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Systematic review of the management of canine osteoarthritis
  1. R. O. Sandersoln, BSc1,
  2. C. Beata, DVM, DipECVBN2,
  3. R-M. Flipo, MD3,
  4. J-P. Genevois, DVM, PhD4,
  5. C. Macias, Ldo Vet, DSAS(Orth), MRCVS5,
  6. S. Tacke, DVM, PhD6,
  7. A. Vezzoni, DVM, DIPECVS7 and
  8. J. F. Innes, BVSc, PhD, CertVR, DSAS(orth), MRCVS1
  1. 1 Small Animal Teaching Hospital and Musculoskeletal Research Group, Faculty of Veterinary Science, University of Liverpool, Leahurst, Neston, Cheshire CH64 7TE
  2. 2 353a Boulevard Grignan, 83000 Toulon, France
  3. 3 Department of Rheumatology, University Hospital, Lille, France
  4. 4 Unité de Chirurgie/Anesthésiologie, Département des Animaux de Compagnie, Ecole Nationale Vétérinaire de Lyon, 1 Avenue Bourgelat, 69280 Marcy L'Etoile, France
  5. 5 Centro Veterinario de Referencia Bahia de Malaga, Parque Empresarial Laurotorre 25, Alhaurin de la Torre, 29130 Malaga, Spain
  6. 6 Klinikum Veterinärmedizin, Klinik für Kleintiere, Chirurgie, Anästhesiologie, Schmerztherapie, Operative Intensivmedizin, Justus-Liebig Universität Giessen, Frankfurter Strasse 108, 35392 Giessen, Germany
  7. 7 Clinica Veterinaria Vezzoni, via Massarotti 60/A, 26100 Cremona, Italy
  1. Correspondence to Professor Innes, e-mail: j.f.innes{at}liverpool.ac.uk

Abstract

This review assesses the evidence for the efficacy of therapies used in the management of osteoarthritis in dogs on the basis of papers published in peerreviewed journals in English between 1985 and July 2007. Sixty-eight papers were identified and evaluated. They considered four alternative therapies, one use of functional food, two intra-articular agents, six nutraceutical agents, 21 pharmacological agents, two physical therapies, three surgical techniques and two combinations of weight control. There was a high level of comfort (strong evidence) for the efficacy of carprofen, firocoxib and meloxicam, and a moderate level of comfort for the efficacy of etodolac in modifying the signs of osteoarthritis. There was a moderate level of comfort for the efficacy of glycosaminoglycan polysulphate, licofelone, elk velvet antler and a functional food containing green-lipped mussel for the modification of the structures involved in the disease. There was weak or no evidence in support of the use of doxycycline, electrostimulated acupuncture, extracorporeal shockwave therapy, gold wire acupuncture, hyaluronan, pentosan polysulphate, P54FP (extract of turmeric), tiaprofenic acid or tibial plateau levelling osteotomy.

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OSTEOARTHRITIS, also referred to as degenerative joint disease (DJD) or osteo arthrosis, is a disease process characterised by pain and lameness associated with pathological changes in the tissues of synovial joints, including the loss of articular cartilage. It has been suggested that 20 per cent of dogs over one year of age are affected by the progressive changes of osteo arthritis (Johnston 1997).

There are no known cures for the disease and it is often managed by combinations of therapy, for example, non-steroidal anti-inflammatory drugs (NSAIDs) (Serni and others 1999) and analgesics, nutraceuticals, functional foods, physical therapy and ‘alternative’ therapies such as acupuncture. Surgery has also been used, either to try to slow the progression of the disease or to replace the whole joint (Cook and Payne 1997). NSAIDs can be defined as acidic anti-inflammatory agents that inhibit the enzyme cyclooxygenase (COX), which catalyses the conversion of arachidonic acid to prostaglandins and thromboxane. There are several NSAIDs licensed for use in dogs in Europe and the USA. Recently, a new class of NSAIDs, the coxibs, has been developed, the action of which is highly selective against the isoenzyme COX-2.

The diversity of such treatments makes it difficult for practitioners to choose the most appropriate. Studies of the efficacy of such treatments have been published in many different journals, and there is therefore a need to review them systematically and consider them in the light of evidence-based (veterinary) medicine, that is, the ‘conscientious, explicit and judicious use of the current best evidence’ in making decisions about the care of individual animals (Cockcroft and Holmes 2003). To do this, it is necessary to collate all the information and evaluate it using set criteria.

The pharmacological and nutraceutical agents used to treat osteoarthritis are subdivided into those aimed at modifying the clinical signs and those aimed at modifying the structure of the joint (Hochberg and others 1997). Structure-modifying agents are defined as agents that are capable of delaying, stabilising or even repairing osteoarthritic lesions (Richette and Bardin 2004); so-called ‘symptom-modifying’ agents can be described as agents that do not affect the progression of the disease but help to alleviate the clinical signs, for example, the pain associated with it. Although technically animals cannot have ‘symptoms’, for the purpose of consistency with the human medical literature, the term ‘symptom modification’ will be used in this report to refer to those agents that might alleviate the clinical signs of osteoarthritis.

It is recognised that the placebo effect can be a significant factor in the assessment of chronic diseases such as osteoarthritis. In human medicine, using patient-based measures of outcome, studies have indicated that there is a sizeable placebo effect in the treatment of osteoarthritis (Clegg and others 2006). In dogs, there is limited evidence of a placebo effect when the outcome is assessed on the basis of the owner's or the veterinarian's opinion (Innes and others 2003). Improvements attributable to specific therapies can be considered positive only when compared with a placebo, because it is recognised that placebo effects can influence the outcome independently of the type of treatment (Turner and others 1994).

To the authors' knowledge, only one systematic review of the management of canine osteoarthritis has been published (Aragon and others 2007). However, it was restricted to pharmacological and nutraceutical treatments, whereas the current management of osteoarthritis may include several other approaches. The aim of this study is to collate all the relevant information to show which therapies have sufficient evidence to support their use, as well as which therapies appear to be of uncertain efficacy, and which therapies require further work. Studies of alternative therapies, functional foods, physical therapies, surgery and weight control have been included. The variations in the design of the studies have been taken into account, and they have been rated on the basis of their explicit identification of a primary measure of outcome, the type of outcomes measures used, and the controls on which the results were based. The results obtained from dogs used in experimental studies have been included in the review, although it is recognised that they do not provide the same level of evidence as randomised, controlled trials in a clinical setting.

Materials and methods

Three online databases, Medline, Scopus and Web of Knowledge, were selected to provide a broad cross-section of the literature. Disease terms used were ‘osteoarthritis,’ ‘osteoarthrosis,’ ‘DJD’ and ‘degenerative’. Species terms searched were ‘dog’ (inclusive of ‘dogs’) and ‘canine’. The disease terms and then the species terms, were combined by using Boolean operators, first in an ‘OR’ combination, and then the two subsequent results were combined in an ‘AND’ combination to give a search looking for a match of any one or more of the disease terms with any one or more of the species terms.

Inclusion criteria

The searches were limited to papers published in English after 1985. In addition, the Medline search was further limited to results indexed for ‘diet therapy’, ‘drug therapy’, ‘surgery’, ‘therapy’ and ‘veterinary’. Papers published in peer-reviewed journals that described techniques for the management, treatment or control of osteoarthritis by methods inclusive of alternative therapies, functional foods, intra-articular agents, nutraceuticals, pharmacotherapies (both symptom modifying and structure modifying), physical therapies, surgery and weight control were included.

For symptom-modifying agents, the evaluation was restricted to studies detailing their effects on functional outcomes measures of osteoarthritis, and excluded studies evaluating any other effects, for example, the biochemical effects of NSAIDs, such as changes in renal parameters. The literature identified was reviewed and evaluated by the following criteria.

Evaluation criteria

The evaluation criteria were as previously reported by Aragon and others (2007) with minor modifications and are detailed in Table 1. They were based on the ranking system for scientific data produced by the US Food and Drug Administration (FDA) (2007), which in turn is based on the Institute for Clinical Systems Improvement as adapted by the American Dietetic Association (Myers and others 2001) and designed to rate the strength of scientific evidence. For candidate structure-modifying agents only, data derived from experimental dogs were categorised as from studies of type III design.

In addition, papers were categorised on the following basis: whether or not they had identified a primary outcome variable; what type of primary outcome variable was used; and whether a placebo control or positive comparative control was used. For candidate symptom-modifying agents, an objective primary outcome measure, for example, a force platform, was graded more highly than a semi-objective or subjective measure, for example, a questionnaire completed by the owner or veterinarian, owing to the lack of robust validation and standardisation of such questionnaires. For candidate structure-modifying agents, a primary outcome measure of histological grading of the structure and integrity of cartilage was graded more highly than ‘surrogate’ outcome measures such as imaging or biochemical markers. The success of the treatment was judged on the basis of the primary outcome alone.

Because of the likelihood of placebo effects in therapeutic studies of osteoarthritis, it was decided that only studies comparing a treatment with a placebo would be classified as of high quality, and studies not including a placebo would be classified as of moderate quality. The rationale for rating placebo-controlled studies higher is that the presence of a treatment, independent of its type, may correlate with an improvement in perceived clinical signs. Improvements attributable to the type of treatment, rather than the presence of a treatment, can only be fully determined by comparison with a placebo control group (Turner and others 1994).

After it had been categorised into one of the above categories, each paper was evaluated in three ways, first, in terms of the design of the study, secondly in terms of its quality, and thirdly in terms of the collective strength of all the evidence for the treatment. All the papers were evaluated independently for their type of design, independently of their quality (Table 1), and their quality was then classified (Table 2).

The collective strength of the papers was assessed in terms of three factors: quantity, consistency, and relevance to disease risk reduction (RDRR). The quantity ratings were based on the number of studies completed and the number of animals in them, with a higher rating indicating a greater ability to generalise and extrapolate the results to the target population (Table 3). The consistency ratings were based on whether studies of the same therapy, conducted with similar or different study designs, reached similar conclusions (Table 4). The RDRR was a measure of how applicable the findings were on a physiological basis (Table 5).

The strength of the evidence provided by the studies was evaluated into four categories, defined in terms of how applicable the conclusions were to the target population. The more scientifically valid the results and the higher the level of comfort, the more likely the study was to be relevant to the target population (Table 6). ‘Level of comfort’ is the phrase used to convey the strength of evidence, as defined by the US FDA's Interim Evidence-based Ranking System for Scientific Data (FDA 2007).

Results

The literature searches were carried out in July 2007. Medline identified 522 references, Scopus identified 714 references and Web of Knowledge identified 1015 references. Many references were duplicated and 68 met the inclusion criteria (Table 7).

Categories and quality ratings of the papers

The 68 papers analysed the effects of four alternative therapies, one use of functional foods, two intra-articular agents, six nutraceutical agents, 21 pharmacological agents, two physical therapies, three surgical techniques and two combinations of weight control.

Alternative therapies Four studies (Hielm-Bjorkman and others 2001, Moreau and others 2004, Kapatkin and others 2006, Crook and others 2007) were identified, of which three were of design type I and high quality, and one was of design type III of moderate quality. Three of them were placebo controlled and they all identified their primary outcome variable. Their efficacy was assessed by the veterinarians and/or the owners of the dogs, and in the trials of elk velvet antler (Moreau and others 2004) and electrostimulated acupuncture (ESA) (Kapatkin and others 2006), force platform analysis was applied.

Functional foods One study (Bui and Bierer 2003) involved functional foods containing green-lipped mussel. The study was of design type I with a placebo control and semi-objective primary outcomes measure.

Intra-articular agents Five studies (Pelletier and others 1994, 1997, Smith and others 2001, 2005, Echigo and others 2006), all of design type III, investigated the use of the intra-articular agents interleukin-1 receptor antagonist and hyaluronan. One study was of low quality and the rest were of moderate quality. Two of the studies identified a primary outcome variable and four were placebo controlled. Three were assessed objectively and the others were assessed semi- objectively.

Nutraceuticals There were eight type I studies of nutraceutical agents including chondroitin sulphate-glucosamine-manganese glucosamine in combination with chondroitin sulphate, glycosylated undenatured type II collagen (UC-II), proanthozone, P54FP and special milk protein concentrate (SMPC) (Impellizeri and others 1998, Gingerich and Strobel 2003, Innes and others 2003, Deparle and others 2005, Dobenecker 2006, Pollard and others 2006, McCarthy and others 2007, Peal and others 2007). Four of them were categorised as of high quality, three of moderate quality, and one of low quality design. Most studies used subjective assessment and the others used objective or semi-objective assessment.

Pharmacological agents There were 40 studies of pharmacological agents as symptom-modifying agents, structure-modifying agents, or both (Altman and others 1989a, b, Howell and others 1991, Myers and others 1991, 1999, Rogachefsky and others 1993, Fernandes and others 1995, 1998, Vasseur and others 1995, Carney 1996, Read and others 1996, Yu and others 1996, Jovanovic and others 1997, Budsberg and others 1999, 2007, Manicourt and others 1999, Pelletier and others 1999, 2005, Smith and others 1999, Doig and others 2000, Innes and others 2000, Boileau and others 2002, Lipscomb and others 2002, Nell and others 2002, Hazewinkel and others 2003, Moreau and others 2003, 2006, 2007, Behets and others 2004, El Hajjaji and others 2004, Lajeunesse and others 2004, Pardy and others 2004, Peterson and Keefe 2004, Hanson and others 2006, Karsdal and others 2006, Mastbergen and others 2006, Pollmeier and others 2006, Ryan and others 2006, Brainard and others 2007, Mansa and others 2007).

Twenty-one of the studies considered symptom-modifying agents such as carprofen, celecoxib, deracoxib, etodolac, firocoxib, ketoprofen, meloxicam and low-dose prednisolone; 12 were of design type I and nine were of design type III. Seven were rated as high-quality studies and 14 of moderate quality; eight were placebo controlled, seven were positive controlled, two used untreated controls and four used no control. The results were assessed objectively in eight cases, semi-objectively in six cases and subjectively in seven cases.

Twenty-five of the studies considered candidate structure-modifying agents. Eight were of design type I and 17 were of design type III; 11 were of high quality and 14 were of moderate quality; and 16 of the 25 studies were placebo controlled, two were positive controlled and seven used untreated controls. The results were assessed objectively in 13 cases, semi-objectively in nine cases and subjectively in three cases.

Physical therapies Two studies (Dahlberg and others 2005, Mueller and others 2007) investigated the use of shockwave therapies; one was of design type I and the other was of design type III. Both were of moderate quality, using untreated controls, and were assessed semi-objectively.

Surgical management Three studies (van Valburg and others 2000, Conzemius and others 2003, Girling and others 2006) of design type III analysed the effect of surgical techniques. They were all of moderate quality, and used either untreated controls or no controls. Two of the studies identified a primary outcome variable that was assessed objectively.

Weight control Three studies (Kealy and others 2000, Mlacnik and others 2006, Smith and others 2006) investigated the value of weight control. One was of design type II and the others were of design type III. They were all of moderate quality, used either untreated controls or no controls, and only one identified a primary outcome variable; they were assessed semi-objectively.

Strength of evidence

The review shows that there were sufficient studies of high quality to provide strong evidence that carprofen, firocoxib and meloxicam were effective in moderating the clinical signs of osteoarthritis. The evidence for the effectiveness of etodolac was moderate.

There was moderate evidence for the effectiveness of the structuremodifying agents glycosaminoglycan polysulphate (GAGPS) and licofelone, and for the use of elk velvet antler and green-lipped mussel, with some likelihood that the results would be applicable to the whole population. However, further high-quality studies of these agents are required.

There was weak or no evidence that the use of doxycycline, ESA, extra corporeal shockwave therapy, gold wire acupuncture, hyaluronan, pentosan polysulphate, P54FP, tiaprofenic acid and tibial plateau-levelling o steo tomy had significant or physiologically meaningful effects in the management of canine osteoarthritis. The studies involving these agents were generally of poor quality with too few animals.

Discussion

Osteoarthritis is a common diagnosis in dogs in veterinary practice, and there is a broad range of licensed and candidate treatments available for the condition. This review shows that their efficacy varied, and that they had different outcomes in different trials, making it essential for veterinarians to be aware of the strength of the evidence for the efficacy of the different treatments in order to make an informed decision on what treatment to use.

The papers were graded according to whether they had identified their primary outcome variable, the nature of their assessment, and whether they had used a placebo or positive controls. This robust approach limited the number of studies rated as being of high quality and also probably reduced the apparent strength of the evidence provided by many studies. For example, the study of the efficacy of P54FP by Innes and others (2003) was considered to provide little evidence that it would have physiologically meaningful and achievable effects, whereas Aragon and others (2007) rated the results of the same paper more favourably.

This review was limited to trials published in peer-reviewed journals in English after 1985. It therefore had language bias and a focus on studies that had been submitted and accepted for publication. In addition, the search criteria were unlikely to have captured all the studies relating to the treatment of osteoarthritis in dogs. For example, some papers evaluating the efficacy of total joint replacement would not have been captured by the search criteria.

The evaluation criteria were amended to include experimental data and to consider the identification of primary outcome variables, the type of assessment and the type of control used. As a result, many papers that were rated as ‘high quality’ by Aragon and others (2007) were downgraded in the present review. The amended criteria emphasise the importance of high-quality studies and the need for future studies to be randomised and placebo controlled, to identify their primary outcome variable and to assess it objectively.

The evaluation of the papers identified in the search design of this review was potentially open to bias because it was not possible to blind the studies identified. To try to deal with this, set quality criteria were established against which each paper was graded. Not all the papers identified in the search provided statistical power data, and owing to the difficulties in retrospective power analysis, it was decided not to calculate this variable (Levine and Ensom 1998).

All forms of candidate therapy were considered, from traditional pharmacotherapy to alternative therapy, defined as any of the various systems of healing or treating disease not included in the traditional medical curricula taught in the USA and the UK (Anon 2007).

Forty of the studies considered the use of pharmacological agents. Owing to the wide range of agents, the number of studies per agent was often limited and this made assessment of consistency and RDRR difficult. The studies also varied in whether they used objective, semi objective or subjective assessments of the outcome variable, and their grading of quality was modified accordingly.

There were seven studies involving carprofen, of which one was classified as high quality and the others as moderate quality. Five were of design type I and two were of design type III. Objective and semi-objective assessments showed that the drug induced a significant improvement, and there was moderate evidence that the results could be extrapolated to the target population. The use of carprofen was supported by the largest number of studies.

The use of firocoxib, a NSAID of the coxib class, was considered in three studies, two of type I and one of type III; one was of high quality and two were of moderate quality. Subjective assessments showed that there were significant improvements in comparison with positive controls. Large numbers of dogs were used in the studies and the findings were considered relevant to the target population. The evidence is strong, but studies using placebo controls and objective assessments would be desirable.

There were five studies of meloxicam, of which four were of type I; three were classified as high quality and two of moderate quality. Objective, semi-objective and subjective assessments of the outcome variables showed that the drug was effective and the studies were considered adequate to apply the findings to the target population. The strength of the evidence indicates that the findings are physiologically meaningful and the conclusions are valid.

Etodolac was analysed in one high-quality type I study, which was placebo controlled and assessed semi-objectively, with the results indicating efficacy. This moderately strong evidence indicates that etodolac could probably be used clinically in dogs with osteoarthritis, but further studies are needed.

GAGPS was the subject of two papers of type I, one of moderate quality and one of high quality. Both were placebo controlled and assessed objectively by histological grading. They provide moderately strong evidence that GAGPS would be clinically effective, but further studies are needed.

There were three type I and two type III studies of licofelone, all evaluated as of high quality; they identified their primary outcome variable, used placebo controls and assessed their results objectively. They provide moderately strong evidence that treatment with licofelone would be clinically effective.

Treatment with elk velvet antler was the subject of a single type I study of high quality. The primary outcome was identified and assessment was placebo controlled and objective. The study provides moderately strong evidence that elk velvet antler may be effective in the treatment of osteoarthritis in dogs. However, further studies involving more dogs are needed to establish how applicable it would be to the target population. In these studies, placebo and treatment periods need to be consistent.

Green-lipped mussel was analysed as part of feed in one type I study. The evidence was moderately strong but further studies are required with larger numbers of dogs and objective outcomes measures to have more confidence recommending this treatment. There is moderately strong evidence that the treatment may potentially be effective, but high-quality studies with sufficient numbers of dogs, the results of which are assessed objectively, are needed before it can be recommended.

There was no evidence that treatments with doxycycline, ESA, extracorporeal shockwave therapy, gold wire acupuncture, hyaluronan, pentosan polysulphate, P54FP, tiaprofenic acid or tibial plateau levelling osteotomy were effective. The studies involving these agents were of moderate and high quality, and of design types I and III. The results showed no statistically significant differences from their respective controls, and none of these treatments has been successful in trials. Hyaluronan and pentosan polysulphate were the only ones to be the subject of more than one study, and more studies are required. They should identify their primary outcome variable, be placebo controlled and assess their results objectively.

There were statistically significant or gross improvements in groups treated with aspirin, calcitonin, diacerhein, glucosamine and chondroitin sulphate, gene delivery, glycosylated UC-II, ketoprofen, passive stretching, proanthozone, SMPC, tenidap and weight control, and the surgical techniques of joint athroplasty and joint distraction. However, the strength of the evidence for these treatments was low, and further, high-quality studies are needed before any of them can be recommended for the treatment of osteoarthritis in dogs.

This systematic review did not consider the safety of any of these therapies and focused solely on their efficacy. Any decision to use them should be considered against the safety profile of each agent and the potential adverse effects for each dog.

Health insurance for pets is becoming more common in some countries, covering them for the treatment of chronic diseases such as osteoarthritis, and there appears to be an increasing awareness of such conditions. As a result, they are being treated more commonly and the market has responded by offering more products. This review has evaluated the literature on these different agents or modalities and identified those that have been shown to be effective and can be recommended for use. It has also identified subjects that need further study and offers advice on the type of studies required. Only high-quality studies will improve knowledge about osteoarthritis and help to improve its management. This review shows that as of July 2007, the literature provides the strongest supportive evidence for the use of carprofen, firocoxib and meloxicam.

Acknowledgements

The authors thank K. Linkman, Subject Librarian, Harold Cohen Library, the University of Liverpool, for his help with the design of the search strategy. ROS was in receipt of a summer studentship stipend from Merial Animal Health, Lyon, France.

References

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