Future Aspects of Clinical Osteoarthritis Therapies in the Continuum of Translational Research

Abstract

Osteoarthritis (OA) affects a significant number of the worldʼs adult population. In recent years different causal approaches to treat OA based on new translational knowledge have been developed. This review article provides, a brief overview of new findings on the pathophysiology and genetics and the interplay between biomechanics, pain and body weight. Current pharmacological and reconstructive surgical treatment options as well as studies on novel regenerative and molecular therapies of OA, such as applying NGF, FGF-18, TNF-α, Wnt signaling pathway inhibitors, and TGF-β1 gene therapy are discussed. The basis of this work is a selective literature search in PubMed, ScienceDirect and Google Scholar. Selected new findings are discussed in the clinical perspective of OA.

Key words

osteoarthritis - knee - clinical studies - translational studies - selective review

• References/Literatur

• 1 Liu-Bryan R, Terkeltaub R. Emerging regulators of the inflammatory process in osteoarthritis. Nat Rev Rheumatol 2015; 11: 35-44
• 2 Urban H, Little CB. The role of fat and inflammation in the pathogenesis and management of osteoarthritis. Rheumatology (Oxford) 2018; 57 (Suppl. 04) iv10-iv21
• 3 Krishnasamy P, Hall M, Robbins SR. The role of skeletal muscle in the pathophysiology and management of knee osteoarthritis. Rheumatology (Oxford) 2018; 57 (Suppl. 04) iv22-iv33
• 4 Bartholdy C, Juhl C, Christensen R. et al. The role of muscle strengthening in exercise therapy for knee osteoarthritis: a systematic review and meta-regression analysis of randomized trials. Semin Arthritis Rheum 2017; 47: 9-21
• 5 Cicuttini FM, Wluka AE. Osteoarthritis: is OA a mechanical or systemic disease?. Nat Rev Rheumatol 2014; 10: 515-516
• 6 Angele P, Madry H, Kon E. Early OA: point of no return or a chance for regenerative approaches. Knee Surg Sports Traumatol Arthrosc 2016; 24: 1741-1742
• 7 Madry H, Luyten FP, Facchini A. Biological aspects of early osteoarthritis. Knee Surg Sports Traumatol Arthrosc 2012; 20: 407-422
• 8 Luyten FP, Denti M, Filardo G. et al. Definition and classification of early osteoarthritis of the knee. Knee Surg Sports Traumatol Arthrosc 2012; 20: 401-406
• 9 Madry H, Kon E, Condello V. et al. Early osteoarthritis of the knee. Knee Surg Sports Traumatol Arthrosc 2016; 24: 1753-1762
• 10 Peffers MJ, Balaskas P, Smagul A. Osteoarthritis year in review 2017: genetics and epigenetics. Osteoarthritis Cartilage 2018; 26: 304-311
• 11 Fernandez-Moreno M, Soto-Hermida A, Vazquez-Mosquera ME. et al. Mitochondrial DNA haplogroups influence the risk of incident knee osteoarthritis in OAI and CHECK cohorts. A meta-analysis and functional study. Ann Rheum Dis 2017; 76: 1114-1122
• 12 Seeliger C, Balmayor ER, van Griensven M. miRNAs related to skeletal diseases. Stem Cells Dev 2016; 25: 1261-1281
• 13 Endisha H, Rockel J, Jurisica I. et al. The complex landscape of microRNAs in articular cartilage: biology, pathology, and therapeutic targets. JCI Insight 2018; 3
• 14 Ai R, Hammaker D, Boyle DL. et al. Joint-specific DNA methylation and transcriptome signatures in rheumatoid arthritis identify distinct pathogenic processes. Nat Commun 2016; 7: 11849
• 15 Withrow J, Murphy C, Liu Y. et al. Extracellular vesicles in the pathogenesis of rheumatoid arthritis and osteoarthritis. Arthritis Res Ther 2016; 18: 286
• 16 De Bari C, Roelofs AJ. Stem cell-based therapeutic strategies for cartilage defects and osteoarthritis. Curr Opin Pharmacol 2018; 40: 74-80
• 17 Bomer N, den Hollander W, Ramos YF. et al. Translating genomics into mechanisms of disease: osteoarthritis. Best Pract Res Clin Rheumatol 2015; 29: 683-691
• 18 Miranda-Duarte A. DNA methylation in osteoarthritis: current status and therapeutic implications. Open Rheumatol J 2018; 12: 37-49
• 19 Simon TC, Jeffries MA. The epigenomic landscape in osteoarthritis. Curr Rheumatol Rep 2017; 19: 30
• 20 Rockel JS, Kapoor M. Autophagy: controlling cell fate in rheumatic diseases. Nat Rev Rheumatol 2016; 12: 517-531
• 21 Heinemeier KM, Schjerling P, Heinemeier J. et al. Radiocarbon dating reveals minimal collagen turnover in both healthy and osteoarthritic human cartilage. Sci Transl Med 2016; 8: 346ra90
• 22 Edd SN, Omoumi P, Andriacchi TP. et al. Modeling knee osteoarthritis pathophysiology using an integrated joint system (IJS): a systematic review of relationships among cartilage thickness, gait mechanics, and subchondral bone mineral density. Osteoarthritis Cartilage 2018; 26: 1425-1437
• 23 Deveza LA, Melo L, Yamato TP. et al. Knee osteoarthritis phenotypes and their relevance for outcomes: a systematic review. Osteoarthritis Cartilage 2017; 25: 1926-1941
• 24 Knoop J, van der Leeden M, Thorstensson CA. et al. Identification of phenotypes with different clinical outcomes in knee osteoarthritis: data from the Osteoarthritis Initiative. Arthritis Care Res (Hoboken) 2011; 63: 1535-1542
• 25 Roos EM, Arden NK. Strategies for the prevention of knee osteoarthritis. Nat Rev Rheumatol 2016; 12: 92-101
• 26 Teichtahl AJ, Wluka AE, Tanamas SK. et al. Weight change and change in tibial cartilage volume and symptoms in obese adults. Ann Rheum Dis 2015; 74: 1024-1029
• 27 King WC, Chen JY, Belle SH. et al. Change in pain and physical function following bariatric surgery for severe obesity. JAMA 2016; 315: 1362-1371
• 28 Gomoll AH, Angele P, Condello V. et al. Load distribution in early osteoarthritis. Knee Surg Sports Traumatol Arthrosc 2016; 24: 1815-1825
• 29 Cho JJ, Totterman S, Elmallah RK. et al. An MRI evaluation of patients who underwent treatment with a cell-mediated gene therapy for degenerative knee arthritis: a phase IIa clinical trial. J Knee Surg 2017; 30: 694-703
• 30 Eckstein F, Benichou O, Wirth W. et al. Magnetic resonance imaging-based cartilage loss in painful contralateral knees with and without radiographic joint space narrowing: Data from the Osteoarthritis Initiative. Arthritis Rheum 2009; 61: 1218-1225
• 31 Eckstein F, Buck R, Wirth W. Location-independent analysis of structural progression of osteoarthritis-Taking it all apart, and putting the puzzle back together makes the difference. Semin Arthritis Rheum 2017; 46: 404-410
• 32 MacKay JW, Low SBL, Smith TO. et al. Systematic review and meta-analysis of the reliability and discriminative validity of cartilage compositional MRI in knee osteoarthritis. Osteoarthritis Cartilage 2018; 26: 1140-1152
• 33 Crema MD, Roemer FW, Marra MD. et al. Articular cartilage in the knee: current MR imaging techniques and applications in clinical practice and research. Radiographics 2011; 31: 37-61
• 34 Trattnig S, Winalski CS, Marlovits S. et al. Magnetic resonance imaging of cartilage repair: a review. Cartilage 2011; 2: 5-26
• 35 Demehri S, Guermazi A, Kwoh CK. Diagnosis and longitudinal assessment of osteoarthritis: review of available imaging techniques. Rheum Dis Clin North Am 2016; 42: 607-620
• 36 Ziegler R, Goebel L, Seidel R. et al. Effect of open wedge high tibial osteotomy on the lateral tibiofemoral compartment in sheep. Part III: analysis of the microstructure of the subchondral bone and correlations with the articular cartilage and meniscus. Knee Surg Sports Traumatol Arthrosc 2015; 23: 2704-2714
• 37 Englund M, Guermazi A, Lohmander LS. The meniscus in knee osteoarthritis. Rheum Dis Clin North Am 2009; 35: 579-590
• 38 Abraham AC, Pauly HM, Donahue TL. Deleterious effects of osteoarthritis on the structure and function of the meniscal enthesis. Osteoarthritis Cartilage 2014; 22: 275-283
• 39 Xie J, Zhang D, Lin Y. et al. Anterior cruciate ligament transection-induced cellular and extracellular events in menisci: implications for osteoarthritis. Am J Sports Med 2018; 46: 1185-1198
• 40 Brophy RH, Zhang B, Cai L. et al. Transcriptome comparison of meniscus from patients with and without osteoarthritis. Osteoarthritis Cartilage 2018; 26: 422-432
• 41 Bloecker K, Wirth W, Guermazi A. et al. Relationship between medial meniscal extrusion and cartilage loss in specific femorotibial subregions: data from the Osteoarthritis Initiative. Arthritis Care Res (Hoboken) 2015; 67: 1545-1552
• 42 Stein T, Mehling AP, Welsch F. et al. Long-term outcome after arthroscopic meniscal repair versus arthroscopic partial meniscectomy for traumatic meniscal tears. Am J Sports Med 2010; 38: 1542-1548
• 43 Persson F, Turkiewicz A, Bergkvist D. et al. The risk of symptomatic knee osteoarthritis after arthroscopic meniscus repair vs. partial meniscectomy vs. the general population. Osteoarthritis Cartilage 2018; 26: 195-201
• 44 Faucett SC, Geisler BP, Chahla J. et al. Meniscus root repair vs. meniscectomy or nonoperative management to prevent knee osteoarthritis after medial meniscus root tears: clinical and economic effectiveness. Am J Sports Med 2018;
• 45 Becker R, Buchner M, Förster J. et al. S2k-Leitlinie Meniskuserkrankung. 2015 Im Internet: https://www.awmf.org/uploads/tx_szleitlinien/033-006l_S2k_Meniskuserkrankungen_2015-07.pdf Stand: 22.05.2018
• 46 Sihvonen R, Paavola M, Malmivaara A. et al. Arthroscopic partial meniscectomy versus sham surgery for a degenerative meniscal tear. N Engl J Med 2013; 369: 2515-2524
• 47 Saberi Hosnijeh F, Zuiderwijk ME, Versteeg M. et al. Cam deformity and acetabular dysplasia as risk factors for hip osteoarthritis. Arthritis Rheumatol 2017; 69: 86-93
• 48 Kowalczuk M, Yeung M, Simunovic N. et al. Does femoroacetabular impingement contribute to the development of hip osteoarthritis? A systematic review. Sports Med Arthrosc Rev 2015; 23: 174-179
• 49 Jones RK, Chapman GJ, Forsythe L. et al. The relationship between reductions in knee loading and immediate pain response whilst wearing lateral wedged insoles in knee osteoarthritis. J Orthop Res 2014; 32: 1147-1154
• 50 Hatfield GL, Cochrane CK, Takacs J. et al. Knee and ankle biomechanics with lateral wedges with and without a custom arch support in those with medial knee osteoarthritis and flat feet. J Orthop Res 2016; 34: 1597-1605
• 51 Jones RK, Chapman GJ, Parkes MJ. et al. The effect of different types of insoles or shoe modifications on medial loading of the knee in persons with medial knee osteoarthritis: a randomised trial. J Orthop Res 2015; 33: 1646-1654
• 52 Heijink A, Gomoll AH, Madry H. et al. Biomechanical considerations in the pathogenesis of osteoarthritis of the knee. Knee Surg Sports Traumatol Arthrosc 2012; 20: 423-435
• 53 Madry H, Grun UW, Knutsen G. Cartilage repair and joint preservation: medical and surgical treatment options. Dtsch Arztebl Int 2011; 108: 669-677
• 54 Birmingham TB, Moyer R, Leitch K. et al. Changes in biomechanical risk factors for knee osteoarthritis and their association with 5-year clinically important improvement after limb realignment surgery. Osteoarthritis Cartilage 2017; 25: 1999-2006
• 55 Sanders TL, Pareek A, Obey MR. et al. High rate of osteoarthritis after osteochondritis dissecans fragment excision compared with surgical restoration at a mean 16-year follow-up. Am J Sports Med 2017; 45: 1799-1805
• 56 Altman RD. Early management of osteoarthritis. Am J Manag Care 2010; 16 Suppl. Management S41-S47
• 57 Schnitzer TJ, Marks JA. A systematic review of the efficacy and general safety of antibodies to NGF in the treatment of OA of the hip or knee. Osteoarthritis Cartilage 2015; 23 (Suppl. 01) S8-S17
• 58 Fransen M, Agaliotis M, Nairn L. et al. Glucosamine and chondroitin for knee osteoarthritis: a double-blind randomised placebo-controlled clinical trial evaluating single and combination regimens. Ann Rheum Dis 2015; 74: 851-858
• 59 Roman-Blas JA, Castaneda S, Sanchez-Pernaute O. et al. Combined treatment with chondroitin sulfate and glucosamine sulfate shows no superiority over placebo for reduction of joint pain and functional impairment in patients with knee osteoarthritis: a six-month multicenter, randomized, double-blind, placebo-controlled clinical trial. Arthritis Rheumatol 2017; 69: 77-85
• 60 Singh JA, Noorbaloochi S, MacDonald R. et al. Chondroitin for osteoarthritis. Cochrane Database Syst Rev 2015; (01) CD005614
• 61 Wandel S, Jüni P, Tendal B. et al. Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: network meta-analysis. BMJ 2010; 341: c4675
• 62 Steinmeyer J, Konttinen YT. Oral treatment options for degenerative joint disease–presence and future. Adv Drug Deliv Rev 2006; 58: 168-211
• 63 Runhaar J, Deroisy R, van Middelkoop M. et al. The role of diet and exercise and of glucosamine sulfate in the prevention of knee osteoarthritis: Further results from the PRevention of knee Osteoarthritis in Overweight Females (PROOF) study. Semin Arthritis Rheum 2016; 45(4 Suppl.): S42-S48
• 64 Stöve J. S2 k-Leitlinie Gonarthrose. 2018 Im Internet: https://www.awmf.org/uploads/tx_szleitlinien/033-004l_S2k_Gonarthrose_2018-01_1.pdf Stand: 23.05.2018
• 65 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: 532-543
• 66 Varenna M, Zucchi F, Failoni S. et al. Intravenous neridronate in the treatment of acute painful knee osteoarthritis: a randomized controlled study. Rheumatology (Oxford) 2015; 54: 1826-1832
• 67 Bellamy N, Campbell J, Robinson V. et al. Viscosupplementation for the treatment of osteoarthritis of the knee. Cochrane Database Syst Rev 2006; (02) CD005321
• 68 Waddell BS, Waddell WH, Waddell DD. Comparison of efficacy and tolerability of hylan G-F 20 in Patients with and without effusions at the time of initial injection. J Knee Surg 2015; 28: 213-222
• 69 Bodick N, Lufkin J, Willwerth C. et al. An intra-articular, extended-release formulation of triamcinolone acetonide prolongs and amplifies analgesic effect in patients with osteoarthritis of the knee: a randomized clinical trial. J Bone Joint Surg Am 2015; 97: 877-888
• 70 Mankin HJ, Conger KA. The acute effects of intra-articular hydrocortisone on articular cartilage in rabbits. J Bone Joint Surg Am 1966; 48: 1383-1388
• 71 McAlindon TE, LaValley MP, Harvey WF. et al. Effect of intra-articular triamcinolone vs. saline on knee cartilage volume and pain in patients with knee osteoarthritis: a randomized clinical trial. JAMA 2017; 317: 1967-1975
• 72 Riis RGC, Henriksen M, Klokker L. et al. The effects of intra-articular glucocorticoids and exercise on pain and synovitis assessed on static and dynamic magnetic resonance imaging in knee osteoarthritis: exploratory outcomes from a randomized controlled trial. Osteoarthritis Cartilage 2017; 25: 481-491
• 73 Cucchiarini M, Madry H. Genetic modification of mesenchymal stem cells for cartilage repair. Biomed Mater Eng 2010; 20: 135-143
• 74 Pers YM, Rackwitz L, Ferreira R. et al. Adipose mesenchymal stromal cell-based therapy for severe osteoarthritis of the knee: a phase i dose-escalation trial. Stem Cells Transl Med 2016; 5: 847-856
• 75 Lamo-Espinosa JM, Mora G, Blanco JF. et al. Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: multicenter randomized controlled clinical trial (phase I/II). J Transl Med 2016; 14: 246
• 76 Gupta PK, Chullikana A, Rengasamy M. et al. Efficacy and safety of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeucel^®): preclinical and clinical trial in osteoarthritis of the knee joint. Arthritis Res Ther 2016; 18: 301
• 77 Pas HI, Winters M, Haisma HJ. et al. Stem cell injections in knee osteoarthritis: a systematic review of the literature. Br J Sports Med 2017; 51: 1125-1133
• 78 Paterson KL, Nicholls M, Bennell KL. et al. Intra-articular injection of photo-activated platelet-rich plasma in patients with knee osteoarthritis: a double-blind, randomized controlled pilot study. BMC Musculoskelet Disord 2016; 17: 67
• 79 Sanchez M, Delgado D, Sanchez P. et al. Combination of intra-articular and intraosseous injections of platelet rich plasma for severe knee osteoarthritis: a pilot study. Biomed Res Int 2016; 2016: 4868613
• 80 Laudy AB, Bakker EW, Rekers M. et al. Efficacy of platelet-rich plasma injections in osteoarthritis of the knee: a systematic review and meta-analysis. Br J Sports Med 2015; 49: 657-672
• 81 Laver L, Marom N, Dnyanesh L. et al. PRP for degenerative cartilage disease: a systematic review of clinical studies. Cartilage 2017; 8: 341-364
• 82 Ohtori S, Orita S, Yamauchi K. et al. Efficacy of direct injection of etanercept into knee joints for pain in moderate and severe knee osteoarthritis. Yonsei Med J 2015; 56: 1379-1383
• 83 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: 623-631
• 84 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: 1820-1831
• 85 Eckstein F, Wirth W, Guermazi A. et al. Brief report: intraarticular sprifermin not only increases cartilage thickness, but also reduces cartilage loss: location-independent post hoc analysis using magnetic resonance imaging. Arthritis Rheumatol 2015; 67: 2916-2922
• 86 Dahlberg LE, Aydemir A, Muurahainen N. et al. A first-in-human, double-blind, randomised, placebo-controlled, dose ascending study of intra-articular rhFGF18 (sprifermin) in patients with advanced knee osteoarthritis. Clin Exp Rheumatol 2016; 34: 445-450
• 87 Onuora S. Osteoarthritis: Wnt inhibitor shows potential as a DMOAD. Nat Rev Rheumatol 2017; 13: 634
• 88 Yazici Y, McAlindon TE, Fleischmann R. et al. A novel Wnt pathway inhibitor, SM04690, for the treatment of moderate to severe osteoarthritis of the knee: results of a 24-week, randomized, controlled, phase 1 study. Osteoarthritis Cartilage 2017; 25: 1598-1606
• 89 Asen AK, Goebel L, Rey-Rico A. et al. Sustained spatiotemporal release of TGF-beta1 confers enhanced very early chondrogenic differentiation during osteochondral repair in specific topographic patterns. FASEB J 2018; 32: 5298-5311
• 90 Cucchiarini M, Thurn T, Weimer A. et al. Restoration of the extracellular matrix in human osteoarthritic articular cartilage by overexpression of the transcription factor SOX9. Arthritis Rheum 2007; 56: 158-167
• 91 Naldini L. Gene therapy returns to centre stage. Nature 2015; 526: 351-360
• 92 Madry H, Cucchiarini M. Gene therapy for human osteoarthritis: principles and clinical translation. Expert Opin Biol Ther 2016; 16: 331-346
• 93 Lee MC, Ha CW, Elmallah RK. et al. A placebo-controlled randomised trial to assess the effect of TGF-ss1-expressing chondrocytes in patients with arthritis of the knee. Bone Joint J 2015; 97-B: 924-932
• 94 Grafe I, Alexander S, Peterson JR. et al. TGF-beta family signaling in mesenchymal differentiation. Cold Spring Harb Perspect Biol 2018; 10
• 95 Zhu Y, Tao H, Jin C. et al. Transforming growth factor-beta1 induces type II collagen and aggrecan expression via activation of extracellular signal-regulated kinase 1/2 and Smad2/3 signaling pathways. Mol Med Rep 2015; 12: 5573-5579
• 96 Cherian JJ, Parvizi J, Bramlet D. et al. Preliminary results of a phase II randomized study to determine the efficacy and safety of genetically engineered allogeneic human chondrocytes expressing TGF-beta1 in patients with grade 3 chronic degenerative joint disease of the knee. Osteoarthritis Cartilage 2015; 23: 2109-2118
• 97 Cho J, Kim T, Park Y. et al. Invossa^™(Tissuegene-C) in patients with osteoarthritis: a phase III trial. Osteoarthritis Cartilage 2016; 24: S190
• 98 Guermazi A, Kalsi G, Niu J. et al. Structural effects of intra-articular TGF-beta1 in moderate to advanced knee osteoarthritis: MRI-based assessment in a randomized controlled trial. BMC Musculoskelet Disord 2017; 18: 461
• 99 Karsdal MA, Michaelis M, Ladel C. et al. Disease-modifying treatments for osteoarthritis (DMOADs) of the knee and hip: lessons learned from failures and opportunities for the future. Osteoarthritis Cartilage 2016; 24: 2013-2021
• 100 Moher D, Liberati A, Tetzlaff J. et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009; 6: e1000097
• 101 Bierma-Zeinstra SMA, Brew J, Stoner K. et al. A new lipid formulation of low dose ibuprofen shows non-inferiority to high dose standard ibuprofen: the FLARE study (flaring arthralgia relief evaluation in episodic flaring knee pain) – a randomised double-blind study. Osteoarthritis Cartilage 2017; 25: 1942-1951
• 102 Garcia-Padilla S, Duarte-Vazquez MA, Gonzalez-Romero KE. et al. Effectiveness of intra-articular injections of sodium bicarbonate and calcium gluconate in the treatment of osteoarthritis of the knee: a randomized double-blind clinical trial. BMC Musculoskelet Disord 2015; 16: 114
• 103 Lopes de Jesus CC, Dos Santos FC, de Jesus L. et al. Comparison between intra-articular ozone and placebo in the treatment of knee osteoarthritis: a randomized, double-blinded, placebo-controlled study. PLoS One 2017; 12: e0179185
• 104 Lozada CJ, Eve del Rio DPR, Smith RA. et al. A double-blind, randomized, saline-controlled study of the efficacy and safety of co-administered intra-articular injections of Tr14 and Ze14 for treatment of painful osteoarthritis of the knee: The MOZArT trial. Eur J Integr Med 2017; 13: 54-63
• 105 Soriano-Maldonado A, Klokker L, Bartholdy C. et al. Intra-articular corticosteroids in addition to exercise for reducing pain sensitivity in knee osteoarthritis: exploratory outcome from a randomized controlled trial. PLoS One 2016; 11: e0149168
• 106 Geusens P, Pavelka K, Rovensky J. et al. A 12-week randomized, double-blind, placebo-controlled multicenter study of choline-stabilized orthosilicic acid in patients with symptomatic knee osteoarthritis. BMC Musculoskelet Disord 2017; 18: 2
• 107 Gordo AC, Walker C, Armada B. et al. Efficacy of celecoxib versus ibuprofen for the treatment of patients with osteoarthritis of the knee: a randomized double-blind, non-inferiority trial. J Int Med Res 2017; 45: 59-74
• 108 Moss P, Benson HAE, Will R. et al. Fourteen days of etoricoxib 60 mg improves pain, hyperalgesia and physical function in individuals with knee osteoarthritis: a randomized controlled trial. Osteoarthritis Cartilage 2017; 25: 1781-1791
• 109 Kongtharvonskul J, Woratanarat P, McEvoy M. et al. Efficacy of glucosamine plus diacerein versus monotherapy of glucosamine: a double-blind, parallel randomized clinical trial. Arthritis Res Ther 2016; 18: 233
• 110 Sterzi S, Giordani L, Morrone M. et al. The efficacy and safety of a combination of glucosamine hydrochloride, chondroitin sulfate and bio-curcumin with exercise in the treatment of knee osteoarthritis: a randomized, double-blind, placebo-controlled study. Eur J Phys Rehabil Med 2016; 52: 321-330
• 111 Verkleij SP, Luijsterburg PA, Willemsen SP. et al. Effectiveness of diclofenac versus paracetamol in knee osteoarthritis: a randomised controlled trial in primary care. Br J Gen Pract 2015; 65: e530-e537
• 112 Wang SX, Abramson SB, Attur M. et al. Safety, tolerability, and pharmacodynamics of an anti-interleukin-1alpha/beta dual variable domain immunoglobulin in patients with osteoarthritis of the knee: a randomized phase 1 study. Osteoarthritis Cartilage 2017; 25: 1952-1961
• 113 Benazzo F, Perticarini L, Padolino A. et al. A multi-centre, open label, long-term follow-up study to evaluate the benefits of a new viscoelastic hydrogel (Hymovis^®) in the treatment of knee osteoarthritis. Eur Rev Med Pharmacol Sci 2016; 20: 959-968
• 114 Ong KL, Anderson AF, Niazi F. et al. Hyaluronic acid injections in medicare knee osteoarthritis patients are associated with longer time to knee arthroplasty. J Arthroplasty 2016; 31: 1667-1673
• 115 Di Martino A, Kon E, Perdisa F. et al. Surgical treatment of early knee osteoarthritis with a cell-free osteochondral scaffold: results at 24 months of follow-up. Injury 2015; 46 (Suppl. 08) S33-S38
• 116 Kon E, Robinson D, Verdonk P. et al. A novel aragonite-based scaffold for osteochondral regeneration: early experience on human implants and technical developments. Injury 2016; 47 (Suppl. 06) S27-S32
• 117 Soler R, Orozco L, Munar A. et al. Final results of a phase I–II trial using ex vivo expanded autologous Mesenchymal Stromal Cells for the treatment of osteoarthritis of the knee confirming safety and suggesting cartilage regeneration. Knee 2016; 23: 647-654
• 118 Montañez-Heredia E, Irízar S, Huertas PJ. et al. Intra-articular injections of platelet-rich plasma versus hyaluronic acid in the treatment of osteoarthritic knee pain: a randomized clinical trial in the context of the Spanish National Health Care System. Int J Mol Sci 2016; 17