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Investigational approaches to the management of osteoarthritis

Shirley Yu, BSc (Med), MBBS, MPH, FRACP
Section Editor
David Hunter, MD, PhD
Deputy Editor
Monica Ramirez Curtis, MD, MPH


The management of osteoarthritis (OA) consists of nonpharmacologic, pharmacologic, and surgical approaches. Conventional pharmacologic therapy for OA has mainly targeted symptomatic relief, with agents such as nonsteroidal antiinflammatory drugs (NSAIDs), acetaminophen, opioid analgesia, and intraarticular injections.

As we gain a better understanding of the pathogenetic mechanisms in OA, there has been a growing interest in the development of drugs whose mechanism of action are directed towards different pain pathways, as well as the inhibition of catabolic processes or stimulation of anabolic processes in the OA joint. These drugs are referred to as disease-modifying OA drugs (DMOADs) or structure-modifying OA drugs (SMOADs).

To date, no pharmacologic agents have been approved of by regulatory authorities for disease modification in OA. Existing trial strategies have failed to detect clinical efficacy of potential disease-modifying OA drugs (DMOADs) based on the lack of responsive outcome measures to record treatment-related improvements in pain, function, or joint structure, or just due to lack of efficacy of these agents. While there has been progress with potential new analgesics, including targeting nerve growth factor, the availability of a potential structural modification agent appears distant.

A review of investigational approaches to the pharmacotherapy of OA will be discussed here. Established therapies for OA and surgical interventions are discussed elsewhere. (See "Overview of surgical therapy of knee and hip osteoarthritis".)


The major goals of osteoarthritis (OA) management are pain control, functional improvement, education about the disease, self-management, and prevention or slowing of structural changes to the joints. However, developing agents to address these goals are challenging given the complexity of pain pathways and the etiology of structural changes.

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Literature review current through: Nov 2017. | This topic last updated: Jan 17, 2017.
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  1. Lane NE, Schnitzer TJ, Birbara CA, et al. Tanezumab for the treatment of pain from osteoarthritis of the knee. N Engl J Med 2010; 363:1521.
  2. Wood JN. Nerve growth factor and pain. N Engl J Med 2010; 363:1572.
  3. Hochberg MC, Tive LA, Abramson SB, et al. When Is Osteonecrosis Not Osteonecrosis?: Adjudication of Reported Serious Adverse Joint Events in the Tanezumab Clinical Development Program. Arthritis Rheumatol 2016; 68:382.
  4. Schnitzer TJ, Ekman EF, Spierings EL, et al. Efficacy and safety of tanezumab monotherapy or combined with non-steroidal anti-inflammatory drugs in the treatment of knee or hip osteoarthritis pain. Ann Rheum Dis 2015; 74:1202.
  5. Fioravanti A, Fabbroni M, Cerase A, Galeazzi M. Treatment of erosive osteoarthritis of the hands by intra-articular infliximab injections: a pilot study. Rheumatol Int 2009; 29:961.
  6. Güler-Yüksel M, Allaart CF, Watt I, et al. Treatment with TNF-α inhibitor infliximab might reduce hand osteoarthritis in patients with rheumatoid arthritis. Osteoarthritis Cartilage 2010; 18:1256.
  7. Magnano MD, Chakravarty EF, Broudy C, et al. A pilot study of tumor necrosis factor inhibition in erosive/inflammatory osteoarthritis of the hands. J Rheumatol 2007; 34:1323.
  8. Chevalier X, Ravaud P, Maheu E, et al. Adalimumab in patients with hand osteoarthritis refractory to analgesics and NSAIDs: a randomised, multicentre, double-blind, placebo-controlled trial. Ann Rheum Dis 2015; 74:1697.
  9. Verbruggen G, Wittoek R, Vander Cruyssen B, Elewaut D. Tumour necrosis factor blockade for the treatment of erosive osteoarthritis of the interphalangeal finger joints: a double blind, randomised trial on structure modification. Ann Rheum Dis 2012; 71:891.
  10. Pelletier JP, Caron JP, Evans C, et al. In vivo suppression of early experimental osteoarthritis by interleukin-1 receptor antagonist using gene therapy. Arthritis Rheum 1997; 40:1012.
  11. Santangelo KS, Nuovo GJ, Bertone AL. In vivo reduction or blockade of interleukin-1β in primary osteoarthritis influences expression of mediators implicated in pathogenesis. Osteoarthritis Cartilage 2012; 20:1610.
  12. Chevalier X, Goupille P, Beaulieu AD, et al. Intraarticular injection of anakinra in osteoarthritis of the knee: a multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum 2009; 61:344.
  13. Cohen SB, Proudman S, Kivitz AJ, et al. A randomized, double-blind study of AMG 108 (a fully human monoclonal antibody to IL-1R1) in patients with osteoarthritis of the knee. Arthritis Res Ther 2011; 13:R125.
  14. Doorenspleet ME, Klarenbeek PL, de Hair MJ, et al. Rheumatoid arthritis synovial tissue harbours dominant B-cell and plasma-cell clones associated with autoreactivity. Ann Rheum Dis 2014; 73:756.
  15. Davidson RK, Waters JG, Kevorkian L, et al. Expression profiling of metalloproteinases and their inhibitors in synovium and cartilage. Arthritis Res Ther 2006; 8:R124.
  16. Ohuchi E, Imai K, Fujii Y, et al. Membrane type 1 matrix metalloproteinase digests interstitial collagens and other extracellular matrix macromolecules. J Biol Chem 1997; 272:2446.
  17. Krzeski P, Buckland-Wright C, Bálint G, et al. Development of musculoskeletal toxicity without clear benefit after administration of PG-116800, a matrix metalloproteinase inhibitor, to patients with knee osteoarthritis: a randomized, 12-month, double-blind, placebo-controlled study. Arthritis Res Ther 2007; 9:R109.
  18. Tu G, Xu W, Huang H, Li S. Progress in the development of matrix metalloproteinase inhibitors. Curr Med Chem 2008; 15:1388.
  19. Loeser RF, Erickson EA, Long DL. Mitogen-activated protein kinases as therapeutic targets in osteoarthritis. Curr Opin Rheumatol 2008; 20:581.
  20. Starkman BG, Cravero JD, Delcarlo M, Loeser RF. IGF-I stimulation of proteoglycan synthesis by chondrocytes requires activation of the PI 3-kinase pathway but not ERK MAPK. Biochem J 2005; 389:723.
  21. Zhang J, Shen B, Lin A. Novel strategies for inhibition of the p38 MAPK pathway. Trends Pharmacol Sci 2007; 28:286.
  22. Schnitzer TJ. New pharmacologic approaches in the management of osteoarthritis. Arthritis Care Res (Hoboken) 2010; 62:1174.
  23. Hellio le Graverand MP, Clemmer RS, Redifer P, et al. A 2-year randomised, double-blind, placebo-controlled, multicentre study of oral selective iNOS inhibitor, cindunistat (SD-6010), in patients with symptomatic osteoarthritis of the knee. Ann Rheum Dis 2013; 72:187.
  24. Song IH, Althoff CE, Hermann KG, et al. Contrast-enhanced ultrasound in monitoring the efficacy of a bradykinin receptor 2 antagonist in painful knee osteoarthritis compared with MRI. Ann Rheum Dis 2009; 68:75.
  25. Meini S, Maggi CA. Knee osteoarthritis: a role for bradykinin? Inflamm Res 2008; 57:351.
  26. Gomis A, Meini S, Miralles A, et al. Blockade of nociceptive sensory afferent activity of the rat knee joint by the bradykinin B2 receptor antagonist fasitibant. Osteoarthritis Cartilage 2013; 21:1346.
  27. Griffith DL, Keck PC, Sampath TK, et al. Three-dimensional structure of recombinant human osteogenic protein 1: structural paradigm for the transforming growth factor beta superfamily. Proc Natl Acad Sci U S A 1996; 93:878.
  28. Elshaier AM, Hakimiyan AA, Rappoport L, et al. Effect of interleukin-1beta on osteogenic protein 1-induced signaling in adult human articular chondrocytes. Arthritis Rheum 2009; 60:143.
  29. Hunter DJ, Pike MC, Jonas BL, et al. Phase 1 safety and tolerability study of BMP-7 in symptomatic knee osteoarthritis. BMC Musculoskelet Disord 2010; 11:232.
  30. Moore EE, Bendele AM, Thompson DL, et al. Fibroblast growth factor-18 stimulates chondrogenesis and cartilage repair in a rat model of injury-induced osteoarthritis. Osteoarthritis Cartilage 2005; 13:623.
  31. Ellman MB, An HS, Muddasani P, Im HJ. Biological impact of the fibroblast growth factor family on articular cartilage and intervertebral disc homeostasis. Gene 2008; 420:82.
  32. Mastbergen SC, Saris DB, Lafeber FP. Functional articular cartilage repair: here, near, or is the best approach not yet clear? Nat Rev Rheumatol 2013; 9:277.
  33. Lohmander LS, Hellot S, Dreher D, et al. Intraarticular sprifermin (recombinant human fibroblast growth factor 18) in knee osteoarthritis: a randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol 2014; 66:1820.
  34. Andia I, Maffulli N. Platelet-rich plasma for managing pain and inflammation in osteoarthritis. Nat Rev Rheumatol 2013; 9:721.
  35. van Buul GM, Koevoet WL, Kops N, et al. Platelet-rich plasma releasate inhibits inflammatory processes in osteoarthritic chondrocytes. Am J Sports Med 2011; 39:2362.
  36. Laudy AB, Bakker EW, Rekers M, Moen MH. Efficacy of platelet-rich plasma injections in osteoarthritis of the knee: a systematic review and meta-analysis. Br J Sports Med 2015; 49:657.
  37. Karsdal MA, Sondergaard BC, Arnold M, Christiansen C. Calcitonin affects both bone and cartilage: a dual action treatment for osteoarthritis? Ann N Y Acad Sci 2007; 1117:181.
  38. Li J, Xie ZG, Xie Y, Dong QR. Calcitonin treatment is associated with less severe osteoarthritis and reduced toll-like receptor levels in a rat model. J Orthop Sci 2014; 19:1019.
  39. Manicourt DH, Azria M, Mindeholm L, et al. Oral salmon calcitonin reduces Lequesne's algofunctional index scores and decreases urinary and serum levels of biomarkers of joint metabolism in knee osteoarthritis. Arthritis Rheum 2006; 54:3205.
  40. Karsdal MA, Byrjalsen I, Alexandersen P, et al. Treatment of symptomatic knee osteoarthritis with oral salmon calcitonin: results from two phase 3 trials. Osteoarthritis Cartilage 2015; 23:532.
  41. Bingham CO 3rd, Buckland-Wright JC, Garnero P, et al. Risedronate decreases biochemical markers of cartilage degradation but does not decrease symptoms or slow radiographic progression in patients with medial compartment osteoarthritis of the knee: results of the two-year multinational knee osteoarthritis structural arthritis study. Arthritis Rheum 2006; 54:3494.
  42. Saag KG. Bisphosphonates for osteoarthritis prevention: "Holy Grail" or not? Ann Rheum Dis 2008; 67:1358.
  43. Spector TD, Conaghan PG, Buckland-Wright JC, et al. Effect of risedronate on joint structure and symptoms of knee osteoarthritis: results of the BRISK randomized, controlled trial [ISRCTN01928173]. Arthritis Res Ther 2005; 7:R625.
  44. Nishii T, Tamura S, Shiomi T, et al. Alendronate treatment for hip osteoarthritis: prospective randomized 2-year trial. Clin Rheumatol 2013; 32:1759.
  45. Laslett LL, Doré DA, Quinn SJ, et al. Zoledronic acid reduces knee pain and bone marrow lesions over 1 year: a randomised controlled trial. Ann Rheum Dis 2012; 71:1322.
  46. Reginster JY, Badurski J, Bellamy N, et al. Efficacy and safety of strontium ranelate in the treatment of knee osteoarthritis: results of a double-blind, randomised placebo-controlled trial. Ann Rheum Dis 2013; 72:179.
  47. Bruyere O, Delferriere D, Roux C, et al. Effects of strontium ranelate on spinal osteoarthritis progression. Ann Rheum Dis 2008; 67:335.
  48. Pelletier JP, Roubille C, Raynauld JP, et al. Disease-modifying effect of strontium ranelate in a subset of patients from the Phase III knee osteoarthritis study SEKOIA using quantitative MRI: reduction in bone marrow lesions protects against cartilage loss. Ann Rheum Dis 2015; 74:422.