Clinical Perspectives on Canine Joint Disease Clinical Perspectives On

Skeletal Health

ClinicalClinical PerspectivesPerspectives ¨ onon CanineCanine JointJoint DiseaseDisease

Presented at The North American Veterinary Conference Orlando, Florida, USA January 17, 2001 Contents

Summary of Contents ...... 2

Author Profiles ...... 6

Articular Cartilage in Health and Disease ...... 8 Allan J. Lepine, PhD; Michael G. Hayek, PhD

The Benefit of Weight Management in Dogs with Joint Problems ...... 18 Mark A. Tetrick, DVM, PhD; Joseph A. Impellizeri, DVM; Peter Muir, BVSc, MVetClinStud, PhD, MACVSc, DACVS, DECVS

Physical Therapy for Dogs with Joint Disease ...... 22 Darryl L. Millis, MS, DVM, Diplomate ACVS

Pathophysiology and Diagnosis of Intervertebral Disk Degeneration ...... 28 Takayoshi Miyabayashi, BVS, MS, PhD, Diplomate ACVR

Balanced Management of Osteoarthritis in Companion Animals ...... 32 Steven A. Martinez, DVM, MS, Diplomate ACVS

Cover illustration: Jeff D. Fulwiler, Pavone Fite Fulwiler

Copyright © 2001 The Iams Company, Dayton, OH 45414, USA All rights reserved. Internet address: www.iams.com Printed in the United States of America. Item #RD 0024 1 Clinical Perspectives on Canine Joint Disease (TNAVC 2001) Summary of Contents

CHAPTER 1: ARTICULAR CARTILAGE IN HEALTH AND DISEASE Allan J. Lepine, Michael G. Hayek Pages 8–17

Summary. Nutritional management of articular cartilage health requires an understanding of the changes that normally occur during life, as well as the alterations caused by disease or injury.

Findings. • Components of articular cartilage extracellular matrix – Proteoglycans – comprised of various glycosaminoglycans – Hyaluronan – Chondroitin sulfate and dermatan sulfate – Heparan sulfate – Keratan sulfate – Collagen • The ability of articular cartilage to respond to compressive stress depends on the characteristics and interrelationships between proteoglycans and collagen • Significant structural changes occur during the maturation of articular cartilage – Amounts and proportions of collagen types change – Proteoglycans become smaller and enriched with keratan sulfate – Result of aging changes is a reduced ability to withstand normal joint functioning forces • Three types of articular cartilage damage – Microdamage or blunt trauma – Chondral fractures – Osteochondral fractures • Osteoarthritis – noninflammatory degenerative joint disease – Changes in proteoglycan amounts and ratios – Matrix degradation often exceeding synthesis – Cytokine release stimulates production of degradation enzymes and suppresses protein biosynthesis in chrondrocytes • Nutritional management of articular cartilage health – Eicosanoid production can be manipulated by dietary fatty acids and thereby assist in inflammation management – Dietary glucosamine and chondroitin sulfate may help increase cartilage biosynthesis and decrease degradation

Application. Dietary fatty acids and chondroprotective nutrients such as chondroitin sulfate and glucosamine may be useful in maintaining joint health and managing joint injury or disease.

CHAPTER 2: THE BENEFIT OF WEIGHT MANAGEMENT IN DOGS WITH JOINT PROBLEMS Mark A. Tetrick, Joseph A. Impellizeri, Peter Muir Pages 18–21

Summary. An observable improvement in lameness can be achieved when overweight dogs lose body weight.

Findings. • Lameness severity was significantly influenced by weight loss in overweight dogs with hip osteoarthritis and lameness

Clinical Perspectives on Canine Joint Disease (TNAVC 2001) 2 Findings. • Rapid or prolonged increases in blood glucose and, therefore, insulin secretion may promote (continued) greater weight gain and fat deposition. Specially formulated foods containing a blend of barley and grain sorghum may help improve glucose tolerance and stabilize blood glucose levels in overweight dogs • Dietary carnitine addition resulted in lower fat mass and greater lean body tissue in dogs during weight loss • Diets containing chromium tripicolinate may lead to an improvement in glucose tolerance and blood glucose stability in overweight pets

Application. Weight loss can influence lameness severity. Achieving weight loss in dogs can be facilitated by the use of specially formulated diets containing carnitine, chromium tripicolinate, and a blend of barley and grain sorghum.

CHAPTER 3: PHYSICAL THERAPY FOR DOGS WITH JOINT DISEASE Darryl L. Millis Pages 22–27

Summary. Joint disease is a common problem in dogs. Patients with osteoarthritis (OA) can have restricted activity, limited ability to perform, pain and discomfort, and decreased quality of life. Physical therapy can enhance or supplement other treatments for OA.

Findings. • Although mechanical stress can cause biochemical, histological and biomechanical changes in articular cartilage, a lifetime of regular low-impact exercise in dogs with normal joints did not cause significant alterations • Older dogs may be more vulnerable to articular cartilage changes from mechanical stress than younger dogs • The goals of therapeutic exercise should be to reduce body weight, increase joint mobility, and reduce joint pain through the use of low-impact weight-bearing exercises designed to strengthen supporting muscles • Exercise should be performed only after correction of major OA risk factors, such as joint instability or obesity • The ideal exercise program is one that provides sufficient benefits without causing discomfort • Initially, antiinflammatory drugs should not be administered prior to exercise so that the proper level of exercise can be determined • Suggested exercise methods include swimming, controlled exercise on a leash, and treadmill walking • Physical agents that can be useful aids in physical therapy include: – Superficial heat modalities – Cryotherapy – Massage – Ultrasound – Neuromuscular Electrical Simulation • Progress should be documented to assist in further treatment decisions and help maintain the dog owner’s enthusiasm for the program

Application. Physical rehabilitation is a valuable, but underused part of the management of dogs with OA. It can be used in combination with nutritional, medical, and surgical management to reduce pain and lameness and improve quality of life.

3 Clinical Perspectives on Canine Joint Disease (TNAVC 2001) CHAPTER 4: PATHOPHYSIOLOGY AND DIAGNOSIS OF INTERVERTEBRAL DISK DEGENERATION Takayoshi Miyabayashi Pages 28–31

Summary. Intervertebral (IV) disk disease is a common neurological condition in dogs that causes pain and motor dysfunction. The age-related degeneration of IV disks in dogs cannot be avoided but it may be possible to delay the process. Research in chondrocyte metabolism and its relationship in degeneration should help in finding ways to maintain canine IV disk health for as long as possible.

Findings. • Intervertebral disks have two distinct components, which work together to act as a shock absorber • Anulus fibrosus – stretches evenly to distribute force • Nucleus pulposus – contains proteglycans that can hold high water content • Degenerative changes of canine IV disks with age are unavoidable – Loss of proteoglycans is initial step – Eventually fissures form within the anulus fibrosus – Nucleus pulposus protrudes through fissures – IV disk space narrows – Spondylosis deformans develops around vertebral end-plates – End-plate sclerosis and malalignment may develop – All IV disk tissues herniate from the IV disk space – Further bony remodeling at end-plates – Finally, protruded nucleus pulposus undergoes endochondral ossification. • As dogs live longer, more severe degenerative changes may be observed that may be confused with discospondylitis or neoplasia, even though the associated motor dysfunction is minor • MRI is the diagnostic method of choice in human radiology but plain radiography and myelography are still the most commonly used imaging methods in diagnosis of IV disk disease in veterinary medicine

Clinical Perspectives on Canine Joint Disease (TNAVC 2001) 4 CHAPTER 5: BALANCED MANAGEMENT OF OSTEOARTHRITIS IN COMPANION ANIMALS Steven A. Martinez Pages 32–37

Summary. No single treatment will adequately manage osteoarthritis (OA) in all dogs. A combination of three treatment components should be considered when medically managing a dog with OA: 1) weight control, 2) exercise/activity, 3) pharmacological/disease-modifying osteoarthritic drugs. Exclusion of one or more of these components from a treatment protocol will usually result in an overall poorer clinical response.

Findings. • Weight Control – Obesity is a major risk factor for the development of OA – Achieving weight control can be challenging – Dogs with OA that inhibits movement cannot utilize consumed or stored fat efficiently – Dogs with underlying endocrine disorders have a tendency to maintain body fat even on a reducing diet – Estimations of dog’s ideal weight and energy requirements are often inaccurate – Owners may not be willing to be proactive in helping dogs reduce weight – All weight-control programs should include an exercise program • Exercise – Controlled exercise is an important aspect in the management of OA in dogs – High-impact activities may over-stress damaged joints and increase inflammation – Low-impact activities are thought to reduce loads on an OA joint and result in less discomfort for patient while maintaining good muscle strength/mass and joint function • Pharmocologics – The primary goal of the pharmacological management of OA is to relieve the patient of discomfort associated with joint movement – Toxicity concerns are present with long-term, chronic therapy with NSAIDs; therefore, they probably should be administered only on a PRN basis, especially for the dog that has only intermittent discomfort due to OA. – Glucosamine and chondroitin sulfate reportedly have a positive effect on cartilage matrix; they enhance proteoglycan production and inhibit catabolic enzyme production or activity in arthritic joints

Application. Osteoarthritis can be a debilitating diseases for dogs; however, new concepts in a balanced management of OA can result in an acceptable quality of life for the OA patient. Medical management must be considered beyond pharmacological treatment to include a balance with exercise/activity and weight control management. Failure to consider this treatment “triad” concept will usually result in a poorer clinical response to therapy and quality of life as perceived by the owner of the arthritic dog.

5 Clinical Perspectives on Canine Joint Disease (TNAVC 2001) Author Profiles

Steven A. Martinez, DVM, MS, Diplomate ACVS Washington State University Dr. Martinez received his MS degree in Comparative Pathology in 1984 and his DVM degree in 1985 from the University of California at Davis. After completing a small animal internship at California Animal Hospital from 1985-1986 and a small animal surgical residency at Michigan State University from 1986-1989, Dr. Martinez accepted an academic appointment as Assistant Professor of Small Animal Surgery at the Atlantic Veterinary College at the University of Prince Edward Island, Canada from 1989-1990. Dr. Martinez returned to Michigan State University and served as Assistant Professor of Small Animal Surgery from 1990-1997. Dr. Martinez has been serving as an Assistant Professor of Small Animal Orthopedic Surgery at Washington State University since 1997. His current research interests include bone grafting, cytokine delivery systems in bone, and gait analysis in dogs.

Darryl L. Millis, MS, DVM, Diplomate ACVS University of Tennessee Dr. Millis received his BS degree in Animal Science from Cornell University in 1981, and his MS degree in Animal Nutrition from the University of Florida in 1983. After receiving his DVM degree from Cornell University in 1987, he completed a small animal internship in 1988 and a surgical residency in 1991, both at Michigan State University. Dr. Millis served as an Assistant Professor of Small Animal Surgery at Mississippi State University from 1991–1993, at which time he joined the faculty at the University of Tennessee where he currently serves as Associate Professor of Orthopedic Surgery and Section Head of Small Animal Surgery. His research interests include physical therapy in small animals, osteoarthritis, and bone healing.

Takayoshi Miyabayashi, BVS, MS, PhD, Diplomate ACVR University of Florida Dr. Miyabayashi received his BVS degree in 1977 from the University of Osaka Prefecture in Japan. After spending two years in private practice, he came to the University of California, Davis to study for MS (1982) and PhD (1994) degrees in comparative pathology. He was a radiology resident at the University of Wisconsin-Madison from 1987 to 1990 when he was hired as an assistant professor of veterinary radiology at The Ohio State University. Dr. Miyabayashi was board certified by the American College of Veterinary Radiology in 1991 and moved to the University of Illinois in 1995. Since 1997, he has served an associate professor in veterinary radiology at the University of Florida. Dr. Miyabayashi’s teaching and research interests include aging changes in intervertebral disks, musculoskeletal disorders, and imaging diagnosis using MRI and other advanced diagnostic techniques.

Clinical Perspectives on Canine Joint Disease (TNAVC 2001) 6 Allan J. Lepine, PhD The Iams Company Dr. Lepine received his PhD in nonruminant nutrition from Cornell University in 1987, after which he joined the faculty at The Ohio State University as an Assistant Professor in the Department of Animal Science. In 1993, he accepted a position in Research and Development at The Iams Company where he is currently Principal Research Nutritionist. His research interests include neonatal nutrition, growth and development as well as the effects of nutrition on reproduction in companion animals. Dr. Lepine has published more than 60 scientific papers and abstracts in peer-reviewed journals.

Mark A. Tetrick, DVM, PhD The Iams Company Dr. Mark Tetrick received his BS degree in Meat and Animal Science in 1984 and Doctor of Veterinary Medicine degree in 1988 from the University of Wisconsin-Madison. After a year in large/companion animal practice, he returned to the University of Wisconsin-Madison and received his PhD in Nutritional Sciences in 1996. His thesis research dealt with utilizing medium chain triglycerides as an energy supplement for newborn animals. In July, 1996, Dr. Tetrick joined the Strategic Research group in the Research and Development division of The Iams Company. His research interests include the clinical impact of nutrition, with emphasis on the influence of nutrition on urinary tract health.

7 Clinical Perspectives on Canine Joint Disease (TNAVC 2001) STRUCTURE AND FUNCTION OF ARTICULAR CARTILAGE

Synovial Joints Synovial joints (diarthroses) are composite structures consisting of articular cartilage, a joint capsule filled with synovial fluid, and underlying osseous structures (Figure 1). A physiologically normal synovial joint provides a virtually Articular wear-resistant and friction-free articulating surface that can withstand considerable compressive, tensile, and shear forces. Cells that line the synovial membrane of the joint capsule produce synovial fluid, a clear and viscous Cartilage in substance. Synovial fluid serves as a protective barrier by providing lubrication to the opposing articular surfaces and preventing contact between surfaces. It also supplies Health and nutrients to the cells of the articular cartilage and removes waste products. Without an adequate protective barrier, rapid joint degeneration can occur when forces, especially Disease weight bearing forces, are applied.

Allan J. Lepine, PhD Bone Michael G. Hayek, PhD Joint Capsule Research and Development Division The Iams Company, Lewisburg, Ohio, USA

Synovial Fluid

Articular Cartilage

INTRODUCTION Understanding the changes in the physiologic and Bone morphologic relationships of articular cartilage during normal life stages, as well as during more dramatic events such as joint trauma or disease, can allow for the application of nutritional management to minimize Figure 1. Basic structure of the synovial joint. (Used with permission. negative outcomes. Nutritional interventions can include Lepine AJ. Structure and function of articular cartilage. In: Reinhart GA, managing growth in those breeds prone to joint problems, Carey DP, eds. Recent Advances in Canine and Feline Nutrition, Vol. III: 2000 Iams Nutrition Symposium Proceedings. Wilmington, decreasing incidence and symptoms of obesity, and OH: Orange Frazer Press, 2000; 481-494.) providing nutrients such as omega-3 fatty acids and chondroprotective agents that aid the inflamed or damaged joint. A review of the structure and function of Components of the Articular Cartilage articular cartilage is important in order to better Extracellular Matrix understand the control and management of companion Proteoglycans. Proteoglycans, a primary component animal joint health. of the articular cartilage extracellular matrix, are comprised

Clinical Perspectives on Canine Joint Disease (TNAVC 2001) 8 of numerous glycosaminoglycan chains that are covalently protein to form proteoglycans, hyaluronan does not bind to linked to a central core protein (Figure 2). Glycosa- a core protein. minoglycans are repeating disaccharide units in which one Aggrecan, the most common and well-defined of the saccharides in each disaccharide is generally a proteoglycan in articular cartilage, is comprised of a core sulfated amino sugar. protein to which as many as 100 glycosaminoglycan chains Four primary glycosaminoglycans associated with are attached. The attachment to the core protein is at a proteoglycans are: (1) hyaluronan, (2) chondroitin sulfate serine residue and is stabilized by a link tetrasaccharide. and dermatan sulfate, (3) heparan sulfate, and (4) keratan While the majority of the glycosaminoglycans in aggrecan sulfate. These glycosaminoglycans are distinguished by the are chondroitin sulfate and keratan sulfate, they are not specific sugar residues included, the type of linkage randomly attached to the core protein but are located between these residues, and the number and location of within specific binding regions. This generally results in sulfate groups.1 Hyaluronan is a repeating disaccharide of aggrecan having a greater chondroitin sulfate content than glucuronate and N-acetyl glucosamine and is the only keratan sulfate since the keratan sulfate-rich binding glycosaminoglycan that is nonsulfated. Chondroitin sulfate region is located closer to the NH2 terminal end of the is a repeating disaccharide of glucuronate and N-acetyl core protein while a larger, chondroitin sulfate-rich galactosamine; dermatan sulfate is derived from binding region is more distal.2 chondroitin sulfate by the epimerization of glucuronate to Aggrecan is generally found as a large aggregate with iduronate. Keratan sulfate is a disaccharide of galactose as many as 200 aggrecan molecules covalently bound to a and N-acetyl glucosamine; heparan sulfate contains single hyaluronan molecule.3 This linkage to hyaluronan is iduronate and N-acetyl glucosamine. While the majority of these glycosaminoglycans are covalently bound to a core Keratan Sulfate Chondroitin Sulfate Chains Chains

GLYCOSAMINOGLYCAN (GAG) CHAINS

Linked To Core Protein

CH2OH CH2OH O O H HO H O O O H H H H H H Keratan Sulfate Condroitin Sulfate Rich Region Rich Region H OH H NHCOCH3 Keratan Sulfate _ _ AGGRECAN COO CH2OSO 3 O O H H HO O O O OH H H H H H Link Protein Core Protein To H OH H NHCOCH3 Form Chondroitin 6-Sulfate

Hyaluronan AGGRECAN AGGREGATE

Figure 2. Proteoglycan, one of the 2 main classes of the articular cartilage extracellular matrix, is a complex structure formed by glycosaminoglycan (GAG) chains covalently linked to core proteins, which are then bound to form the proteoglycan, aggrecan. (Used with permission. Lepine AJ. Structure and function of articular cartilage. In: Reinhart GA, Carey DP, eds. Recent Advances in Canine and Feline Nutrition, Vol. III: 2000 Iams Nutrition Symposium Proceedings. Wilmington, OH: Orange Frazer Press, 2000; 481-494.)

9 Clinical Perspectives on Canine Joint Disease (TNAVC 2001) Molecules stabilized by a small glycoprotein self-assemble 4 referred to as link protein. The to form link protein is homologous with Collagen the NH2 terminal region of Fibril aggrecan, thus allowing hyalur- Collagen Molecules onan to covalently bind to both (triple helix of polypeptide α-chains) Collagen Fibril link protein and aggrecan. These bonds serve to stabilize the aggrecan aggregate.1 To provide further stabilization, cross-links between the link proteins and the core protein are also present. Collagen. Collagen, a second primary component of the Fibrils extracellular matrix, is composed aggregate of a triple helix of polypeptide Collagen Fiber to form α -chains (Figure 3). These Collagen polypeptide chains of collagen are Fiber unique, relative to other proteins of animal origin, due to high Figure 3. Collagen, the second main class of the articular cartilage extracellular matrix, is formed by proportions of hydroxylysine and a triple helix of polypetide a-chains which self-assemble into collagen fibrils which then aggregate to form hydroxyproline residues. The a collagen fiber. (Used with permission. Lepine AJ. Structure and function of articular cartilage. In: collagen molecules self assemble Reinhart GA, Carey DP, eds. Recent Advances in Canine and Feline Nutrition, Vol. III: 2000 into collagen fibrils. Within those Iams Nutrition Symposium Proceedings. Wilmington, OH: Orange Frazer Press, 2000; 481-494.) fibrils, interchain hydrogen bonds and covalent intramolecular cross-links form between The proteoglycans are hydrophilic in nature and modified lysine residues of adjacent triple helices. These thus provide an extremely high hydration capacity. bonds and cross-links help to stabilize not only the triple Proteoglycans swell as water is attracted to the matrix, helix, but ultimately the collagen structure. Collagen however, the degree of swelling is limited to about 20% of fibrils then aggregate into a single collagen fiber. the maximum potential since the proteoglycans are Several collagen variations are distinguished by the imbedded in a matrix of collagen fibers.3 Inherent in the composition of the α-chains that form the triple helix. In fibrillar structure of collagen and enhanced by the cross- articular cartilage, approximately 90–95% of the collagen links between collagen molecules,3 collagen fibers exhibit is type II3,5 with the remaining collagen types reported to maximal tensile strength. The tensile stress imposed upon be types V, VI, IX, and XI.5 The incorporation of these the collagen network by the swelling pressure of the minor amounts of collagen types into the collagen matrix proteoglycans demonstrates the importance of the tensile may be important to the physical organization of the strength of collagen. One important outcome of this matrix. For example, type IX collagen is located at the functional relationship is that the collagen network holds surface of the type II collagen fibril linked by a lysine- the proteoglycan molecules within the extracellular matrix derived hydroxypyridinium cross-link.6,7 Two regions of the and prevents their escape (Figure 4). This is particularly type IX collagen, the COL3 arm and the NC4 domain, important since there are no covalent links between project out from the surface and are suspected to serve as collagen and the proteoglycans8 and it is solely the size of binding sites for other matrix components. It is also the hydrated proteoglycans that maintains them within speculated that fibril thickness is controlled by Type XI the articular cartilage. collagen which is present within the type II fibrils.3 The ability of the articular cartilage matrix to respond to compressive loads is dependent upon the Function of Extracellular Matrix Components characteristics and interrelationships between proteo- The unique physiologic relationship between the glycans and collagen. The compressive force placed on proteoglycans and collagen makes articular cartilage a articular cartilage upon loading forces the fluid phase to biphasic material with a porous-permeable fiber-reinforced flow through the permeable solid phase. As the compres- solid phase and a freely flowing fluid phase.3 It is precisely sive force increases, the hydraulic pressure increases.8 This because of this biphasic nature that articular cartilage has is due to decreased pore size as the solid matrix is the biomechanical properties necessary to withstand the compressed causing increased resistance to fluid flow until stresses associated with normal joint functioning. an equilibrium is reached with the compressive force

Clinical Perspectives on Canine Joint Disease (TNAVC 2001) 10 EXTRACELLULAR MATRIX

Collagen Proteoglycan

Maximum Tensile Strength High Hydration Capacity

Figure 4. The components of articular cartilage function together to produce a biphasic matrix that can withstand the stress of normal joint function. (Used with permission. Lepine AJ. Structure and function of articular cartilage. In: Reinhart GA, Carey DP, eds. Recent Advances in Canine and Feline Nutrition, Vol. III: 2000 Iams Nutrition Symposium Proceedings. Wilmington, OH: Orange Frazer Press, 2000; 481-494.) resulting in a ceasing of cartilage deformation. Further Zone 1 — Superficial or tangential zone. Contains contributing to this equilibrium is the increasing negative flattened, elongated chondrocytes and collagen charge density within the matrix as water is extruded from fibrils that are parallel to the articular surface. 3 the matrix following increased compression. After Zone 2 — Transitional or intermediate zone. compression ceases, water and nutrients reenter the Chondrocytes are oval or round, are distributed cartilage matrix, thereby allowing the proteoglycans to randomly, and contain greater numbers of swell and the cartilage to recover to its nondeformed mitochondria, rough endoplasmic reticulum, and conformation. golgi apparatus. Collagen fibrils are more oblique As cartilage deformation occurs in response to and appear less organized. compressive forces, considerable tensile forces are placed upon the collagen network. Without adequate resistance Zone 3 — Radiate or deep zone. Chondrocytes are to tension by the collagen fibers the cartilage would large and rounded, arranged in columns rupture as the compressions increase. The experimental perpendicular to the articular surface. removal of glycosaminoglycans from bovine articular Zone 4 — Calcified zone. Farthest removed from the cartilage9 clearly demonstrated the importance of the articular surface. The “tidemark” delineates zones 3 proteoglycan–collagen relationship in articular cartilage. and 4. The few chondrocytes observed are necrotic In this study, the compressive strength of the cartilage was due to the calcified matrix. largely eliminated but the rupture strength of the cartilage was only slightly reduced. Within the transitional and deep zones, chondrocytes are the most metabolically active and have the capacity to synthesize and degrade all components of DEVELOPMENT OF MATURE the extracellular matrix, including the precursors for ARTICULAR CARTILAGE collagen and the proteoglycans.10,11 Aggrecan, link protein, “Zones” are descriptive reference points for the and hyaluronan are extruded into the extracellular matrix organizational layers that encompass the thickness of where they spontaneously aggregate.8 The collagen fibrils mature articular cartilage5,8,10 (Figure 5). in zone 3 are arranged perpendicular to the articular

11 Clinical Perspectives on Canine Joint Disease (TNAVC 2001) ARTICULAR SURFACE sulfate and possibly also decreased core protein length.15,16 ZONE I This reduced proteoglycan size is likely due to the action of extracellular matrix proteases. The proteoglycans become proportionately enriched with keratan sulfate as a result of ZONE II the decreased chain lengths of chondroitin sulfate and core protein. The specific chondroitin sulfate chains that are present within the articular cartilage also are altered with ZONE III maturity. Immature cartilage has a ratio of chondroitin-4- sulfate to chondroitin-6-sulfate of 1:1 with this ratio decreasing as age increases.15 These maturational changes are likely of functional significance since the stiffness of the cartilage and the resultant resistance to deformation ZONE IV TIDE are dependent upon the fixed charge density and MARK glycosaminoglycan content. In this respect, keratan sulfate influences stiffness to a greater degree than chondroitin sulfate, thereby providing a potential advantage to keratan sulfate-rich proteoglycans in articular cartilage subjected to high load such as is the case in the adult.15 SUBCHONDRAL BONE The amounts and proportions of collagen types changes throughout development. A study of fetal and neonatal rabbits14 revealed that the cartilage of a 17-day- old rabbit fetus contained collagen types I, III, and V but Figure 5. Structural demarcations in mature articular cartilage. (Used no type II collagen. By day 25, the fetal articular cartilage with permission. Lepine AJ. Structure and function of articular cartilage. still contained type I collagen but no type II. It was only by In: Reinhart GA, Carey DP, eds. Recent Advances in Canine and 6 weeks postnatally that type II collagen was present and Feline Nutrition, Vol. III: 2000 Iams Nutrition Symposium type I collagen disappeared. Furthermore, the concentra- Proceedings. Wilmington, OH: Orange Frazer Press, 2000; 481-494.) tion of hydroxyproline increased 2-fold in the chicken through 22 days of age indicative of an increased surface. The deep zone forms an interlocking network that concentration of collagen in the articular cartilage of the anchors the cartilage to the bony substrate.12 The young animal.17 These collagen changes are likely due to concentration and composition of collagen and proteo- structural modifications that are necessary as the stresses glycans varies depending on the specific articular cartilage on the articular cartilage are increased. zone. For example, the concentration of collagen is highest An important aspect of appropriate maturation in in the superficial zone and decreases by approximately 15% response to increasing joint-related forces is the ability of within the deep zone.2 In contrast, proteoglycan concen- articular cartilage to develop differentially from growth tration is lowest in the superficial zone and highest in the plate cartilage, structures that are similar during early life. deep zone. Furthermore, the proteoglycan composition A primary difference is in the maturation of the varies across these zones with less keratan sulfate apparent chondrocytes of these two cartilage types. In contrast to in the superficial zone as compared to the deeper zones.2 articular cartilage chondrocytes, growth plate chondrocytes Significant structural modifications occur during the undergo hypertrophy and maturation as the extracellular maturation process of articular cartilage. It is interesting to matrix matures.18 Although the mechanism by which this note that developing cartilage does not exhibit the zone distinction occurs remains equivocal, evidence exists that distinctions observed in mature articular cartilage. The tenascin-C, a large glycoprotein found in the extracellular zones seen in adult articular cartilage are not entirely matrix of some embryonic and adult tissues18 (also called distinguishable, as shown in research in the young rabbit cytotacin or hexabrachion), may have a role in assembly (6–8 weeks of age).13 At 6–7 weeks of age, a surface zone and restructuring of the cartilage matrix.19 It is suggested (likely encompassing both the surface and transitional that tenascin-C may promote a stable phenotype (round) zones) and the deep zone layers are present. By 8 weeks of of the articular cartilage chondrocyte while the absence of age a distinction is apparent between the surface and tenascin-C in the growth plate may allow flattening, transitional zones but tidemark is not seen until 12–14 proliferation, and maturation of the chondrocytes and weeks of age.14 thereby the replacement of the cartilage with bone. The The composition of the extracellular matrix presence of tenascin-C throughout life in the articular continues to change during growth and development. cartilage, albeit at decreasing concentrations with increas- Proteoglycans become smaller as the body matures, most ing age, allows functional chondrocytes to be maintained likely due to a decreased chain length of the chondroitin throughout life in contrast to epiphyseal bone growth.

Clinical Perspectives on Canine Joint Disease (TNAVC 2001) 12 PHYSIOLOGIC CHANGES underlying bone, resulting in chondrocyte damage ASSOCIATED WITH AGING and marrow cell involvement. Since vascular It is normal for articular cartilage to undergo structures are now involved, inflammation occurs. physiological changes throughout the aging process. Swine This is in contrast to the lack of inflammatory studies have shown age-related decreases in hydration, response to less traumatic articular cartilage injuries collagen (dry matter basis), glycosaminoglycan resulting from the inherent avascular nature of this concentration (especially chondroitin sulfate), and tissue. Following a full thickness injury, fibroblasts proteoglycan size.20,21 Although the total glycosamino- differentiate into chondrocytes and repair of the glycan concentration may not vary much with increased tissue is attempted, but the fibrocartilaginous repair age, the ratio of keratan sulfate to chondroitin sulfate does tissue produced is not “normal” articular cartilage.23,24 increase.21 With respect to chondroitin sulfate it was also After several phases of remodeling, the repair tissue noted that the 4-sulfated compound decreased while the 6- has a lower proteoglycan content and a substantial sulfated compound increased. The alteration of component of type I collagen rather than type II.24 proteoglycan composition and size is most likely the result Therefore, the resulting repair is often of suboptimal of proteolytic cleavages that are not limited to the period quality resulting in compromised joint function. of growth and maturation but appear to occur throughout the aging process in all species.22 The link proteins are also subject to proteolytic cleavage as aging progresses.22 This is EFFECTS OF OSTEOARTHRITIS likely a normal component of aging and could contribute Osteoarthritis is defined as a noninflammatory to the destabilization of the proteoglycan component of degenerative joint disease characterized by degeneration of the extracellular matrix. The inherent result of these the articular cartilage, hypertrophy of the bone at the normal age-related changes of the articular cartilage will margins, and changes in the synovial membrane. be a matrix of reduced capability to withstand the forces Chondrocytes are normally able to synthesize the associated with normal joint functioning. proteoglycans, collagen, fibronectin, and other components needed to maintain joint homeostasis and integrity due to the relatively low turnover of the EFFECTS OF JOINT DISEASE/INJURY extracellular matrix. When chronic trauma or disease Articular cartilage injuries are characterized by the disrupts this homeostasis, however, the articular cartilage degree of involvement of the extracellular matrix may progressively degenerate, ultimately resulting in the composition and resultant damage to the chondrocytes and development of osteoarthritis. generally fall into three categories.23,24 During the initial stage of osteoarthritis, responses similar to those seen in subchondral injury of the articular Microdamage or blunt trauma — Microdamage cartilage occur. Chondrocyte proliferation is observed with may be caused by a single impact or repetitive blunt subsequent increased synthesis of extracellular matrix. In trauma and is characterized by a loss of matrix early osteoarthritic cartilage the concentration of keratan components, most notably proteoglycans, without sulfate is decreased, the length of the chondroitin sulfate chondrocyte damage. If the traumatic event is short side chain is reduced25 and the ratio of chondroitin-4- in duration, the chondrocytes may be able to repair sulfate to chondroitin-6-sulfate is increased.26 The newly the cartilage by restoring the lost proteoglycans and synthesized proteoglycan subunits do not demonstrate matrix components. Damage resulting from normal aggregation with hyaluronic acid.26 sustained blunt trauma, however, may eventually Concurrent with the increased synthetic response by become irreversible.24 the chondrocyte is matrix degradation, often proceeding at a rate exceeding that of synthesis. Proteoglycan and Chondral fractures — Chondral fractures result collagen breakdown is mediated by an increase in matrix from a penetrating traumatic event disrupting the metalloproteinases, serine proteases, lysosomal enzymes articular surface not effecting the subchondral plate. and other proteases at the articular surface early in the The pathophysiological response of articular degenerative process and are responsible for the extensive cartilage surrounding the injury results in matrix degradation associated with osteoarthritis.27 In chondrocyte proliferation and synthesis of healthy articular cartilage the activity of the extracellular matrix protein. Unfortunately, since metalloproteinases is low. Enzyme activity is regulated by chondrocytes cannot migrate to the lesion, these the presence of tissue inhibitors of metalloproteinases efforts do not result in complete repair.23 (TIMPs) resulting in a low turnover of extracellular matrix Osteochondral fractures — This injury is proteins. During the osteoarthritic disease process the considered a full thickness defect and is characterized production of metalloproteinases greatly exceeds the by an insult crossing the tidemark into the ability of heightened release of TIMPs to maintain

13 Clinical Perspectives on Canine Joint Disease (TNAVC 2001) homeostasis.28 Cytokines such as IL-1 and TNF-α and lipoxygenase or arachidonic acid (an omega-6 fatty stimulate chondrocytes to synthesize metalloproteinases acid) and eicosapentaenoic acid (an omega-3 fatty acid).33 and serine proteases that subsequently further degrade the Eicosanoids mediate inflammation, pain and fever, blood extracellular matrix components.25,26 The cytokines also pressure, blood clotting, several reproductive functions, serve to suppress protein biosynthesis by the chondrocytes, and the sleep/ wake cycle.33 further depleting the extracellular matrix.29 Both IL-1 as NSAIDs and Corticosteroids. Administration of well as TNF-α can cause substantial loss of matrix molecules, NSAIDs or corticosteroids is often included in treatment presumably by inducing proteolytic degradation.30 The regimens for patients with traumatic and degenerative joint presence of fibronectin fragments and possibly other problems. Both drug therapies are aimed at reducing the peptides further enhance catabolic activity and levels of production of arachidonic acid metabolites, which are cytokines.29 IL-1 also stimulates chondrocytes and synovial released as a result of cell membrane damage and cause 34 cells to release arachidonic acid metabolites such as PGE2, inflammation and pain. These drugs act directly to leukotriene B4 and thromboxane. Inflammation of the inhibit the enzymes that help produce these eicosanoids synovium is present in established osteoarthritis although (Figure 6). the inflammatory response is considerably less than would be Membrane Phospholipids expected in other joint diseases.27 NSAIDS Corticosteroids One of the earliest changes Phospholipase A2 seen in an experimental model of Corticosteroids osteoarthritis was an increase in Arachidonic Acid hydration (2–3%) in the entire 31 cartilage of the joint. This Cyclooxygenase15-Lipoxygenase 12-Lipoxygenase 5-Lipoxygenase hydration appears to be the result of the cleavage of type II collagen by PGG2 15-HPETE 15-HPETE 5-Lipoxygenase collagenase. The functional collagen network is disrupted thereby permitting the proteoglycans, the PGH2 12-HETE hydration capacity of which are no 15-HETE 12-HETE Leukotriene A4 longer restricted by the collagen TXA2 PGE2 network, to bind increased amounts Leukotriene C4 Leukotriene B4 of water resulting in the cartilage PGI2 swelling described in early 26-28,32 osteoarthritis. Figure 6. Effect of corticosteroids and non-steroidal antiinflammatory drugs on the arachidonic acid Chondrocyte necrosis is cascade. (Used with permission. Hayek MG, Lepine AJ, Sunvold GD, Reinhart GA. Nutritional evident as osteoarthritis progresses. management of joint problems in dogs, in Proceedings. Articular Cartilage and Joint Health. 27th The synthesis of extracellular matrix Annual VOS Conference, 2000; 18-23. ceases while degradative activity remains elevated. The collagen network becomes Dietary Fat. Dietary fatty acids can also effectively increasingly disorganized and disintegrated. The content of manipulate eicosanoid production. A total dietary several extracellular components including collagen and approach alters the substrates presented to the enzymes proteoglycans are progressively reduced.26 The removal of which dictate the types of eicosanoids produced. For functional proteoglycans from the extracellular matrix instance, feeding omega-3 fatty acids results in the results in decreased water content of the cartilage and a replacement of arachidonic acid (omega-6) in the cell subsequent loss of biomechanical properties, such as membrane with eicosapentanoic acid.35 The eicosanoids resilience and elasticity. As a result the chondrocytes are derived from arachidonic acid (prostaglandin E2, subjected to increasing mechanical stress and trauma leukotriene B4, leukotriene C4, and thromboxane A2) are thereby accelerating the osteoarthritic process.26 proinflammatory,36,37 whereas eicosanoids synthesized from eicosapentaenoic acid (prostaglandin E3 and leukotriene B5) are less inflammatory. NUTRITIONALLY MANAGING THE EFFECTS It has been reported that feeding dogs a diet that OF JOINT DISEASE AND INJURY contains an omega-6 to omega-3 fatty acid ratio between Eicosanoids. Eicosanoids are local chemical 5:1 and 10:1 results in decreased leukotriene B4 and mediators (leukotrienes, thromboxanes, prostaglandins, and increased leukotriene B5 secretion in skin and neutrophils prostacyclins) produced by the actions of cyclooxygenase compared to dogs fed higher fatty acid ratios (25:1, 50:1,

Clinical Perspectives on Canine Joint Disease (TNAVC 2001) 14 and 100:1).38 Caution should be raised in feeding diets Glucosamine and chondroitin sulfate have not with very low omega-6 to omega-3 fatty acid ratios since produced reports of safety concerns. One study found that high consumption of omega-3 fatty acids may result in glucosamine and chondroitin sulfate (2 capsules, PO, q 12; problems such as increased bleeding times, delayed wound daily dose of 800 mg sodium chondroitin sulfate; 1,000 mg healing, and depressed immune responses.39,40 glucosamine hydrochloride; and 152 mg manganese ascorbate) administered to 13 clinically normal Beagles for Chondroprotective Agents 30 days produced statistically significant but clinically Oral chondroprotective agents, including unimportant changes in hematocrit, hemoglobin, WBC, glucosamine and chondroitin sulfate, may modulate joint segmented neutrophils, and RBC; however, no changes structure and physiology.41 were seen in the prothrombin time, activated partial Glucosamine. Glucosamine is a ubiquitous thromboplastin time, or mucosal bleeding time.48 amino sugar used in the synthesis of the disaccharide units In considering oral supplementation of glucosamine of GAGs.42 In humans, an oral dose of glucosamine sulfate and chondroitin sulfate for management of joint problems is 90% absorbed and 26% bioavailable.43 A recent study one must be cognizant of the route of supplementation. If found the bioavailability, pharmacokinetics, and excretion capsules or pills are utilized owner compliance may be an pattern in the human to be consistent with those of the issue of concern. Inclusion of these compounds in a total dog.44 Chondrocyte studies in vitro found that diet will eliminate any concerns for compliance. glucosamine has a stimulatory effect causing increased production of normal collagen and proteoglycans.41 Using rat models of subacute inflammation and subacute CONCLUSION mechanical arthritis, oral glucosamine was found to be The structure/function relationship of articular 50–300 times less potent than indomethacin but its cartilage is clearly demonstrated in the structural chronic toxicity is 1,000–4,000 times less than modifications observed during growth and development of indomethacin which suggests a therapeutic margin 10–30 the joint in response to the increasing forces naturally times more favorable for using glucosamine in prolonged applied during this period. It is also clear that traumatic oral treatments.45 injury or disease can substantially disrupt the normal Chondroitin sulfate. Chondroitin sulfate is a architecture of the joint by altering the concentrations of GAG which can be sulfated on the fourth or sixth glycosaminoglycans, proteoglycans, collagens, and carbon.41 Chondroitin-4-sulfate is the predominant GAG associated structures within the cartilage. Failure to correct in growing mammalian hyaline cartilage but, with age, such damage can allow for the progression to advanced joint production of chondroitin-4-sulfate decreases and the disease from which complete reversal may not be possible. production of other types of GAGs is increased by An overall regimen for treatment of primary and chondrocytes.41 Two chondroprotective activities secondary joint diseases should include weight produced by chondroitin sulfate but not by glucosamine management (discussed elswhere in these proceedings), are prevention of thrombi formation in microvasculature exercise modification, and administration of nonsteroidal and inhibition of metalloproteases via the modulation of antiinflammatory drugs (NSAIDs), glucocorticoids, or interleukin-3.41 A recent study in humans with mono- or polysulfated glycosaminoglycans (GAGs).49 Several of bilateral-knee osteoarthritis found that both chondroitin these treatments either directly require or may be sulfate-dosing regimen (40 people received a single daily influenced by nutritional management. The provision of dose of 1,200 mg of chondroitin sulfate in an oral gel and nutritional compounds that decrease cartilage degradation, 43 received 400 mg capsules TID) produced improvement increase matrix synthesis, provide matrix precursors, or of the subjective symptoms and improved mobility.46 assist in the control of the inflammatory response must be a Chondroitin sulfate and glucosamine. In a primary directive in the control and management of joint recent study,47 13 Beagles (age < 1 year, weight 4.2–5.1 kg) health of the companion animal. received 2 capsules of glucosamine, chondroitin sulfate, and ascorbate orally twice daily for 30 days (daily dose of 800 mg sodium chondroitin sulfate, 1,000 mg glucosamine hydrochloride, and 152 mg manganese ascorbate). Serum GAGs (12 dogs) were elevated by 37% with no change in circulating hexosamine (3 dogs). Calf cartilage segments were incubated in serum collected (9 dogs) before and after treatment. Biosynthetic activity increased 50% and proteolytic degradation decreased 59%.

15 Clinical Perspectives on Canine Joint Disease (TNAVC 2001) REFERENCES 1. Hardingham TE, Fosang AJ. Proteoglycans: many forms and many 23. Buckwalter JA, Rosenberg LC, Hunziker EB. Articular cartilage functions. FASEB J 1992; 6:861-870. composition structure response to injury and methods of facilitating 2. Mow VC, Ratcliffe A. Structure and function of articular cartilage repair. In: Bristol-Myers/Zimmer Orthopaedic Symposium: Articular and meniscus. In: Mow VC, Hayes WC, eds. Basic Orthopaedic Cartilage and Knee Joint Function Anonymous. New York: Raven Press, Biomechanics. New York: Raven Press, 1991; 143-198. 1988; 19-56. 3. Kuettner KE, Aydelotte MB, Thonar EJ. Articular cartilage matrix 24. Frenkel SR, Di Cesare PE. Degradation and repair of articular and structure: a minireview. J Rheumatol Suppl 1991; 27:46-48. cartilage. Front Biosci 1999; 4:671-685. 4. Hardingham TE, Bayliss MT. Proteoglycans of articular cartilage 25. Poole AR. An introduction to the pathophysiology of osteoarthritis. change in aging and joint disease. Semin Arth Rheum Suppl 1990; Front Biosci 1999; 4:662-670. 1:12-33. 26. Dijkgraaf LC, De Bont LG, Boering G, Liem RS. The structure, 5. Nixon AJ. Articular cartilage surface structure and function. Equine biochemistry, and metabolism of osteoarthritic cartilage: a review of Vet Educ 1991; 3:72-75. the literature. J Oral Maxillofac Surg 1995; 53:1182-1192. 6. Van der Rest M, Aubert-Foucher E, Dublet B, Eichenberger D, Font 27. Malemud CJ, Goldberg VM. Future directions for research and B, Goldschmidt D. Structure and function of the fibril-associated treatment of osteoarthritis. Front Biosci 1999; 4:762-771. collagens. Biochem Soc Trans 1991; 19:820-824. 28. Muir H. Cartilage structure and metabolism and basic changes in 7. Van der Rest M, Mayne R. Type IX collagen proteoglycan from degenerative joint disease. Aust/NZ J Med 1978; 8:1-5. cartilage is covalently cross-linked to type II collagen. J Biol Chem 29. Dingle JT. Cartilage maintenance in osteoarthritis: interaction of 1988; 263:1615-1618. cytokines, NSAID and prostaglandins in articular cartilage damage 8. Cohen NP, Foster RJ, Mow VC. Composition and dynamics of and repair. J Rheumatol Suppl 1991; 28:30-37. articular cartilage: structure, function, and maintaining healthy state. 30. Krane SM, Goldring MB. Clinical implications of cartilage J Orthop Sports Phys Ther 1998; 28:203-215. metabolism in arthritis. Eur J Rheumatol Inflamm 1990; 10:4-9. 9. Broom ND, Silyn-Roberts H. Collagen-collagen versus collagen- 31. Hwang WS, Li B, Jin LH, Ngo K, Schachar NS, Hughes GN. proteoglycan interactions in the determination of cartilage strength. Collagen fibril structure of normal, aging, and osteoarthritic cartilage. Arthritis Rheum 1990; 33:1512-1517. J Pathol 1992; 167: 425-433. 10. Ghadially FN. Structure and function of articular cartilage. Clin 32. Malemud CJ. Fundamental pathways in osteoarthritis: an overview. Rheum Dis 1981; 7:3-28. Front Biosci 1999; 4:659-661. 11. Dijkgraaf LC, De Bont LG, Boering G, Liem RS. Normal cartilage 33. Voet D, Voet JG. Biochemistry. New York, NY: John Wiley & Sons, structure, biochemistry, and metabolism: a review of the literature. J Inc., 1990; 658-665. Oral Maxillofac Surg 1995; 53:924-929. 34. Johnston SA, Fox SM. Mechanism of action of anti-inflammatory 12. Castano OM, Quintans RM, Crespo AA, Giraldez GM, Saavedra medications used for the treatment of osteoarthritis. JAVMA 1997; GM, Jorge BF. Variation in articular cartilage in rabbits between 210:1486-1492. weeks six and eight. Anat Rec 1995; 241:34-38. 35. Hayek MG, Reinhart GA. Utilization of omega-3 fatty acids in 13. Oreja MTC, Rodriguez MQ, Abelleira AC, Garcia MAG, Garcia companion animal nutrition. World Rev Nutr Diet 1998; 83:176-185. MAS, Barreiro FJJ. Variation in articular cartilage in rabbits between 36. Goetzl EJ. Oxygenation products of arachidonic acid as mediators weeks six and eight. Anat Rec 1995; 241:34-38. of hypersensitivity and inflammation. Med Clin North Am 1981; 14. Bland YS, Ashhurst DE. Development and aging of the articular 65:809-828. cartilage of the rabbit knee joint: distribution of the fibrillar 37. Lee TH, Austen KF. Arachidonic acid metabolism by the 5- collagens. Anat Embryol (Berl) 1996; 194:607-619. lipoxygenase pathway, and the effects of alternative dietary fatty 15. Sweet MB, Thonar EJ, Marsh J. Age-related changes in proteoglycan acids. Adv Immunol 1986; 39:145-175. structure. Arch Biochem Biophys 1979; 198:439-448. 38. Vaughn DM, Reinhart GA, Swaim SF, Lauten SD, Garner CA, 16. Garg HG, Swann DA. Age-related changes in the chemical Boudreaus MK, Spano JS, Hoffman CE, Conner B. Evaluation of composition of bovine articular cartilage. The structure of high- effects of dietary n-6 to n-3 fatty acid ratios on leukotriene B density proteoglycans. Biochem J 1981; 193:459-468. synthesis in dog skin and neutrophils. Vet Dermatol 1994; 5:163-173. 17. Nakano T, Sim JS. Growth dependent changes in the chemical 39. Vaughn DM, Reinhart GA. Dietary fatty acid ratios and eicosanoid composition of proximal tibial articular cartilage and growth plate of production, in Proceedings. 13th ACVIM Forum, 1995. broiler chickens. Can J Anim Sci 1995; 75:433-437. 40. Wander RC, Hall JA, Gradin JL, Du SH, Jewell DE. The ratio of 18. Pacifici M. Tenascin-C and the development of articular cartilage. dietary (n-6) to (n-3) fatty acids influences immune system function, Matrix Biol 1995; 14:689-698. eicosanoid metabolism, lipid peroxidation and vitamin E status in 19. Savarese JJ, Erickson H, Scully SP. Articular chondrocyte Tenascin- aged dogs. J Nutr 1997; 127:1198-1205. C production and assembly into de novo extracellular matrix. J 41. Anderson MA. Oral chondroprotective agents. Part I. Common Orthop Res 1996; 14:273-281. compounds. Compendium 1999; 21:601-609. 20. Nakano T, Aherne FX, Thompson JR. Changes in swine knee 42. McNamara PS, Spencer AJ, Todhunter RJ. Slow-acting, disease- articular cartilage during growth. Can J Anim Sci 1979; 59:167-179. modifying osteoarthritis agents. Osteoarthritis 1997; 27:863-881. 21. Venn MF. Variation of chemical composition with age in human 43. Wlock K. Glucosamine sulfate in the treatment of osteoarthritis. femoral head cartilage. Ann Rheum Dis 1978; 37:168-174. CPJ/RPC. 1997; October: 34-35. 22. Roughley PJ. Changes in cartilage proteoglycan structure during 44. Setnikar I, Giacchetti C, Zanolo G. Pharmacokinetics of glucosamine ageing: origin and effects—a review. Agents Actions Suppl 1986; in the dog and in man. Drug Res 1986; 36:729-735. 18:19-29.

Clinical Perspectives on Canine Joint Disease (TNAVC 2001) 16 45. Setnikar I, Pacini MA, Revel L. Antiarthritic effects of glucosamine sulfate studied in animal models. Drug Res 1991; 41:542-545. 46. Bourgeois P, Chales G, Dehais J, Delcambre B, Kuntz J-L, Rozenberg S. Efficacy and tolerability of chondroitin sulfate 1200 mg/day vs chondroitin sulfate 3x400 mg/day vs placebo. Osteoarthritis and Cartilage 1998; 6(Supplement A):25-30. 47. Lippiello L, Idouraine A, McNamara PS, Barr SC, McLaughlin RM. Cartilage stimulatory and antiproteolytic activity is present in sera of dogs treated with a chondroprotective agent. Canine Pract 1999; 24:18-19. 48. McNamara PS, Barr SC, Erb HN. Hematologic, hemostatic, and biochemical effects in dogs receiving an oral chondroprotective agent for thirty days. Am J Vet Res 1996; 57:1390-1394. 49. DeHaan JJ, Beale BS. The Skeletal System. In: Goldston RT, Hoskins JD, eds. Geriatrics and Gerontology of the Dog and Cat. Philadelphia, Pa: W.B. Saunders, 1995; 291-312.Suppl 1991; 27:46-48.

17 Clinical Perspectives on Canine Joint Disease (TNAVC 2001) important cause of lameness in dogs of all ages,7 we selected naturally-occurring cases of obese dogs with hip osteoarthritis to evaluate the hypothesis that lameness severity would be significantly influenced by weight loss.

A RECENT STUDY: INFLUENCE OF WEIGHT MANAGEMENT ON JOINT HEALTH8 The influence of weight reduction on pelvic limb The Benefit function was prospectively examined in 9 overweight client-owned dogs with hip osteoarthritis and lameness. Dogs studied were at least 10% over their ideal body of Weight weight. Dogs were screened using a serum chemistry panel with thyroid screen and complete blood count to rule out concurrent systemic disease. A numerical rating scale Management (NRS; Figure 1) and a visual analog scale (VAS; Figure 2) were used to subjectively assess lameness (by JI) prior to the dogs beginning a weight loss program. The weight loss in Dogs with program included Eukanuba Veterinary Diets® Nutritional Weight Loss Formula™ Restricted-Calorie™/Canine fed at 60% of maintenance calories for initial body weight. Joint Problems Lameness assessment was repeated at the mid-point and end of the 10- to 19-week weight loss period. The effect of time on lameness and body condition were evaluated using repeated-measures analysis-of-variance and Mark A. Tetrick, DVM, PhD the Friedman test. Differences were considered significant Research and Development Division at P<.05. Over the weight loss period, dogs lost between 11 The Iams Company, Lewisburg, Ohio and 18% of their initial body weight. Body weight decreased linearly over time (P<.001) and body condition score Joseph A. Impellizeri, DVM improved (P<.05). Numerical rating lameness scores University of Illinois Cancer Care Center improved significantly with time (P<.05) and there was also a linear improvement in VAS scores with time University of Illinois School of Veterinary Medicine, (P<.005). Visual analog scale assessment scores for Urbana, Illinois lameness improved 76% over the study period. No dog was Peter Muir, BVSc, MVetClinStud, PhD, withdrawn from the study because of worsening lameness. MACVSc, DACVS, DECVS School of Veterinary Medicine, Hind Limb Lameness Score Department of Surgical Sciences Score Criteria University of Wisconsin-Madison, Madison, Wisconsin 0 Clinically sound 1 Barely detectable lameness 2 Mild lameness INTRODUCTION 3 Moderate lameness 4 Severe lameness (carries limb when trotting) Obesity is recognized as an important factor 5 Could not be more lame influencing the clinical expression of osteoarthritis in humans.1-3 The incidence of obesity in the canine population has been estimated to be on the order of 25% Figure 1. Numerical rating scale (NRS). and likely affects at least this proportion of dogs with 4-6 osteoarthrtis. While veterinarians have used nutritional Clinically Could not be therapy to achieve weight reduction in overweight sound more lame osteoarthritic dogs, no data describing the effect of weight loss on lameness severity or the effect of weight loss on the Figure 2. Visual analog scale (VAS) score using a 100 mm prevalence or progression of osteoarthritis in dogs has been horizontal line. This method is considered to be a more sensitive described. Because osteoarthritis of the hip joint is an assessment method.

Clinical Perspectives on Canine Joint Disease (TNAVC 2001) 18 Data from this study support the hypothesis that such as diabetes, hyperthyroidism or hypothyroidism, lameness severity can be significantly influenced by weight hyperadrenocorticism, and heart disease. loss (Figure 3). Weight loss alone can result in a Weight Assessment. Next evaluate the patient’s significant decrease in lameness. Increased emphasis weight. Comparing the dog’s weight to breed standards should be placed on normalizing body weight in dogs with where appropriate can be a first step to evaluating the hip osteoarthritis. Although not examined in this study, degree of obesity. Given the wide ranges within breeds and normalization of the body weight of the osteoarthritic the popularity of mixed breed dogs, assigning a Body patient also has the potential to slow disease progression. Condition Score (BCS) may be a more practical approach to determining level of obesity. Determining a BCS requires a visual and tactile evaluation of the ribs, spine, pelvis, waist, and abdomen (Figure 4). If you don’t put your hands 120 on the dog you have not completed an accurate BCS! a b 100 c 80 a Body Weight (lb) 60 Thin Dog Ribs, lumbar vertebrae, and 40 b pelvic bones easily visible VAS Score (Trotting) No palpable fat 20 c Obvious waist and abdominal tuck Prominent pelvic bones 0 Baseline Midpoint Final

Values between time points with different superscripts Underweight Dog are significantly different P<.05 Ribs easily palpable Minimal fat covering Figure 3. Body weight and visual analog scale ratings of lameness Waist easily noted when viewed during weight loss for lame, overweight dogs. from above Abdominal tuck evident

Current medical treatments for the management of dogs with osteoarthritis are primarily symptomatic. Longer Ideal Dog treatment courses using nonsteroidal antiinflammatory Ribs palpable, but not visible Waist observed behind ribs when drugs should not be given without using a concurrent viewed from above nutritional program to normalize the dog’s body weight. Abdomen tucked up when viewed Many overweight dogs with lameness due to hip osteo- from the side arthritis may not require drug treatment after excess weight has been lost. Overweight Dog Ribs palpable, with slight excess of fat covering ACHIEVING WEIGHT LOSS Waist discernable when viewed Weight loss in dogs can some-times be difficult to from above, but not prominent achieve. As in this study it is advisable to thoroughly Abdominal tuck apparent evaluate the patient before beginning an obesity management program. Diet History. Start with a dietary history to Obese Dog determine the types and quantities of food fed. Include Ribs not easily palpable feeding patterns such as the times fed per day and who under a heavy fat covering feeds the pet. Also evaluate the activity level and overall Fat deposits over lumbar area and tail base lifestyle of the pet. You may need to continue to probe to Waist barely visible to absent get a complete picture of the situation — does anyone else No abdominal tuck; may exhibit (a neighbor?) feed or treat the dog? A physical exam, obvious abdominal distention. including a serum chemistry panel with thyroid screen and urine tests, is important to rule out medical conditions Figure 4.

19 Clinical Perspectives on Canine Joint Disease (TNAVC 2001) Owner Involvement. One of the most important nutrition. Carbohydrate contains less than half the calories factors in achieving successful weight loss (including the of fat, which allows clients to feed an amount of food they weight loss in this study) is to involve the owner. The perceive as adequate while reducing calories consumed by owner must want the pet to lose weight. Recognition of the pet. Reduced quantities of fat necessitate attention to the dog’s obesity is a big step in enlisting the owner’s the type and quality of the dietary fat. Ensuring that the commitment to weight loss. Demonstrate to the owner ratio of omega-6:omega-3 fatty acids is between 5:1 and 10:1 using visual cues or palpation that the dog is overweight. will help promote healthy skin and coat during weight loss. Ensure that the client understands the health risks Likewise, it is important to carefully select the starch associated with obesity. sources used to replace fat in the diet. The carbohydrate For the purposes of this study specific weight loss component of pet foods provides the primary source of the goals, timelines, and periodic weigh-ins were established increase in blood glucose after a meal. Starch sources and agreed to from the beginning. The same holds for any behave very differently in the way that they influence successful weight loss program. Setting short- and long- blood glucose and insulin responses. Grain sorghum and term weight-loss goals with target dates for the owner barley are utilized as starch sources in the Restricted allows for interim goals with positive reinforcement. These Calorie diet. This weigh-ins can be every 1–2 weeks at first to ensure the results in lower program gets off to a good start and can be less frequent as postprandial blood Specially formulated foods the program progresses. glucose levels and containing a blend of barley Diet. Determine the daily caloric allotment that lower blood insulin and grain sorghum may help will achieve the targeted degree of weight loss and ultimate levels than if other BCS. Be sure the client understands that this allotment starch sources such improve glucose intolerance may change during the program, depending on the amount as wheat or rice are and stabilize blood glucose of exercise and/or metabolic adaptations that occur. Make used as the source levels in overweight pets. the client responsible for restricting the food appropriately. of starch.9 By Encourage them to measure and record all food given. minimizing post Involve everyone in the household who provides treats or prandial increases in blood glucose and insulin, specially food for the dog. formulated foods containing a blend of barley and grain Exercise. Although an exercise regime was not sorghum may help improve glucose intolerance and included as part of this study, exercise can play an stabilize blood glucose levels in overweight pets. important role in weight loss. Varying degrees of exercise Caloric density of the diet may also be reduced by can be prescribed, depending on the health of the client the addition of fiber to the diet. The Restricted-Calorie and the patient. Goals can be set for increasing duration diet contains normal levels of moderately fermentable fiber and intensity of exercise, but keep it reasonable. Exercise is instead of high levels of nonfermentable fiber such as just one additional facet of the entire weight loss program. cellulose. Increased nonfermentable fiber levels can result Client Support. Provide support and positive in increased stool volume, poor skin and coat quality, and reinforcement. Celebrate success. For the purposes of this ultimately result in poor client compliance. study, rewards (such as a leash) for reaching certain study weight loss milestones were provided. Rewards need not be expensive. Inexpensive but meaningful rewards such as a ENHANCING WEIGHT LOSS certificate documenting the target weight loss and progress Other dietary approaches, beyond feeding a low-fat, toward that goal serves both as a reminder and a reward. low-calorie diet to assist with canine weight management is to affect the way nutrients are metabolized to help promote weight loss and improve body composition. DIETARY CONSIDERATIONS Chromium can help optimize body composition during The major contributing factor to obesity is excess weight loss. Dogs fed diets containing supplemental caloric intake in relation to the dog’s caloric requirements.6 chromium (as chromium tripicolinate) had greater loss of In this study Eukanuba Veterinary Diets® Nutritional fat mass compared with that from feeding a diet Weight Loss Formula™ Restricted-Calorie™/ Canine supplemented with carnitine only (data on file; The Iams (Restricted-Calorie) was fed at 60% of maintenance Company). In addition to its role in improving body calories for initial body weight. Several features of this diet composition during weight loss, dogs fed diets help to acceptably reduce caloric intake. supplemented with chromium tripicolinate had improved By replacing some dietary fat with carbohydrate glucose tolerance and an increased rate of glucose removal instead of fiber, the caloric density of the Restricted- from the bloodstream after intravenous glucose infusion.10 Calorie diet is reduced while maintaining a high level of By enhancing tissue use of glucose, diets containing

Clinical Perspectives on Canine Joint Disease (TNAVC 2001) 20 chromium tripicolinate may lead to an overall REFERENCES improvement in glucose tolerance and blood glucose 1. Felson DT, Chaisson CE. Understanding the relationship between stability in overweight pets. body weight and osteoarthritis. Ballieres Clin Rheumatol 1997; Another dietary component that can affect nutrient 11:671-681. metabolism is carnitine. Carnitine is a water-soluble, 2. Cooper C, Inskip H, Croft P, Campbell L, Smith G, McLaren M, vitamin-like compound made in the body from the amino Coggon D. Individual risk factors for hip osteoarthritis: obesity, hip injury and physical activity. Am J Epidemiol 1998; 147:516-522. acids lysine and methionine. It is naturally present in 3. Oliveria SA, Felson DT, Cirillo PA, Reed JI, Walker AM. Body animal-based protein ingredients. By forming acyl- weight, body mass index and incident symptomatic osteoarthritis of carnitines, carnitine “escorts” fatty acids into the cells’ the hand, hip and knee. Epidemiology 1999; 10:161-166. mitochondria for oxidation and energy production. In this 4. Mason E. Obesity in pet dogs. Vet Rec 1970; 86:612-616. way, carnitine helps reduce body fat storage and blood lipid 5. Edney AT, Smith PM. Study of obesity in dogs visiting veterinary practices in the United Kingdom. Vet Rec 1986; 118:391-396. levels. When added to a canine weight-loss diet, carnitine 6. Sloth C. Practical management of obesity in dogs and cats. J Small resulted in a tendency for lower fat mass and greater lean Anim Prac 1992; 33:178-182. body mass, even with greater energy intake11 (Figure 5). 7. Kealy RD, Lawler DF, Ballam JM, Lust G, Smith GK, Biery DN, Olsson SE. Five-year longitudinal study on limited food consumption and development of osteoarthritis in coxofemoral joints of dogs. J Am Vet Med Assoc 1997; 210:222-225. 7% Diet Without Carnitine 8. Impellizeri JA, Tetrick MA, Muir P. Effect of weight reduction on clinical signs of lameness in dogs with hip osteoarthritis. JAVMA 6% Diet With Carnitine 2000; 216:1089-1091. 9. Sunvold GD, Bouchard GF. The glycemic response to dietary starch. 5% In: Reinhart GA, Carey DP, eds. Recent Advances in Canine and Feline Nutrition, Vol II: 1998 Iams Nutrition Symposium Proceedings. 4% Wilmington, OH: Orange Frazer Press, 1998; 123-131. 10. Spears JW, Brown TT Jr, Sunvold GD, Hayek MG. Influence of 3% chromium on glucose metabolism and insulin sensitivity. In: Reinhart GA, Carey DP, eds. Recent Advances in Canine and Feline 2% Nutrition, Vol II: 1998 Iams Nutrition Symposium Proceedings. 1% Wilmington, OH: Orange Frazer Press, 1998; 103-112. 11. Sunvold GD, Vickers RJ, Kelley R, Tetrick MA, Davenport GM, 0% Bouchard GF. Effect of dietary carnitine during energy restriction in the canine. FASEB J 1999; 13:A268. % Weight Loss % Body Fat Loss 12. Sunvold GD, Tetrick MA, Davenport GM, Bouchard GF. Carnitine After 7 Weeks After 7 Weeks supplementation promotes weight loss and decreased adiposity in the canine, in Proceedings. World Small Anim Vet Assoc 1998; 746.

Figure 5. Greater weight and body fat loss in dogs with carnitine, even with ad libitum feeding.12

CONCLUSION Achieving weight loss in overweight dogs can be challenging. However, successful weight loss can be achieved by engaging the owner, agreeing to achievable weight loss milestones with positive feedback, and by using diets with dietary features that can help achieve the desired weight loss. Additional motivation for successful weight loss can also be derived from the observable improvement in lameness as lame overweight dogs lose weight.

Eukanuba Veterinary Diets is a registered trademark of The Iams Company. Nutritional Weight Loss Formula and Restricted-Calorie are trademarks of The Iams Company.

21 Clinical Perspectives on Canine Joint Disease (TNAVC 2001) EXERCISE AND OSTEOARTHRITIS Although the exact relationship between exercise and OA is uncertain, several factors have been identified in people, and most of these likely apply to animals.6,7 It is generally believed that mild to moderate exercise and training in normal humans and dogs do not cause OA by themselves, but biochemical, histologic, and biomechan- ical changes do occur in articular cartilage. Cartilage of dogs regularly subjected to high levels of stress shows a Physical Therapy higher proteoglycan (PG) content and is stiffer than cartilage exposed to low stress levels. Most studies of running exercise have indicated that this activity produces for Dogs with no injury to articular cartilage, assuming that there are no abnormal biomechanical stresses acting on the joints. Running exercise of 4 km/day for 15 weeks in young Beagle Joint Disease dogs caused a 6% increase in stiffness of cartilage of the stifle joint.8 Thickness of the cartilage also increased so it is likely that moderate exercise has an anabolic effect on the physiological properties of cartilage, and may diminish Darryl L. Millis, MS, DVM, Diplomate ACVS the chance of developing OA. Using the same model, Department of Small Animal Clinical Sciences running exercise of 20 km/day for 15 weeks did not further College of Veterinary Medicine improve the mechanical properties of articular cartilage. University of Tennessee, Knoxville, Tennessee Another study evaluated whether an increased level of low-impact lifelong weight-bearing exercise causes degeneration of articular cartilage by exercising dogs on a treadmill at 3 kilometers per hour for 75 minutes, 5 days/week for 527 weeks while wearing jackets weighing 130% of their body weight.9 Ten control dogs were allowed unrestricted activity in cages for 550 weeks. No joints had ligament or meniscal injuries, cartilage erosions, or osteophytes. Furthermore, tibial articular cartilage thick- ness and mechanical properties did not differ between the two groups. These results suggest that a lifetime of regular low-impact exercise in dogs with normal joints does not cause alterations in articular cartilage. Heavy training programs may result in changes INTRODUCTION which predispose to the development of OA. In one study, Joint disease is a common problem in dogs. Patients dogs underwent a gradually increasing treadmill exercise with osteoarthritis (OA) have restricted activity, limited regimen of up to 40 km/day, while control dogs lived ability to perform, pain and discomfort, and decreased normally in their cages.10 The articular cartilage response quality of life.1-3 As animals reduce their activity level, a to training was site dependent. After the year-long exercise vicious cycle of decreased flexibility, joint stiffness, and loss period, stiffness of the cartilage decreased by 12-14 percent of strength occurs. Traditional management of dogs with in the lateral, but not in the medial condyles of the femur OA has included weight loss, antiinflammatory and and tibia. Similar changes were seen in glycosaminoglycan analgesic drugs, changes in lifestyle and exercise habits content of the superficial zone of cartilage, confirming the (usually restricted), and surgical management. role that PGs have in modulated cartilage stiffness. Advances in the management of human OA by Although there was no overt cartilage damage, the physical modalities have reduced the severity of symptoms softening of the cartilage may jeopardize the ability of the and reliance on medications to control pain and cartilage to maintain its normal structural and functional discomfort.4,5 Some of the benefits include increasing properties over time. In another study, strenuous running muscle strength and endurance, increasing joint range of of old dogs at 6-8 mph with 20 degrees uphill inclination motion (ROM), decreasing edema, decreasing muscle for 1 hour per day, 6 days/week for 8 months, led to spasm and pain, and improving performance, speed, quality accelerated matrix degradation in the femoral head. of movement, and function. Proteoglycan content decreased and there was irreversible

Clinical Perspectives on Canine Joint Disease (TNAVC 2001) 22 destruction of collagen fibrils. Older dogs may be more possible. Antiinflammatory medications are also prescribed vulnerable to mechanical stress changes than younger as needed for comfort. Body composition is documented to animals. Therefore, although mild to moderate training establish the percent body fat. That, combined with the protocols have an anabolic effect on cartilage, rather weight of the animal, gives the veterinarian and the owner severe training protocols may result in detrimental a target to reduce a specific amount of body fat. In general, alterations in cartilage. our goal is to reduce fat composition to 20–25% of body Certain activities are associated with OA of weight. In many cases, the owners feel that the dog is particular joints, presumably because of the chronic doing well enough clinically after weight loss and the impacts on joints which may not be biomechanically initiation of an exercise program that they no longer wish sound or are placed under abnormal loads. For example, to pursue surgery. Huskies tend to have more OA of the hips and shoulders associated with pulling sleds. Young dogs with coxofemoral joint laxity develop OA over time if corrective surgery, THERAPEUTIC EXERCISE such as triple pelvic osteotomy, is not performed to The goals of therapeutic exercise should be to improve joint biomechanics. Pathologic motion in a joint, reduce body weight, increase joint mobility, and reduce such as cranial drawer as a result of a ruptured cranial joint pain through the use of low-impact weight-bearing cruciate ligament, results in progressive OA changes. exercises designed to strengthen supporting muscles.19 Human runners with abnormal joint conformation appear Muscle disuse results in atrophy and weakness. Muscles to be predisposed to OA, while humans with normal joint also act as shock absorbers and strengthening of periartic- conformation do not.11,12 ular muscles may help protect joints. Mild weight-bearing Although initiating an improper exercise program in exercise also helps stimulate cartilage metabolism and a patient with abnormal joints may hasten the progression increases nutrient diffusion. Exercise may also increase of OA, a well-designed training program increases muscle endogenous opiate production and relieve OA pain. strength and tone, which may help stabilize joints, and Exercise should only be performed after correction of possibly decrease abnormal stresses on joints. Human major risk factors, such as joint instability or obesity. patients with knee OA in a supervised walking program Exercising a dog with an unstable cranial cruciate ligament walk farther in a period of time, have decreased pain, and speeds the development of OA. An initial exercise use medication less frequently to control pain.13 Patients program should consist of several short periods interspersed that exercise have improved strength, ROM, function, and with rest periods throughout the day. The exercise periods decreased need for medication.14 should be evenly spaced throughout the day. Regular intermittent cartilage loading may increase cartilage metabolism and glycosaminoglycan synthesis as compared THE ROLE OF OBESITY IN OSTEOARTHRITIS to constant loading or very slow loading. It is best to have Obesity is strongly associated with the development regular exercise periods throughout the week, rather than of OA in people and its management is important in the compacting all of the weekly activity into a weekend. treatment of OA.15 Heavy people are 3.5 times more likely Increased levels of exercise should occur gradually and to develop OA than light people, and loss of 5 kg decreases progressively. the odds of developing OA by over 50%.16 This may have The ideal exercise program is one which provides implications on the initiation of exercise programs for sufficient benefits without causing discomfort. If joint pain obese animals with OA. Overloading joints should be is greater after exercise than prior to exercise, the length of minimized by performing activities such as walking and activity should be decreased by half. It is important to swimming until weight loss occurs. In man, weight loss differentiate joint pain from muscle soreness. Some results in less joint pain and a decreased need for muscular discomfort may be expected early in exercise medication to treat OA. After weight loss, 90% of people programs. The level of exercise must be prescribed for each in one study had complete relief of pain in one or more individual based on the severity of OA, response to con- joints.17 A similar report exists in veterinary medicine, in current therapy, the patient’s pain tolerance, and the owner. which overweight dogs with hip dysplasia underwent Ideally, antiinflammatory drugs should not initially weight reduction.18 Losses of 11–18% of body weight be administered prior to exercise because it is important to resulted in significant improvements in body condition determine if the level of exercise is too great and causes scores and the severity of hind limb lameness. Currently, I joint pain following a training period. After titrating the do not perform total hip replacements in obese patients appropriate level of exercise so that pain is not worsened with hip dysplasia. Rather, these patients are placed on a with exercise, oral antiinflammatory drugs should be weight loss program combined with a low-impact exercise administered about 1 hour prior to exercise. Treatment program of walking, jogging (if tolerated), and swimming if with an antiinflammatory drug allows a small increase in

23 Clinical Perspectives on Canine Joint Disease (TNAVC 2001) activity and stress to the tissues to gradually increase stopping. In prescribing the activity, owner compliance function. As training events are stepped up over time, must be considered, and an exercise prescription should antiinflammatory agents are withheld to allow a true accommodate the owner’s schedule and benefit the animal. evaluation of the patient without the aid of medication. Light jogging on grass may be added as the dog tolerates The goal is to reach the desired level of function and increased activity. For additional muscle strengthening, maintain that level without the aid of long-term 1–2 pound strap-on weights may be fastened to the lower antiinflammatory drugs. Early in the training program, limbs (Figure 2). A back- however, antiinflammatory drugs may help address minor pack with weights may also muscle and joint soreness as tissues adapt to the new be used. Walking up and stresses placed upon them. down inclines or stairs are good low-impact activities Type of Exercise that are easily incorporated Exercise programs must be tailored to account for into a walking program and the typical course of exacerbations and remissions of OA. improve muscle strength The animal should not be forced to exercise during times and cardiovascular fitness. If of aggravation. Vigorous exercise may increase strengthening the pelvic inflammation. During pain-free times, low-impact limb muscles is desired in exercises are beneficial to maintain muscle strength, joint dogs with hip dysplasia, mobility and function. Stretching of affected muscle groups repeated rising from a sitting and joints during a warmup period is recommended.20,21 position may be beneficial. Application of superficial heat may relax tissues and the Some assistance may ini- dog and allow more effective stretching of muscles, tially be required in the tendons, ligaments, and joint capsules. form of sling support. High- Figure 2. Strap-on weights can be fastened to the limbs to aid in Common activities include controlled activity on impact exercises should be muscle strengthening. leash, treadmill walking (Figure 1), swimming, going up avoided. and down stairs or ramped inclines, and holding either the If facilities and climate allow, swimming is one of front or rear half of the dog up and encouraging the other the best activities for dogs. The buoyancy of water is half to exercise.3,22 Long leash walks provide good low significant and limits impact on joint surfaces, while impact, aerobic forms of exercise. The length of walks promoting muscle strength and tone, joint motion, and should be titrated so there is no increased pain after cardiovascular fitness. Clean lakes or pools may be used. activity. Also, it is better in the early phases of training to Self-contained tubs with whirlpool action are also provide three 20-minute walks than one 60-minute walk. available. Careful patient monitoring and assistance are The walks should be brisk and purposeful, minimizing important to prevent excessive thrashing. Fear of water must be addressed to avoid injury. Initially, dogs may swim for 1–3 minutes once daily, for 3 to 7 days per week. As strength and stamina improve, dogs may swim 5–10 minutes per session. When done carefully, swimming is an effective, functional exercise. We have been using an underwater treadmill for dogs with OA and have been impressed with the results (Figure 3). In general, a 2-week training period in the

Figure 1. A variable speed ground treadmill is useful to provide Figure 3. An underwater treadmill is useful to exercise dogs a consistent pace and footing for exercising dogs. with joint osteoarthritis.

Clinical Perspectives on Canine Joint Disease (TNAVC 2001) 24 underwater treadmill may increase peak weight-bearing forces by 5–15%, which is similar to that typically achieved with medication. We have performed force plate analysis of gait and documented a 10% increase in weight-bearing immediately following exercise, which carries over for a period of time. The length of the workout, speed of the treadmill, and the height of the water may be adjusted as training progresses (Figure 4). Even dogs which fear water generally perform well in this unit because the water rises around the dog, rather than lowering the dog into the water. Following exercise, a 10-minute warmdown period is necessary to allow muscles to cool down. The first 5 Figure 5. Commercially available cold packs can be kept minutes may be spent walking at a slower pace after a brisk cold until needed and then inserted into a cloth covering walk or swimming. Range of motion exercises may be which is then strapped on to the affected area. repeated for the next 5 minutes. Finally, ice may be applied to painful areas for 15–20 minutes to control post-exercise including less stiffness and pain, and improved joint ROM, inflammation. Massage is commonly used to decrease pain, although some discomfort is initially associated with swelling, and muscle spasm. application of cold.

Massage Massage is the systematic and scientific manipulation of soft tissues.25 The different types of massage include 38% effleurage, vigorous cross-fiber friction over muscles or 85% ligaments to break up adhesions, Swedish massage, deep tissue massage, neuromuscular massage, accupressure, 91% myofascial release, and reflexology. The beneficial effects of massage include relaxation of soft tissues, decreased muscle spasm and trigger points, increased muscle flexibility, improved venous and Figure 4. The buoyancy effect of water depends on the water level. lymphatic flow with reduction of edema, and increased Raising the water level decreases the weight that distal joints experience. local blood flow to an area. Massage has been used to increase blood flow to muscles to “warm up” the area PHYSICAL AGENTS before activity, and to decrease stiffness after activity.

Superficial heat modalities Ultrasound Superficial heating agents typically heat the skin Ultrasound (US) has been used to treat OA, and subcutaneous tissues to a depth of 1–2 cm.23,24 The rheumatoid arthritis, and bursitis (Figure 6).1,2 The most tissue is usually heated to 40–45˚ C for 15 to 20 minutes. Superficial heating agents include hot packs (moist and dry), circulating warm water heating blankets, and warm baths. Heat increases blood flow to the area, promotes tissue extensibility, decreases pain, muscle spasm and joint stiffness, and causes general relaxation. Heat is contra- indicated if swelling or edema are present.

Cryotherapy The application of cold decreases blood flow, inflammation, hemorrhage, and metabolic rate.23,24 Commercially available cold packs or ice wrapped in a towel may be applied to an area for 15 to 20 minutes, 3 to 6 times daily (Figure 5). An entire limb or limbs may be immersed in a cold water or water and ice bath to decrease inflammation. Most studies of cryotherapy treatment for OA indicate that patients experience positive benefits, Figure 6. Therapeutic ultrasound is applied to the affected area.

25 Clinical Perspectives on Canine Joint Disease (TNAVC 2001) common frequencies are 1 and 3 MHz. Most US units have THE ROLE OF THE ENVIRONMENT IN continuous and pulsed modes. Ultrasound has thermal and THE MANAGEMENT OF OSTEOARTHRITIS non-thermal effects. These effects are related to the Animals with severe OA require modifications in treatment time, intensity, frequency, and the area being their habitat. The principles of environmental modification treated. Thermal effects include decreased pain, and for dogs are similar to those of people. Whenever possible, increased blood flow, metabolic rate, and tissue animals should be moved from a cold, damp outdoor extensibility. Non-thermal effects include increased cell environment to a warm, dry inside environment. A soft, membrane permeability, calcium transport across cell well-padded bed or waterbed should be provided. A membranes, nutrient exchange, and phagocytic activity of circulating warm-water blanket under the blankets provides macrophages. heat which may reduce morning stiffness. Ultrasound is capable of heating tissues deeper than The playful activities of other pets may be a source superficial heating agents, heating tissues 5 cm deep to of irritation to dogs with moderate to severe OA. Affected 40–45˚ C, without overheating the superficial tissues. animals may attempt to keep up, and in the process, Generally, 10 minutes of US application to a small area become more lame and painful. In some instances, adequately increases tissue temperature. Because the tissue however, play with other animals stimulates activity and temperature increase is short-lived, stretching of joints and provides a welcome break in the exercise routine. tissues should be performed during the latter half of Severely affected patients may no longer be able to treatment or immediately after. The indications, negotiate stairs. Changes may be necessary to minimize contraindications, and physiological effects must be stair climbing. Steps are negotiated easier if they are wider thoroughly understood. and spaced farther apart. A ramp may be used instead of steps. In climates with ice and snow, walks should be Neuromuscular Electrical Stimulation shoveled and ice cleared to minimize the risk of falling. A wide variety of neuromuscular electrical stimu- lators (NMES) are available (Figure 7). Neuromuscular electrical stimulators provide benefits, including increasing SUMMARY muscle strength and joint ROM, decreasing edema and Physical rehabilitation is a valuable, but underused pain, and helping to improve part of the management of dogs with OA. The function.26-28 Pulsed AC veterinarian, physical therapist, veterinary technician, and units are the most useful for owner are vital to determine and carry out an appropriate increasing muscle strength therapeutic regimen. A variety of physical rehabilitation and joint ROM, and techniques are available to supplement and enhance other decreasing edema and pain. treatments for OA. To maintain enthusiasm for the The commonly used TENS program and to help with decision-making for further (transcutaneous electrical treatment, progress should be documented. nerve stimulation) refers only to a particular type of electrical stimulator that is applied for pain control, but is not used for muscle strengthening or other Figure 7. A neuromuscular applications. electrical stimulation unit is used In general, neuromus- to elicit muscle contractions. cular electrical stimulation appears to relieve pain in human patients with OA as long as the treatment is continued. Its role in pain relief of OA in animals is unknown, but it appears to attenuate muscle atrophy following some surgical procedures.

Clinical Perspectives on Canine Joint Disease (TNAVC 2001) 26 REFERENCES 1. Bromiley MW. In: Physiotherapy in Veterinary Medicine. Oxford, 22.Tanger CH. Physical therapy in small animal patients: basic England: Blackwell Scientific Publications, 1991. principles and application. Compend Cont Educ Pract Vet 1984; 2. Downer AH. In: Physical Therapy for Animals: Selected Techniques. 6:933. Springfield, IL: Thomas Publishers, 1978. 23.Hecox B, Mehreteab TA, Weisberg J. Physical agents: a comprehensive 3. Millis DL, Levine D. The role of exercise and physical modalities in text for physical therapists. East Norwalk, CT: Appleton and Lange, the treatment of osteoarthritis. Vet Clin N Amer Sm Anim Prac 1997; 1994. 27:913-930. 24.Michlovitz SL. Thermal Agents in Rehabilitation. Philadelphia: FA 4. Minor MA, Gewett JE, Webel RR. Exercise and disease related Davis, 1990. measures in patients with rheumatoid arthritis and osteoarthritis. 25.Tappan FM. Healing Massage Techniques: Holistic, Classic, and Arthritis Rheum 1988; 32:1396. Energizing Methods. East Norwalk, CT: Appleton and Lange, 1988. 5. Nicholas JJ. Physical modalities in rheumatological rehabilitation. 26. Johnson JM, Johnson AL, Pijanowski GJ, Kneller SK, Schaeffer DJ, Arch Phys Med Rehabil 1994; 75:994. Smith CW, Swan KS. Rehabilitation of dogs with surgically treated 6. Felson DT. The epidemiology of knee osteoarthritis: results from the cranial cruciate ligament-deficient stifles by use of electrical Framingham osteoarthritis study. Semin Arthritis Rheum 1990; 20(3 stimulation of muscles. Am J Vet Res 1997; 58:1473-1478. suppl 1):42. 27. Caggiano E, Emrey T, Shirley S. Effects of electrical stimulation or 7. McDonough AL. Effects of immobilization and exercise on articular voluntary contraction for strengthening the quadriceps femoris cartilage - a review of literature. J Orthop Sports Phys Ther 1981; 3:2-5. muscles in an aged male population. J Orthop Sports Phys Ther 1994; 8. Jurvelin J, Kiviranta I, Tammi M. Effect of physical exercise on 20:22-28. indentation stiffness of articular cartilage in the canine knee. 28. Morrissey MC, Brewster CE, Shields-CL J. The effects of electrical International-journal-of-sports-medicine-(Stuttgart) 1986; 7:106-110. stimulation on the quadriceps during postoperative knee 9. Newton PM, Mow VC, Gardner TR. The effect of lifelong exercise immobilization. Am J Sports Med. 1985; 13:40-45. on canine articular cartilage. Amer J Sports Med 1997; 25:282-287. 10. Arokoski J, Jurvelin J, Kiviranta I, et al. Softening of the lateral condyle articular cartilage in the canine knee joint after long distance (up to 40 km/day) running training lasting one year. Inter J Sports Med. 1994; 15:254-260. 11. Hallett MB, Andrish JT. Effects of exercise on articular cartilage. Sports Med Arthroscop Rev. 1994; 2:29-37. 12. McKeag DB. The relationship of osteoarthritis and exercise. Clinics in Sports Med 1992; 11:471. 13. Kovar PA, Allegrante JP, Mackenzie CR. Supervised fitness walking in patients with osteoarthritis of the knee. A randomized, controlled trial. Ann Intern Med 1992; 116:529. 14. Lewis C. Arthritis and exercise. In: Biegel L, ed. Physical Fitness and the Older Person: A Guide to Exercise for Health Care Professionals. Rockville, MD: Aspen Systems Co, 1984; 129. 15. Felson DT, Zhang Y, Anthony JM. Weight loss reduces the risk for symptomatic knee osteoarthritis in women. Ann Intern Med 1992; 116:535. 16. Schrager M. Slimming down reduces arthritis risk. Physician and Sportsmedicine 1995; 23:22. 17. McGoey BV, Deitel M, Saplys RJ. Effect of weight loss on musculoskeletal pain in the morbidly obese. J Bone Joint Surg 1990; 72-B:323. 18. Impellizeri JA, Tetrick MA, Muir P. Effect of weight reduction on clinical signs of lameness in dogs with hip osteoarthritis. J Amer Vet Med Assn 2000; 216:1089-1091. 19. Harkcom TM, Lampman RM, Banwell BF. Therapeutic value of graded aerobic exercise training in rheumatoid arthritis. Arthritis Rheum 1985; 28:32. 20. Halbertsma JP, van-Bolhuis AI, Goeken LN. Sport stretching: effect on passive muscle stiffness of short hamstrings. Arch. Phys. Med. Rehabil. 1996;77:688-692. 21. Magnusson SP. Passive properties of human skeletal muscle during stretch maneuvers. A review. Scand. J. Med. Sci. Sports 1998; 8:65-77.

27 Clinical Perspectives on Canine Joint Disease (TNAVC 2001) disk protrusion or extrusion is the most common cause.1 In this presentation, pathophysiological changes of IV disk degeneration are reviewed along with radiographic abnormalities. In this discussion, an aging model is used. Furthermore, a type III IV disk degeneration pattern is introduced and fully discussed with differential diagnoses in aged dogs.

Pathophysiology ANATOMY AND PHYSIOLOGY Intervertebral disks have two distinctive components: anulus fibrosus and nucleus pulposus. The and Diagnosis anulus fibrosus is in the outer layer, encasing the gelatinous nucleus pulposus (Figure 1). Although anulus fibrosus implies a circular structure, it is not a concentric ring-like of Intervertebral structure. The dorsal aspect is thin and incomplete. Thus, nucleus pulposus is located in a dorsal location. The anulus fibrosus and nucleus pulposus work together to act as a Disk shock absorber. The anulus fibrosus can stretch to evenly distribute a force due to their alignment of collagen fibers or fibrous tissues.8 The nucleus pulposus contains Degeneration proteoglycans that can hold high water contents. The results of biochemical analysis of the anulus fibrosus and nucleus pulposus show their similarity to articular cartilage. Takayoshi Miyabayashi, BVS, MS, As seen in the articular cartilage, IV disks lose their proteoglycans with aging or degeneration.9-12 This is most PhD, Diplomate ACVR likely caused by altered metabolic function of Department of Small Animal Clinical Sciences chondrocytes. However, compared to articular cartilage, College of Veterinary Medicine information regarding metabolic function of chondrocytes University of Florida, Gainesville, Florida, USA is limited in canine IV disk research.

INTRODUCTION Intervertebral (IV) disk disease is a common neuro- logical disease that causes pain and motor dysfunction. Results of complete clinical history and thorough physical examination facilitate neuroanatomical localization of a Figure 1. Normal lumbar intervertebral disk. Transverse and lesion. In addition, results of neurological examinations sagittal views. Concentric rings of anulus fibrosus are evident. further localize the lesion.1 Then, imaging examinations The inner nucleus pulposus is located in a slightly dorsal location. are in order to confirm the neuroanatomical location of the lesion, not only longitudinal (for example, at C6-7) but also transverse (for example, extradural, intradural and SIGNIFICANCE OF PROTEOGLYCANS extramedullary, intramedullary) location. Plain radiography, A significance of proteoglycans can be readily myelography, computed tomography, and magnetic demonstrated in a chemonucleolysis study of IV disks.13 resonance imaging have been used to accomplish this.2-6 Normal IV disk widths are maintained by healthy anulus Additional examination such as cerebraspinal fluid analysis fibrosus and nucleus pulposus. When proteolytic enzymes assists ruling in and out of certain differential diseases such such as collagenase, chymopapain, and chondroitinase as neoplasia and infection (for example, meningitis).7 ABC are injected directly into the nucleus pulposus, the Among many different causes of spinal cord proteoglycans are lost. Consequently, the IV disk spaces dysfunction, extradural spinal cord compression due to IV collapse. This chemical change can be readily noted on

Clinical Perspectives on Canine Joint Disease (TNAVC 2001) 28 magnetic resonance imaging (MRI) (Figure 2). It is and mild dorsal protrusion of the anulus fibrosus occured reasonable to assume that these chemical changes are around 7 years of age. A narrowed IV disk space was also developing in a more subtle fashion in clinical situations noted with this change. A sagittal section of the vertebrae most likely modulated by altered metabolic function of showed disorientation of the anulus fibrosus and fissure chondrocytes. Yet, again the information is limited in the tracts through which the nucleus pulposus protruded literature. dorsally. Color of the nucleus pulposus was whitish and opaque. Around 9 years of age, further dorsal bulging of the anulus fibrosus was noted. The anulus fibrosus lost its layered appearance, and it was blended with protruded nucleus pulposus. Further degenerative changes were noted in the spine of a 10-year-old dog. The dorsal bulging of IV disks was seen with disorientation of the anulus fibrosus with separation of layers in the ventral side and fissure in the dorsal area. The nucleus pulposus appeared as blended with the anulus fibrosus. There was collapse of the IV disk space with dorsal and ventral protrusions of both anulus fibrosus and nucleus pulposus. The protruded nucleus had yellowish discoloration. Cartilaginous end-plates were not present, leaving smooth ground surfaces of the bony or vertebral end-plates. This change was seen most prominently in the ventral half of the vertebral end-plates which had thickened, whitish plate of bones. Along the Figure 2. Sagittal T2-weighted magnetic resonance image. Note ventral surfaces of vertebrae, new bone was formed decreased signal in an intervertebral disk that was treated by chymopapain (chemonucleolysis). Due to a loss of water-rich proteoglycans, the signal adjacent to the cortex as spondylosis deformans. intensity is not as bright as the rest of normal intervertebral disks. Malalignment of the adjacent vertebrae was also noted. These changes were noted in both cervical and lumbar vertebrae. The most common and severe changes DEGENERATION OF IV DISKS AND were centered around C5-6 and C6-7 in the cervical spine SIGNIFICANCE OF BREEDS and T13-L1 through L2-3 in the lumbar spine. Unfortunately, degenerative changes of IV disks are The pattern described above can be called as unavoidable. With aging, the composition of proteoglycans Hansen type II degeneration and develops commonly in changes, causing a loss of water contents. A wear-and-tear non-chondrodystrophic breeds.16 Since IV disks lose their occurs in IV disks, and eventually fissures form within the proteoglycans gradually, the onset of IV disk disease is anulus fibrosus. This may be called a progressive aging usually gradual and at middle ages. Good examples of these pattern. that become clinically significant are seen in the cervical In a study using a colony of Beagle dogs, the spine of Dobermans and as a cauda equina syndrome at a following aging pattern was noted (Figure 3).14,15 Gross lumbosacral junction in large breed dogs. pathological change developed around 5 years of age. Hansen also noted much earlier degeneration of IV Orientation and order of the anulus fibrosus was altered disks in chondrodystrophic dogs such as Dachshunds, Miniature Poodles, etc.16 Histologically, these breeds of dogs showed degenerative changes as early as 4 months of age. In addition, “chondroid” degeneration occurred with early calcification of the nucleus pulposus. Calcification of IV disks or nucleus pulposus does not allow IV disks to work as a shock absorber. Thus, unusual force can cause extrusion of the nucleus pulposus. This process is acute and causes severe spinal cord damage leading to paralysis of legs (Figure 4). Here, it is imperative to remember that 6 years 8 years 10 years chondrodystrophic dogs have a narrow spinal canal that tightly accommodates the spinal cord. Thus, even a minor Figure 3. Sagittal histology slides of lumbar intervertebral extrusion can cause severe clinical signs. disks of Beagle dogs. Disruption of anulus fibrosus and dorsal herniation of nucleus pulposus are expected aging changes.

29 Clinical Perspectives on Canine Joint Disease (TNAVC 2001) Plain radiography and myelography are still the most commonly used imaging modality in diagnosis of IV disk disease in veterinary medicine.6 Although the degree of degeneration cannot be directly assessed with these studies, it is often possible to suspect the site based on abnormal radiographic findings in light of clinical signs. For example, a 4-year-old Dachshund is presented with acute hind leg paralysis. Plain lateral and dorsoventral radiographs showed a narrowed IV disk space at L1-2 with an increased opacity in the intervertebral foramen and narrowed facet joint at the same level. Since this is a relatively young dog Figure 4. Lateral lumbar myelogram of a 7-year-old Dachshund with acute history of paraparalysis, this is most likely due with acute paraparalysis. The ventral contrast column is deviated to IV disk disease. If the surgery is desired, myeolography dorsally. Severe spinal cord compression is noted. In addition, a can confirm the site and lateralize the lesion. Decom- mineralized disk material is noted in the ventral spinal canal. This pressive surgery such as hemilaminectomy can certainly is a classic appearance of Type I intervertebral disk extrusion. facilitate the recovery of motor function. However, if this is a 10-year-old Dachshund, the imaging diagnosis can be confusing at best with narrowed or collapsed IV disk spaces IMAGING DIAGNOSIS OF IV DISK in many levels with moderate spondylosis deformans. DEGENERATION We need to assume that IV disks are degenerated in aged animals. Currently, MRI is the diagnostic modality of TYPE III IV DISK DEGENERATION PATTERN 17 choice in human radiology. Degenerated IV disks do not The aging or degenerative pattern described above is contain water-rich proteoglycans, and thus they appear progressive. With the life expectancy of dogs prolonged, hypointense on T2-weighted images compared to normal we are now facing a drastic degenerative change in IV IV disks. In addition, sagittal and transverse images can disks. This change can be referred to as the type III delineate the dorsal border of the protruding disks and degenerative change.15 spinal cord compression. This modality is also exclusively Radiographically, the IV disk degenerative changes used for detection of spinal diseases in some veterinary develop as a narrowed IV disk space, sclerosis of vertebral institutions, but its availability is limited. Most veterinary end-plates, and spondylosis deformans. With time, this specialists agree to use this modality in a cauda equina further progresses to a collapsed IV disk space with severe syndrome, ruling in and out IV disk protrusion at the spondylosis. At the same time, remodeling of vertebral 2 lumbosacral junction (Figure 5). bodies may result in malalignment or kyphosis. At older ages, around 15 years or so, the IV disk spaces are totally collapsed and a mineralized mass appears in the spinal canal. This mass is a protruded or extruded IV disk tissue (mainly nucleus pulposus) that is subsequently calcified and ossified (Figure 6). The ossification is the result of endochondral ossification of the protruded nucleus that

Figure 5. Sagittal T2-weighted magnetic resonance image of a 3-year- old German Shepherd Dog with clinical signs of cauda equina syndrome. Figure 6. High-detail radiograph of a thin section of lumbar spine. The signal intensity of the lumbosacral intervertebral disk is significantly This is an example of Type III intervertebral disk degeneration. The lost compared to the L6-7 intervertebral disk. In addition, severe dorsal dorsally-protruded disk is calcified. A mottled mineral opacity suggests protrusion of disk material is noted with marked narrowing of the spinal ossification within the mass. The intervertebral disk is completely gone canal. High signal intensity areas dorsal and dorsocranial to the with severe remodeling changes of the vertebral end-plates. Ventral protruded disk is most likely due to fluid accumulation in the facet joint. spondylosis deformans are also evident.

Clinical Perspectives on Canine Joint Disease (TNAVC 2001) 30 contains chondrocytes and neovascularization. At the REFERENCES same time, severe vertebral end-plate changes are 1. Hoerlein BF. Canine Neurology. Diagnosis and Treatment. 3rd ed. recognized (Figure 6). Protrusion of the IV disk tissue Philadelphia: W. B. Saunders Company, 1978. through the vertebral end-plates can occur (Schmorl’s 2. de Haan JJ, Shelton SB, Ackerman N. Magnetic resonance imaging in the diagnosis of degenerative lumbosacral stenosis in four dogs. node). In one Beagle dog that had extrusion of calcified Vet Surg 1993; 22:1-4. disks at 2 years of age, the dog eventually developed a large 3. Kärkkäinen M, Mero M, Nummi P, Punto L. Low field magnetic bony bridge on the dorsal aspect of the vertebral body resonance imaging of the canine central nervous system. Vet Radiol within the spinal canal. Again, endochondral ossification 1991; 32:717-4. was the apparent cause of this change. 4. Kärkkäinen M, Punto LU, Tulamo R-M. Magnetic resonance Clinical significance of type III IV disk degneration imaging of canine degenerative lumbar spine disease. Vet Radiol Ultrasound 1993; 34:399-404. is the recognition of the condition. The type III disk 5. Thomson CE, Kornegay JN, Burn RA, Drayer BP, Hadley DM, degeneration appears so severe that this can be confused Levesque DC, Gainsburg LA, Lane SB, Sharp NJH, Wheeler SJ. with discospondylitis or even neoplasia. The condition can Magnetic resonance imaging: a general overview of principles and also make remodeling changes of the pedicles due to long- examples in veterinary neurodiagnosis. Vet Radiol Ultrasound 1993; standing presence of a mass at the spinal canal. The spinal 34:2-17. 6. Widmer WR. Intervertebral disc disease and myelography. In: Thrall cord is certainly misshapen due to the presence of the DE, ed. Textbook of Veterinary Diagnostic Radiology. Philadelphia: mass. Yet, a gradual onset appears to allow the spinal cord W. B. Saunders Company, 1998; 89-104. to adapt to the condition, causing only mild motor 7. Thomson CE, Kornegay JN, Stevens JB. Analysis of cerebrospinal dysfunction. Decompressive surgery may not be indicated fluid from the cerebellomedullary and lumbar cisterns of dogs with in these cases. focal neurologic disease: 145 cases (1985-1987). JAVMA 1990; 196:1841-1844. 8. Johnson EF, Caldwell RW, Berryman HE, Miller A, Chetty K. Elastic fibers in the anulus fibrosus of the dog intervertebral disc. Acta Anat CONCLUSION 1984; 118:238-42. Pathophysiology of IV disk degeneration involves 9. Ghosh P, Taylor TKF, Braund KG, Larsen LH. A comparative biochemical changes developing in IV disks. A loss of chemical and histochemical study of the chondrodystrophoid and non-chondrodystrophoid canine intervertebral disc. Vet Pathol 1976; proteoglycans appears to be the initial step to 13:414-427. degeneration. A predictable course follows with disruption 10. Ghosh P, Taylor TKF, Braund KG, Larsen LH. The collagenous and of anulus fibrosus and protrusion of nucleus pulposus non-collagenous protein of the canine intervertebral disc and their through these fissures. As a result, the IV disk space variation with age, spinal level and breed. Gerontol 1976; 22:124-134. narrows, and this can be readily detected by radiography. 11. Ghosh P, Taylor TKF, Braund KG. The variation of the With persistent instability, spondylosis deformans develops glycosaminoglycans of the canine intervertebral disc with aging. I. Chondrodystrophoid breed. Gerontol 1977; 23:87-98. around the end-plates. The end-plates sclerosis and 12. Ghosh P, Taylor TKF, Braund KG. Variation of the malalignment may develop. With advanced aging, all IV glycosaminoglycans of the intervertebral disc with aging. disk tissues escape from II. Non-chondrodystrophoid breed. Gerontol 1977; 23:99-109. the IV disk space. 13. Miyabayashi T, Takiguchi M. Chemonucleolysis with chymopapain The degenerative process followed by magnetic resonance imaging: A pilot study, in Proceedings. Spondylosis deformans of IV disks cannot be 1993 American College of Veterinary Radiology Annual Scientific continues to develop. Meeting, 1993. avoided. Yet, it is possible Further remodeling 14. Morgan JP, Miyabayashi T. Degenerative changes in the vertebral to delay the process. occurs at the end-plates. column of the dog: A review of radiographic findings. Vet Radiol Dorsally protruded 1988; 29:72-77. nucleus pulposus under- 15. Miyabayashi T. Aging changes in the spine of Beagle dogs, in Division of Comparative Pathology. 1994, University of California, goes endochondral ossification. The spinal cord adapts to Davis: Davis; 117. this gradual process of spinal cord compression. The 16. Hansen H-J. A pathologic-anotomical study on disc degeneration in mineralized mass can be readily detectable on radiographs. dog, with special reference to the so-called enchondrosis This should not be confused with discospondylitis or intervertebralis. Acta Orthop Acand 1952; Suppl. XI. neoplasia. 17. Chafetz N, Genant HK, Gillespy T, et al. Magnetic resonance imaging. In: Kricun ME, eds. Imaging Modalities in Spinal Disorders. It is important to understand that the degenerative Philadelphia: W. B. Saunders Company, 1988; 478-502. process of IV disks cannot be avoided. Yet, it is possible to delay the process. Research in chondrocyte metabolism and its relationship with degeneration should broaden understanding of maintaining healthy IV disks.

31 Clinical Perspectives on Canine Joint Disease (TNAVC 2001) the diarthrodial joint better than the older term “degenerative joint disease”. Typically, OA is an insidiously progressive, degenerative condition that targets high motion synovial joints. Etiologies may include infectious (eg, septic arthritis) or noninfectious (eg, immune mediated, trauma, developmental/congenital) environ- ment development within the joint. This discussion will be limited to medical management of secondary low- inflammatory-based OA or what has been classically Balanced labeled “secondary degenerative joint disease” or non- infectious, nonimmune-mediated osteoarthritis. Micro and macroscopic changes within the synovial Management joint may result in the clinical signs of lameness due to joint pain (synovitis, microfractures of of Osteoarthritis subchondral bone, Typically, osteoarthritis is osteophytes, and joint an insidiously progressive, effusion/distention). degenerative condition in Companion The clinical signs associated with OA that targets high motion vary from patient to synovial joints. Animals patient and may range from subclincal to a severe functional disability. Fundamentally, no one treatment will be all encompassing for all patients with OA. A balance of a “triad” of treatment components must be Steven A. Martinez, DVM, MS, considered when medically managing a patient with OA: Diplomate ACVS 1) weight control, 2) exercise/activity, 3) pharmacologic/ Department of Veterinary Clinical Sciences disease modifying osteoarthritic drugs (Figure 1). College of Veterinary Medicine Exclusion of one or more of these components from a Washington State University, Pullman, Washington, USA treatment protocol will result in an overall poorer clinical response from the patient.

WEIGHT CONTROL Obesity is a major risk factor for the development of OA1,2 while weight loss can reduce the symptomatic effects

INTRODUCTION Osteoarthritis (OA, syn. ostoarthrosis, degenerative joint disease, DJD) is a syndrome that affects synovial or PHARMACOLOGIC diarthrodial joints and may manifest its presence by TREATMENT causing pain in association with degeneration of articular cartilage (loss of extracellular cell matrix and chondrocytes, inflammatory response of synovium, and critical changes in proteoglycan ratios within matrix and synovial fluid) and changes in periarticular soft tissues. Since typically a low-grade inflammatory process is associated with the development and maintenance of the EXERCISE/ WEIGHT ACTIVITY degenerative process of articular cartilage, the underlying CONTROL subchondral bone response (eg, sclerosis), intra and MANAGEMENT periarticular response (eg, synovial hypertrophy, fibrosis), the term “osteoarthritis” describes the disease process of

Figure 1. “Triad” of osteoarthritis treatment.

Clinical Perspectives on Canine Joint Disease (TNAVC 2001) 32 of OA in humans.3,4 Until recently, it was assumed that additional calories in the form of table scraps or “dog the same held true in other animals. A recent clinical treats”. Also important is the frequency of feeding. Dogs study investigating the effects of obesity on dogs with hip on weight-reducing plans appear to be less hungry if fed a dysplasia concluded that divided volume of the reducing diet over the course of the Obesity is a major overweight dogs that achieved day. In addition, feeding in-between “snacks” of low an 11–18% body weight calorie and high fiber quality (raw carrot sticks, raw celery risk factor for the reduction were significantly sticks, non-flavored rice cakes) or ice cubes will satisfy development of less lame compared to their most dogs. Appropriate caloric restriction should result in osteoarthritis. pre-weight reduction lameness the loss of 1–2% of body weight per week.6 scores.5 Currently, Washington All weight reduction/control programs must include State University is performing an exercise program to ensure constant weight loss and a study to examine the effects of obesity on the clinical eventual body weight expression of OA in dogs with canine hip dysplasia. maintenance. To All weight reduction/ Weight control can be one of the most challenging encourage activity in aspects of the medical management of OA in dogs for the debilitated OA control programs must several reasons. Any one or a combination of the following patient, regular phar- include an exercise factors will maintain a patient in an obese condition macologic treatment program to ensure indefinitely. may be required for a short period until the constant weight loss 1. A patient that is clinically inhibited by moving an patient becomes more and eventual body OA joint(s) will not be able to utilize consumed ambulatory. or stored body energy efficiently and will instead weight maintenance. increase body stores of energy (fat) when given a constant caloric intake. 2. Dogs with underlying endocrine disease (eg, MODIFICATION OF EXERCISE AND ACTIVITY hyperadrenocorticism, hypothyroidism) will have It is known from the human literature that exercise the metabolic propensity to maintain body fat is very important in maintaining strength, stamina, joint stores even in the face of a reducing diet. range of motion, and reducing dependency on medication when OA patients are allowed to exercise.7–11 It is assumed 3. Dogs that are in a multi-pet household (eg, other that the same is true in other animals as well and dogs and cats) are more prone to consume greater supported by a recent study in hamsters.12 Therefore, an volumes of food than dogs in single-pet households. important aspect in the management of OA in animals 4. Inaccurate estimation of animal’s ideal body weight. should be a controlled exercise. Depending on the animal’s activity history, it may be necessary to modify a patient’s 5. Inaccurate estimation of animal’s energy regular level and type of activity that is part of that requirements. animal’s daily exercise regime. 6. Most critical is the owner’s lack of willingness to be It may be intuitive that an OA animal should not be proactive in trying to reduce their pet’s body weight. allowed to have hard-impact, prolonged exercise activity, but controlled clinical studies have not been performed to Prior to starting a weight-reducing program, a evaluate this recommendation; however, from clinical complete physical exam should be performed. If the experience, practitioners are used to hearing the usual clinical history (attempted weight reduction in the past owner’s report of greater clinical signs in OA patients after with poor results, lethargy, “heat seeking”, PU/PD, etc.) hard, prolonged activity. It is known from kinetic and and physical exam findings (pendulous abdomen, kinematic gait analysis that dogs with OA will modify symmetrical alopecia, recurrent dematopathy, etc.) their gait to reduce the load of weight-bearing and motion indicate, a complete minimum data base (CBC, serum of the affected joint.13–15 It is therefore safe to assume that chemistry profile, UA) should also be obtained. prolonged “over activity” should result in greater Weight reduction can be obtained in healthy modification of gait due to exacerbation of the discomfort patients by simply reducing current caloric intakes; using associated with an OA joint. Some recommendations for reductions by 1⁄3 to 1⁄2 of the “normal” volume of the the duration of certain activities in dogs have been made,16 regular diet, calculating caloric content of regular diet and but recommendations for activity duration can also be caloric needs based on basal metabolic rates, or using based on “common sense” and the observations made by specially formulated commercial diets with recommended the owner of their pet’s apparent gait response/comfort intake volumes per the manufacturer, and avoiding level to an activity period.

33 Clinical Perspectives on Canine Joint Disease (TNAVC 2001) Just as important as duration of activity is the type of NSAIDs have a toxicity potential especially if a patient activity involved with the animal’s daily life style. Low- has underlying hepatic or renal disease, or a impact activities (eg, walking, cycling) have positive thrombocytopathy. Several in vivo studies using effects on human OA patients.7,8,17 In veterinary medicine, chondrocyte cell cultures or cartilage explants have low-impact activities (walking, swimming) have been reported a decrease in proteoglycan synthesis in those traditionally favored over hard-impact aerobic activities tissues incubated with selected NSAIDs.25–28 It would (jumping, hard starting/running, vigorous climbing/ appear to be a wiser clinical practice to administer running on irregular terrain), which can over-stress NSAIDs on a PRN basis especially for the patient that has degenerative joints. High-impact activities may over-stress only intermittent discomfort due to osteoarthritis. degenerative joints and increase the inflammatory Disease-modifying osteoarthritis agents (DMOA) condition of OA. Low-impact activities are thought to have recently been developed for the treatment of human reduce loads on an OA joint and result in less discomfort and veterinary OA patients. These agents have become for patient in maintaining good muscle strength/mass and common-place in the treatment of OA despite the lack of joint function. Walking under controlled conditions (leash definitive scientific studies confirming their efficacy. Most restraint) and/or swimming can be recommended to the of these products contain mixtures of glucosamine and owner with further instructions to eventually attempt to chondroitin sulfate, which supposedly enhance cartilage have the patient increase the duration of these activities health by providing the necessary precursors to maintain gradually so long as the animal appears to remain and repair cartilage. Glucosamine and chondroitin sulfate comfortable in doing so. reportedly have a positive effect on cartilage matrix, enhance proteoglycan production, and inhibit catabolic enzyme production or activity in OA joints. These PHARMACOLOGIC/DISEASE-MODIFYING properties have contributed to the labeling of these agents OA AGENTS TREATMENT as “condroprotective”.29 With the exception of one The primary goal with the pharmacologic product which is a true pharmaceutical by definition management of OA is to relieve the patient of discomfort (Adequan®, Luitpold Pharmaceuticals, FDA approved in associated with joint movement. Ideally, this would involve oral or Table 1. Selected nonsteroidal antiinflammatory drug doses for the dog injectable agents with analgesic, antiinflammatory, and potential condromodulating properties Drug Dose Route Strength Side Effects (disease-modifying OA agents, carprofen 2.2 mg/kg q PO 25, 50, 75, 100 Vomiting, diarrhea, changes in appetite, aka “DMOA”). Such agents (Rimadyl) 12hr (inj. soon) mg tablets lethargy, behavioral changes, constipation would ideally biochemically block etodolac 10-15 PO 150, 300 Vomiting, lethargy, diarrhea/loose stool, the inducible cyclooxegenase-2 (Etogesic) mg/kg q mg tablets hypoproteinemia, behavior change, (COX-2) and lipoxygenase 24hr uticaria, anorexia, regurgitation pathways. Nonsteroidal anti- *ketoprofen 1-2 mg/kg PO 12.5 mg Vomiting, diarrhea, serum increase of inflammatory drugs (NSAID) (Orudis) loading tablets creatinine have been developed for this (once) 1 mg/kg q purpose (Table 1) but generally, 24 hr do not all selectively block mainly (maint.) the COX-2 pathway18–20 or 1 mg/kg q SC Injectable leukotrienes production from the 24 hr lipoxygenase pathway.21–23 *meloxicam .1-.2 PO, SC Suspension Vomiting Two NSAIDs (carprofen, (Metacam; mg/kg q Injectable etodolac) have been recently approved 24 hr only in approved for use in dogs. These Europe) NSAIDs are considered to have a *piroxicam 0.3 mg/kg q PO 10, 20 mg Vomiting low COX-2:COX-1 ratio, but 24 hr or capsules have toxicity potential as with once, e.o.d any NSAID. Concerns are present *rofecoxib 5 mg/kg PO 12.5, 25, 50 Vomiting with long-term, chronic therapy (Vioxx™) mg tablets with NSAIDs. Hepatic toxicosis Suspension due to NSAID administration has *aspirin 10-20 mg/kg q PO 325 mg Vomiting, lethargy, been reported24; however, all (Ascriptin) 8-12 hr (w/ Malox) gastroduodenal ulceration

*currently not labeled for small animal use

Clinical Perspectives on Canine Joint Disease (TNAVC 2001) 34 horses and dogs), these agents are marketed as oral that were not treated with Adequan.35 Coxofemoral joint nutritional supplements and not “drugs” and as such, the assessment made post euthanasia was not significantly Federal Drug Administration does not require the different from untreated dogs.35 A clinical study manufacturer to provide efficacy data of their product. investigating the use of PSGAG on hip dysplasia patients Bioavailability reported of orally-ingested forms of found no significant difference in orthopedic scores glucosamine and chondroitin sulfate are 87%30,31 and (lameness, range of motion, pain on manipulation of hip 70%32 in humans and experimental animals, respectively. joints) compared to PSGAG non-treated dogs.36 In a Limited investigations have been preformed on the in vitro menisectomy model in dogs, PSGAG provided partial and in vivo activity of glucosamine and chondroitin sulfate protection to articular cartilage damage associated with the separately, but products containing both agents have menesectomy.37 Polysulfated glycosaminoglycan has been become popular for treating OA symptoms in humans and reported to have chondroprotective properties in joints other animals. with a chemically-induced articular cartilage damage Two commonly used combination glucosamine and model versus no effect on a physical articular cartilage chondroitin sulfate oral products in dogs are Cosequin damage model in horses.38 Recently, there have been (Nutramax) and Glycoflex (Vetri-Science Laboratories). anecdotal reports indicating that there may be a positive Although clinically noted not to have predicable efficacy synergism between injectable PSGAG and oral in all dogs, this combination of glycosaminoglycans appears glucosamine and chondroitin sulfate when administered to have a prophylactic effect on the development of OA in concurrently to a patient. dogs. Dogs undergoing a Pond-Nuki model for the Hyaluronic acid (sodium hyaluronate, HA) is a development of OA with or without stifle stabilization that major component of synovial fluid. Hyaluronic acid is were administered Cosequin for 5 months following surgery, postulated to enhance joint health by increasing the subjectively had less OA and less periarticular fibrosis than viscosity of the joint fluid and by reducing inflammation dogs not receiving Cosequin.33 Chymopapain-induced and scavenging free radicals. A study using a Pond-Nuki acute carpal synovitis was significantly attenuated based on model for OA in dogs followed by intraarticular injections nuclear scintigraphy and lameness evaluation when dogs of HA did not modify OA and reduced overall were pre-treated with glucosamine and chondroitin sulfate proteoglycan concentrations in treated stifles.39 (Cosequin).34 Current research suggests that glucosamine Other products reported that have disease-modifying, and chondroitin sulfate products may be prophylactically anti-OA potential include pentosan polysulfate, beneficial in patients that are prone to develop OA (eg, tetracyclines (doxycycline, minocycline, and modifications CHD, elbow dysplasia, OCD, cranial cruciate ligament of these molecules), S-adenosyl-L-methionine (SAMe), injury, etc.) or patients that may aggravate preexisting OA methylsulfonylmethane (MSM), capsaicin, and fatty acid with activity. Further controlled clinical studies are still ratio manipulation (omega-6:omega-3). To date, the truly warranted to support these statements. limited number of studies conducted suggest that some of these products may eventually have a place as adjuncts to Current research suggests that glucosamine the treatment of OA in animals.40–48 Adjuncts to pharmacologic, exercise/activity, and and chondroitin sulfate products may be weight control treatment are the application of heat, cold, prophylactically beneficial in patients that massage, hydrotherapy, ultrasound/diathermy, and electro- are prone to develop osteoarthritis or therapy.16 Although based on antidotal observations only, these adjuncts appear to help some patients. Well- patients that may aggravate preexisting controlled clinical trials are needed to test the supposition osteoarthritis with activity. that these modalities are as positively effective in veterinary OA patients as they are in human OA patients.

Injectable forms of DMOA available are Adequan, which is a polysulfated glycosaminoglycans (PSGAG) SUMMARY product, and hyaluronic acid (HA), a non-sulfated GAG. Osteoarthritis can be a debilitating disease for dogs; The U.S. and European product (Arteparon) has been however, new concepts in a balanced management of OA used in horses and dogs. Though conflicting evidence can result in an acceptable quality of life for the OA exists that PSGAG have a positive anabolic effect on patient. Medical management must be considered beyond hyaline cartilage, studies have shown that PSGAG may conventional and nonconventional pharmacologic decrease hyaline cartilage catabolism. In one study, treatment to include a balance created with immature dogs prone to hip dysplasia administered exercise/activity and weight control management. Failure Adequan developed better hip conformation than dogs to consider this treatment “triad” concept will usually

35 Clinical Perspectives on Canine Joint Disease (TNAVC 2001) result in a poorer clinical response to therapy and quality 12. Otterness IG, Eskra JD, Bliven ML, Shay AK, Pelletier JP, Milici AJ. of life as perceived by the owner of the OA patient. Exercise protects against articular cartilage degeneration in the Excellent progress continues in the development of new hamster. Arthritis Rheum 1998; 41:2068-2076. 13. Jevens DJ, DeCamp CE, Hauptman J, Braden TD, Richter M, pharmacologics and other agents to combat or even Robinson R. Use of force-plate analysis of gait to compare two reverse the degenerative processes of OA. In contrast, surgical techniques for treatment of cranial cruciate ligament rupture research and development into exercise/activity in dogs. Am J Vet Res 1996; 57:389-393. management for the 14. Bennett RL, DeCamp CE, Flo GL, Hauptman JG, Stajich M. OA companion animal Kinematic gait analysis in dogs with hip dysplasia. Am J Vet Res 1996; New concepts in a 57:966-971. lags significantly behind 15. DeCamp CE. Kinetic and kinematic gait analysis and the assessment balanced management that of human medicine, of lameness in the dog. Vet Clin North Am Small Anim Pract 1997; of osteoarthritis can but since the mid-1990’s, 27:825-840. is beginning to grow in 16. Millis DL, Levine D. The role of exercise and physical modalities in result in an acceptable interest in veterinary the treatment of osteoarthritis. Vet Clin North Am Small Anim Pract quality of life for the 1997; 27:913-930. medicine. Nonetheless, 17. Mangione KK, McCully K, Gloviak A, Lefebvre I, Hofmann M, osteoarthritis patient. large controlled clinical Craik R. The effects of high-intensity and low-intensity cycle trials are needed for ergometry in older adults with knee osteoarthritis. J Gerontol A Biol developing balanced Sci Med Sci 1999; 54:184-190. treatment protocols that will allow us to treat our OA 18. Lanza FL: Gastrointestinal toxicity of newer NSAIDs. Am J Gastroenterol 1993; 88:1318-1323. patients beyond the “clinical experience”. 19. Vasseur PB, Johnson AL, Budsberg SC, Lincoln JD, Toombs JP, Whitehair JG, Lentz EL. Randomized, controlled trial of the efficacy of carprofen, a nonsteroidal anti-inflammatory drug, in the treatment of osteoarthritis in dogs. J Am Vet Med Assoc 1995; 206:807-811. 20. Budsberg SC, Johnston SA, Schwarz PD, DeCamp CE, Claxton R. Efficacy of etodolac for the treatment of osteoarthritis of the hip REFERENCES joints in dogs. J Am Vet Med Assoc 1999; 214:206-210. 1. Felson DT. Weight and osteoarthritis. Am J Clin Nutr 1996; 21. Brooks PM, Day RO. Nonsteroidal antiinfllammatory drugs- 63(Suppl):430S-432S. differences and similarities. N Engl J Med 1991; 324:1716-1725. 2. Oliveria SA, Felson DT, Cirillo PA, Reed JI, Walker AM. Body 22. Dawson W, Boot JR, Harvey J, Walker JR. The pharmacology of weight, body mass index, and incident symptomatic osteoarthritis of benoxaprofen with particular to effects on lipoxygenase product the hand, hip, and knee. Epidemiology 1999; 10:161-166. formation. Eur J Rheumatol Inflamm 1982; 5:61-68. 3. Felson DT, Zhang Y, Anthony JM, Naimark A, Anderson JJ. Weight 23. Vane JR, Botting RM. The mode of action of anti-inflammatory loss reduces the risk for symptomatic knee osteoarthritis in women. drugs. Postgrad Med J 1990; 66 (suppl):S2-17. The Framingham Study. Ann Intern Med 1992; 116:535-539. 24. Bjorkman D. Nonsteroidal anti-inflammatory drug-associated 4. Toda Y, Toda T, Takemura S, Wada T, Morimoto T, Ogawa R. toxicity of the liver, lower gastrointestinal tract, and esophagus. Am J Change in body fat, but not body weight or metabolic correlates of Med 1998; 105:17S-21S. obesity, is related to symptomatic relief of obese patients with knee 25. Manicourt DH, Druetz-Van Egeren A, Haazen L, Nagant de osteoarthritis after a weight control program. J Rheumatol 1998; Deuxchaisnes C. Effects of tenoxicam and aspirin on the metabolism 25:2181-2186. of proteoglycans and hyaluronan in normal and osteoarthritic human 5. Impellizeri JA, Tetrick MA, Muir P. Effect of weight reduction on articular cartilage. Br J Pharmacol 1994; 113:1113-1120. clinical signs of lameness in dogs with hip osteoarthritis. J Am Vet 26. Srinivas GR, Chichester CO, Barrach HJ, Matoney AL. Effects of Med Assoc 2000; 216:1089-1091. certain antiarthritic agents on the synthesis of type II collagen and 6. LaFlamme DP, Kuhlman G, Lawler DF, et al. Obesity management in glycosaminoglycans in rat chondrosarcoma cultures. Agents Actions dogs. Vet Clin Nutr 1994; 1:59-65. 1994; 41:193-199. 7. Kovar PA, Allegrante JP, MacKenzie CR, Peterson MG, Gutin B, 27. Bassleer C, Magotteaux J, Geenen V, Malaise M. Effects of Charlson ME. Supervised fitness walking in patients with meloxicam compared to acetylsalicylic acid in human articular osteoarthritis of the knee. A randomized, controlled trial. Ann Intern chondrocytes. Pharmacology 1997; 54:49-56. Med 1992; 116:529-534. 28. Wang B, Chen MZ. Effects of indomethacin on secretory function of 8. Ferrell BA, Josephson KR, Pollan AM, Loy S, Ferrell BR. A synoviocytes from adjuvant arthritis rats. Int J Tissue React 1998; randomized trial of walking versus physical methods for chronic pain 20:91-94. management. Aging (Milano) 1997; 9:99-105. 29. Gosh P, Smith M, Wells C. Second line agents in osteoarthritis. In: 9. Rogind H, Bibow-Nielsen B, Jensen B, Moller HC, Frimodt-Moller Dixon JS and Furst DE, Eds. Second Line Agents in the Treatment of H, Bliddal H. The effects of a physical training program on patients Rheumatic Diseases. Marcel Dekker, New York, 1992; 363. with osteoarthritis of the knees. Arch Phys Med Rehabil 1998; 30. Setnikar I, Giachetti C, Zanolo G. Absorption, distribution and 79:1421-1427. excretion of radioactivity after a single intravenous or oral 10. O’Reilly SC, Muir KR, Doherty M. Effectiveness of home exercise on administration of [14C] glucosamine to the rat. Pharmatherapeutica pain and disability from osteoarthritis of the knee: a randomized 1984; 3:538-550. controlled trial. Ann Rheum Dis 1999; 58:15-19. 31. Setnikar I, Giacchetti C, Zanolo G. Pharmacokinetics of 11. Minor MA. Exercise in the treatment of osteoarthritis. Rheum Dis glucosamine in the dog and in man. Arzneimittelforschung 1986; Clin North Am 1999; 25:397-415. 36:729-735.

Clinical Perspectives on Canine Joint Disease (TNAVC 2001) 36 32. Conte A, Volpi N, Palmieri L, Bahous I, Ronca G. Biochemical and pharmacokinetic aspects of oral treatment with chondroitin sulfate. Arzneimittelforschung 1995; 45:918-925. 33. Hulse DS, Hart D, Slatter M, Beal BS. The effect of Cosequin in cranial cruciate deficient and reconstructed stifle joints in dogs, in Proceedings. Veterinary Orthopedic Society 25th Annual Conference, Snowmass, CO, February, 1998. (abst) p 68. 34. Canapp SO Jr, McLaughlin RM Jr, Hoskinson JJ, Roush JK, Butine MD. Scintigraphic evaluation of dogs with acute synovitis after treatment with glucosamine hydrochloride and chondroitin sulfate. Am J Vet Res 1999; 60:1552-1557. 35. Lust G, Williams AJ, Burton-Wurster N, Beck KA, Rubin G. Effects of intramuscular administration of glycosaminoglycan polysulfates on signs of incipient hip dysplasia in growing pups. Am J Vet Res 1992; 53:1836-1843. 36. de Haan JJ, Goring RL, Beale BS. Evaluation of polysulfated glycosaminoglycan for the treatment of hip dysplasia in dogs. Vet Surg 1994; 23:177-181. 37. Hannan N, Ghosh P, Bellenger C, Taylor T. Systemic administration of glycosaminoglycan polysulphate (arteparon) provides partial protection of articular cartilage from damage produced by meniscectomy in the canine. J Orthop Res 1987; 5:47-59. 38. Yovich JV, Trotter GW, McIlwraith CW, Norrdin RW. Effects of polysulfated glycosaminoglycan on chemical and physical defects in equine articular cartilage. Am J Vet Res 1987; 48:1407-1414. 39. Smith GN Jr, Myers SL, Brandt KD, Mickler EA. Effect of intraarticular hyaluronan injection in experimental canine osteoarthritis. Arthritis Rheum 1998; 41:976-985. 40. Smith MM, Ghosh P, Numata Y, Bansal MK. The effects of orally administered calcium pentosan polysulfate on inflammation and cartilage degradation produced in rabbit joints by intraarticular injection of a hyaluronate-polylysine complex. Arthritis Rheum 1994; 37:125-136. 41. Ghosh P. The pathobiology of osteoarthritis and the rationale for the use of pentosan polysulfate for its treatment. Semin Arthritis Rheum 1999; 28:211-267. 42. Barcelo HA, Wiemeyer JC, Sagasta CL, Macias M, Barreira JC. Effect of S-adenosylmethionine on experimental osteoarthritis in rabbits. Am J Med 1987 Nov 20; 83:55-59. 43. Kalbhen DA, Jansen G. [Pharmacologic studies on the antidegenerative effect of ademetionine in experimental arthritis in animals]. Arzneimittelforschung 1990; 40:1017-1021. 44. de Bri E, Lei W, Svensson O, Chowdhury M, Moak SA, Greenwald RA. Effect of an inhibitor of matrix metalloproteinases on spontaneous osteoarthritis in guinea pigs. Adv Dent Res 1998; 12:82-85. 45. Shlopov BV, Smith GN Jr, Cole AA, Hasty KA. Differential patterns of response to doxycycline and transforming growth factor beta1 in the down-regulation of collagenases in osteoarthritic and normal human chondrocytes. Arthritis Rheum 1999; 42:719-727. 46. Rosenstein ED. Topical agents in the treatment of rheumatic disorders. Rheum Dis Clin North Am 1999; 25:899-918. 47. Volker D, Fitzgerald P, Major G, et al. Efficacy of fish oil concentrate in the treatment of rheumatoid arthritis. J Rheumatol 2000; 27:2343- 2346. 48. Kearns RJ, Hayek MG, Turek JJ, Meydani M, Burr JR, Greene RJ, Marshall CA, Adams SM, Borgert RC, Reinhart GA. Effect of age, breed and dietary omega-6 (n-6): omega-3 (n-3) fatty acid ratio on immune function, eicosanoid production, and lipid peroxidation in young and aged dogs. Vet Immunol Immunopathol 1999; 69:165-83.

37 Clinical Perspectives on Canine Joint Disease (TNAVC 2001)

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Check box next to proceedings requested.

❑ Current Research in Canine Dermatology; Proceedings from a Symposium at the Fourth World Congress of Veterinary Dermatology, San Francisco, California, USA, 2000.

❑ Feline Clinical Nutrition Symposium; Proceedings from a Pre-Congress Symposium held at the World Congress 2000 of the World Small Animal Veterinary Association, Amsterdam, The Netherlands, 2000.

❑ Articular Cartilage and Joint Health; Proceedings from a Symposium at the Veterinary Orthopedic Society 27th Annual Conference, Val d’ Isere, France, 2000.

❑ Management of Feline Chronic Renal Failure; Presented at The North American Veterinary Conference, 2000.

❑ Recent Advances in Clinical Management of Diabetes Mellitus; Presented at the North American Veterinary Conference, 1999.

❑ Iams Clinical Nutrition Symposium; Proceedings from a Pre-Congress Symposium held at the XXIII Congress of the World Small Animal Veterinary Association, Buenos Aires, Argentina, 1998.

❑ Canine and Feline Nutritional Immunology; Presented at the 16th Annual Veterinary Medical Forum of ACVIM, 1998.

❑ New Concepts in Management of Renal Failure; Presented at the North American Veterinary Conference, 1998.

❑ Canine Reproductive Health; Presented at the North American Veterinary Conference, 1998.

❑ Canine Skeletal Development & Soundness; Presented at the North American Veterinary Conference, 1998.

❑ Gastrointestinal Health Symposium; Proceedings from a Pre-Congress Symposium held at the XXII Congress of the World Small Animal Veterinary Association, Birmingham, United Kingdom, 1997.

❑ Canine and Feline Geriatric Nutrition; Presented at the 15th Annual Veterinary Medical Forum of ACVIM, 1997.

❑ Managing Canine Reproduction; Presented at the 15th Annual Veterinary Medical Forum of ACVIM, 1997.

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