Therapeutics of Musculoskeletal Disease in the Horse

CLINICAL PHARMACOLOGY AND THERAPEUTICS

0749-0739 /99 $8.00 + .00

THERAPEUTICS OF MUSCULOSKELETAL DISEASE IN THE HORSE Cynthia Kollias-Baker, DVM, PhD

Veterinarians in equine practice treat numerous types of musculoskeletal disease daily. Therapy for these conditions is often multifactorial, involving rest, therapeutic shoeing, various types of physical therapy, and pharmacotherapy. This article focuses on the indications and appropriate use of therapeutic medications for musculoskeletal diseases. Because in-depth discussions regarding the causes and pathogeneses of these diseases are beyond the scope of this article, the reader is directed, where possible, to specific reviews on these topics. PHARMACOTHERAPV FOR INFECTIOUS DISEASES AFFECTING THE MUSCULOSKELETAL SYSTEM Botulism

The organism Clostridium botulinum, a gram-positive obligate anaerobe, produces an exotoxin that causes flaccid paralysis of skeletal muscles. Intoxication can occur from three sources: (1) ingestion of toxin preformed in a feed source, (2) absorption of the toxin through the gut wall following growth of C. botulism in the gastrointestinal system, and (3) systemic absorption of the toxin from a C. botulism-infected wound. There are several different toxin types, which are associated, to some extent, with different geographic locations. 17 All of the different botulism toxins act by blocking cholinergic nerve transmission. The severity of clinical signs of botulism depends on the amount of toxin absorbed. Most commonly, adult horses present with flaccid muscle paralysis without central nervous system involvement. The signs, however, can be mild with generalized weakness, or, in contrast, the animal may be found dead without displaying previous clinical signs. 17 From the California Veterinary Diagnostic Laboratory System, School of Veterinary Medicine, University of California, Davis, California

VETERINARY CLINICS OF NORTH AMERICA: EQUINE PRACTICE VOLUME 15 • NUMBER 3 • DECEMBER 1999

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Treatment

Horses suffering from mild cases of botulism may survive with only supportive care. The chances of survival, however, are greatly improved by the administration of polyvalent botulism antitoxin (200 mL for a foal and 500 mL for an adult horse administered intravenously [IV] or intramuscularly [IM] at a rate of 100-150 IU / mL). 64 Although the antitoxin is available commercially (Vet Dynamics, Templeton, CA), it is expensive. If wound botulism is suspected, debridement and treatment with sodium or potassium penicillin (22,000-44,000 IU/kg IV every 6 hours) is recommended.4 4 Complications of botulism toxicity can include aspiration pneumonia as a result of pharyngeal dysfunction, which may require broad-spectrum antibiotic therapy such as sodium or potassium penicillin (15,000-20,000 IU/kg IV or IM every 6 hours), gentamicin (6.6 mg/kg IM once a day or divided twice a day), or possibly m etronidazole (20-25 mg / kg orally [PO] every 12 hours).8 9• 31 Supportive therapy should include fluids, nutritional support, and nursing care to prevent decubital ulcers, impactions, and other complications associated with horses in prolonged recumbency.

Tetanus

The organism Clostridium tetani, a gram-positive obligate anaerobe, produces an exotoxin that causes spasticity and tetany of skeletal muscles. Intoxication is generally associated with a penetrating wound infected with C. tetani. By preventing the release of the inhibitory neurotransmitter glycine, the exotoxin blocks postsynaptic inhibition of spinal motor neurons. This blockade results in generalized muscle spasms and, eventually, tetany.4 3 Treatment

Prevention of C. tetani infections by tetanus toxoid immunization and proper wound care is the best approach. Once clinical signs of an infection are present, the prognosis for recovery is exceedingly poor. If treatment is attempted, the administration of tetanus antitoxin is appropriate. The recommended dose of antitoxin ranges from 10 to 220 IU /kg IV, IM, or subcutaneously every 3 to 5 days.4 3• 49 Because the antitoxin antibody does not cross the blood- brain barrier, it does not neutralize toxin already present in the central nervous system. Therefore, repeated high doses of the antitoxin are not warranted and are unnecessarily expensive.43 The administration of tetanus toxoid at a separate injection site is also recommended along with appropriate wound debridement. Sodium or potassium penicillin (22,000-44,000 IU/kg IV four times a day) is the antibiotic of choice, although tetracycline (6.6-11 mg/ kg IV twice a day) may be used in penicillin-allergic horses. 43 To help control muscle spasms, the horse should be kept in a darkened quiet stall, because sudden noises and other external stimulation can trigger seizures. Sedation with promazine (0.5-1 mg/ kg IM) or acepromazine maleate (0.04-0.1 mg/kg IM) two to four times a day may also be helpful. 43• 65 Short-acting muscle relaxants such as guaifenesin (up to 110 mg/kg of a 5% solution IV per package insert for Guailaxin; Fort Dodge Animal Health, Fort Dodge, IA) and diazepam (0.05-0.4 mg/kg IV) may terminate acute spasms, but their brief duration of effect limits their usefulness.43 Longer acting agents such as methocarbamol (10-20 mg / kg, IV three times a day) may be more efficacious for chronic therapy.43 Concurrent pain and pyrexia can be treated with nonsteroidal anti-inflammatory drugs (NSAIDs) such as

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flunixin meglumine (1.1 mg/kg IV, IM, or PO every 12 hours) or phenylbutazone (2--4 mg/ kg IV or PO every 12 hours ). 64 Finally, good nursing care to prevent decubital ulcers and to provide adequate nutrition and fluids is critical for longterm survival.

Muscle Abscesses

Horses occasionally develop sterile inflammatory reactions following intramuscular injections (e.g., annual immunizations) that usually resolve uneventfully. Rarely, suppurative myositis develops following intramuscular injections or puncture wounds. The most common organisms isolated from these abscesses are Staphylococcus spp., Streptococcus spp., and Corynebacterium pseudotuberculosis.38 A severe and life-threatening disease can occur when Clostridium spp. infect injection sites or puncture wounds. In addition to C. botulinum and C. tetani, as discussed above, Clostridium septicum, Clostridium perfringens, Clostridium novyi, Clostridium sordelli, and Clostridiu,n chavoei have all been associated with abscess formation in horses. Clostridial abscesses are often associated with severe tissue necrosis, gas production, and signs of systemic toxemia. Occasionally, the animals are found dead in their stalls without displaying previous clinical signs. 38 Treatment

For sterile inflammatory reactions, warm-water hosing or warm compresses and NSAIDs may decrease pain and swelling. If these reactions persist, microscopic and ultrasound examinations and cultures of needle aspirates can help to differentiate sterile inflammatory reactions from infected abscesses. If infection is present, poultices and warm-water hosing may help to mature the abscess prior to establishing drainage. Systemic antibiotics may be necessary, but most infections with aerobic organisms resolve when proper drainage is established. Because gram-positive agents are the most common bacteria isolated from abscesses, empiric therapy with penicillin (sodium, potassium, or procaine salts) is often used. If an anaerobic infection is suspected, prompt drainage with surgical debridement and systemic antibiotics are indicated. Sodium or potassium penicillin (22,000--44,000 IU /kg IV every 6 hours) is the antibiotic of choice initially, although intramuscular procaine penicillin (20,000 JU /kg IM every 12 hours) may be used during what is usually a prolonged recovery period.38 Metronidazole (20-25 mg / kg PO every 12 hours) may also be indicated, especially if the initial response to penicillin is unsatisfactory."

Osteomyelitis

In the horse, infection is the most common cause of osteomyelitis, inflammation of bony tissue and the medullary canal. In foals, osteomyelitis frequently involves the growth plates and most commonly occurs secondary to hematogenous spread of bacteria. In contrast, in mature horses, osteomyelitis is usually associated with penetrating wounds, kicks, open fractures, or internal fixation of closed fractures. Vertebral osteomyelitis has occasionally been reported in mature horses secondary to Streptococcus equi, Bruce/la abortus, or Mycobacterium spp. (tuberculosis) infections and in foals secondary to Rhodococcus equi infections.

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Treatment

Osteomyelitis should be treated with aggressive antibiotic therapy. Biopsy or blood cultures should be taken prior to initiation of therapy, and antibiotic coverage should be broad spectrum pending culture results. An example of such therapy would be sodium or potassium penicillin (15,000-20,000 IU / kg IV or IM every 6 hours) or gentamicin (6.6 mg / kg IV or IM once a day or divided twice a day). 8• 3 1 Even with aggressive antibiotic therapy, osteomyelitis can be difficult to treat. The doctrine that held that a blood-bone barrier prevented antibiotics from distributing into bony tissue has been disproved. In fact, penicillins and aminoglycosides, the most common antibiotics used to treat osteomyelitis in horses, have been shown to readily distribute into the interstitial fluid of bony tissue. 26 More likely, osteomyelitis is often refractory to treatment because of the presence of surgical implants, necrotic tissue, or a sequestrum. In these refractory cases, successful treatment often requires not only antibiotic therapy but surgical intervention as well. The presence of a sequestrum, a fistulous tract, or abscessation in the subperiosteal space or within the medullary cavity is a strong indication for surgical exploration and debridement. Destabilization of the bone, which can have catastrophic consequences, needs to be considered and can significantly complicate treatment. 56 In addition to systemic antibiotic therapy and surgical debridement, the use of antibiotic-impregnated polymethyl methacrylate (PMMA) implants has recently proven to be useful in the prevention or treatment of osteomyelitis. 6" Antibiotics that have been used with PMMA implants include cefazolin, amikacin, gentamicin, and tobramycin. 39 The antibiotics are released from the PMMA implants by diffusion, and their concentrations in the surrounding tissues can be maintained above the minimum inhibitory concentrations for many common pathogens for close to 3 months. 3" In severe or chronic cases, a combination of systemic and local (PMMA implants) antibiotic therapy and surgical intervention may be necessary. Novel modes of drug delivery such as PMMA are discussed in another article in this issue.

PHARMACOTHERAPY FOR DEGENERATIVE DISEASES OF THE MUSCULOSKELETAL SYSTEM Osteoarthritis Osteoarthritis is one of several terms used for the many forms of degenerative joint disease commonly seen in athletic horses. Its classic presentation may include synovitis, capsulitis, cartilage damage, osteophyte fractures, meniscal tears, and desmitis of the intra-articular and periarticular ligaments.4° Clinically, horses may be mildly to severely lame with varying degrees of joint swelling and pain. Although the pathogenesis is not entirely understood, the condition is most commonly associated with horses in athletic careers. Usually, the more intense the athletic endeavor, the earlier in the horse's career it is that symptoms develop. Therefore, the term use trauma has been proposed to refer to the primary etiologic factor associated with osteoarthritis in horses.4° McI!wraith50 has written a concise but detailed review of the proposed pathogenesis and possible etiologies of osteoarthritis.

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Treatment

Because osteoarthritis is so common in performance horses, there is a great deal of interest in therapies to prevent and treat the condition. Traditional therapies include rest, therapeutic shoeing, physical therapy, and pharmacotherapy. In the past, the backbone of pharmacotherapy was intra-articular administration of corticosteroids and systemic administration of NSAIDs. In recent years, however, various biologic compounds that are constituents of normal healthy joint tissue have been used to treat inflamed arthritic joints in horses as well as other species. 10• 12• 13 The term slow-acting disease modifying osteoarthritis (SADMO) agents has been proposed for this class of drugs, but it remains to be determined whether this is an accurate description of their effects. 51 Slow-Acting Disease Modifying Osteoarthritis Agents

Although a number of these agents have clearly been demonstrated to be efficacious in the treatment of osteoarthritis, their mechanism(s) of action remains unclear. Several general mechanisms have been proposed. First, SADMO agents have been hypothesized to be a source of precursor compounds, which are in limited supply in the osteoarthritic joint. 3" Although theoretically appealing, there is little evidence to support this mechanism of action. A second theory, for which there is substantial evidence, is that these agents inhibit cartilage degradation. 45 Finally, some of these agents may act by stimulating the production of normal joint tissue components.77 SADMO agents can be divided into those that are administered parenterally and those that are administered orally. The parenteral agents such as hyaluronate (HA) and glycosaminoglycans (GAGs) have received US Food and Drug Administration approval for efficacy and safety. Partly for this reason, there is generally more information available on these agents than on their orally administered counterparts. Nevertheless, there has recently been an increase in the availability of nutritional supplements, or nutraceuticals, that claim to have beneficial effects on osteoarthritis. Many of these nutritional products contain various combinations of cartilage components and precursors. Although they are hypothesized to work like their parentally administered counterparts, there is a great deal of debate regarding their bioavailability. The efficacy of most of these products has not been well demonstrated in controlled studies, but there exists a great deal of anecdotal evidence for their effectiveness. Slow-Acting Disease Modifying Osteoarthritis Parenteral Agents: Hyaluronate

The linear polydisaccharide HA is a polyanionic nonsulfated GAG consisting of repeating disaccharide units of o-glucuronic acid and N-acetylglucosamine linked by (1,3) glycosidic bonds. These disaccharide units are then linked to form long unbranched chains.4(' In the joint, HA serves a number of important functions; for example, it confers viscoelasticity to the joint fluid, lubricates the synovial membrane and articular cartilage, and may influence the composition of synovial fluid by steric exclusion of active plasma components and leukocytes.40 HA is also a minor but important component of the articular cartilage matrix. The use of HA as a therapy for arthritic disease was first suggested by Balazs in 1942. 11 In the 1970s and 1980s, numerous studies were carried out evaluating the efficacy of intra-articular administration of HA as therapy for

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arthritis in human beings and horses. 5· 6 1• 8 1 In a recent study carried out in human patients suffering from osteoarthritis, five weekly treatments of intraarticular HA resulted in a significant improvement in knee function and relief of pain for up to 3 months. 80 Because horses commonly suffer from osteoarthritis in multiple joints, relying on intra-articular administration of HA can become laborious, time-consuming, and expensive. For this reason, the intravenous administration of HA to horses for the treatment of osteoarthritis has gained in favor in the last few years. Although its effects are not as well documented as those of intra-articular administration, there is evidence that intravenous administration of HA can be effective. In one study carried out in 12 horses with experimentally created osteochondral chip fractures, intravenous HA administration decreased the severity of osteoarthritis compared with that in salinetreated controls.•• Altogether, the preponderance of evidence indicates that HA administered either intra-articularly or intravenously can be effective in the treatment of osteoarthritis in horses. Although HA appears to be efficacious in the treatment of osteoarthritis, the mechanism(s) by which it is effective remains to be determined. Some have hypothesized that HA acts by increasing the viscosity of synovial fluid." This theory of viscosupplementation derives from the observation that the viscosity of synovial fluid from arthritic joints is usually less than normal and that HA therapy is often associated with an increase in synovial fluid viscosity. 13• 59 There is also evidence, however, that HA has numerous anti-inflammatory properties in the joint. For example, HA h as been shown to inhibit granulocyte and macrophage chemotaxis, phagocytic activity, and lymphocyte migration and proliferationY· 19• 20• 28• 29• 34• 71 In addition, HA has been shown to decrease the concentration of inflammatory mediators such as prostaglandin E, and cyclic adenosine monophosphate in synovial fluid from human patients suffering from arthritis. 63 In contrast to those results, in one recent study, various HA products did not significantly inhibit collagenase activity in cultured equine synoviocytes collected from normal or inflamed joints.48 Nevertheless, it may be that antiinflammatory activities are the most significant mechanism by which HA is effective in the treatment of osteoarthritis. There are several HA products approved for veterinary use in the United States. Legend (Bayer Corporation, Pittsburgh, PA) is the only product approved for intravenous and intra-articular administration. The manufacturer recommends that the HA treatment (40 mg IV or 20 mg intra-articularly) be administered at weekly intervals for a total of three treatments and then repeated as needed. Hyalovet (Fort Dodge Animal Health, Fort Dodge, IA), Hylartin V (Luitpold Pharmaceuticals, Shirley, NY), and Hyvisc (Boehringer Ingelheim Vetmedica, St. Joseph, MO) are all approved for intra-articular administration at a recommended dose of 20 mg for small- to medium-sized joints. Treatments may be repeated as needed but not more often than once or twice a week. There is some controversy as to the effectiveness of high-versus low-molecular weight HA in the treatment of osteoarthritis. In general, proponents of the viscosupplementation theory of activity hold that the higher molecular weight products are more effective. 60 Others have suggested that the activity of HA is mediated via pharmacologic rather than physical effects and that the molecular weight of the HA is therefore not significant. 6 The results of one recent study, however, indicated that the smaller rather than the larger molecular weight products may actually be more effective.4 More study on the importance of the molecular weight of HA is needed. The range of the molecular weights of the veterinary HA products is quite wide. Hylartin V has the highest listed molecular weight at 3 million daltons. The mean reported molecular weights of Hyvisc and Hyalovet are 2 and 1 million daltons, respectively. Although Bayer does not

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list the molecular weight of the Legend product, it has been reported to be less than 0.5 million daltons. 48 Slow-Acting Disease Modifying Osteoarthritis Parenteral Agents: Polysulfated Glycosaminoglycans

Polysulfated GAGs (PSGAGs) are semisynthetic agents that are prepared by extracting GAGs, primarily chondroitin sulfates, from cartilage (commonly, bovine trachea) and then subjecting the GAGs to sulfate esterification (Adequan information packet, Luitpold Pharmaceuticals, Shirley, NY). Adequan is the only veterinary PSGAG product approved for use in the treatment of osteoarthritis in the United States. Numerous studies in the horse and other species have demonstrated that PSGAGs can be efficacious in the prevention or treatment of osteoarthritis. Early studies carried out in dogs demonstrated that PSGAGs dramatically improved the morphologic characteristics of cartilage compared with that in untreated controls using a joint instability model of osteoarthritis.74 Similar results were obtained in additional canine and rabbit studies. 2• 4 1 The results of numerous studies in horses have shown PSGAGs to be effective in the prevention and treatment of osteoarthritis. For example, intra-articular administration of PSGAGs was shown to prevent or decrease the severity of clinical signs in naturally occurring and chemically induced arthritis. 35 • 82 When the effects of PSGAGs in horses were evaluated using an articular cartilage defect model of osteoarthritis, the results of some studies showed PSGAGs to be effective in reducing the development of osteoarthritis, 14• 82 although others failed to show any significant difference between PSGAG-treated and untreated groups. 72 • 73 Although Adequan is approved for both intra-articular and intramuscular administration, there is less evidence as to the efficacy of intramuscular administration than that of intra-articular administration of PSGAGs. Nevertheless, Adequan is widely administered intramuscularly, and anecdotal reports of its efficacy via this route abound. There are a number of mechanisms by which PSGAGs are proposed to be effective in modifying the signs of osteoarthritis. First, PSGAGs have been shown to bind to macromolecules in the cartilage matrix and may thereby protect it from further damage. 21· 32• 42 Second, PSGAGs have also been shown to decrease the activity of various lysosomal enzymes associated with cartilage degradation. 3• 1° Finally, the results of some studies indicate that PSGAGs stimulate the production of HA and proteoglycans. 21 • 76 Although the results of many studies indicate that PSGAGs have positive anabolic effects in the joint, the results of others indicate that they may also increase the synthesis of agents such as fibronectin that are associated with degenerative changes in the joint. 22• 70 Thus, the mechanism(s) by which PSGAGs act and the degree to which they are effective in the treatment of osteoarthritis is still controversial. Slow-Acting Disease Modifying Osteoarthritis Oral Agents: Nutraceuticals

Most nutraceuticals sold as supplements for osteoarthritis contain combinations of cartilage components and precursor molecules such as chondroitin sulfates and glucosamine. The monosaccharide glucosamine, which is readily formed in the body as glucosamine-6-phosphate from glucose and glutamine, is a precursor for numerous compounds, including glycolipids, glycoproteins, and GAGs. There is some evidence that glucosamine may have pharmacologic activities that could be beneficial in the treatment of osteoarthritis. For example, in

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one in vitro study, glucosamine was show n to stimulate GAG, proteoglycan, and collagen synthesis by chondrocytes and fibroblasts.45 In addition, glucosamine may also have anti-inflammatory properties and may stimulate HA synthesis.45 • 67 Chondroitin sulfates, components of hyaline cartilage, are GAGs that are readily isolated from bovine trachea and nasal septum, shark skeletons, and other natural sources. Similar to glucosamine, chondroitin sulfates have been shown to inhibit histamine-induced inflammation and cartilage-degradative enzymes.57 In addition, there is some evidence that they can stimulate the synthesis of proteoglycan, GA Gs, and collagen. 15• 58 The primary controversy surrounding the use of orally administered SADMO agents is the question of their bioavailability, because it seem s unlikely that these complex molecules could escape enzymatic degradation in the gastrointestinal tract. The results of a few studies, however, do provide some evidence that these agents are absorbed from the gastrointestinal tract intact. For example, the results of one study, which used radiolabeled glucosamine, su ggest that up to 87% of the glucosamine is absorbed in the dog and in humans. 67 In addition, several studies have demonstrated that at least some portion, perhaps as much as 70%, of chondroitin sulfates are absorbed intact in dogs. 25• 52 Nevertheless, the results of these studies are far from definitive in demonstrating the bioavailability of these compounds, and additional work is needed in this area. The author could find few published studies evaluating the effects of nutraceutical products. In a prospective study of one p roduct in horses (Cosequin; Nutramax Laboratories, Baltimore, MD) which contains chondroitin sulfates, glucosamine, and other precursor products such as manganese, clinical signs of lameness caused by naturally occurring osteoarthritis were shown to be reduced.37 The report of this study, however, h as only been published in abstract form and has not been subject to peer review. In another study in horses using an acute chemically induced arthritis model, the same product failed to produce any significant improvement in lam eness p arameters as compared with those in untreated controls. 79 There are also several studies carried out in humans that provide some evidence that oral glucosamine decreases pain and increases function in arthritic joints. 24· 54 Although there are a lack of significant data demonstrating efficacy of these products, they are tremendously popular with lay people and are used quite commonly in spite of their considerable expense. Intra-Articular Corticosteroid Therapy for Osteoarthritis

Although the administration of corticosteroids intra-articularly has decreased with the advent of HA and PSGAG products, they are still commonly used and can be extremely effective therapy for osteoarthritis. Corticosteroids are powerful anti-inflammatory agents that suppress the immune response on almost all levels. 7· 47 Although they can be administered via any number of routes, including intramuscularly, intravenously, and orally, they are most commonly administered intra-articularly for treatment of osteoarthritis. Corticosteroids have been used in h orses since 1955 as treatment for various diseases in which inflammation is a primary component. 78 By the late 1960s, however, the negative side effects and consequences of long-term use of these agents began to become apparent. 55 Since that time, multiple studies have confirmed that these agents can have numerous negative effects on arthritic joints, including decreased proteoglycan synthesis, chondrocyte necrosis, and increased ossification of synovial soft tissue structures.23• 62 The results of these and others studies with similar findings led to a backlash against the use of intra-articular corticosteroids

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in equine medicine. More recent studies, however, have demonstrated both beneficial and detrimental effects of intra-articular corticosteroid therapy in humans and horses.' · 18• 30• 33 • 68 There are many variables that determine whether it is the beneficial or detrimental effects of corticosteroid therapy that predominate in any given clinical case. These variables include but are not limited to the specific corticosteroid administered, the dose and frequency of drug administration, and the presence or absence of osteochondral fragments. Methylprednisolone Acetate. In horses, methylprednisolone is the most common corticosteroid administered intra-articularly. The dose administered varies between 20 and 240 mg per joint (product insert for Depo-Medrol; Upjohn, Kalamazoo, Ml). Although it is still frequently used, the results of several studies indicate that methylprednisolone can cause negative effects in equine cartilage, including necrosis of chondrocytes and decreased proteoglycan content. 2J, 62 These studies, however, examined the effects of relatively high concentrations and frequent administrations of methylprednisolone on articular cartilage. For example, the dose and frequency of methylprednisolone that was used in the Chunekamrai et al study 23 (i.e., 120 mg per joint at weekly intervals for 8 weeks) is quite high compared with those of standard practice protocols. Betamethasone. The effects of intra-articular administration of betamethasone in horses have been examined in several studies. 27• 75 In contrast to methylprednisolone, the preponderance of evidence suggests that betamethasone does not detrimentally affect articular cartilage. The doses and frequency of betamethasone administered in these studies (e.g., 15.9 mg administered twice 2 weeks apart), however, more closely reflect doses used in practice. The more physiologically relevant administration protocols used in these studies may account in part for the lack of detrimental effects observed, but the possibility of drug-specific effects cannot be eliminated. Triamcinolone Acetonide. The effects of intra-articularly administered triamcinolone acetonide have been studied in children with naturally occurring chronic arthritis and in horses with arthritis secondary to experimentally created osteochondral chip fractures." 30• so The results of these studies indicate that triamcinolone acetonide can be an effective treatment for osteoarthritis and that it causes few side effects. In addition, in horses, there is evidence that triamcinolone acetonide may have chondroprotective effects.Jo For example, in the Frisbie et al study,J0 triamcinolone acetonide minimized the development of osteoarthritis secondary to osteochondral chip fractures. Interestingly, these positive effects of triamcinolone acetonide were observed whether it was administered into the affected joint or at a remote site. Once again, the dose and frequency of drug administration (12 mg administered twice 2 weeks apart) used in the study would be considered appropriate for clinical cases. Because of their potent effects and abuse potential, the use of intra-articularly administered corticosteroids in horses remains controversial. At this time, however, there is little scientific evidence to indicate that low to moderate doses administered infrequently have detrimental effects on articular cartilage. In fact, there is evidence that some agents such as triamcinolone acetonide may actually have a beneficial chondroprotective effect.Jo More studies are needed to determine how these agents can be used most effectively in the treatment of osteoarthritis in horses. Nonsteroidal Anti-Inflammatory Agent Therapy for Osteoarthritis

The NSAID phenylbutazone may well be more commonly administered to horses than any other drug. Other NSAIDs such as flunixin meglumine, ketoprofen, and naproxen are also frequently administered to horses for treatment of

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osteoarthritis and other inflammatory conditions. For a detailed review of the use of these agents in the horse, the reader is referred to the article on analgesia on page 705 in this issue.

INHERITED MUSCULOSKELETAL DISEASES Hyperkalemic Periodic Paralysis

Hyperkalemic periodic paralysis (HYPP) is a syndrome that has been characterized by increased muscle size and often intermittent episodes of muscle weakness, tremors, and, in severe cases, extreme paresis. It is a genetic disease of horses descended from the Quarter Horse sire Impressive. HYPP is inherited as an autosomal dominant trait. 53 The clinical signs of the disease result from a defect in the sodium channel, which results in a depolarization of resting muscle cells. 53 Episodes of HYPP can vary in severity from mild muscle fasciculations to extreme paresis. Other signs can include increased respiratory rate, stridor, sweating, pain, and prolapse of the third eyelid(s). As the name implies, during these episodes, serum potassium can increase dramatically up to 12 mEq/L as a result of the release of potassium from repetitively contracting muscles. 51 Most episodes resolve spontaneously, and the horse appears to suffer few lasting effects. 69 In severe cases, however, HYPP can cause serious cardiac arrhythmias occasionally resulting in death. For a detailed review of the pathogenesis of HYPP, the reader is referred to a report by Naylor. 53

Treatment

Mild episodes of HYPP often resolve without treatment, but severe attacks generally require therapy. Treatment during acute attacks is aimed at decreasing or antagonizing the effects of the hyperkalemia. Intravenous administration of potassium-free fluids can help to dilute serum potassium and increase renal potassium excretion. In addition, the translocation of potassium from the extracellular space into intracellular fluid can be enhanced by the administration of 5% dextrose (4.4-6.6 mL/kg IV) or sodium bicarbonate (1 mEq/kg IV [slowly]). 69 Alternatively, calcium gluconate (0.2-0.4 mL/kg of a 23°/c, solution diluted in 1-2 L of 5% dextrose IV [slowly]) can be administered. Finally, although phenytoin has been shown to prevent the skeletal muscle signs, it does not alter the hyperkalemia that can be life threatening. 16 Chronic therapy is aimed at preventing or minimizing the occurrence of future episodes. Dietary and stabling changes are extremely important in the long-term management of HYPP. The potassium content of the horse's diet should be decreased by reducing the amount of alfalfa hay fed, as high potassium intake has been implicated as a trigger for HYPP episodes. In addition, keeping the horse in a paddock or pasture is preferred to stall housing, as this allows the horse regular low-grade exercise. Sudden changes in temperature, diet, exercise, and other stressors should be avoided, as they may also trigger episodes. For cases that do not respond to these changes, acetazolamide (2.2 mg/kg PO every 8 to 12 hours), a carbonic anhydrase inhibitor diuretic, can significantly decrease the frequency and severity of episodes. 69

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SUMMARY

Therapeutic medications play a crucial role in the successful therapy of many musculoskeletal diseases that occur in horses. For example, appropriate antibiotic therapy is extremely important in the treatment of diseases caused by infections with microorganisms such as botulism, tetanus, osteomyelitis, and muscle abscesses. In addition, numerous prescription medications and nutritional supplements are available for the treatment of osteoarthritis in horses. Many of these agents currently on the market fall into a new class of drugs called SADMO agents. Unfortunately, the efficacy and mechanism(s) of action for many of these agents have not been well defined. There does exist a fair amount of data indicating that the parenterally administered compounds HA and PSGAGs, commonly used to treat osteoarthritis, can decrease the severity of clinical signs and perhaps slow the progression of disease. Although there are fewer data available to support the efficacy of orally administered SADMO agents, these compounds are used commonly by lay people as osteoarthritis therapies. Finally, pharmaceutical agents such as acetozolamide can play an important role in the management of the inherited HYPP condition in horses.

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