Distal tarsal joints osteoarthritis: Evidence behind bisphosphonates and NSAIDs to improve lameness

a Knowledge Summary by

Julia Dubuc DMV, DÉS, DACVS-LA, M.Sc, MRCVS ^1*

¹University of Nottingham, Sutton Bonnington Campus, Sutton Bonnington, Leicestershire, LE12 5RD
^*Corresponding Author (julia.dubuc@nottingham.ac.uk)

Clinical scenario

You are presented with an 18-year-old retired 3 star eventer, predominantly used now for low level work in the manège. The owner reports the horse lacks impulsion prior to jumping and that he now engages both hindlimbs much less under saddle. On lameness exam, no proper lameness is observed, but the full flexion of both hindlimbs is clearly positive. You elect to perform bilateral tarsal radiographs, which highlight periarticular osteophytes over the dorsomedial aspect of both the distal intertarsal and tarsometatarsal joints. On the dorsoplantar view, some lysis of these joint spaces is observed and is surrounded by sclerosis. You diagnose the horse with bilateral osteoarthritis (OA) of the distal tarsal joints.

The evidence

Only two relevant studies were identified, one of which is a field study with no mandatory radiographs required to enter the study, indicating the horses included were not necessarily diagnosed with distal tarsal joints OA. The second study is a randomised double-blind placebo control study, but it was not entirely blinded. The level of evidence of the studies summarised below is low regarding the use of bisphosphonates as a treatment for distal tarsal joint OA. There is a more substantial body of literature focusing on the use of bisphosphonates as a treatment of navicular syndrome in horses. There is no study in the literature providing a direct comparison of non-steroidal anti-inflammatory drugs (NSAIDs) and bisphosphonates for the long-term alleviation of lameness related to distal tarsal joints OA and for navicular syndrome.

Summary of the evidence

Appraisal, application and reflection

There is no prospective clinical study comparing the effects of NSAIDs versus bisphosphonates on improvement of lameness related to bone spavin in horses. There are two generations of biosphosphonates. The early generation, contains nitrogen and includes tiludronate and clodronate, which are considered less potent. The latest generation comprises pamidronate and zoledronate and are highly potent.

There are more publications looking into bisphosphonates as a treatment for navicular disease (Denoix, J. M. et al., 2003; Dyson, S. J. et al., 2005; Mitchell, A. et al., 2019; and Whitfield, C.T. et al., 2016), but the work of Gough et al. (2010) appears to be the only publication found by the author on the use of bisphosphonates as a treatment for bone spavin in horses. A review of the efficacy of tiludronate in horses (Kamm, L. et al., 2008) mentions several smaller studies, namely a case series (Riccio, B. et al., 2002) and clinical observations (Dyson, S. J. et al., 2004) that were never officially published. None of these provide sufficient evidence that bisphosphonates are truly beneficial in cases of distal tarsal joints OA.

In both of the publications presented here, lameness is used as the principal outcome evaluated to determine if either firocoxib or tiludronate are effective in improving the lameness of the horses with distal tarsal joints OA. As lameness evaluation is a very subjective process and taken together with the fact both studies are “multicentric”, the accuracy of the outcome evaluation is questionable. Unlike more recent studies on the topic (Mitchell, A. et al. 2019 and Whitfield, C.T. et al. 2016), no inertial sensor system nor ground-mounted stationary force plate system was employed. Further publications with more objective lameness evaluations and other measured outcomes are needed. For example, in a similar study comparing the efficacy of phenylbutazone versus firocoxib in horses with naturally occurring osteoarthritis (Doucet, M. Y. et al., 2008), lameness was used as the outcome evaluated, as well as other more objective measures: reaction to manipulation/joint flexion, joint swelling, joint circumference and range of motion.

In the study by Orsini et al. (2012), the lamenesses were graded on the AAEP Lameness Scale (Grade 0–5) by a veterinary surgeon on days 0, 7 and 14, but were also graded by the horses’ caregivers on days 7 and 14. As there was no placebo or control group in this study, none of these individuals were blinded and all were aware the horse was under treatment with firocoxib. In the study by Gough et al. (2010), the lameness was graded on a scale of 0-10 by a veterinary surgeon on days 0, 60 and 120 in a randomised double-blind placebo control study. However, the authors state that horses not responsive to treatment at day 60 could receive the standard dose of tiludronate at that time, voiding the double-blind aspect of the study design. These breaches in study designs introduce biases, namely in the assessment of the lameness and this greatly impacts on the reliability of the results.

Interestingly, the author only found the study from Orsini et al. (2012) looking at firocoxib as an NSAID medication for distal tarsal joints OA and “none” using phenylbutazone. The study from Orsini et al. (2012) is in fact a clinical trial investigating the efficacy of firocoxib in management of musculoskeletal pain and lameness associated with osteoarthritis. While 197/390 (50.5%) of the horses had signs of musculoskeletal pain or lameness associated with one joint, 79/197 (40.1%) of these were thought to involve the tarsus (radiographs were not mandatory to confirm the diagnosis). The results are presented in such a way that it is not possible to determine how many of these horses affected with tarsal OA really improved because of firocoxib administration. The authors report 80% improvement of lameness overall after 14 days. In a very similar study (Doucet, M. Y. et al., 2008), published prior to the above mentioned, there was no difference in lameness scores between the firocoxib group (0.1 mg/kg, PO, SID for 14 days) and the phenylbutazone group (4.4 mg/kg, PO, SID for 14 days) for pain related to naturally occurring osteoarthritis (which was confirmed radiographically prior to entering the study). In the latter as in the former, there is no clear groups separating the effect of each NSAIDs on horses affected by tarsal OA compared to any other degenerative joint disease. However, the author chose not to present the work of Doucet here as all horses fell under one large category: naturally occurring OA.

Based on the current literature, there is insufficient evidence to advocate for the use of NSAIDs more than bisphosphonates or the contrary for the treatment of distal tarsal joints OA in horses. The longest follow-up period was 4 months in the study from Gough et al. (2010) and 2 weeks for Orsini et al. (2012). There is a need for a prospective double-blind clinical trial including one bisphosphonates group, one NSAID group and one control group with long-term follow-up of the horses lameness as well as other more objective outcomes.

For an overview of the efficacy and effects of bisphosphonates in horses with navicular disease, the reader can consult recent publications, including different administration routes: IM (Mitchell, A. et al. 2019), IV or intravenous regional limb perfusion (IV-RLP) (Whitfield, C.T. et al. 2016; Schoonover, M.J. et al. 2019).

Methodology Section

Search Strategy
Databases searched and dates covered:	CAB Abstracts 1973 to Week 28 2018 PubMed NCBI 1910 to Week 28 2018
Search strategy:	CAB Abstracts equine or equines or horse or horses or equus or equid or equids or mare or mares or broodmare or broodmares or pony or ponies or filly or fillies or colt or colts or yearling or yearlings or stallion or stallions or thoroughbred or thoroughbreds or standardbred or standardbreds or racehorse or racehorses or "race horse" or "race horses" or exp horses/ or exp equus/ or exp equidae/ or exp mares/ or exp colts/ or exp foals/ or exp stallions/ or exp thoroughbred/ or exp racehorses/ arthritis or arthritic or arthritogenic or arthritical or osteoarthritis or osteoarthritic or osteo-arthritis or osteo-arthritic or synovitis or "joint disease" or "joint diseases" or OA or DJD or osteoarthrosis or osteo-arthrosis or lame or lameness or spavin or gait or exp osteoarthritis/ or exp arthritis/ or exp joint diseases/ tarsal or tarsals or tarsale or tarsometatarsal or tarsometatarsus or tarsometatarsals or tarso-metatarsal or tarso-metatarsals or carpus or carpuses or carpometacarpal or carpometacarpals or carpo-metacarpal or carpo-metacarpals or hock or hocks or carpal or carpals or exp tarsus/ or exp carpus/ bisphosphonate or bisphosphonates or biphosphonate or biphosphonates or bisphosponate or bisphosponates or biphosponate or biphosponates or disphosponate or disphosponates or diphosphonate or diphosphonates or diphosponate or diphosponates or disphosphonate or disphosphonates or osphosReg or tiludronate or tiludronic or tildren or tildrenReg or clodronate or clodronic NSAID or NSAIDs or "non steroidal anti inflammatory" or "non steroidal anti inflammatories" or "non steroidal antiinflammatory" or "non steroidal antiinflammatories" or "nonsteroidal anti inflammatory" or "nonsteroidal anti inflammatories" or "nonsteroidal antiinflammatory" or "nonsteroidal antiinflammatories" or phenylbutazone or phenylbutazones or PBZ or firocoxib or firocoxibs or FIRO or cox-2-selectives or cox-2-selective or exp antiinflammatory agents/ or exp non-steroidal antiinflammatory agents/ 1 and 2 and 3 and (4 or 5)   PubMed equine or equines or horse or horses or equus or equid or equids or mare or mares or broodmare or broodmares or pony or ponies or filly or fillies or colt or colts or yearling or yearlings or stallion or stallions or thoroughbred or thoroughbreds or standardbred or standardbreds or racehorse or raceshorses arthritis or arthritic or arthritogenic or arthritical or osteoarthritis or osteoarthritic or osteo-arthritis or osteo-arthritic or synovitis or "joint disease" or "joint diseases" or OA or DJD or osteoarthrosis or osteo-arthrosis or lame or lameness or spavin or gait tarsal or tarsals or tarsale or tarsometatarsal or tarsometatarsus or tarsometatarsals or tarso-metatarsal or tarso-metatarsals or carpus or carpuses or carpometacarpal or carpometacarpals or carpo-metacarpal or carpo-metacarpals or hock or hocks or carpal or carpals bisphosphonate or bisphosphonates or biphosphonate or biphosphonates or bisphosponate or bisphosponates or biphosponate or biphosponates or disphosponate or disphosponates or diphosphonate or diphosphonates or diphosponate or diphosponates or disphosphonate or disphosphonates or osphosReg or tiludronate or tiludronic or tildren or tildrenReg or clodronate or clodronic NSAID or NSAIDs or "non steroidal anti inflammatory" or "non steroidal anti inflammatories" or "non steroidal antiinflammatory" or "non steroidal antiinflammatories" or "nonsteroidal anti inflammatory" or "nonsteroidal anti inflammatories" or "nonsteroidal antiinflammatory" or "nonsteroidal antiinflammatories" or phenylbutazone or phenylbutazones or PBZ or firocoxib or firocoxibs or FIRO or cox-2-selectives or cox-2-selective 1 and 2 and 3 and (4 or 5)
Dates searches performed:	25/7/2018 and 27/7/2018

Exclusion / Inclusion Criteria
Exclusion:	Articles not relevant to PICO question Carpal joints Induced arthritis Ex vivo research Conference papers/proceedings not published/review paper Publications in other languages than French or English
Inclusion:	Relevant to PICO question Tarsal joints/hocks OA Bisphosphonates/Tildren/tiludronate/clodronate/ NSAIDs

Search Outcome
Database	Number of results	Excluded – other languages	Excluded – Not relevant to PICO	Excluded – duplicates	Excluded – conference papers or proceedings not published, book chapters	Total relevant papers
CAB abstracts	72	10	50	0	10	2
PubMed	45	1	23	21	0	0
Total relevant papers						2

The author declares no conflicts of interest.

1. Denoix, J.M., Thibaud, D. & Riccio, B. Tiludronate as a new therapeutic agent in the treatment of navicular disease: a double‐blind placebo‐controlled clinical trial. Equine Veterinary Journal. 2003; 35(4): 407–13. DOI: https://doi.org/10.2746/042516403776014226
2. Dyson, S. Are There any Advances in the Treatment of Distal Hock Joint Pain? Proceedings International Symposium on Diseases of the Icelandic Horse, 2004.
3. Dyson S.J., Murray R. & Schramme M.C. Lameness associated wth foot pain: results of magnetic resonance imaging in 199 horses (January 2001–December 2003) and response to treatment. Equine Veterinary Journal. 2005; 37: 113–121. DOI:  https://doi.org/10.2746/0425164054223804
4. Gough, M.R., Thibaud, D. & Smith, R.K. Tiludronate infusion in the treatment of bone spavin: a double blind placebo-controlled trial. Equine Veterinary Journal. 2010; 42(5): 381–7. DOI: https://doi.org/10.1111/j.2042-3306.2010.00120.x
5. Kamm, L., McIlwraith, W. & Kawcak, C. A review of the efficacy of tiludronate in the horse. Journal of Equine Veterinary Science. 2008; 28(4): 209–14. DOI: https://doi.org/10.1016/j.jevs.2008.02.007
6. Riccio, B., Thibaud, D. & Denoix, J.M. A double-blind placebo-controlled trial of tiludronate in the treatment of bone spavin. BEVA Congress; 2002.
7. Doucet, M.Y., Bertone, A.L., Hendrickson, D., Hughes, F., Macallister, C., McClure, S., Reinemeyer, C., Rossier, Y., Sifferman, R., Vrins, Andre A., White, G., Kunkle, B., Alva, R., Romano, D. & Hanson, P.D. Comparison of efficacy and safety of paste formulations of firocoxib and phenylbutazone in horses with naturally occurring osteoarthritis. Journal of the American Veterinary Medical Association. 2008; 232(1): 91–7. DOI: https://doi.org/10.2460/javma.232.1.91
8. Orsini, J.A., Ryan, W.G., Carithers, D.S. & Boston, R.C. Evaluation of oral administration of firocoxib for the management of musculoskeletal pain and lameness associated with osteoarthritis in horses. American Journal of Veterinary Research. 2012; 73(5): 664–71. DOI: https://doi.org/10.2460/ajvr.73.5.664
9. Mitchell, A., Wright, G., Sampson, S.N., Martin, M., Cummings, K., Gaddy, D. & Watts, A.E. Clodronate improves lameness in horses without changing bone turnover markers. Equine Veterinary Journal. 2019; 51: 356–63. DOI: https://doi.org/10.1111/evj.13011 
10. Whitield, C.T., Schoonover, M.J., Holbrook, T.C., Payton, M.E. & Sippel, K.M. Quantitative assessment of two methods of tiludronate administration for the treatment of lameness caused by navicular syndrome in horses. American Journal of Veterinary Research. 2016; 77(2): 167–73. DOI: https://doi.org/10.2460/ajvr.77.2.167 
11. Schoonover, M.J., Whitield, C.T., Young, J.M., Sippel, K.M. & Payton, M.E. Quantitative assessment of intravenous regional limb perfusion of tiludronate as an adjunctive treatment for lameness caused by navicular syndrome in horses. American Journal of Veterinary Research. 2018; 79(12): 1313–1320. DOI: https://doi.org/10.2460/ajvr.79.12.1313 

RCVS Knowledge was supported in producing this Knowledge Summary by an educational grant from Petplan Charitable Trust.