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01-01-2015 | Osteoarthritis | Book Chapter | Article

10. Drug/Agent Treatments for Osteoarthritis: Present and Future

Authors: Camille Roubille, MD, Jean-Pierre Pelletier, MD, Johanne Martel-Pelletier, PhD

Publisher: Springer International Publishing

Abstract

  • Osteoarthritis (OA) management is currently based on a wide spectrum of therapeutic options to relieve pain, but other OA drugs with disease-modifying properties (DMOADs) are being developed.
  • There are presently agents that are symptomatic slow-acting drugs for OA (SYSADOA), which not only reduce joint pain but could also slow the structural disease progression in the joint.
  • Targeting cartilage changes (catabolism and anabolism), subchondral bone remodeling, and synovial inflammation are the three main thrusts of research in DMOAD development. Promising emerging therapies include platelet-rich plasma (PRP), bone remodeling modulators, and inflammatory inhibitors.
  • OA should be considered a dynamic process and may be a systemic disease with several tissues and pathways to target for DMOAD development.
  • With the advent of DMOADs, physicians should aim at treating the “patient” rather than the “disease.” Combining therapeutics at both local and systemic levels to impact both symptoms and joint structural changes will likely be the future strategy instead of a sole drug, at least at the beginning of the treatment.
  • Selectively targeting some phenotypes of OA patients evidenced by sensitive tools, such as magnetic resonance imaging (MRI), may allow the development of DMOADs based on personalized medicine.
Literature
1.
Jordan KM, Arden NK, Doherty M, Bannwarth B, Bijlsma JW, Dieppe P, et al. EULAR Recommendations 2003: an evidence based approach to the management of knee osteoarthritis: Report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). Ann Rheum Dis. 2003;62:1145–55.PubMedCentralCrossRefPubMed
2.
Zhang W, Moskowitz RW, Nuki G, Abramson S, Altman RD, Arden N, et al. OARSI recommendations for the management of hip and knee osteoarthritis, part II: OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage. 2008;16:137–62.CrossRefPubMed
3.
Zhang W, Nuki G, Moskowitz RW, Abramson SB, Altman RD, Arden NK, et al. OARSI recommendations for the management of hip and knee osteoarthritis: part III: changes in evidence following systematic cumulative update of research published through January 2009. Osteoarthritis Cartilage. 2010;18:476–99.CrossRefPubMed
4.
Hochberg MC, Altman RD, April KT, Benkhalti M, Guyatt G, McGowan J, et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res (Hoboken). 2012;64:455–74.CrossRef
5.
Zhang W, Jones A, Doherty M. Does paracetamol (acetaminophen) reduce the pain of osteoarthritis? A meta-analysis of randomised controlled trials. Ann Rheum Dis. 2004;63:901–7.PubMedCentralCrossRefPubMed
6.
Towheed TE, Maxwell L, Judd MG, Catton M, Hochberg MC, Wells G. Acetaminophen for osteoarthritis. Cochrane Database Syst Rev. 2006;(1):CD004257.
7.
Curhan GC, Knight EL, Rosner B, Hankinson SE, Stampfer MJ. Lifetime nonnarcotic analgesic use and decline in renal function in women. Arch Intern Med. 2004;164:1519–24.CrossRefPubMed
8.
Forman JP, Rimm EB, Curhan GC. Frequency of analgesic use and risk of hypertension among men. Arch Intern Med. 2007;167:394–9.CrossRefPubMed
9.
Rahme E, Barkun A, Nedjar H, Gaugris S, Watson D. Hospitalizations for upper and lower GI events associated with traditional NSAIDs and acetaminophen among the elderly in Quebec, Canada. Am J Gastroenterol. 2008;103:872–82.CrossRefPubMed
10.
Heard KJ, Green JL, Dart RC. Serum alanine aminotransferase elevation during 10 days of acetaminophen use in nondrinkers. Pharmacotherapy. 2010;30:818–22.PubMedCentralCrossRefPubMed
11.
Miller M, Sturmer T, Azrael D, Levin R, Solomon DH. Opioid analgesics and the risk of fractures in older adults with arthritis. J Am Geriatr Soc. 2011;59:430–8.PubMedCentralCrossRefPubMed
12.
Avouac J, Gossec L, Dougados M. Efficacy and safety of opioids for osteoarthritis: a meta-analysis of randomized controlled trials. Osteoarthritis Cartilage. 2007;15:957–65.CrossRefPubMed
13.
Hochberg MC, Wohlreich M, Gaynor P, Hanna S, Risser R. Clinically relevant outcomes based on analysis of pooled data from 2 trials of duloxetine in patients with knee osteoarthritis. J Rheumatol. 2012;39:352–8.CrossRefPubMed
14.
Skljarevski V, Zhang S, Iyengar S, D’Souza D, Alaka K, Chappell A, et al. Efficacy of duloxetine in patients with chronic pain conditions. Curr Drug Ther. 2011;6:296–303.PubMedCentralCrossRefPubMed
15.
Trelle S, Reichenbach S, Wandel S, Hildebrand P, Tschannen B, Villiger PM, et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ. 2011;342:c7086.PubMedCentralCrossRefPubMed
16.
Tugwell PS, Wells GA, Shainhouse JZ. Equivalence study of a topical diclofenac solution (pennsaid) compared with oral diclofenac in symptomatic treatment of osteoarthritis of the knee: a randomized controlled trial. J Rheumatol. 2004;31:2002–12.PubMed
17.
Underwood M, Ashby D, Cross P, Hennessy E, Letley L, Martin J, et al. Advice to use topical or oral ibuprofen for chronic knee pain in older people: randomised controlled trial and patient preference study. BMJ. 2008;336:138–42.PubMedCentralCrossRefPubMed
18.
McCleane G. The analgesic efficacy of topical capsaicin is enhanced by glyceryl trinitrate in painful osteoarthritis: a randomized, double blind, placebo controlled study. Eur J Pain. 2000;4:355–60.CrossRefPubMed
19.
Gammaitoni AR, Galer BS, Onawola R, Jensen MP, Argoff CE. Lidocaine patch 5% and its positive impact on pain qualities in osteoarthritis: results of a pilot 2-week, open-label study using the Neuropathic Pain Scale. Curr Med Res Opin. 2004;20 Suppl 2:S13–9.CrossRefPubMed
20.
Bellamy N, Campbell J, Robinson V, Gee T, Bourne R, Wells G. Intraarticular corticosteroid for treatment of osteoarthritis of the knee. Cochrane Database Syst Rev. 2006;(2):CD005328.
21.
Raynauld JP, Buckland-Wright C, Ward R, Choquette D, Haraoui B, Martel-Pelletier J, et al. Safety and efficacy of long-term intraarticular steroid injections in osteoarthritis of the knee: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2003;48:370–7.CrossRefPubMed
22.
Bellamy N, Campbell J, Robinson V, Gee T, Bourne R, Wells G. Viscosupplementation for the treatment of osteoarthritis of the knee. Cochrane Database Syst Rev. 2005;(2):CD005321.
23.
Reginster JY, Deroisy R, Rovati LC, Lee RL, Lejeune E, Bruyere O, et al. Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial. Lancet. 2001;357:251–6.CrossRefPubMed
24.
Pavelka K, Gatterova J, Olejarova M, Machacek S, Giacovelli G, Rovati LC. Glucosamine sulfate use and delay of progression of knee osteoarthritis: a 3-year, randomized, placebo-controlled, double-blind study. Arch Intern Med. 2002;162:2113–23.CrossRefPubMed
25.
Bruyere O, Pavelka K, Rovati LC, Deroisy R, Olejarova M, Gatterova J, et al. Glucosamine sulfate reduces osteoarthritis progression in postmenopausal women with knee osteoarthritis: evidence from two 3-year studies. Menopause. 2004;11:138–43.CrossRefPubMed
26.
Poolsup N, Suthisisang C, Channark P, Kittikulsuth W. Glucosamine long-term treatment and the progression of knee osteoarthritis: systematic review of randomized controlled trials. Ann Pharmacother. 2005;39:1080–7.CrossRefPubMed
27.
Lee YH, Woo JH, Choi SJ, Ji JD, Song GG. Effect of glucosamine or chondroitin sulfate on the osteoarthritis progression: a meta-analysis. Rheumatol Int. 2010;30:357–63.CrossRefPubMed
28.
Hochberg MC, Zhan M, Langenberg P. The rate of decline of joint space width in patients with osteoarthritis of the knee: a systematic review and meta-analysis of randomized placebo-controlled trials of chondroitin sulfate. Curr Med Res Opin. 2008;24:3029–35.CrossRefPubMed
29.
Wildi LM, Raynauld JP, Martel-Pelletier J, Beaulieu A, Bessette L, Morin F, et al. Chondroitin sulphate reduces both cartilage volume loss and bone marrow lesions in knee osteoarthritis patients starting as early as 6 months after initiation of therapy: a randomised, double-blind, placebo-controlled pilot study using MRI. Ann Rheum Dis. 2011;70:982–9.PubMedCentralCrossRefPubMed
30.
Pelletier JP, Yaron M, Haraoui B, Cohen P, Nahir MA, Choquette D, et al. Efficacy and safety of diacerein in osteoarthritis of the knee: a double-blind, placebo-controlled trial. The Diacerein Study Group. Arthritis Rheum. 2000;43:2339–48.CrossRefPubMed
31.
Dougados M, Nguyen M, Berdah L, Mazieres B, Vignon E, Lequesne M, et al. Evaluation of the structure-modifying effects of diacerein in hip osteoarthritis: ECHODIAH, a three-year, placebo-controlled trial. Evaluation of the Chondromodulating Effect of Diacerein in OA of the Hip. Arthritis Rheum. 2001;44:2539–47.CrossRefPubMed
32.
Maheu E, Mazieres B, Valat JP, Loyau G, Le Loet X, Bourgeois P, et al. Symptomatic efficacy of avocado/soybean unsaponifiables in the treatment of osteoarthritis of the knee and hip: a prospective, randomized, double-blind, placebo-controlled, multicenter clinical trial with a six-month treatment period and a two-month followup demonstrating a persistent effect. Arthritis Rheum. 1998;41:81–91.CrossRefPubMed
33.
Maheu E, Cadet C, Marty M, Moyse D, Kerloch I, Coste P, et al. Randomised, controlled trial of avocado-soybean unsaponifiable (Piascledine) effect on structure modification in hip osteoarthritis: the ERADIAS study. Ann Rheum Dis. 2014;73:376–84.PubMedCentralCrossRefPubMed
34.
Nuesch E, Rutjes AW, Trelle S, Reichenbach S, Juni P. Doxycycline for osteoarthritis of the knee or hip. Cochrane Database Syst Rev. 2009;(4):CD007323.
35.
Jelic M, Pecina M, Haspl M, Kos J, Taylor K, Maticic D, et al. Regeneration of articular cartilage chondral defects by osteogenic protein-1 (bone morphogenetic protein-7) in sheep. Growth Factors. 2001;19:101–13.CrossRefPubMed
36.
Gavenis K, Heussen N, Schmidt-Rohlfing B. Effects of low concentration BMP-7 on human osteoarthritic chondrocytes: comparison of different applications. J Biomater Appl. 2012;26:845–59.CrossRefPubMed
37.
Hunter DJ, Pike MC, Jonas BL, Kissin E, Krop J, McAlindon T. Phase 1 safety and tolerability study of BMP-7 in symptomatic knee osteoarthritis. BMC Musculoskelet Disord. 2010;11:232.PubMedCentralCrossRefPubMed
38.
Moore EE, Bendele AM, Thompson DL, Littau A, Waggie KS, Reardon B, 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.CrossRefPubMed
39.
Lohmander LS, Hellot S, Dreher D, Krantz EF, Kruger DS, Guermazi A, et al. Intraarticular sprifermin (recombinant human fibroblast growth factor 18) in knee osteoarthritis: a randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol. 2014;66:1820–31.CrossRefPubMed
40.
Anitua E, Andia I, Ardanza B, Nurden P, Nurden AT. Autologous platelets as a source of proteins for healing and tissue regeneration. Thromb Haemost. 2004;91:4–15.PubMed
41.
Dhillon RS, Schwarz EM, Maloney MD. Platelet-rich plasma therapy – future or trend? Arthritis Res Ther. 2012;14:219.PubMedCentralCrossRefPubMed
42.
Patel S, Dhillon MS, Aggarwal S, Marwaha N, Jain A. Treatment with platelet-rich plasma is more effective than placebo for knee osteoarthritis: a prospective, double-blind, randomized trial. Am J Sports Med. 2013;41:356–64.CrossRefPubMed
43.
Taylor DW, Petrera M, Hendry M, Theodoropoulos JS. A systematic review of the use of platelet-rich plasma in sports medicine as a new treatment for tendon and ligament injuries. Clin J Sport Med. 2011;21:344–52.CrossRefPubMed
44.
Kon E, Mandelbaum B, Buda R, Filardo G, Delcogliano M, Timoncini A, et al. Platelet-rich plasma intra-articular injection versus hyaluronic acid viscosupplementation as treatments for cartilage pathology: from early degeneration to osteoarthritis. Arthroscopy. 2011;27:1490–501.CrossRefPubMed
45.
Kon E, Buda R, Filardo G, Di Martino A, Timoncini A, Cenacchi A, et al. Platelet-rich plasma: intra-articular knee injections produced favorable results on degenerative cartilage lesions. Knee Surg Sports Traumatol Arthrosc. 2010;18:472–9.CrossRefPubMed
46.
Sampson S, Reed M, Silvers H, Meng M, Mandelbaum B. Injection of platelet-rich plasma in patients with primary and secondary knee osteoarthritis: a pilot study. Am J Phys Med Rehabil. 2010;89:961–9.CrossRefPubMed
47.
Sanchez M, Anitua E, Azofra J, Aguirre JJ, Andia I. Intra-articular injection of an autologous preparation rich in growth factors for the treatment of knee OA: a retrospective cohort study. Clin Exp Rheumatol. 2008;26:910–3.PubMed
48.
Filardo G, Kon E, Di Martino A, Di Matteo B, Merli ML, Cenacchi A, et al. Platelet-rich plasma vs hyaluronic acid to treat knee degenerative pathology: study design and preliminary results of a randomized controlled trial. BMC Musculoskelet Disord. 2012;13:229.PubMedCentralCrossRefPubMed
49.
Sanchez M, Fiz N, Azofra J, Usabiaga J, Aduriz Recalde E, Garcia Gutierrez A, et al. A randomized clinical trial evaluating plasma rich in growth factors (PRGF-Endoret) versus hyaluronic acid in the short-term treatment of symptomatic knee osteoarthritis. Arthroscopy. 2012;28:1070–8.CrossRefPubMed
50.
Martel-Pelletier J, Wildi LM, Pelletier JP. Future therapeutics for osteoarthritis. Bone. 2012;51:297–311.CrossRefPubMed
51.
Pelletier JP, Jovanovic D, Fernandes JC, Manning P, Connor JR, Currie MG, et al. Reduced progression of experimental osteoarthritis in vivo by selective inhibition of inducible nitric oxide synthase. Arthritis Rheum. 1998;41:1275–86.CrossRefPubMed
52.
Graverand MP, Clemmer RS, Redifer P, Brunell RM, Hayes CW, Brandt KD, 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;72:187–95.CrossRef
53.
Suri S, Walsh DA. Osteochondral alterations in osteoarthritis. Bone. 2012;51:204–11.CrossRefPubMed
54.
Kwan Tat S, Lajeunesse D, Pelletier JP, Martel-Pelletier J. Targeting subchondral bone for treating osteoarthritis: what is the evidence? Best Pract Res Clin Rheumatol. 2010;24:51–70.CrossRefPubMed
55.
Lajeunesse D, Pelletier JP, Martel-Pelletier J. Osteoporosis and osteoarthritis: bone is the common battle ground. Medicographia. 2010;32:391–8.
56.
Pelletier JP, Troncy E, Bertaim T, Thibaud D, Goulet AC, Abram F, et al. Treatment with tiludronic acid helps reduce the development of experimental osteoarthritis lesions in dogs with anterior cruciate ligament transection followed by reconstructive surgery: a 1-year study with quantitative magnetic resonance imaging. J Rheumatol. 2011;38:118–28.CrossRefPubMed
57.
Moreau M, Rialland P, Pelletier JP, Martel-Pelletier J, Lajeunesse D, Boileau C, et al. Tiludronate treatment improves structural changes and symptoms of osteoarthritis in the canine anterior cruciate ligament model. Arthritis Res Ther. 2011;13:R98.PubMedCentralCrossRefPubMed
58.
Carbone LD, Nevitt MC, Wildy K, Barrow KD, Harris F, Felson D, et al. The relationship of antiresorptive drug use to structural findings and symptoms of knee osteoarthritis. Arthritis Rheum. 2004;50:3516–25.CrossRefPubMed
59.
Spector TD, Conaghan PG, Buckland-Wright JC, Garnero P, Cline GA, Beary JF, 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:R625–33.PubMedCentralCrossRefPubMed
60.
Bingham 3rd CO, Buckland-Wright JC, Garnero P, Cohen SB, Dougados M, Adami S, 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;54:3494–507.CrossRefPubMed
61.
Laslett LL, Dore DA, Quinn SJ, Boon P, Ryan E, Winzenberg TM, et al. Zoledronic acid reduces knee pain and bone marrow lesions over 1 year: a randomised controlled trial. Ann Rheum Dis. 2012;71:1322–8.CrossRefPubMed
62.
Tat SK, Pelletier JP, Mineau F, Caron J, Martel-Pelletier J. Strontium ranelate inhibits key factors affecting bone remodeling in human osteoarthritic subchondral bone osteoblasts. Bone. 2011;49:559–67.CrossRefPubMed
63.
Henrotin Y, Labasse A, Zheng SX, Galais P, Tsouderos Y, Crielaard JM, et al. Strontium ranelate increases cartilage matrix formation. J Bone Miner Res. 2001;16:299–308.CrossRefPubMed
64.
Pelletier JP, Kapoor M, Fahmi H, Lajeunesse D, Blesius A, Maillet J, et al. Strontium ranelate reduces the progression of experimental dog osteoarthritis by inhibiting the expression of key proteases in cartilage and of IL-1beta in the synovium. Ann Rheum Dis. 2013;72:250–7.CrossRefPubMed
65.
Bruyere O, Delferriere D, Roux C, Wark JD, Spector T, Devogelaer JP, et al. Effects of strontium ranelate on spinal osteoarthritis progression. Ann Rheum Dis. 2008;67:335–9.CrossRefPubMed
66.
Reginster JY, Badurski J, Bellamy N, Bensen W, Chapurlat R, Chevalier X, 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;72:179–86.PubMedCentralCrossRefPubMed
67.
Bruyere O, Reginster JY, Bellamy N, Chapurlat R, Richette P, Cooper C, et al. Clinically meaningful effect of strontium ranelate on symptoms in knee osteoarthritis: a responder analysis. Rheumatology (Oxford). 2014;53:1457–64.CrossRef
68.
Pelletier JP, Roubille C, Raynauld JP, Abram F, Dorais M, Delorme P, 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(2):422–9.
69.
Tat SK, Pelletier JP, Velasco CR, Padrines M, Martel-Pelletier J. New perspective in osteoarthritis: the OPG and RANKL system as a potential therapeutic target? Keio J Med. 2009;58:29–40.CrossRefPubMed
70.
Kwan Tat S, Pelletier JP, Lajeunesse D, Fahmi H, Lavigne M, Martel-Pelletier J. The differential expression of osteoprotegerin (OPG) and receptor activator of nuclear factor kappaB ligand (RANKL) in human osteoarthritic subchondral bone osteoblasts is an indicator of the metabolic state of these disease cells. Clin Exp Rheumatol. 2008;26:295–304.PubMed
71.
Kwan Tat S, Amiable N, Pelletier JP, Boileau C, Lajeunesse D, Duval N, et al. Modulation of OPG, RANK and RANKL by human chondrocytes and their implication during osteoarthritis. Rheumatology (Oxford). 2009;48:1482–90.CrossRef
72.
Pilichou A, Papassotiriou I, Michalakakou K, Fessatou S, Fandridis E, Papachristou G, et al. High levels of synovial fluid osteoprotegerin (OPG) and increased serum ratio of receptor activator of nuclear factor-kappa B ligand (RANKL) to OPG correlate with disease severity in patients with primary knee osteoarthritis. Clin Biochem. 2008;41:746–9.CrossRefPubMed
73.
Kadri A, Ea HK, Bazille C, Hannouche D, Liote F, Cohen-Solal ME. Osteoprotegerin inhibits cartilage degradation through an effect on trabecular bone in murine experimental osteoarthritis. Arthritis Rheum. 2008;58:2379–86.CrossRefPubMed
74.
Josse R, Khan A, Ngui D, Shapiro M. Denosumab, a new pharmacotherapy option for postmenopausal osteoporosis. Curr Med Res Opin. 2013;29:205–16.CrossRefPubMed
75.
Cohen SB, Dore RK, Lane NE, Ory PA, Peterfy CG, Sharp JT, et al. Denosumab treatment effects on structural damage, bone mineral density, and bone turnover in rheumatoid arthritis: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, phase II clinical trial. Arthritis Rheum. 2008;58:1299–309.CrossRefPubMed
76.
Hayami T, Zhuo Y, Wesolowski GA, Pickarski M, le Duong T. Inhibition of cathepsin K reduces cartilage degeneration in the anterior cruciate ligament transection rabbit and murine models of osteoarthritis. Bone. 2012;50:1250–9.CrossRefPubMed
77.
Sampson ER, Hilton MJ, Tian Y, Chen D, Schwarz EM, Mooney RA, et al. Teriparatide as a chondroregenerative therapy for injury-induced osteoarthritis. Sci Transl Med. 2011;3:101ra93.PubMedCentralCrossRefPubMed
78.
Manicourt DH, Azria M, Mindeholm L, Thonar EJ, Devogelaer JP. 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;54:3205–11.CrossRefPubMed
79.
Esenyel M, Icagasioglu A, Esenyel CZ. Effects of calcitonin on knee osteoarthritis and quality of life. Rheumatol Int. 2013;33:423–7.CrossRefPubMed
80.
Karsdal MA, Alexandersen P, John MR, Loeffler J, Arnold M, Azria M, et al. Oral calcitonin demonstrated symptom-modifying efficacy and increased cartilage volume: results from a 2-year Phase 3 trial in patients with osteoarthritis of the knee. Osteoarthritis Cartilage. 2011;19:S35.CrossRef
81.
Reginster JY, Pelousse F, Bruyere O. Safety concerns with the long-term management of osteoporosis. Expert Opin Drug Saf. 2013;12:507–22.CrossRefPubMed
82.
McAlindon T, LaValley M, Schneider E, Nuite M, Lee JY, Price LL, et al. Effect of vitamin D supplementation on progression of knee pain and cartilage volume loss in patients with symptomatic osteoarthritis: a randomized controlled trial. JAMA. 2013;309:155–62.PubMedCentralCrossRefPubMed
83.
Cao Y, Jones G, Cicuttini F, Winzenberg T, Wluka A, Sharman J, et al. Vitamin D supplementation in the management of knee osteoarthritis: study protocol for a randomized controlled trial. Trials. 2012;13:131.PubMedCentralCrossRefPubMed
84.
Kapoor M, Martel-Pelletier J, Lajeunesse D, Pelletier JP, Fahmi H. Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nat Rev Rheumatol. 2011;7:33–42.CrossRefPubMed
85.
Wu X, Kondragunta V, Kornman KS, Wang H, Duff GW, Renner JB, et al. IL-1 receptor antagonist gene as a predictive biomarker of progression of knee osteoarthritis in a population cohort. Osteoarthritis Cartilage. 2013;21:930–8.PubMedCentralCrossRefPubMed
86.
Caron JP, Fernandes JC, Martel-Pelletier J, Tardif G, Mineau F, Geng C, et al. Chondroprotective effect of intraarticular injections of interleukin-1 receptor antagonist in experimental osteoarthritis. Suppression of collagenase-1 expression. Arthritis Rheum. 1996;39:1535–44.CrossRefPubMed
87.
Chevalier X, Giraudeau B, Conrozier T, Marliere J, Kiefer P, Goupille P. Safety study of intraarticular injection of interleukin 1 receptor antagonist in patients with painful knee osteoarthritis: a multicenter study. J Rheumatol. 2005;32:1317–23.PubMed
88.
Chevalier X, Goupille P, Beaulieu AD, Burch FX, Bensen WG, Conrozier T, et al. Intraarticular injection of anakinra in osteoarthritis of the knee: a multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum. 2009;61:344–52.CrossRefPubMed
89.
Bacconnier L, Jorgensen C, Fabre S. Erosive osteoarthritis of the hand: clinical experience with anakinra. Ann Rheum Dis. 2009;68:1078–9.CrossRefPubMed
90.
Cohen SB, Proudman S, Kivitz AJ, Burch FX, Donohue JP, Burstein D, 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.PubMedCentralCrossRefPubMed
91.
Chevalier X, Conrozier T, Richette P. Desperately looking for the right target in osteoarthritis: the anti-IL-1 strategy. Arthritis Res Ther. 2011;13:124.PubMedCentralCrossRefPubMed
92.
Xoma to stop testing drug as arthritis treatment. Reuters Health. 2014. Available at: http://​www.​reuters.​com/​article/​2014/​03/​05/​us-xoma-arthritisdrug-idUSBREA241IP201​40305. Accessed 25 May 2015.
93.
Martel-Pelletier J, Pelletier JP. Osteoarthritis: a single injection of anakinra for treating knee OA? Nat Rev Rheumatol. 2009;5:363–4.CrossRefPubMed
94.
Yang KG, Raijmakers NJ, van Arkel ER, Caron JJ, Rijk PC, Willems WJ, et al. Autologous interleukin-1 receptor antagonist improves function and symptoms in osteoarthritis when compared to placebo in a prospective randomized controlled trial. Osteoarthritis Cartilage. 2008;16:498–505.CrossRef
95.
Baltzer AW, Moser C, Jansen SA, Krauspe R. Autologous conditioned serum (Orthokine) is an effective treatment for knee osteoarthritis. Osteoarthritis Cartilage. 2009;17:152–60.CrossRefPubMed
96.
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;29:961–5.CrossRefPubMed
97.
Maksymowych WP, Russell AS, Chiu P, Yan A, Jones N, Clare T, et al. Targeting tumour necrosis factor alleviates signs and symptoms of inflammatory osteoarthritis of the knee. Arthritis Res Ther. 2012;14:R206.PubMedCentralCrossRefPubMed
98.
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;71:891–8.PubMedCentralCrossRefPubMed
99.
Magnano MD, Chakravarty EF, Broudy C, Chung L, Kelman A, Hillygus J, et al. A pilot study of tumor necrosis factor inhibition in erosive/inflammatory osteoarthritis of the hands. J Rheumatol. 2007;34:1323–7.PubMed
100.
Chevalier X, Ravaud P, Maheu E, Baron G, Rialland A, Vergnaud P, et al. Adalimumab in patients with hand osteoarthritis refractory to analgesics and NSAIDs: a randomised, multicentre, double-blind, placebo-controlled trial. Ann Rheum Dis. 2014. doi:10.​1136/​annrheumdis-2014-205348.PubMed
101.
Chevalier X, Eymard F, Richette P. Biologic agents in osteoarthritis: hopes and disappointments. Nat Rev Rheumatol. 2013;9:400–10.CrossRefPubMed