Review Article | Published:

Spontaneous dog osteoarthritis — a One Medicine vision

Nature Reviews Rheumatologyvolume 15pages273287 (2019) | Download Citation


Osteoarthritis (OA) is a global disease that, despite extensive research, has limited treatment options. Pet dogs share both an environment and lifestyle attributes with their owners, and a growing awareness is developing in the public and among researchers that One Medicine, the mutual co-study of animals and humans, could be beneficial for both humans and dogs. To that end, this Review highlights research opportunities afforded by studying dogs with spontaneous OA, with a view to sharing this active area of veterinary research with new audiences. Similarities and differences between dog and human OA are examined, and the proposition is made that suitably aligned studies of spontaneous OA in dogs and humans, in particular hip and knee OA, could highlight new avenues of discovery. Developing cross-species collaborations will provide a wealth of research material and knowledge that is relevant to human OA and that cannot currently be obtained from rodent models or experimentally induced dog models of OA. Ultimately, this Review aims to raise awareness of spontaneous dog OA and to stimulate discussion regarding its exploration under the One Medicine initiative to improve the health and well-being of both species.

Key points

  • Dogs have many analogous spontaneous diseases that result in end-stage osteoarthritis (OA).

  • Inbreeding and the predisposition of certain dog breeds for OA enable easier identification of candidate genetic associations than in outbred humans.

  • Dog OA subtypes offer a potential stratification rationale for aetiological differences and alignment to analogous human OA phenotypes.

  • The relatively compressed time course of spontaneous dog OA offers longitudinal research opportunities.

  • Collaboration with veterinary researchers can provide tissue samples from early-stage OA and opportunities to evaluate new therapeutics in a spontaneous disease model.

  • Awareness of the limitations and benefits of using clinical veterinary patients in research is important.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Canine Comparative Oncology Genomics Consortium:

Cornell Veterinary Biobank:

UK National Veterinary Canine Hip Replacement Registry:

Vetmeduni Vienna VetBiobank:


  1. 1.

    Murphy, L. & Helmick, C. G. The impact of osteoarthritis in the United States: a population-health perspective: a population-based review of the fourth most common cause of hospitalization in U.S. adults. Orthop. Nurs. 31, 85–91 (2012).

  2. 2.

    March, L. et al. Osteoarthritis: a serious disease. (2016).

  3. 3.

    Little, C. B. & Zaki, S. What constitutes an ‘animal model of osteoarthritis’ – the need for consensus? Osteoarthritis Cartilage 20, 261–267 (2012).

  4. 4.

    Pond, M. J. & Nuki, G. Experimentally-induced osteoarthritis in the dog. Ann. Rheum. Dis. 32, 387–388 (1973).

  5. 5.

    Stockwell, R. A., Billingham, M. E. & Muir, H. Ultrastructural changes in articular cartilage after experimental section of the anterior cruciate ligament of the dog knee. J. Anat. 136, 425–439 (1983).

  6. 6.

    Moskowitz, R. W. et al. Experimentally induced degenerative joint lesions following partial meniscectomy in the rabbit. Arthritis Rheum. 16, 397–405 (1973).

  7. 7.

    Malfait, A.-M. & Little, C. B. On the predictive utility of animal models of osteoarthritis. Arthritis Res. Ther. 17, 225 (2015).

  8. 8.

    Vincent, T. L. et al. Mapping pathogenesis of arthritis through small animal models. Rheumatology 51, 1931–1941 (2012).

  9. 9.

    Li, N. et al. A novel p.Gly630Ser mutation of COL2A1 in a Chinese family with presentations of Legg-Calvé-Perthes disease or avascular necrosis of the femoral head. PLoS ONE 9, e100505 (2014).

  10. 10.

    Kol, A. et al. Companion animals: translational scientist’s new best friends. Sci. Transl Med. 7, 308ps21 (2015).

  11. 11.

    Bendele, A. M. Animal models of osteoarthritis. J. Musculoskelet. Neuronal Interact. 1, 363–376 (2001).

  12. 12.

    Anderson, K. L. et al. Prevalence, duration and risk factors for appendicular osteoarthritis in a UK dog population under primary veterinary care. Sci. Rep. 8, 5641 (2018).

  13. 13.

    Johnston, S. A. Osteoarthritis. Joint anatomy, physiology, and pathobiology. Vet. Clin. North Am. Small Anim. Pract. 27, 699–723 (1997).

  14. 14.

    Innes, J. F., Barr, A. R. & Sharif, M. Efficacy of oral calcium pentosan polysulphate for the treatment of osteoarthritis of the canine stifle joint secondary to cranial cruciate ligament deficiency. Vet. Rec. 146, 433–437 (2000).

  15. 15.

    Mehler, S. J., May, L. R., King, C., Harris, W. S. & Shah, Z. A prospective, randomized, double blind, placebo-controlled evaluation of the effects of eicosapentaenoic acid and docosahexaenoic acid on the clinical signs and erythrocyte membrane polyunsaturated fatty acid concentrations in dogs with osteoarthritis. Prostaglandins Leukot. Essent. Fatty Acids 109, 1–7 (2016).

  16. 16.

    Gregory, M. H. et al. A review of translational animal models for knee osteoarthritis. Arthritis 2012, 764621 (2012).

  17. 17.

    Liu, W. et al. Spontaneous and experimental osteoarthritis in dog: similarities and differences in proteoglycan levels. J. Orthop. Res. 21, 730–737 (2003).

  18. 18.

    Page, A. E. et al. Determination of loading parameters in the canine hip in vivo. J. Biomech. 26, 571–579 (1993).

  19. 19.

    Pearson-Ceol, J. Literature review on the effects of obesity on knee osteoarthritis. Orthop. Nurs. 26, 289–292 (2007).

  20. 20.

    Lauten, S. D. Nutritional risks to large-breed dogs: from weaning to the geriatric years. Vet. Clin. North Am. Small Anim. Pract. 36, 1345–1359 (2006).

  21. 21.

    Smith, G. K. et al. Lifelong diet restriction and radiographic evidence of osteoarthritis of the hip joint in dogs. J. Am. Vet. Med. Assoc. 229, 690–693 (2006).

  22. 22.

    Kealy, R. D. et al. Five-year longitudinal study on limited food consumption and development of osteoarthritis in coxofemoral joints of dogs. J. Am. Vet. Med. Assoc. 210, 222–225 (1997).

  23. 23.

    Newman, R. G. et al. The effects of lifetime food restriction on the development of osteoarthritis in the canine shoulder. Vet. Surg. 37, 102–107 (2008).

  24. 24.

    Huck, J. L. et al. A longitudinal study of the influence of lifetime food restriction on development of osteoarthritis in the canine elbow. Vet. Surg. 38, 192–198 (2009).

  25. 25.

    Yusuf, E. et al. Association between weight or body mass index and hand osteoarthritis: a systematic review. Ann. Rheum. Dis. 69, 761–765 (2009).

  26. 26.

    Francisco, V. et al. Biomechanics, obesity, and osteoarthritis. The role of adipokines: when the levee breaks. J. Orthop. Res. 23, 1233 (2017).

  27. 27.

    Ryan, V. H. et al. Adipokine expression and secretion by canine adipocytes: stimulation of inflammatory adipokine production by LPS and TNFα. Pflugers Arch. 460, 603–616 (2010).

  28. 28.

    Lane, N. E. et al. Association of mild acetabular dysplasia with an increased risk of incident hip osteoarthritis in elderly white women: the study of osteoporotic fractures. Arthritis Rheum. 43, 400–404 (2000).

  29. 29.

    Thomas, G. E. R. et al. Subclinical deformities of the hip are significant predictors of radiographic osteoarthritis and joint replacement in women. A 20 year longitudinal cohort study. Osteoarthritis Cartilage 22, 1504–1510 (2014).

  30. 30.

    Cachon, T. et al. Risk of simultaneous phenotypic expression of hip and elbow dysplasia in dogs. Vet. Comp. Orthop. Traumatol. 23, 28–30 (2009).

  31. 31.

    Rhodes, A. M. L. & Clarke, N. M. P. A review of environmental factors implicated in human developmental dysplasia of the hip. J. Child Orthop. 8, 375–379 (2014).

  32. 32.

    Jacobsen, S. Adult hip dysplasia and osteoarthritis. Studies in radiology and clinical epidemiology. Acta Orthop. Suppl. 77, 1–37 (2006).

  33. 33.

    Baker-LePain, J. C. & Lane, N. E. Relationship between joint shape and the development of osteoarthritis. Curr. Opin. Rheumatol. 22, 538–543 (2010).

  34. 34.

    Weinstein, S. L. Natural history of congenital hip dislocation (CDH) and hip dysplasia. Clin. Orthop. Relat. Res. 225, 62–76 (1987).

  35. 35.

    Pascual-Garrido, C. et al. Canine hip dysplasia: a natural animal model for human developmental dysplasia of the hip. J. Orthop. Res. 36, 1807–1817 (2017).

  36. 36.

    Todhunter, R. J. et al. Evaluation of multiple radiographic predictors of cartilage lesions in the hip joints of eight-month-old dogs. Am. J. Vet. Res. 64, 1472–1478 (2003).

  37. 37.

    Jacobsen, S. & Sonne-Holm, S. Hip dysplasia: a significant risk factor for the development of hip osteoarthritis. A cross-sectional survey. Rheumatology 44, 211–218 (2005).

  38. 38.

    Todhunter, R. J. et al. Onset of epiphyseal mineralization and growth plate closure in radiographically normal and dysplastic Labrador Retrievers. J. Am. Vet. Med. Assoc. 210, 1458–1462 (1997).

  39. 39.

    Greisen, H. A., Summers, B. A. & Lust, G. Ultrastructure of the articular cartilage and synovium in the early stages of degenerative joint disease in canine hip joints. Am. J. Vet. Res. 43, 1963–1971 (1982).

  40. 40.

    Feng, W. J., Wang, H., Shen, C., Zhu, J. F. & Chen, X. D. Severe cartilage degeneration in patients with developmental dysplasia of the hip. IUBMB Life 69, 179–187 (2017).

  41. 41.

    Loder, R. T. & Todhunter, R. J. The demographics of canine hip dysplasia in the United States and Canada. J. Vet. Med. 2017, 5723476 (2017).

  42. 42.

    Smith, G. K. et al. Chronology of hip dysplasia development in a cohort of 48 Labrador Retrievers followed for life. Vet. Surg. 41, 20–33 (2012).

  43. 43.

    Ganz, R. et al. Femoroacetabular impingement: a cause for osteoarthritis of the hip. Clin. Orthop. Relat. Res. 417, 112–120 (2003).

  44. 44.

    Kotlarsky, P., Haber, R., Bialik, V. & Eidelman, M. Developmental dysplasia of the hip: what has changed in the last 20 years? World J. Orthop. 6, 886–901 (2015).

  45. 45.

    Pollet, V., Percy, V. & Prior, H. J. Relative risk and incidence for developmental dysplasia of the hip. J. Pediatr. 181, 202–207 (2017).

  46. 46.

    de Hundt, M. et al. Risk factors for developmental dysplasia of the hip: a meta-analysis. Eur. J. Obstet. Gynecol. Reprod. Biol. 165, 8–17 (2012).

  47. 47.

    Li, L. et al. Heritability and sibling recurrent risk of developmental dysplasia of the hip in Chinese population. Eur. J. Clin. Invest. 43, 589–594 (2013).

  48. 48.

    Feldman, G. J. et al. Variable expression and incomplete penetrance of developmental dysplasia of the hip: clinical challenge in a 71-member multigeneration family. J. Arthroplasty 27, 527–532 (2012).

  49. 49.

    Hogervorst, T., Eilander, W., Fikkers, J. T. & Meulenbelt, I. Hip ontogenesis: how evolution, genes, and load history shape hip morphotype and cartilotype. Clin. Orthop. Relat. Res. 470, 3284–3296 (2012).

  50. 50.

    Kaneene, J. B., Mostosky, U. V. & Miller, R. Update of a retrospective cohort study of changes in hip joint phenotype of dogs evaluated by the OFA in the United States, 1989–2003. Vet. Surg. 38, 398–405 (2009).

  51. 51.

    Breur, G. J., Lambrecht, N. E. & Todhunter, R. J. in The Genetics of the Dog 2nd edn (eds Ostrander, E. A. & Ruvinsky, A.) 136–153 (CABI Publishing, 2012).

  52. 52.

    Hayward, J. J. et al. Complex disease and phenotype mapping in the domestic dog. Nat. Commun. 7, 10460 (2016).

  53. 53.

    Huang, M. et al. A novel iterative mixed model to remap three complex orthopedic traits in dogs. PLoS ONE 12, e0176932 (2017).

  54. 54.

    Bartolomé, N. et al. A genetic predictive model for canine hip dysplasia: integration of genome wide association study (GWAS) and candidate gene approaches. PLoS ONE 10, e0122558 (2015).

  55. 55.

    Sánchez-Molano, E. et al. Quantitative trait loci mapping for canine hip dysplasia and its related traits in UK Labrador Retrievers. BMC Genomics 15, 833 (2014).

  56. 56.

    Fels, L. & Distl, O. Identification and validation of quantitative trait loci (QTL) for canine hip dysplasia (CHD) in German Shepherd dogs. PLoS ONE 9, e96618 (2014).

  57. 57.

    Kadri, N. K., Guldbrandtsen, B., Sørensen, P. & Sahana, G. Comparison of genome-wide association methods in analyses of admixed populations with complex familial relationships. PLoS ONE 9, e88926 (2014).

  58. 58.

    Lavrijsen, I. C. et al. Genome wide analysis indicates genes for basement membrane and cartilage matrix proteins as candidates for hip dysplasia in Labrador Retrievers. PLoS ONE 9, e87735 (2014).

  59. 59.

    Pfahler, S. & Distl, O. Identification of quantitative trait loci (QTL) for canine hip dysplasia and canine elbow dysplasia in Bernese Mountain Dogs. PLoS ONE 7, e49782 (2012).

  60. 60.

    Zhou, Z. et al. Differential genetic regulation of canine hip dysplasia and osteoarthritis. PLoS ONE 5, e13219 (2010).

  61. 61.

    Todhunter, R. J. Gene expression in hip soft tissues in incipient canine hip dysplasia and osteoarthritis. J. Orthop. Res. 37, 313–324 (2019).

  62. 62.

    Feldman, G. J. et al. Developmental dysplasia of the hip: linkage mapping and whole exome sequencing identify a shared variant in CX3CR1 in all affected members of a large multigeneration family. J. Bone Miner. Res. 28, 2540–2549 (2013).

  63. 63.

    Feldman, G. J., Parvizi, J., Sawan, H., Erickson, J. A. & Peters, C. L. Linkage mapping and whole exome sequencing identify a shared variant in CX3CR1 in a large multi-generation family. J. Arthroplasty 29, 238–241 (2014).

  64. 64.

    Li, L. et al. CX3CR1 polymorphisms associated with an increased risk of developmental dysplasia of the hip in human. J. Orthop. Res. 35, 377–380 (2017).

  65. 65.

    Xiao, Y. et al. Macrophages and osteoclasts stem from a bipotent progenitor downstream of a macrophage/osteoclast/dendritic cell progenitor. Blood Adv. 1, 1993–2006 (2017).

  66. 66.

    Feldman, G., Offemaria, A., Sawan, H., Parvizi, J. & Freeman, T. A. A murine model for developmental dysplasia of the hip: ablation of CX3CR1 affects acetabular morphology and gait. J. Transl Med. 15, 233 (2017).

  67. 67.

    Hatzikotoulas, K. et al. Genome-wide association study of developmental dysplasia of the hip identifies an association with GDF5. Commun. Biol. 1, 56 (2018).

  68. 68.

    Beals, R. K. Familial primary acetabular dysplasia and dislocation of the hip. Clin. Orthop. Relat. Res. 406, 109–115 (2003).

  69. 69.

    Sandell, L. J. Etiology of osteoarthritis: genetics and synovial joint development. Nat. Rev. Rheumatol. 8, 77–89 (2012).

  70. 70.

    Friedenberg, S. G. et al. Evaluation of a fibrillin 2 gene haplotype associated with hip dysplasia and incipient osteoarthritis in dogs. Am. J. Vet. Res. 72, 530–540 (2011).

  71. 71.

    Sadee, W. et al. Missing heritability of common diseases and treatments outside the protein-coding exome. Hum. Genet. 133, 1199–1215 (2014).

  72. 72.

    Lust, G. et al. Joint laxity and its association with hip dysplasia in Labrador Retrievers. Am. J. Vet. Res. 54, 1990–1999 (1993).

  73. 73.

    Runge, J. J., Kelly, S. P., Gregor, T. P., Kotwal, S. & Smith, G. K. Distraction index as a risk factor for osteoarthritis associated with hip dysplasia in four large dog breeds. J. Small Anim. Pract. 51, 264–269 (2010).

  74. 74.

    Giorgi, M., Carriero, A., Shefelbine, S. J. & Nowlan, N. C. Effects of normal and abnormal loading conditions on morphogenesis of the prenatal hip joint: application to hip dysplasia. J. Biomech. 48, 3390–3397 (2015).

  75. 75.

    de Rooster, H., de Bruin, T. & Van Bree, H. Morphologic and functional features of the canine cruciate ligaments. Vet. Surg. 35, 769–780 (2006).

  76. 76.

    Bozynski, C. et al. Evaluation of partial transection versus synovial debridement of the ACL as novel canine models for management of ACL injuries. J. Knee Surg. 28, 404–410 (2015).

  77. 77.

    Lahm, A. et al. An experimental canine model for subchondral lesions of the knee joint. Knee 12, 51–55 (2005).

  78. 78.

    Panula, H. E., Helminen, H. J. & Kiviranta, I. Slowly progressive osteoarthritis after tibial valgus osteotomy in young beagle dogs. Clin. Orthop. Relat. Res. 343, 192–202 (1997).

  79. 79.

    Frost-Christensen, L. N. et al. Degeneration, inflammation, regeneration, and pain/disability in dogs following destabilization or articular cartilage grooving of the stifle joint. Osteoarthritis Cartilage 16, 1327–1335 (2008).

  80. 80.

    Simon, D. et al. The relationship between anterior cruciate ligament injury and osteoarthritis of the knee. Adv. Orthop. 2015, 1–11 (2015).

  81. 81.

    Innes, J. F., Costello, M., Barr, F. J., Rudorf, H. & Barr, A. R. S. Radiographic progression of osteoarthritis of the canine stifle joint: a prospective study. Vet. Radiol. Ultrasound 45, 143–148 (2004).

  82. 82.

    Comerford, E. J. et al. Update on the aetiopathogenesis of canine cranial cruciate ligament disease. Vet. Comp. Orthop. Traumatol. 24, 91–98 (2011).

  83. 83.

    Taylor-Brown, F. E. et al. Epidemiology of cranial cruciate ligament disease diagnosis in dogs attending primary-care veterinary practices in England. Vet. Surg. 44, 777–783 (2015).

  84. 84.

    Pritzker, K. P. Animal models for osteoarthritis: processes, problems and prospects. Ann. Rheum. Dis. 53, 406–420 (2004).

  85. 85.

    Wilke, V. L. et al. Inheritance of rupture of the cranial cruciate ligament in Newfoundlands. J. Am. Vet. Med. Assoc. 228, 61–64 (2006).

  86. 86.

    Buote, N., Fusco, J. & Radasch, R. Age, tibial plateau angle, sex, and weight as risk factors for contralateral rupture of the cranial cruciate ligament in Labradors. Vet. Surg. 38, 481–489 (2009).

  87. 87.

    Cook, J. L. Cranial cruciate ligament disease in dogs: biology versus biomechanics. Vet. Surg. 39, 270–277 (2010).

  88. 88.

    Blanke, F. et al. Risk of noncontact anterior cruciate ligament injuries is not associated with slope and concavity of the tibial plateau in recreational alpine skiers: a magnetic resonance imaging-based case-control study of 121 patients. Am. J. Sports Med. 44, 1508–1514 (2016).

  89. 89.

    Trompeter, A. J., Gill, K., Appleton, M. A. C. & Palmer, S. H. Predicting anterior cruciate ligament integrity in patients with osteoarthritis. Knee Surg. Sports Traumatol. Arthrosc. 17, 595–599 (2009).

  90. 90.

    Lohmander, L. S., Englund, P. M., Dahl, L. L. & Roos, E. M. The long-term consequence of anterior cruciate ligament and meniscus injuries. Am. J. Sports Med. 35, 1756–1769 (2017).

  91. 91.

    Joseph, A. M. et al. A multisport epidemiologic comparison of anterior cruciate ligament injuries in high school athletics. J. Athl. Train. 48, 810–817 (2013).

  92. 92.

    Flynn, R. K. et al. The familial predisposition toward tearing the anterior cruciate ligament: a case control study. Am. J. Sports Med. 33, 23–28 (2005).

  93. 93.

    Trojian, T. H. & Collins, S. The anterior cruciate ligament tear rate varies by race in professional women’s basketball. Am. J. Sports Med. 34, 895–898 (2006).

  94. 94.

    O’Connell, K. et al. Interactions between collagen gene variants and risk of anterior cruciate ligament rupture. Eur. J. Sport Sci. 15, 341–350 (2015).

  95. 95.

    Khoury, L. E. et al. ELN and FBN2 gene variants as risk factors for two sports-related musculoskeletal injuries. Int. J. Sports Med. 36, 333–337 (2015).

  96. 96.

    Rahim, M. et al. The association of genes involved in the angiogenesis-associated signaling pathway with risk of anterior cruciate ligament rupture. J. Orthop. Res. 32, 1612–1618 (2014).

  97. 97.

    Stepien-Słodkowska, M. et al. The +1245g/t polymorphisms in the collagen type I alpha 1 (col1a1) gene in polish skiers with anterior cruciate ligament injury. Biol. Sport 30, 57–60 (2013).

  98. 98.

    Posthumus, M. et al. Genetic risk factors for anterior cruciate ligament ruptures: COL1A1 gene variant. Br. J. Sports Med. 43, 352–356 (2009).

  99. 99.

    Mannion, S. et al. Genes encoding proteoglycans are associated with the risk of anterior cruciate ligament ruptures. Br. J. Sports Med. 48, 1640-1646 (2014).

  100. 100.

    Kim, S. K. et al. Genome-wide association screens for Achilles tendon and ACL tears and tendinopathy. PLoS ONE 12, e0170422 (2017).

  101. 101.

    Kaynak, M., Nijman, F., van Meurs, J., Reijman, M. & Meuffels, D. E. Genetic variants and anterior cruciate ligament rupture: a systematic review. Sports Med. 47, 1637–1650 (2017).

  102. 102.

    Khoschnau, S. et al. Type I collagen alpha1 Sp1 polymorphism and the risk of cruciate ligament ruptures or shoulder dislocations. Am. J. Sports Med. 36, 2432–2436 (2008).

  103. 103.

    Posthumus, M., September, A. V., Schwellnus, M. P. & Collins, M. Investigation of the Sp1-binding site polymorphism within the COL1A1 gene in participants with Achilles tendon injuries and controls. J. Sci. Med. Sport 12, 184–189 (2009).

  104. 104.

    Ficek, K. et al. Gene variants within the COL1A1 gene are associated with reduced anterior cruciate ligament injury in professional soccer players. J. Sci. Med. Sport 16, 396–400 (2013).

  105. 105.

    Wilke, V. L., Zhang, S., Evans, R. B., Conzemius, M. G. & Rothschild, M. F. Identification of chromosomal regions associated with cranial cruciate ligament rupture in a population of Newfoundlands. Am. J. Vet. Res. 70, 1013–1017 (2009).

  106. 106.

    Baird, A. E. G., Carter, S. D., Innes, J. F., Ollier, W. & Short, A. Genome-wide association study identifies genomic regions of association for cruciate ligament rupture in Newfoundland dogs. Anim. Genet. 45, 542–549 (2014).

  107. 107.

    Baird, A. E. G., Carter, S. D., Innes, J. F., Ollier, W. E. & Short, A. D. Genetic basis of cranial cruciate ligament rupture (CCLR) in dogs. Connect. Tissue Res. 55, 275–281 (2014).

  108. 108.

    Baker, L. A. et al. Genome-wide association analysis in dogs implicates 99 loci as risk variants for anterior cruciate ligament rupture. PLoS ONE 12, e0173810 (2017).

  109. 109.

    Brandt, K. D. et al. Anterior (cranial) cruciate ligament transection in the dog: a bona fide model of osteoarthritis, not merely of cartilage injury and repair. J. Rheumatol. 18, 436–446 (1991).

  110. 110.

    Innes, J. F., Bacon, D., Lynch, C. & Pollard, A. Long-term outcome of surgery for dogs with cranial cruciate ligament deficiency. Vet. Rec. 147, 325–328 (2000).

  111. 111.

    Bleedorn, J. A. et al. Synovitis in dogs with stable stifle joints and incipient cranial cruciate ligament rupture: a cross-sectional study. Vet. Surg. 40, 531–543 (2011).

  112. 112.

    Little, J. P. et al. Arthroscopic assessment of stifle synovitis in dogs with cranial cruciate ligament rupture. PLoS ONE 9, e97329 (2014).

  113. 113.

    Muir, P. et al. Lymphocyte populations in joint tissues from dogs with inflammatory stifle arthritis and associated degenerative cranial cruciate ligament rupture. Vet. Surg. 40, 753–761 (2011).

  114. 114.

    Kraus, V. B. et al. Direct in vivo evidence of activated macrophages in human osteoarthritis. Osteoarthritis Cartilage 24, 1613–1621 (2016).

  115. 115.

    Yarnall, B. et al. Synovial macrophage polarization in dogs with degenerative cranial cruciate ligament rupture [abstract]. Vet. Surg. 46, E1–E75 (2017).

  116. 116.

    de Bruin, T., de Rooster, H., Van Bree, H., Duchateau, L. & Cox, E. Cytokine mRNA expression in synovial fluid of affected and contralateral stifle joints and the left shoulder joint in dogs with unilateral disease of the stifle joint. Am. J. Vet. Res. 68, 953–961 (2007).

  117. 117.

    Sample, S. J. et al. Radiographic and magnetic resonance imaging predicts severity of cruciate ligament fiber damage and synovitis in dogs with cranial cruciate ligament rupture. PLoS ONE 12, e0178086 (2017).

  118. 118.

    Faryniarz, D. A., Bhargava, M., Lajam, C., Attia, E. T. & Hannafin, J. A. Quantitation of estrogen receptors and relaxin binding in human anterior cruciate ligament fibroblasts. In Vitro Cell. Dev. Biol. Anim. 42, 176–181 (2006).

  119. 119.

    Liu, S. H., Al-Shaikh, R. A., Panossian, V., Finerman, G. A. & Lane, J. M. Estrogen affects the cellular metabolism of the anterior cruciate ligament. A potential explanation for female athletic injury. Am. J. Sports Med. 25, 704–709 (1997).

  120. 120.

    Slauterbeck, J. R. et al. The menstrual cycle, sex hormones, and anterior cruciate ligament injury. J. Athl. Train. 37, 275–278 (2002).

  121. 121.

    Slauterbeck, J. R., Pankratz, K., Xu, K. T., Bozeman, S. C. & Hardy, D. M. Canine ovariohysterectomy and orchiectomy increases the prevalence of ACL injury. Clin. Orthop. Relat. Res. 429, 301–305 (2004).

  122. 122.

    McGreevy, P. D. et al. Prevalence of obesity in dogs examined by Australian veterinary practices and the risk factors involved. Vet. Rec. 156, 695–702 (2005).

  123. 123.

    Linn, S., Murtaugh, B. & Casey, E. Role of sex hormones in the development of osteoarthritis. PM R 4, S169–S173 (2012).

  124. 124.

    Demko, J. & Mclaughlin, R. Developmental orthopedic disease. Vet. Clin. North Am. Small Anim. Pract. 35, 1111–1135 (2005).

  125. 125.

    Bohndorf, K. Osteochondritis (osteochondrosis) dissecans: a review and new MRI classification. Eur. Radiol. 8, 103–112 (1998).

  126. 126.

    Schenck, R. C. & Goodnight, J. M. Osteochondritis dissecans. J. Bone Joint Surg. Am. 78, 439–456 (1996).

  127. 127.

    Yonetani, Y. et al. Histological evaluation of juvenile osteochondritis dissecans of the knee: a case series. Knee Surg. Sports Traumatol. Arthrosc. 18, 723–730 (2010).

  128. 128.

    Leighton, R. L. Historical perspectives of osteochondrosis. Vet. Clin. North Am. Small Anim. Pract. 28, 1–16 (1998).

  129. 129.

    Wall, E. & Stein, Von, D. Juvenile osteochondritis dissecans. Orthop. Clin. North Am. 34, 341–353 (2003).

  130. 130.

    Jans, L. B. O., Jaremko, J. L., Ditchfield, M. & Verstraete, K. L. Evolution of femoral condylar ossification at MR imaging: frequency and patient age distribution. Radiology 258, 880–888 (2011).

  131. 131.

    Olivieri, M. et al. Arthroscopic treatment of osteochondritis dissecans of the shoulder in 126 dogs. Vet. Comp. Orthop. Traumatol. 20, 65–69 (2007).

  132. 132.

    Fitzpatrick, N., Van Terheijden, C., Yeadon, R. & Smith, T. J. Osteochondral autograft transfer for treatment of osteochondritis dissecans of the caudocentral humeral head in dogs. Vet. Surg. 39, 925–935 (2010).

  133. 133.

    Staines, K. A. et al. Endochondral growth defect and deployment of transient chondrocyte behaviors underlie osteoarthritis onset in a natural murine model. Arthritis Rheumatol. 68, 880–891 (2016).

  134. 134.

    Fuerst, M. et al. Calcification of articular cartilage in human osteoarthritis. Arthritis Rheum. 60, 2694–2703 (2009).

  135. 135.

    Teunissen, M. et al. Growth plate expression profiling: large and small breed dogs provide new insights in endochondral bone formation. J. Orthop. Res. 211, 109 (2017).

  136. 136.

    Rawlinson, S. C. F. et al. Genetic selection for fast growth generates bone architecture characterised by enhanced periosteal expansion and limited consolidation of the cortices but a diminution in the early responses to mechanical loading. Bone 45, 357–366 (2009).

  137. 137.

    Pitsillides, A. A., Rawlinson, S. C., Mosley, J. R. & Lanyon, L. E. Bone’s early responses to mechanical loading differ in distinct genetic strains of chick: selection for enhanced growth reduces skeletal adaptability. J. Bone Miner. Res. 14, 980–987 (1999).

  138. 138.

    Chaudhry, S., Phillips, D. & Feldman, D. Legg-Calvé-Perthes disease: an overview with recent literature. Bull. Hosp. Jt Dis. (2013) 72, 18–27 (2014).

  139. 139.

    Wynne-Davies, R. Acetabular dysplasia and familial joint laxity: two etiological factors in congenital dislocation of the hip. A review of 589 patients and their families. J. Bone Joint Surg. Br. 52, 704–716 (1970).

  140. 140.

    Wiig, O., Terjesen, T., Svenningsen, S. & Lie, S. A. The epidemiology and aetiology of Perthes’ disease in Norway. A nationwide study of 425 patients. J. Bone Joint Surg. Br. 88, 1217–1223 (2006).

  141. 141.

    Hall, D. J. Genetic aspects of Perthes’ disease. A critical review. Clin. Orthop. Relat. Res. 209, 100–114 (1986).

  142. 142.

    Perry, D. C. et al. Perthes’ disease: deprivation and decline. Arch. Dis. Child. 96, 1124–1128 (2011).

  143. 143.

    Vasseur, P. B., Foley, P., Stevenson, S. & Heitter, D. Mode of inheritance of Perthes’ disease in Manchester terriers. Clin. Orthop. Relat. Res. 244, 281–292 (1989).

  144. 144.

    LaFond, E., Breur, G. J. & Austin, C. C. Breed susceptibility for developmental orthopedic diseases in dogs. J. Am. Anim. Hosp. Assoc. 38, 467–477 (2002).

  145. 145.

    Starr-Moss, A. N., Nowend, K. L., Alling, K. M., Zepp, E. J. & Murphy, K. E. Exclusion of COL2A1 in canine Legg-Calvé-Perthes disease. Anim. Genet. 43, 112–113 (2012).

  146. 146.

    Srzentic´, S. et al. Predictive genetic markers of coagulation, inflammation and apoptosis in Perthes disease—Serbian experience. Eur. J. Pediatr. 174, 1085–1092 (2015).

  147. 147.

    Zheng, P., Yang, T., Ju, L., Jiang, B. & Lou, Y. Epigenetics in Legg-Calvé-Perthes disease: a study of global DNA methylation. J. Int. Med. Res. 43, 758–764 (2015).

  148. 148.

    Metcalfe, D., Van Dijck, S., Parsons, N., Christensen, K. & Perry, D. C. A twin study of Perthes disease. Pediatrics 137, e20153542 (2016).

  149. 149.

    Knoop, J. et al. Identification of phenotypes with different clinical outcomes in knee osteoarthritis: data from the osteoarthritis initiative. Arthritis Care Res. 63, 1535–1542 (2011).

  150. 150.

    Dell’Isola, A., Allan, R., Smith, S. L., Marreiros, S. S. P. & Steultjens, M. Identification of clinical phenotypes in knee osteoarthritis: a systematic review of the literature. BMC Musculoskelet. Disord. 17, 425 (2016).

  151. 151.

    Kraus, V. B., Blanco, F. J., Englund, M., Karsdal, M. A. & Lohmander, L. S. Call for standardized definitions of osteoarthritis and risk stratification for clinical trials and clinical use. Osteoarthrits Cartilage 23, 1233–1241 (2015).

  152. 152.

    Deveza, L. A. & Loeser, R. F. Is osteoarthritis one disease or a collection of many? Rheumatology 57, (Suppl. 4) iv34–iv42 (2017).

  153. 153.

    Hoffman, J. M., Creevy, K. E., Franks, A., O’Neill, D. G. & Promislow, D. E. L. The companion dog as a model for human aging and mortality. Aging Cell 13, e12737 (2018).

  154. 154.

    Murchison, E. P. et al. Transmissible dog cancer genome reveals the origin and history of an ancient cell lineage. Science 343, 437–440 (2014).

  155. 155.

    Dingli, D. & Nowak, M. A. Cancer biology: infectious tumour cells. Nature 443, 35–36 (2006).

  156. 156.

    Paoloni, M. et al. Prospective molecular profiling of canine cancers provides a clinically relevant comparative model for evaluating personalized medicine (PMed) trials. PLoS ONE 9, e90028 (2014).

  157. 157.

    Attur, M. et al. Increased interleukin-1β gene expression in peripheral blood leukocytes is associated with increased pain and predicts risk for progression of symptomatic knee osteoarthritis. Arthritis Rheum. 63, 1908–1917 (2011).

  158. 158.

    Lotz, M. et al. Value of biomarkers in osteoarthritis: current status and perspectives. Ann. Rheum. Dis. 72, 1756–1763 (2013).

  159. 159.

    de Bakker, E., Stroobants, V., VanDael, F., van Ryssen, B. & Meyer, E. Canine synovial fluid biomarkers for early detection and monitoring of osteoarthritis. Vet. Rec. 180, 328–329 (2017).

  160. 160.

    Hay, C. W., Chu, Q., Budsberg, S. C., Clayton, M. K. & Johnson, K. A. Synovial fluid interleukin 6, tumor necrosis factor, and nitric oxide values in dogs with osteoarthritis secondary to cranial cruciate ligament rupture. Am. J. Vet. Res. 58, 1027–1032 (1997).

  161. 161.

    Fujita, Y. et al. Direct and indirect markers of cartilage metabolism in synovial fluid obtained from dogs with hip dysplasia and correlation with clinical and radiographic variables. Am. J. Vet. Res. 66, 2028–2033 (2005).

  162. 162.

    Ramírez, S. C., Molano, R. F. S. & Castaño, G. J. Biomarkers variability in a canine hip osteoarthritis model. Osteoarthritis Cartilage 25, S106 (2017).

  163. 163.

    Messier, S. P., Loeser, R. F., Hoover, J. L., Semble, E. L. & Wise, C. M. Osteoarthritis of the knee: effects on gait, strength, and flexibility. Arch. Phys. Med. Rehabil. 73, 29–36 (1992).

  164. 164.

    Muller, C. et al. Evaluation of clinical metrology instrument in dogs with osteoarthritis. J. Vet. Intern. Med. 30, 836–846 (2016).

  165. 165.

    Brunner, H. I. et al. Health of children with chronic arthritis: relationship of different measures and the quality of parent proxy reporting. Arthritis Rheum. 51, 763–773 (2004).

  166. 166.

    Warden, V., Hurley, A. C. & Volicer, L. Development and psychometric evaluation of the Pain Assessment in Advanced Dementia (PAINAD) scale. J. Am. Med. Dir. Assoc. 4, 9–15 (2003).

  167. 167.

    Brown, D. C., Boston, R., Coyne, J. C. & Farrar, J. T. A novel approach to the use of animals in studies of pain: validation of the canine brief pain inventory in canine bone cancer. Pain Med. 10, 133–142 (2009).

  168. 168.

    Brown, D. C., Boston, R. C., Coyne, J. C. & Farrar, J. T. Ability of the canine brief pain inventory to detect response to treatment in dogs with osteoarthritis. J. Am. Vet. Med. Assoc. 233, 1278–1283 (2008).

  169. 169.

    Walton, M. B., Cowderoy, E., Lascelles, D. & Innes, J. F. Evaluation of construct and criterion validity for the ‘Liverpool Osteoarthritis in Dogs’ (LOAD) clinical metrology instrument and comparison to two other instruments. PLoS ONE 8, e58125 (2013).

  170. 170.

    Knazovicky, D., Tomas, A., Motsinger-Reif, A. & Lascelles, B. D. X. Initial evaluation of nighttime restlessness in a naturally occurring canine model of osteoarthritis pain. PeerJ 3, e772 (2015).

  171. 171.

    Belshaw, Z., Asher, L. & Dean, R. S. Systematic review of outcome measures reported in clinical canine osteoarthritis research. Vet. Surg. 45, 480–487 (2016).

  172. 172.

    Sanchez-Bustinduy, M. et al. Comparison of kinematic variables in defining lameness caused by naturally occurring rupture of the cranial cruciate ligament in dogs. Vet. Surg. 39, 523–530 (2010).

  173. 173.

    Moreau, M., Lussier, B., Ballaz, L. & Troncy, E. Kinetic measurements of gait for osteoarthritis research in dogs and cats. Can. Vet. J. 55, 1057–1065 (2014).

  174. 174.

    Rialland, P. et al. Clinical validity of outcome pain measures in naturally occurring canine osteoarthritis. BMC Vet. Res. 8, 162 (2012).

  175. 175.

    Lascelles, B. D. X. et al. Evaluation of a digitally integrated accelerometer-based activity monitor for the measurement of activity in cats. Vet. Anaesth. Analg. 35, 173–183 (2008).

  176. 176.

    Hansen, B. D., Lascelles, B. D. X., Keene, B. W., Adams, A. K. & Thomson, A. E. Evaluation of an accelerometer for at-home monitoring of spontaneous activity in dogs. Am. J. Vet. Res. 68, 468–475 (2007).

  177. 177.

    Lascelles, B. D. X. et al. A canine-specific anti-nerve growth factor antibody alleviates pain and improves mobility and function in dogs with degenerative joint disease-associated pain. BMC Vet. Res. 11, 101 (2015).

  178. 178.

    Briley, J. D., Williams, M. D., Freire, M., Griffith, E. H. & Lascelles, B. D. X. Feasibility and repeatability of cold and mechanical quantitative sensory testing in normal dogs. Vet. J. 199, 245–250 (2014).

  179. 179.

    Williams, M. D. et al. Feasibility and repeatability of thermal quantitative sensory testing in normal dogs and dogs with hind limb osteoarthritis-associated pain. Vet. J. 199, 63–67 (2014).

  180. 180.

    Cook, P. F., Brooks, A., Spivak, M. & Berns, G. S. Regional brain activations in awake unrestrained dogs. J. Vet. Behav. 16, 104–112 (2016).

  181. 181.

    Berns, G. S., Brooks, A. & Spivak, M. Replicability and heterogeneity of awake unrestrained canine FMRI responses. PLoS ONE 8, e81698 (2013).

  182. 182.

    Arendt-Nielsen, L. et al. Association between experimental pain biomarkers and serologic markers in patients with different degrees of painful knee osteoarthritis. Arthritis Rheumatol. 66, 3317–3326 (2014).

  183. 183.

    Arendt-Nielsen, L. et al. Sensitization in patients with painful knee osteoarthritis. Pain 149, 573–581 (2010).

  184. 184.

    Rialland, P. et al. Association between sensitisation and pain-related behaviours in an experimental canine model of osteoarthritis. Pain 155, 2071–2079 (2014).

  185. 185.

    Knazovicky, D. et al. Widespread somatosensory sensitivity in naturally occurring canine model of osteoarthritis. Pain 157, 1325–1332 (2016).

  186. 186.

    Tomas, A., Marcellin-Little, D. J., Roe, S. C., Motsinger-Reif, A. & Lascelles, B. D. X. Relationship between mechanical thresholds and limb use in dogs with coxofemoral joint OA-associated pain and the modulating effects of pain alleviation from total hip replacement on mechanical thresholds. Vet. Surg. 43, 542–548 (2014).

  187. 187.

    Aranda-Villalobos, P. et al. Normalization of widespread pressure pain hypersensitivity after total hip replacement in patients with hip osteoarthritis is associated with clinical and functional improvements. Arthritis Rheum. 65, 1262–1270 (2013).

  188. 188.

    Brown, D. C. Resiniferatoxin: the evolution of the ‘molecular scalpel’ for chronic pain relief. Pharmaceuticals (Basel) 9, E47 (2016).

  189. 189.

    Moreau, M. et al. A posteriori comparison of natural and surgical destabilization models of canine osteoarthritis. Biomed. Res. Int. 2013, 180453 (2013).

  190. 190.

    Hooijmans, C. R., Leenaars, M. & Ritskes-Hoitinga, M. A gold standard publication checklist to improve the quality of animal studies, to fully integrate the Three Rs, and to make systematic reviews more feasible. Altern. Lab. Anim. 38, 167–182 (2010).

  191. 191.

    Sanga, P. et al. Efficacy, safety, and tolerability of fulranumab, an anti-nerve growth factor antibody, in the treatment of patients with moderate to severe osteoarthritis pain. Pain 154, 1910–1919 (2013).

  192. 192.

    Yu, L. P. et al. Reduction of the severity of canine osteoarthritis by prophylactic treatment with oral doxycycline. Arthritis Rheum. 35, 1150–1159 (1992).

  193. 193.

    Moreau, M. et al. Efficacy of licofelone in dogs with clinical osteoarthritis. Vet. Rec. 160, 584–588 (2007).

  194. 194.

    Iadarola, M. J., Sapio, M. R., Raithel, S. J., Mannes, A. J. & Brown, D. C. Long-term pain relief in canine osteoarthritis by a single intra-articular injection of resiniferatoxin, a potent TRPV1 agonist. Pain 159, 2105–2114 (2018).

  195. 195.

    Raynauld, J.-P. et al. Protective effects of licofelone, a 5-lipoxygenase and cyclo-oxygenase inhibitor, versus naproxen on cartilage loss in knee osteoarthritis: a first multicentre clinical trial using quantitative MRI. Ann. Rheum. Dis. 68, 938–947 (2009).

  196. 196.

    Brandt, K. D. et al. Effects of doxycycline on progression of osteoarthritis: results of a randomized, placebo-controlled, double-blind trial. Arthritis Rheum. 52, 2015–2025 (2005).

  197. 197.

    Arrich, J. et al. Intra-articular hyaluronic acid for the treatment of osteoarthritis of the knee: systematic review and meta-analysis. CMAJ 172, 1039–1043 (2005).

  198. 198.

    Carapeba, G. O. L. et al. Intra-articular hyaluronic acid compared to traditional conservative treatment in dogs with osteoarthritis associated with hip dysplasia. Evid. Based Complement. Alternat. Med. 2016, 2076921 (2016).

  199. 199.

    Kriston-Pál, É. et al. Characterization and therapeutic application of canine adipose mesenchymal stem cells to treat elbow osteoarthritis. Can. J. Vet. Res. 81, 73–78 (2017).

  200. 200.

    Vilar, J. M. et al. Assessment of the effect of intraarticular injection of autologous adipose-derived mesenchymal stem cells in osteoarthritic dogs using a double blinded force platform analysis. BMC Vet. Res. 10, 143 (2014).

  201. 201.

    Allen, M. J. Advances in total joint replacement in small animals. J. Small Anim. Pract. 53, 495–506 (2012).

  202. 202.

    Skurla, C. P. et al. Assessing the dog as a model for human total hip replacement. Analysis of 38 canine cemented femoral components retrieved at post-mortem. J. Bone Joint Surg. Br. 87, 120–127 (2005).

  203. 203.

    Clarke, I. C. et al. Development of a ceramic surface replacement for the hip. An experimental Sialon model. Biomater. Med. Devices Artif. Organs 7, 111–126 (1979).

  204. 204.

    Harris, W. H. & Jasty, M. Bone ingrowth into porous coated canine acetabular replacements: the effect of pore size, apposition, and dislocation. Hip 1985, 214–234 (1985).

  205. 205.

    Jasty, M. et al. Porous-coated uncemented components in experimental total hip arthroplasty in dogs. Effect of plasma-sprayed calcium phosphate coatings on bone ingrowth. Clin. Orthop. Relat. Res. 280, 300–309 (1992).

  206. 206.

    Kim, Y. H., Kim, J. S., Park, J. W. & Joo, J. H. Comparison of total hip replacement with and without cement in patients younger than 50 years of age: the results at 18 years. J. Bone Joint Surg. Br. 93, 449–455 (2011).

  207. 207.

    Johnston, S. A., McLaughlin, R. M. & Budsberg, S. C. Nonsurgical management of osteoarthritis in dogs. Vet. Clin. North Am. Small Anim. Pract. 38, 1449–1470 (2008).

  208. 208.

    National Institute for Health and Care Excellence. Osteoarthritis: care and management. (2014).

  209. 209.

    Bowen, A. & Casadevall, A. Increasing disparities between resource inputs and outcomes, as measured by certain health deliverables, in biomedical research. Proc. Natl Acad. Sci. USA 112, 11335–11340 (2015).

  210. 210.

    Klinck, M. P. et al. Translational pain assessment. Pain 158, 1633–1646 (2017).

  211. 211.

    U.S. Food and Drug Administration. Osteoarthritis: structural endpoints for the development of drugs, devices, and biological products for treatment guidance for industry. (2018).

  212. 212.

    Eitner, A., Hofmann, G. O. & Schaible, H.-G. Mechanisms of osteoarthritic pain. studies in humans and experimental models. Front. Mol. Neurosci. 10, 349 (2017).

  213. 213.

    Hannan, M. T., Felson, D. T. & Pincus, T. Analysis of the discordance between radiographic changes and knee pain in osteoarthritis of the knee. J. Rheumatol. 27, 1513–1517 (2000).

  214. 214.

    Gordon, W. J. et al. The relationship between limb function and radiographic osteoarthrosis in dogs with stifle osteoarthrosis. Vet. Surg. 32, 451–454 (2003).

  215. 215.

    Walsh, K. Chronic pain management in dogs and cats. In Pract. 38, 155–165 (2016).

  216. 216.

    Conaghan, P. G. Parallel evolution of OA phenotypes and therapies. Nat. Rev. Rheumatol. 9, 68–70 (2013).

  217. 217.

    Bierma-Zeinstra, S. M. A. & Verhagen, A. P. Osteoarthritis subpopulations and implications for clinical trial design. Arthritis Res. Ther. 13, 213 (2011).

  218. 218.

    Guermazi, A., Roemer, F. W., Haugen, I. K., Crema, M. D. & Hayashi, D. MRI-based semiquantitative scoring of joint pathology in osteoarthritis. Nat. Rev. Rheumatol. 9, 236–251 (2013).

  219. 219.

    Felson, D. T. et al. Correlation of the development of knee pain with enlarging bone marrow lesions on magnetic resonance imaging. Arthritis Rheum. 56, 2986–2992 (2007).

  220. 220.

    Neogi, T. Structural correlates of pain in osteoarthritis. Clin. Exp. Rheumatol. 35 (Suppl. 107), 75–78 (2017).

  221. 221.

    Winegardner, K. R., Scrivani, P. V., Krotscheck, U. & Todhunter, R. J. Magnetic resonance imaging of subarticular bone marrow lesions in dogs with stifle lameness. Vet. Radiol. Ultrasound 48, 312–317 (2007).

  222. 222.

    Olive, J., d’Anjou, M.-A., Cabassu, J., Chailleux, N. & Blond, L. Fast presurgical magnetic resonance imaging of meniscal tears and concurrent subchondral bone marrow lesions. Study of dogs with naturally occurring cranial cruciate ligament rupture. Vet. Comp. Orthop. Traumatol. 27, 1–7 (2014).

  223. 223.

    Budsberg, S. C., Torres, B. T., Kleine, S. A., Sandberg, G. S. & Berjeski, A. K. Lack of effectiveness of tramadol hydrochloride for the treatment of pain and joint dysfunction in dogs with chronic osteoarthritis. J. Am. Vet. Med. Assoc. 252, 427–432 (2018).

  224. 224.

    Forster, K. E. et al. Complications and owner assessment of canine total hip replacement: a multicenter internet based survey. Vet. Surg. 41, 545–550 (2012).

  225. 225.

    Cook, J. L. et al. Proposed definitions and criteria for reporting time frame, outcome, and complications for clinical orthopedic studies in veterinary medicine. Vet. Surg. 39, 905–908 (2010).

  226. 226.

    Takashima, G. & Day, M. Setting the One Health agenda and the human-companion animal bond. Int. J. Environ. Res. Public Health 11, 11110–11120 (2014).

  227. 227.

    Saunders, L. Z. Virchow’s contributions to veterinary medicine: celebrated then, forgotten now. Vet. Pathol. 37, 199–207 (2000).

  228. 228.

    Cassidy, A. in Investigating Interdisciplinary Collaboration: Theory and Practice Across Disciplines (eds Frickel, S., Albert, M. & Prainsack, B.) 213–236 (Rutgers Univ. Press, 2016).

  229. 229.

    Little, D. et al. Functional outcome measures in a surgical model of hip osteoarthritis in dogs. J. Exp. Orthop. 3, 17 (2016).

  230. 230.

    Conzemius, M. G. & Vandervoort, J. Total joint replacement in the dog. Vet. Clin. North Am. Small Anim. Pract. 35, 1213–1231 (2005).

  231. 231.

    Lascelles, B. D. X. et al. Evaluation of functional outcome after BFX total hip replacement using a pressure sensitive walkway. Vet. Surg. 39, 71–77 (2010).

  232. 232.

    Dow, C., Michel, K. E., Love, M. & Brown, D. C. Evaluation of optimal sampling interval for activity monitoring in companion dogs. Am. J. Vet. Res. 70, 444–448 (2009).

  233. 233.

    Vaughan, L. C. The history of canine cruciate ligament surgery from 1952–2005. Vet. Comp. Orthop. Traumatol. 23, 379–384 (2010).

  234. 234.

    Slocum, B. & Slocum, T. D. Tibial plateau leveling osteotomy for repair of cranial cruciate ligament rupture in the canine. Vet. Clin. North Am. Small Anim. Pract. 23, 777–795 (1993).

  235. 235.

    Murawski, C. D., van Eck, C. F., Irrgang, J. J., Tashman, S. & Fu, F. H. Operative treatment of primary anterior cruciate ligament rupture in adults. J. Bone Joint Surg. Am. 96, 685–694 (2014).

Download references

Reviewer information

Nature Reviews Rheumatology thanks A. Mobasheri and the other anonymous reviewers for their contribution to the peer review of this work.

Author information


  1. Skeletal Biology Group, Comparative Biomedical Sciences, Royal Veterinary College, University of London, London, UK

    • Richard L. Meeson
    •  & Andrew A. Pitsillides
  2. Department of Clinical Services and Sciences, Royal Veterinary College, University of London, London, UK

    • Richard L. Meeson
  3. Institute of Orthopaedics and Musculoskeletal Science, University College London, London, UK

    • Richard L. Meeson
    •  & Gordon Blunn
  4. Department of Clinical Sciences, Cornell University, Ithaca, NY, USA

    • Rory J. Todhunter
  5. Cornell Veterinary Biobank, Cornell University, Ithaca, NY, USA

    • Rory J. Todhunter
  6. School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK

    • Gordon Blunn
  7. Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK

    • George Nuki


  1. Search for Richard L. Meeson in:

  2. Search for Rory J. Todhunter in:

  3. Search for Gordon Blunn in:

  4. Search for George Nuki in:

  5. Search for Andrew A. Pitsillides in:


R.L.M. researched data for the article. R.L.M., R.J.T. and A.A.P. contributed substantially to discussions of content. All authors wrote the article and reviewed or edited the manuscript before submission.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Andrew A. Pitsillides.


Stifle joints

An analogous term for the knee joints in quadrupedal animals.

Pond-Nuki model

An experimental model of knee instability-driven osteoarthritis in dogs involving surgical cranial cruciate ligament transection.

Ortolani test

Physical examination test performed in dogs and infants to assess for excessive laxity in the hip joint that allows dislocation.

Norberg angle

An angle based upon a radiographic measure of a line that connects the centres of both femoral heads and the craniodorsal rim of the acetabulum on the same side; used as a surrogate measure of hip laxity and femoral head coverage by the acetabulum.

Force plate analysis

Instruments that measure ground reaction forces as they are walked over by a human or an animal; used to provide parameters of gait and limb function.

Telemetric accelerometry

A device that measures and records proper acceleration; used to determine activity and gait parameters.

Quantitative Sensory Testing

A non-invasive test of nerve function and/or pain that uses temperature or skin vibration.

Peak vertical force

A biomechanics term that identifies a component of locomotor ground reaction force.

‘Three Rs’ agenda

An initiative to improve the use of or reduce the numbers of animals used in scientific research through three key initiatives — replacement, reduction and refinement.

Vertical impulse

An index of limb function generated from force plate analysis and derived from the vertical vector force applied and the duration that it is imparted for.

About this article

Publication history


Issue Date