fatty acid chain. The main dietary PUFAs are omega-3s [e.g., linolenic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA)] (Figure 1) and omega-6s (e.g., linoleic acid and arachidonic acid)]. Omega-3 and omega-6 fatty acids are metabolized by the COX and 5-LOX pathways into distinct eicosanoids (Figure 2). The omega-6-derived eicosanoids—PGE2, TXA2, and LTB4—tend to be proinflammatory; whereas the omega-3-derived eicosanoids tend to be anti-inflammatory. A study using long-chain omega-3 PUFAs showed improved biochemical parameters in associated with canine osteoarthritis.28

Figure 2

Since the omega-3 PUFAs EPA and DHA act as competitive inhibitors of the conversion of arachidonic acid to proinflammatory eicosanoids, dietary habits may have a considerable influence on an individual's propensity to become and remain inflamed. Long-chain omega-3 fatty acids are available in fish and plant sources and commercially available as nutraceuti-cal supplements and veterinary diets, such as Purina Veterinary Diets JM Joint Mobility Canine Formula.

NSAIDs: NSAIDs are designed to reduce proinflammatory mediators, such as prostaglandins, by inhibiting cyclooxygenase 1 and 2 (COX-1 and COX-2). The six registered NSAIDs for the treatment of canine osteoarthritis commonly used in veterinary medicine were developed to preferentially inhibit COX-2.23 NSAIDs are the most widely used analgesics in veterinary medicine, and all have some toxic potential. The most common adverse effects of NSAIDs are gastrointestinal, renal, hepatic, and coagulation disorders. The effectiveness of using NSAIDs in managing osteoarthritis should be balanced with their potential to cause side effects, and they should be titrated to their lowest effective dosage. The effectiveness of NSAIDs can be enhanced by physical therapy, use of DMOADs, and diet and exercise to control weight. With a multimodal treatment regime, one may even be able to exclude the use of NSAIDs.

Since osteoarthritis is a chronic disease, it may be the perfect paradigm of a pathology where multimodal management is better positioned to provide long-term benefits. For example, a nutritional compound may have significant benefits that are reached gradually; however, many nutritional compounds have the benefit of containing active compounds that target multiple pathways. Pharmacologic interventions often have monomodal modes of action, which may explain why they can fail to completely control the clinical signs of osteoarthritis.29 Therefore, multimodal management could provide a welcome alternative to pharmacologic therapy for osteoarthritis.

Implementing multi-modal management

Canine osteoarthritis is an enormous subject to discuss, and many points regarding its pathophysiology and treatment are still being debated. Multiple pathways contribute to the clinical signs of canine osteoar-thritis, and it is important to understand that there is no cure or silver bullet for treatment. In order to be most effective, after identifying and localizing osteoarthritis in our canine patients, we must address it on many fronts, including:

• weight management (by using targeted diet modification and moderate low-impact activities)

• use of DMOADs

• use of physical therapy to aid in increasing range of motion and muscle mass

• limitation of NSAID usage to treating acute flare ups (e.g., weekend-warrior syndrome).

The plan must be customized for each patient affected by osteoarthritis, depending on the joints affected and the severity of symptoms.

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