Treatment with Cosequin of Bilateral Coxofemoral Osteoarthritis in a Great Dane

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                                                                                   The Nutramax/Cosequin®
                                                                                   CASE byCASE
                                                                                   Student Competition
                                                                                      winning entry

 Treatment with Cosequin®
 of Bilateral Coxofemoral
 Osteoarthritis in a Great Dane
                                                                                              Oklahoma State University
                                                                                              Allison R. Hoffman, DVM
  This article represents the second of two winning entries in the Nutramax/Cosequin®
  Case by Case Student Competition. Dr. Hoffman was a senior student at Oklahoma
  State University when she wrote this case study. She is currently affiliated with Cali-
  fornia Eye Clinic for Animals, Tustin, California.

   Osteoarthritis (OA), the most             modifying agents; or a combina-                the progression of OA while pro-
common cause of degenerative                 tion of both. The most commonly                viding some symptomatic relief.
joint disease (DJD) in dogs, is a            used antiinflammatory agents for                  The first substance that over-
chronic, progressive, noninfectious          treating OA are NSAIDs. Al-                    came these shortcomings was Ade-
joint disorder that leads to degen-          though NSAIDs are effective in                 quan® Canine (Luitpold Pharma-
eration of articular cartilage and           reducing pain, these agents can re-            ceuticals, Shirley, NY). Adequan®,
proliferative changes. Damage to             sult in unwanted side effects such             an injectable polysulfated gly-
articular cartilage may result from          as gastrointestinal upset, hepato-             cosaminoglycan (PSGAG), 10 has
abnormal stresses that disrupt the           cellular toxicosis, renal disease,             been shown to positively affect the
normal articular surface, in turn            and occasionally death.2–4 In addi-            cartilage degradation associated
leading to joint instability. Conse-         tion, the newer cyclooxygenase-2               with OA. 10,11 Early research has
quently, the normal wear pattern             inhibitors have been associated                shown that very young, growing
as well as the turnover of articular         with side effects.3 Dose-depend-               dogs predisposed to hip dysplasia
matrix are accelerated.1 This process        ent, nonsteroidal therapy can also             treated with this PSGAG had bet-
is also accelerated by cytokines and         result in a decrease in the gly-               ter hip conformation than did
prostaglandins released by synovial          cosaminoglycan content in the                  control dogs.12 The drawback to
cells into the joint. As a result, the       cartilage, causing OA to worsen                Adequan® use is that it must be
joint capsule thickens and periar-           over time.5–8 The current rationale            given by injection. Because many
ticular osteophytes form in an ef-           is not to use NSAIDs continually               owners are unable to comply with
fort to improve joint stability.             unless they are needed to control              this route of administration, re-
                                             inflammation associated with per-              search has focused on the use of
OSTEOARTHRITIS TREATMENT                     sistent pain.9 The shortcomings of             oral products.
  Current therapy for sympto-                NSAIDs have encouraged research                   The oral product most com-
matic treatment of OA in dogs in-            efforts toward safe, disease-modi-             monly used to treat cartilage-relat-
cludes the use of antiinflammatory           fying substances that can be used              ed problems in veterinary medi-
medications; slow-acting, disease-           long term and can possibly alter               cine is Cosequin ® (Nutramax
Compendium October 2001                                                                                                                        Small Animal/Exotics 889

 Laboratories, Edgewood, MD).                          which is found in the structural                                    cartilage breakdown. Low-molecu-
 Cosequin® is a patented nutraceuti-                   matrix of joints. Glucosamine is not                                lar-weight chondroitin sulfate has
 cal combination of glucosamine                        a glycosaminoglycan but an amino                                    been shown to be efficacious in
 hydrochloride, low-molecular-                         sugar that has shown bioavailability                                treating OA in humans.25 Human
 weight chondroitin sulfate, and                       in dogs.21 Its primary biologic role                                trials using low-molecular-weight
 manganese ascorbate. Some practi-                     seems to be its ability to stimulate                                chondroitin sulfate show a carry-
 tioners recommend combining                           chondrocytes to produce gly-                                        over effect of up to 3 months after
 modalities by starting with PSGAG                     cosaminoglycans. 14 Glucosamine                                     cessation of therapy.26 This is im-
 injections then switching to Cose-                    does not have any effect on inhibi-                                 portant because it may take up to
 quin® for long-term therapy.10                        tion of proteases or their degradato-                               3 months for signs to return when
    In my opinion, the use of oral                     ry components to the cartilage ma-                                  therapy is stopped or medication
 nutraceuticals is gaining in popu-                    trix. Glucosamine has two main                                      changed. In two human trials,26,27
 larity. Much of the early research                    salts, which are available in hy-                                   chondroitin sulfate was shown to
 associated with their use has been                    drochloride and sulfate forms. The                                  slow the progression of OA.
 subjective (e.g., positive feedback                   hydrochloride form seems to deliver                                 Chondroitin sulfate also has an
 from owners). However, controlled                     more bioavailable glucosamine than                                  antiinflammatory action similar to
 experimental data as well as clini-                   does the sulfate form.22 To date, vet-                              that of NSAIDs, possibly because
 cal data on mechanism of action,                      erinary research has evaluated only                                 of its mechanism of action.27
 efficacy, and safety in animals have                  the hydrochloride salt in combina-                                     Glucosamine and chondroitin
 been reported recently.1,13–20                        tion with low-molecular-weight                                      sulfate have different mechanisms
                                                       chondroitin sulfate.                                                of action, which are evident when
 NUTRACEUTICAL                                            Chondroitin sulfate (whether                                     comparative studies are evaluat-
 COMPONENTS                                            absorbed intact or broken into                                      ed. 28,29 The combination of glu-
    It is important to remember that                   constituents) may also provide for                                  cosamine and chondroitin sulfate
 the first major biochemical change                    the formation of a healthy joint                                    used in the study presented here
 that occurs in cartilage disease and                  matrix. Chondroitin sulfate is the                                  was thought to protect the carti-
 DJD is the loss of proteoglycans.10                   most common glycosaminoglycan                                       lage matrix as well as slow the pro-
 Therefore, based on their compo-                      found in cartilage and has also                                     gression of arthritic changes, as
 nents (e.g., glucosamine–chon-                        shown bioavailability in dogs when                                  shown in an animal instability
 droitin sulfate–manganese combi-                      given in a pure form.23 The molec-                                  model of DJD. 14 Because of its
 nations), nutraceuticals may                          ular weight of the chondroitin sul-                                 glucosamine, chondroitin sulfate,
 theoretically have some beneficial                    fate has an effect on its bioavail-                                 and manganese ascorbate compo-
 effects in small animals. These sub-                  ability. 24 The primary role of                                     nents, Cosequin ® is believed to
 strates are the backbone needed for                   chondroitin sulfate is to inhibit                                   provide the raw materials essential
 the formation of proteoglycan,                        degradatory enzymes that lead to                                    for synovial fluid synthesis and the

                                Chondrocytes and other
                                connective tissue cells
                                                                                                                           Hyaluronic acid
                                                                                                                           (50% Glucosamine)
                                                              se                                                             the backbone of
                                                     +Mangane                                                                 proteoglycans
       Glucose          Glucosamine                   +Mang
                                                             anese                                      Core protein
                                                            +Sulfa           GAGs
                                                                   te                                                      Link protein                Proteoglycan
     Chondroitin
         sulfate   Zinc, manganese,   Stimulates                                                                                                    Hyaluronic
                       vitamin C                                otein                                                                                  acid
                                                       d link pr
                                               +Core an
                                                                                    }
                                                                                     }

   Amino acids             Procollagen
                                                                                      }

                                                                                                  Keratin
                                                                                                  sulfates
                                                                                    Chondroitin                 Other
                                                                                     sulfates                saccharides
                                          Copper, iron, vitamin C, silicon

                                                                                Glycosaminoglycans (GAGs)                                            Core
                                                                                                                                                    protein
                         COLLAGEN

                                                                                                                                                     Link
                                                                                                                                                    protein

 FIGURE 1—Mechanism of action of Cosequin®.
890 Small Animal/Exotics                                                                             Compendium October 2001

 complete cartilage matrix, includ-                                                        exercises, and measurements of
 ing collagen, hyaluronic acid, and                                                        thigh circumference. Quantitative
 glycosaminoglycans (Figure 1).                                                            evaluations included state-of-the-
                                                                                           art force-plate technology (piezo-
 CASE PRESENTATION                                                                         electric quartz-crystal type) to de-
   A 1-year-old, 51-kg, spayed Great                                                       termine if there was improved
 Dane was presented to the Boren                                                           joint function and analyze how
 Veterinary Medical Teaching Hos-                                                          these data correlated with the
 pital at Oklahoma State University                                                        qualitative data.
 on October 20, 1998, with a                                                                  During the 6-month evalua-
 shortened limb stride bilaterally,                                                        tion period, there was a decrease
 quadriceps fibrosis, an intermittent                                                      in the dog’s lameness scores
 “bunny-hop” gait, and hyperexten-                                                         (Table 1). Initial lameness scores
 sion of the tarsi. The patient                                                            were established using the fol-
 demonstrated severe loss of hip                                                           lowing criteria:
 range of motion and became ag-
 gressive on palpation of the cox-
                                          FIGURE 2—Ventrodorsal radiograph of
                                                                                           • Grade I—Subtle and inconsis-
 ofemoral joints. No other abnor-         the pelvis obtained during the initial patient     tent lameness not apparent at a
 malities were observed on history,       evaluation revealed good congruity of              walk and not consistently iden-
 physical examination, complete           both coxofemoral joints, a mild degree of          tified at a trot
 blood count, or biochemical analy-       periarticular osteophytosis along the cranial
 sis. Radiography revealed good
                                          borders of both acetabula, and underlying        • Grade II—Consistent and
                                          subchondral sclerosis. The femoral heads
 joint congruity, bilateral periarticu-   have no such osteophytosis or subchondral
                                                                                             mild lameness at a trot
 lar osteophytosis, and a mild de-        sclerosis.
                                                                                           • Grade III—Consistent mod-
 gree of bilateral subchondral scle-                                                         erate lameness at a walk
 rosis (Figure 2).                        during treatment with the nu-
                                          traceutical. This approach could              • Grade IV—Severe, non–
 TREATMENT AND                            then be used as a standard by which             weight-bearing lameness
 CLINICAL COURSE                          other patients with DJD
    A twofold hypothesis was made.        could be evaluated,         TABLE 1. Lameness Scores
 First, it was thought that the com-      whether untreated or
                                                                      During the Treatment Period
 bination of glucosamine, chon-           treated with a nutraceu-
 droitin sulfate, and manganese           tical or pharmaceutical.     Time Period                         Grade
 ascorbate would slow the progres-           Qualitative evaluations
 sion of DJD. Secondly, it was hy-        at 3 weeks, 4 months,        Initial evaluation                   III
 pothesized that treatment with a         and 6 months after the       3-week follow-up                     III
 nutraceutical would show objective       initial examination in-      4-month follow-up                     II
 evidence of weight transfer from         cluded lameness scores,
 the forelimbs to the hindlimbs, in-      hindlimb goniometry          6-month follow-up                    I/II
 dicating improved coxofemoral            using range-of-motion
 joint function as demonstrated by
 force-plate analysis.                     TABLE 2. Thigh Circumference Measurements
    The patient was started on Cose-       During the Treatment Period
 quin® DS at a dose of two capsules
 in the morning and one in the              Time Period                          Right (inches)            Left (inches)
 evening. Each tablet contains glu-
 cosamine (500 mg), sodium chon-            Initial evaluation                       15.75                     16
 droitin sulfate (400 mg), ascorbate        3-week follow-up                         15.75                     16
 (66 mg), and manganese (10 mg).            4-month follow-up                        16.75                    17.25
 The dog required several reevalua-         6-month follow-up                          17                     17.5
 tions over time; therefore, a quanti-      Total increase                            1.25                     1.5
 tative and qualitative method was
 designed to evaluate the patient
Compendium October 2001                                                                                            Small Animal/Exotics 891

  TABLE 3. Hindlimb Goniometry Evaluation

   Time Period                  Right Extension            Right Abduction                   Left Extension            Left Abduction
   Initial evaluation                 90˚                          40˚                            70˚                         60˚
   3-week follow-up                   90˚                          40˚                            80˚                         60˚
   4-month follow-up                  120˚                         50˚                            90˚                         70˚
   6-month follow-up                  130˚                         90˚                           110˚                         75˚
   Net increase                       40˚                          50˚                            40˚                         15˚

 The patient initially presented with           Radiographs obtained 6 months                      the 6-month follow-up, the dog
 grade III lameness. On the final            after the initial evaluation revealed                 showed pronounced clinical im-
 evaluation, the dog tested at lame-         that the OA was still present, as                     provement with Cosequin® treat-
 ness grade I/II.                            were periarticular osteophytes and                    ment over the 6-month period
   Thigh circumference was also as-          subchondral sclerosis (Figure 5).                     with no side effects. This improve-
 sessed. With the dog in a standing                                                                ment was assessed qualitatively by
 position, thigh circumference was           DISCUSSION                                            a decrease in lameness score, a bi-
 measured high in the flank region at           This is the first known published                  lateral increase in thigh circumfer-
 the level of the ischiatic tuberosity.      clinical evaluation regarding the use                 ence, and a bilateral goniometric
 The measuring tape was kept paral-          of an oral nutraceutical in a young                   increase. Final analysis of the
 lel to the ground. There was a 1.25-        animal with radiographically evi-                     force-plate graphs revealed an in-
 inch increase in right thigh circum-        dent hip dysplasia and using the de-                  crease in the vertical force applied
 ference and a 1.5-inch increase in          fined parameters for
 left thigh circumference during the         qualitative-quantitative         500

 treatment period (Table 2).                 analysis. Traditionally,                                           Force in a plane perpendicular
                                                                                                                to direction of movement
    Hindlimb goniometry using                these compounds have                                               Parallel force
 range-of-motion exercises was per-          been used in older ani-          400
                                                                                                                Vertical force

 formed during the testing period.           mals with established
 During the final evaluation, go-            disease or as a preventive
 niometry revealed a 40˚ increase for        measure in predisposed
 both the right and left hindlimb ex-        dogs.10 In a retrospective       300

 tensions. Increases for right and left      survey, 3000 veterinari-
 hindlimb abduction were 50˚ and             ans who evaluated thou-
                                                                                 Force (N)

 15˚, respectively (Table 3).                sands of dogs (96% of
                                                                              200
    Evaluation of Cosequin® efficacy         which were older than 5
 also involved trotting the patient          years of age) concluded
 across a force plate. Four trials for       that Cosequin® alleviat-
 the right and left forelimbs and            ed the pain and discom-          100
 hindlimbs were conducted during             fort of OA with less than
 the four evaluations, generating 64         2% of the animals show-
 graphs (Figure 3). Data generated           ing side effects.30
                                                                                0
 by the graphs indicated an upward              The study presented
 slope, demonstrating an overall in-         here evaluated a young
 crease in hindlimb loading by a             Great Dane with radi-
 44-N average or an 11-lb differ-            ographic and clinical           -100
 ence for the treatment period (Fig-         signs of hip dysplasia               0  0.5 1.0  1.5  2.0  2.5   3.0      3.5      4.0    4.5       5.0
 ure 4). A significant increase was          with secondary OA                                     Time (seconds)
 detected using the r 2 analysis (co-        changes. Although the
 efficient of determination) with a          patient still had radi- FIGURE         3—Standard force-plate graph. The
                                                                         hindlimb vertical force detected by the force plate
 P value of less than .001.                  ographic OA changes at is shown as the second spike on the graph.
892 Small Animal/Exotics                                                                                                            Compendium October 2001

                                325 –
  Hindlimb vertical force (N)

                                300 –

                                275 –

                                250 –

                                225 –                                             r 2 = .42
                                                                                  P < .001
                                200 –

                                175 –
                                    –

                                         –

                                                    –

                                                              –

                                                                       –

                                                                                  –

                                                                                              –
                                     0   10         20       30        40         50          60
                                             Days between 4- and 6-month evaluations

 FIGURE 4—Analysis of force plate measurements yields
 a 44-N average increase in hindlimb loading during the
 treatment period.

 to the hindlimbs that was in fact                                          promote topical or
 transferred from the forelimbs, sug-                                       liquid products as
 gesting improved joint function.                                           having improved FIGURE 5—Ventrodorsal radiograph of the pelvis
    Veterinarians often prescribe oral                                      bioavailability, but obtained at the 6-month follow-up evaluation.
                                                                                                      Periarticular osteophytosis and subchondral sclerosis
 nutraceuticals alone or in combina-                                        there is no research were still evident with significant remodeling.
 tion with NSAIDs. When given                                               to document this
 this combined therapy, patients re-                                        claim. A recent study24
 ceive the benefits of quick pain re-                                       showed that some products contain             Dane treated in this case study re-
 lief and minimal side effects from                                         none of the label ingredients. In re-         sponded quickly to treatment and
 the NSAID as well as the safe, long-                                       sponse to these findings, the Arthri-         maintained improvement. Other
 term, disease-modifying potential                                          tis Foundation recommends using               dysplastic dogs treated for a 40-day
 provided by the nutraceutical. Hu-                                         caution when choosing products for            period with injectable low-molecu-
 man trials using the equivalent of                                         the treatment of OA.36                        lar-weight chondroitin sulfate have
 the test agent showed a decreased                                             Because this report evaluated              also shown clinical improvement.12
 dependence on NSAIDs. 31 This                                              only a single dog, it is impossible to        However, a large percentage of
 case study reported the efficacy of                                        assess whether the treatment slowed           young dogs with secondary OA
 an agent that has been used with                                           the progression of the OA disease             will improve over an 18-month
 good clinical results in both veteri-                                      process. There currently does not             period without clinical treatment.38
 nary and human medicine.13,19,20,31,32                                     exist a validated method to radi-             Therefore, further controlled stud-
 The same agent has also recently                                           ographically assess OA progression            ies should be completed in young
 been shown to palliate joint inflam-                                       in animals. It is also unknown                dogs to confirm or dismiss the re-
 mation and protect cartilage when                                          whether 6 months is enough time               sults found in this study.
 given prior to cartilage insult.13,33                                      to show significant change. Human                The knowledge base regarding
 This may result in the further use of                                      trials have used validating tech-             the use of oral nutraceuticals con-
 oral disease-modifying agents as                                           niques to show that the low-molec-            tinues to grow; however, much re-
 preventive agents.                                                         ular-weight chondroitin sulfate               mains unknown about their rele-
    Because oral nutraceuticals are                                         found in Cosequin® has slowed the             vance in veterinary medicine.
 not drug compounds, their purity,                                          progression of OA in knees and                Also, when evaluating slow-acting,
 molecular size, and efficacy can vary                                      hands.26,37 Experimental placebo-             disease-modifying agents, the out-
 greatly. Some compounds promoted                                           controlled trials in animal models            come measurements used to study
 as disease-modifying agents (e.g.,                                         of arthritis have also shown a carti-         faster-acting antiinflammatory
 Perna mussel supplements) cannot                                           lage protective effect of the same            agents may be inappropriate.
 be substantiated.34,35 Products that                                       studied combination.1,13,14,33                However, the combined qualita-
 make such claims (e.g., cures arthri-                                                                                    tive and quantitative evaluations
 tis, regenerates and rebuilds carti-                                       CONCLUSION                                    used in this study may be an ac-
 lage) should be considered as ques-                                           Osteoarthritis in young dogs is a          ceptable protocol in which to
 tionable. Some manufacturers                                               variable disease process. The Great           monitor patients with joint insta-
Compendium October 2001                                                                                               Small Animal/Exotics 893

 bility, regardless of the treatment                   Compend Contin Educ Pract Vet 16(4):           23. Conte A, Volpi N, Palmieri L: Bio-
                                                       501–506, 1994.                                     chemical and pharmacokinetic aspects
 selected.
                                                 12.   Lust G, Williams A, Burton-Wurster                 of oral treatment with chondroitin sul-
    At the 28-month follow-up eval-                    N, et al: Effects of intramuscular ad-             phate. Arzniemittelforschung 45(8):
 uation, the patient was reported to                   ministration of glycosaminoglycan                  918–925, 1995.
 be showing little or no clinical                      polysulfates on signs of incipient hip         24. Adebowale A, Cox D, Eddington N:
 signs of joint discomfort while con-                  dysplasia in growing pups. Am J Vet                Analysis of glucosamine and chon-
                                                       Res 53(10):1836–1843, 1992.
 tinuing treatment with Cosequin®.                                                                        droitin sulfate content in marketed
                                                 13.   Canapp SO, McLaughlin RM,                          products and the Caco-2 permeability
                                                       Hoskinson JJ, et al: Scintigraphic eval-           of chondroitin sulfate raw materials.
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