Disease-modifying drugs in osteoarthritis: current understanding and future therapeutics

References

• Hunter DJ, Schofield D, Callander E. The individual and socioeconomic impact of osteoarthritis. Nat Rev Rheumatol. 2014 Jul;10(7):437–441.
   PubMed Web of Science ®Google Scholar
• Turkiewicz A, Gerhardsson de Verdier M, Engstrom G, et al. Prevalence of knee pain and knee OA in southern Sweden and the proportion that seeks medical care. Rheumatology (Oxford). 2015 May;54(5):827–835.
   PubMed Web of Science ®Google Scholar
• Thomas E, Peat G, Croft P. Defining and mapping the person with osteoarthritis for population studies and public health. Rheumatology (Oxford). 2014 Feb;53(2):338–345.
   PubMed Web of Science ®Google Scholar
• Cross M, Smith E, Hoy D, et al. The global burden of hip and knee osteoarthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis. 2014 Jul;73(7):1323–1330.
   PubMed Web of Science ®Google Scholar
• Kotlarz H, Gunnarsson CL, Fang H, et al. Insurer and out-of-pocket costs of osteoarthritis in the US: evidence from national survey data. Arthritis Rheum. 2009 Dec;60(12):3546–3553.
   PubMed Web of Science ®Google Scholar
• Ackerman IN, Pratt C, Gorelik A, et al. Projected burden of Osteoarthritis and rheumatoid arthritis in Australia: a population-level analysis. Arthritis Care Res (Hoboken). 2018 Jun;70(6):877–883.
   PubMed Web of Science ®Google Scholar
• Abhishek A, Doherty M. Diagnosis and clinical presentation of osteoarthritis. Rheum Dis Clin North Am. 2013 Feb;39(1):45–66.
   PubMed Web of Science ®Google Scholar
• Guilak F. Biomechanical factors in osteoarthritis. Best Pract Res Clin Rheumatol. 2011 Dec;25(6):815–823.
   PubMed Web of Science ®Google Scholar
• Jotanovic Z, Mihelic R, Sestan B, et al. Emerging pathways and promising agents with possible disease modifying effect in osteoarthritis treatment. Curr Drug Targets. 2014 Jun;15(6):635–661.
   PubMed Web of Science ®Google Scholar
• Glasson SS, Askew R, Sheppard B, et al. Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature. 2005;434:644–648.
   Web of Science ®Google Scholar
• Berenbaum F. Osteoarthritis as an inflammatory disease (osteoarthritis is not osteoarthrosis!). Osteoarthritis Cartilage. 2013;21(1):16–21.
   PubMed Web of Science ®Google Scholar
• Karsdal MA, Bay-Jensen AC, Lories RJ, et al. The coupling of bone and cartilage turnover in osteoarthritis: opportunities for bone antiresorptives and anabolics as potential treatments? Ann Rheum Dis. 2014;73(2):336–348.
   PubMed Web of Science ®Google Scholar
• 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 Dec;24(12):2013–2021.
   PubMed Web of Science ®Google Scholar
• McAlindon TE, Bannuru RR, Sullivan MC, et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis Cartilage. 2014 Mar;22(3):363–388.
   PubMed Web of Science ®Google Scholar
• Tsertsvadze A, Grove A, Freeman K, et al. Total hip replacement for the treatment of end stage arthritis of the hip: a systematic review and meta-analysis. PLoS ONE. 2014;9(7):e99804.
   PubMed Web of Science ®Google Scholar
• Yu SP, Hunter DJ. Emerging drugs for the treatment of knee osteoarthritis. Expert Opin Emerg Drugs. 2015 Sep;20(3):361–378.
   PubMed Web of Science ®Google Scholar
• US Food and Drug Administration. All manufacturers of prescription combination drug products with more than 325 mg of acetaminophen have discontinued marketing. 2014. [cited: 2018 Aug 25]. Available from: https://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm390509.htm
   Google Scholar
• Towheed TE, Maxwell L, Judd MG, et al. Acetaminophen for osteoarthritis. Cochrane Database Syst Rev. 2006 Jan;25(1):Cd004257.
   Google Scholar
• Zhang W, Ouyang H, Dass CR, et al. Current research on pharmacologic and regenerative therapies for osteoarthritis [review article]. Bone Res. 2016;4:15040.
   PubMed Web of Science ®Google Scholar
• Wright EA, Katz JN, Abrams S, et al. Trends in prescription of opioids from 2003–2009 in persons with knee osteoarthritis. Arthritis Care Res (Hoboken). 2014 Oct;66(10):1489–1495.
   PubMed Web of Science ®Google Scholar
• Hochberg MC, Altman RD, April KT, 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 Apr;64(4):465–474.
   PubMed Web of Science ®Google Scholar
• 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 ( Clinical research ed). 2010;341:c4675.
   Google Scholar
• Bannuru RR, Brodie CR, Sullivan MC, et al. Safety of repeated injections of Sodium Hyaluronate (SUPARTZ) for knee osteoarthritis: a systematic review and meta-analysis. Cartilage. 2016 Oct;7(4):322–332.
   PubMed Web of Science ®Google Scholar
• European Medicines Agency. Guideline on clinical investigation ofmedicinal products used in the treatment of osteoarthritis. 2010. [cited: 2018 Aug 23]. Available from: https://www.ema.europa.eu/documents/scientific-guideline/guideline-clinical-investigation-medicinal-products-used-treatment-osteoarthritis_en.pdf
   Google Scholar
• US Food and Drug Administration. Clinical development programs for drugs, devices, and biological products intended for the treatment of osteoarthritis (OA). 1999. [cited: 2018 June 27]. Available from: https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071577.pdf
   Google Scholar
• Murray CJ, Vos T, Lozano R, et al. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the global burden of disease study 2010. Lancet. 2012 Dec 15;380(9859):2197–2223.
   PubMed Web of Science ®Google Scholar
• Matthews GL, Hunter DJ. Emerging drugs for osteoarthritis. Expert Opin Emerg Drugs. 2011 Sep;16(3):479–491.
   PubMed Web of Science ®Google Scholar
• Losina E, Weinstein AM, Reichmann WM, et al. Lifetime risk and age at diagnosis of symptomatic knee osteoarthritis in the US. Arthritis Care Res (Hoboken). 2013 May;65(5):703–711.
   PubMed Web of Science ®Google Scholar
• White AG, Birnbaum HG, Janagap C, et al. Direct and indirect costs of pain therapy for osteoarthritis in an insured population in the United States. J Occup Environ Med. 2008 Sep;50(9):998–1005.
   PubMed Web of Science ®Google Scholar
• Le TK, Montejano LB, Cao Z, et al. Health care costs in US patients with and without a diagnosis of osteoarthritis. J Pain Res. 2012;5:23–30.
   PubMedGoogle Scholar
• Kotlarz H, Gunnarsson CL, Fang H, et al. Osteoarthritis and absenteeism costs: evidence from US national survey data. J Occup Environ Med. 2010 Mar;52(3):263–268.
   PubMed Web of Science ®Google Scholar
• Le TK, Montejano LB, Cao Z, et al. Healthcare costs associated with osteoarthritis in US patients. Pain Pract. 2012 Nov;12(8):633–640.
   PubMed Web of Science ®Google Scholar
• Dunn JD, Pill MW. A claims-based view of health care charges and utilization for commercially insured patients with osteoarthritis. Managed Care (Langhorne, Pa). 2009 Dec;18(12):44–50.
   PubMedGoogle Scholar
• Collier R. Drug development cost estimates hard to swallow. CMAJ = Journal De l’Association Medicale Canadienne. 2009 Feb 3;180(3):279–280.
   PubMed Web of Science ®Google Scholar
• Morgan S, Grootendorst P, Lexchin J, et al. The cost of drug development: a systematic review. Health Policy. 2011 Apr;100(1):4–17.
   PubMed Web of Science ®Google Scholar
• Losina E, Daigle ME, Suter LG, et al. Disease-modifying drugs for knee osteoarthritis: can they be cost-effective? Osteoarthritis Cartilage. 2013;21(5):655–667.
   PubMed Web of Science ®Google Scholar
• Wei Y, Bai L. Recent advances in the understanding of molecular mechanisms of cartilage degeneration, synovitis and subchondral bone changes in osteoarthritis. Connect Tissue Res. 2016 Jul;57(4):245–261.
   PubMed Web of Science ®Google Scholar
• 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 Jan 23;93(2):878–883.
   PubMed Web of Science ®Google Scholar
• Merrihew C, Kumar B, Heretis K, et al. Alterations in endogenous osteogenic protein-1 with degeneration of human articular cartilage. J Orthop Res. 2003 Sep;21(5):899–907.
   PubMed Web of Science ®Google Scholar
• Cook SD, Patron LP, Salkeld SL, et al. Repair of articular cartilage defects with osteogenic protein-1 (BMP-7) in dogs. J Bone Joint Surg Am Vol. 2003;85-A Suppl 3:116–123.
   PubMedGoogle Scholar
• Chubinskaya S, Kuettner KE. Regulation of osteogenic proteins by chondrocytes. Int J Biochem Cell Biol. 2003;35(9):1323–1340.
   PubMed Web of Science ®Google Scholar
• 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 Oct 10;11:232.
   PubMed Web of Science ®Google Scholar
• Davidson D, Blanc A, Filion D, et al. Fibroblast growth factor (FGF) 18 signals through FGF receptor 3 to promote chondrogenesis. J Biol Chem. 2005;280(21):20509–20515.
   PubMed Web of Science ®Google Scholar
• Ellsworth JL, Berry J, Bukowski T, et al. Fibroblast growth factor-18 is a trophic factor for mature chondrocytes and their progenitors. Osteoarthritis Cartilage. 2002 Apr;10(4):308–320.
   PubMed Web of Science ®Google Scholar
• Valverde-Franco G, Binette JS, Li W, et al. Defects in articular cartilage metabolism and early arthritis in fibroblast growth factor receptor 3 deficient mice. Hum Mol Genet. 2006 Jun 1;15(11):1783–1792.
   PubMed Web of Science ®Google Scholar
• 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 Jul;66(7):1820–1831.
   PubMed Web of Science ®Google Scholar
• Roemer FW, Aydemir A, Lohmander S, et al. Structural effects of sprifermin in knee osteoarthritis: a post-hoc analysis on cartilage and non-cartilaginous tissue alterations in a randomized controlled trial. BMC Musculoskelet Disord. 2016 Jul;9(17):267.
   Google Scholar
• 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 Nov;67(11):2916–2922.
   PubMed Web of Science ®Google Scholar
• 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 May–Jun;34(3):445–450.
   PubMed Web of Science ®Google Scholar
• MC GA H, Guehring H, Aydemir A, et al. Efficacy and safety of intra-articular sprifermin in symptomatic radiographic knee osteoarthritis. Results of the 2-year primary analysis from a 5-year randomised, placebo-controlled, phase II study. [abstract]. Arthritis Rheumatol. 2015;69(suppl 10).
   Google Scholar
• Hochberg M, Guermazi A, Guehring H, et al. OP0059 Efficacy and safety of intra-articular sprifermin in symptomatic radiographic knee osteoarthritis: pre-specified analysis of 3-year data from a 5-year randomised, placebo-controlled, phase ii study. Ann Rheum Dis. 2018;77(Suppl 2):80–81.
   Google Scholar
• Roemer F, Kraines J, Aydemir A, et al. FRI0538 Structural effects of intra-articular sprifermin in symptomatic radiographic knee osteoarthritis: a post-hoc analysis of cartilage and non-cartilaginous tissue alterations of the 2-year data from a 5-year randomised, placebo-controlled, phase ii study. Ann Rheum Dis. 2018;77(Suppl 2):795–796.
   PubMedGoogle Scholar
• Anitua E, Andia I, Ardanza B, et al. Autologous platelets as a source of proteins for healing and tissue regeneration. Thromb Haemost. 2004 Jan;91(1):4–15.
   PubMed Web of Science ®Google Scholar
• Dhillon RS, Schwarz EM, Maloney MD. Platelet-rich plasma therapy - future or trend? Arthritis Res Ther. 2012 Aug 8;14(4):219.
   PubMed Web of Science ®Google Scholar
• Bennell KL, Hunter DJ, Paterson KL. Platelet-rich plasma for the management of hip and knee osteoarthritis. Curr Rheumatol Rep. 2017;19(5):24–25.
   PubMed Web of Science ®Google Scholar
• Jevotovsky DS, Alfonso AR, Einhorn TA, et al. Osteoarthritis and stem cell therapy in humans: a systematic review. Osteoarthritis Cartilage. 2018 Jun;26(6):711–729.
   PubMed Web of Science ®Google Scholar
• Lee WY-W, Wang B. Cartilage repair by mesenchymal stem cells: clinical trial update and perspectives. J Orthop Translat. 2017;9:76–88.
   PubMed Web of Science ®Google Scholar
• Madry H, Cucchiarini M. Advances and challenges in gene-based approaches for osteoarthritis. J Gene Med. 2013 Oct;15(10):343–355.
   PubMed Web of Science ®Google Scholar
• Evans CH, Gouze JN, Gouze E, et al. Osteoarthritis gene therapy [Review]. Gene Ther. 2004;11:379.
   PubMed Web of Science ®Google Scholar
• 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 Sep;30(7):694–703.
   PubMed Web of Science ®Google Scholar
• Guermazi A, Kalsi G, Niu J, et al. Structural effects of intra-articular TGF-β1 in moderate to advanced knee osteoarthritis: MRI-based assessment in a randomized controlled trial [journal article]. BMC Musculoskelet Disord. 2017 Nov 16;18(1):461.
   PubMedGoogle Scholar
• Kim MK, Ha CW, In Y, et al. A multicenter, double-blind, phase III clinical trial to evaluate the efficacy and safety of a cell and gene therapy in knee osteoarthritis patients. Hum Gene Ther Clin Dev. 2018 Feb 27;29(1):48–59.
   Web of Science ®Google Scholar
• Tugwood JD, Kelsall J, Coverley LC, et al. Fibrodysplasia induced in dog skin by a Matrix Metalloproteinase (MMP) inhibitor—A mechanistic analysis. Toxicol Sci. 2012;127(1):236–245.
   PubMed Web of Science ®Google Scholar
• Brewster M, Lewis EJ, Wilson KL, et al. Ro 32-3555, an orally active collagenase selective inhibitor, prevents structural damage in the STR/ORT mouse model of osteoarthritis. Arthritis Rheum. 1998 Sep;41(9):1639–1644.
   PubMedGoogle Scholar
• Lewis EJ, Bishop J, Bottomley KM, et al. Ro 32-3555, an orally active collagenase inhibitor, prevents cartilage breakdown in vitro and in vivo. Br J Pharmacol. 1997 Jun;121(3):540–546.
   PubMed Web of Science ®Google Scholar
• 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(5):R109–R109.
   PubMed Web of Science ®Google Scholar
• Fingleton B. MMPs as therapeutic targets–still a viable option? Semin Cell Dev Biol. 2008 Feb;19(1):61–68.
   PubMed Web of Science ®Google Scholar
• Wang M, Sampson ER, Jin H, et al. MMP13 is a critical target gene during the progression of osteoarthritis. Arthritis Res Ther. 2013;15(1):R5–R5.
   PubMed Web of Science ®Google Scholar
• Abula K, Muneta T, Miyatake K, et al. Elimination of BMP7 from the developing limb mesenchyme leads to articular cartilage degeneration and synovial inflammation with increased age. FEBS Lett. 2015 May 8;589(11):1240–1248.
   PubMed Web of Science ®Google Scholar
• Baragi VM, Becher G, Bendele AM, et al. A new class of potent matrix metalloproteinase 13 inhibitors for potential treatment of osteoarthritis: evidence of histologic and clinical efficacy without musculoskeletal toxicity in rat models. Arthritis Rheum. 2009 Jul;60(7):2008–2018.
   PubMed Web of Science ®Google Scholar
• Smith GN Jr., Yu LP Jr., Brandt KD, et al. Oral administration of doxycycline reduces collagenase and gelatinase activities in extracts of human osteoarthritic cartilage. J Rheumatol. 1998 Mar;25(3):532–535.
   PubMed Web of Science ®Google Scholar
• Brandt KD, Mazzuca SA, Katz BP, et al. Effects of doxycycline on progression of osteoarthritis: results of a randomized, placebo-controlled, double-blind trial. Arthritis Rheum. 2005 Jul;52(7):2015–2025.
   PubMed Web of Science ®Google Scholar
• Snijders GF, van Den Ende CH, van Riel PL, et al. The effects of doxycycline on reducing symptoms in knee osteoarthritis: results from a triple-blinded randomised controlled trial. Ann Rheum Dis. 2011 Jul;70(7):1191–1196.
   PubMed Web of Science ®Google Scholar
• Da Costa BR, Nüesch E, Reichenbach S, et al. Doxycycline for osteoarthritis of the knee or hip. Cochrane Database Syst Rev.2012;11:CD007323. pub3.
   PubMed Web of Science ®Google Scholar
• Ge X, Ma X, Meng J, et al. Role of Wnt-5A in interleukin-1beta-induced matrix metalloproteinase expression in rabbit temporomandibular joint condylar chondrocytes. Arthritis Rheum. 2009 Sep;60(9):2714–2722.
   PubMedGoogle Scholar
• Wu L, Huang X, Li L, et al. Insights on biology and pathology of HIF-1alpha/-2alpha, TGFbeta/ BMP,Wnt/beta-catenin, and NF-kappaB pathways in osteoarthritis. Curr Pharm Des. 2012;18(22):3293–3312.
   PubMed Web of Science ®Google Scholar
• 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(10):1598–1606.
   PubMed Web of Science ®Google Scholar
• Neogi T. Clinical significance of bone changes in osteoarthritis. Ther Adv Musculoskelet Dis. 2012 Aug;4(4):259–267.
   PubMedGoogle Scholar
• Burr DB, Gallant MA. Bone remodelling in osteoarthritis [review article]. Nat Rev Rheumatol. 2012;8:665.
   PubMed Web of Science ®Google Scholar
• Goldring SR. The role of bone in osteoarthritis pathogenesis. Rheum Dis Clin North Am. 2008;34(3):561–571.
   PubMed Web of Science ®Google Scholar
• Hayami T, Pickarski M, Zhuo Y, et al. Characterization of articular cartilage and subchondral bone changes in the rat anterior cruciate ligament transection and meniscectomized models of osteoarthritis. Bone. 2006 Feb;38(2):234–243.
   PubMed Web of Science ®Google Scholar
• Brandt KD, Myers SL, Burr D, et al. Osteoarthritic changes in canine articular cartilage, subchondral bone, and synovium fifty-four months after transection of the anterior cruciate ligament. Arthritis Rheum. 1991 Dec;34(12):1560–1570.
   PubMed Web of Science ®Google Scholar
• Sharma AR, Jagga S, Lee -S-S, et al. Interplay between cartilage and subchondral bone contributing to pathogenesis of osteoarthritis. Int J Mol Sci. 2013;14(10):19805–19830.
   PubMed Web of Science ®Google Scholar
• Nagae M, Hiraga T, Wakabayashi H, et al. Osteoclasts play a part in pain due to the inflammation adjacent to bone. Bone. 2006;39(5):1107–1115.
   PubMed Web of Science ®Google Scholar
• Walsh DA, Chapman V. Bisphosphonates for osteoarthritis [journal article]. Arthritis Res Ther. 2011 Sep 30;13(5):128.
   PubMed Web of Science ®Google Scholar
• 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 Nov;54(11):3494–3507.
   PubMed Web of Science ®Google Scholar
• Laslett LL, Dore 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 Aug;71(8):1322–1328.
   PubMed Web of Science ®Google Scholar
• Nishii T, Tamura S, Shiomi T, et al. Alendronate treatment for hip osteoarthritis: prospective randomized 2-year trial. Clin Rheumatol. 2013 Dec;32(12):1759–1766.
   PubMed Web of Science ®Google Scholar
• 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(3):R625–R633.
   PubMed Web of Science ®Google Scholar
• Laslett LL, Kingsbury SR, Hensor EM, et al. Effect of bisphosphonate use in patients with symptomatic and radiographic knee osteoarthritis: data from the osteoarthritis initiative. Ann Rheum Dis. 2014 May;73(5):824–830.
   PubMed Web of Science ®Google Scholar
• Neogi T, Li S, Peloquin C, et al. Effect of bisphosphonates on knee replacement surgery. Ann Rheum Dis. 2018;77(1):92–97.
   PubMed Web of Science ®Google Scholar
• Fu S-H, Wang C-Y, Yang R-S, et al. Bisphosphonate use and the risk of undergoing total knee arthroplasty in osteoporotic patients with osteoarthritis: a nationwide cohort study in Taiwan. JBJS. 2017;99(11):938–946.
   PubMed Web of Science ®Google Scholar
• Li H-Z, Xu X-H, Lu H-D. Bisphosphonates reduce the risk of knee replacement: we need more analyses! Ann Rheum Dis. 2018. DOI:10.1136/annrheumdis-2018-213052
   Web of Science ®Google Scholar
• Lems WF. Bisphosphonates: a therapeutic option for knee osteoarthritis? Ann Rheum Dis. 2018 Sep;77(9):1247–1248.
   PubMed Web of Science ®Google Scholar
• Castaneda S, Roman-Blas JA, Largo R, et al. Subchondral bone as a key target for osteoarthritis treatment. Biochem Pharmacol. 2012 Feb 1;83(3):315–323.
   PubMed Web of Science ®Google Scholar
• Vaysbrot EE, Osani MC, Musetti MC, et al. Are bisphosphonates efficacious in knee osteoarthritis? A meta-analysis of randomized controlled trials. Osteoarthritis Cartilage. 2018 Feb;26(2):154–164.
   PubMed Web of Science ®Google Scholar
• Cai DA G, Laslett L, Hill C, et al. A multicentre randomised controlled trial of zoledronic acid for osteoarthritis of the knee with bone marrow lesions (Abstract). Ann Rheum Dis. 2014;77(supplement):A57.
   Google Scholar
• Henrotin Y, Labasse A, Zheng SX, et al. Strontium ranelate increases cartilage matrix formation. J Bone Miner Res. 2001 Feb;16(2):299–308.
   PubMed Web of Science ®Google Scholar
• Gulhan I, Bilgili S, Gunaydin R, et al. The effect of strontium ranelate on serum insulin like growth factor-1 and leptin levels in osteoporotic post-menopausal women: a prospective study. Arch Gynecol Obstet. 2008 Nov;278(5):437–441.
   PubMed Web of Science ®Google Scholar
• 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 Feb;72(2):179–186.
   PubMed Web of Science ®Google Scholar
• 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 Feb;74(2):422–429.
   PubMed Web of Science ®Google Scholar
• Bolland MJ, Grey A. Ten years too long: strontium ranelate, cardiac events, and the European Medicines Agency. BMJ ( Clinical research ed). 2016;354:i5109.
   PubMedGoogle Scholar
• Lindström E, Rizoska B, Tunblad K, et al. The selective cathepsin K inhibitor MIV-711 attenuates joint pathology in experimental animal models of osteoarthritis. J Transl Med. 2018;16:56.
   PubMed Web of Science ®Google Scholar
• Granholm S, Lundberg P, Lerner UH. Expression of the calcitonin receptor, calcitonin receptor-like receptor, and receptor activity modifying proteins during osteoclast differentiation. J Cell Biochem. 2008 Jun 1;104(3):920–933.
   PubMed Web of Science ®Google Scholar
• Nielsen RH, Bay-Jensen AC, Byrjalsen I, et al. Oral salmon calcitonin reduces cartilage and bone pathology in an osteoarthritis rat model with increased subchondral bone turnover. Osteoarthritis Cartilage. 2011 Apr;19(4):466–473.
   PubMed Web of Science ®Google Scholar
• Sondergaard BC, Madsen SH, Segovia-Silvestre T, et al. Investigation of the direct effects of salmon calcitonin on human osteoarthritic chondrocytes. BMC Musculoskelet Disord. 2010 Apr;5(11):62.
   Google Scholar
• European Medicines Agency. European Medicines Agency recommends limiting long-term use of calcitonin medicines 2012. [cited: 2018 Aug 23]. Available from: https://www.ema.europa.eu/news/european-medicines-agency-recommends-limiting-long-term-use-calcitonin-medicines
   Google Scholar
• Sampson ER, Hilton MJ, Tian Y, et al. Teriparatide as a chondroregenerative therapy for injury-induced osteoarthritis. Sci Transl Med. 2011 Sep 21;3(101):101ra93.
   PubMed Web of Science ®Google Scholar
• Bellido M, Lugo L, Roman-Blas JA, et al. Improving subchondral bone integrity reduces progression of cartilage damage in experimental osteoarthritis preceded by osteoporosis. Osteoarthritis Cartilage. 2011 Oct;19(10):1228–1236.
   PubMed Web of Science ®Google Scholar
• Sridharan B, Sharma B, Detamore MS. A road map to commercialization of cartilage therapy in the United States of America. Tissue Eng Part B Rev. 2016;22(1):15–33.
   Web of Science ®Google Scholar
• Hopwood B, Tsykin A, Findlay DM, et al. Microarray gene expression profiling of osteoarthritic bone suggests altered bone remodelling, WNT and transforming growth factor-β/bone morphogenic protein signalling [journal article]. Arthritis Res Ther. 2007 Sept 27;9(5):R100.
   PubMed Web of Science ®Google Scholar
• McGuire D, Lane N, Segal N, et al. TPX-100 leads to marked, sustained improvements in subjects with knee osteoarthritis: pre-clinical rationale and results of a controlled clinical trial. Osteoarthritis Cartilage. 2018;26:S243.
   Web of Science ®Google Scholar
• Malemud CJ. Anticytokine therapy for osteoarthritis: evidence to date. Drugs Aging. 2010 Feb 1;27(2):95–115.
   PubMed Web of Science ®Google Scholar
• Mathiessen A, Conaghan PG. Synovitis in osteoarthritis: current understanding with therapeutic implications. Arthritis Res Ther. 2017 Feb 2;19(1):18.
   PubMed Web of Science ®Google Scholar
• Siebuhr AS, Bay-Jensen AC, Jordan JM, et al. Inflammation (or synovitis)-driven osteoarthritis: an opportunity for personalizing prognosis and treatment? Scand J Rheumatol. 2016;45(2):87–98.
   PubMed Web of Science ®Google Scholar
• Chevalier X, Giraudeau B, Conrozier T, et al. Safety study of intraarticular injection of interleukin 1 receptor antagonist in patients with painful knee osteoarthritis: a multicenter study. J Rheumatol. 2005 Jul;32(7):1317–1323.
   PubMed Web of Science ®Google Scholar
• 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 Mar 15;61(3):344–352.
   PubMed Web of Science ®Google Scholar
• 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 Jul 29;13(4):R125.
   PubMed Web of Science ®Google Scholar
• Wang SX, Abramson SB, Attur M, et al. Safety, tolerability, and pharmacodynamics of an anti-interleukin-1α/β dual variable domain immunoglobulin in patients with osteoarthritis of the knee: a randomized phase 1 study. Osteoarthritis Cartilage. 2017;25(12):1952–1961.
   PubMed Web of Science ®Google Scholar
• Zheng S, Hunter DJ, Xu J, et al. Monoclonal antibodies for the treatment of osteoarthritis. Expert Opin Biol Ther. 2016 Dec;16(12):1529–1540.
   PubMed Web of Science ®Google Scholar
• Dougados M, Nguyen M, Berdah L, 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 Nov;44(11):2539–2547.
   PubMedGoogle Scholar
• Pham T, Le Henanff A, Ravaud P, et al. Evaluation of the symptomatic and structural efficacy of a new hyaluronic acid compound, NRD101, in comparison with diacerein and placebo in a 1 year randomised controlled study in symptomatic knee osteoarthritis. Ann Rheum Dis. 2004 Dec;63(12):1611–1617.
   PubMed Web of Science ®Google Scholar
• Fidelix TS, Macedo CR, Maxwell LJ, et al. Diacerein for osteoarthritis. Cochrane Database Syst Rev. 2014 Feb;10(2):Cd005117.
   Google Scholar
• European Medicines Agency. Prac re-examines diacerein and recommends that it remain available with restrictions. 2014. [ cited 2018 July 25]. Available from: http://viglya.com/ema-prac-re-examines-diacerein-and-recommends-that-it-remain-available-with-restrictions/
   Google Scholar
• Verbruggen G, Wittoek R, Vander Cruyssen B, et al. 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 Jun;71(6):891–898.
   PubMed Web of Science ®Google Scholar
• 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 Jun;34(6):1323–1327.
   PubMed Web of Science ®Google Scholar
• 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 Sep;74(9):1697–1705.
   PubMed Web of Science ®Google Scholar
• Fioravanti A, Fabbroni M, Cerase A, et al. Treatment of erosive osteoarthritis of the hands by intra-articular infliximab injections: a pilot study. Rheumatol Int. 2009 Jun;29(8):961–965.
   PubMed Web of Science ®Google Scholar
• Kloppenburg M, Ramonda R, Kwok W-Y, et al. OP0095 Randomized, placebo-controlled trial to evaluate clinical efficacy and structure modifying properties of subcutaneous Etanercept (ETN) in patients with erosive inflammatory hand Osteoarthritis (OA). Ann Rheum Dis. 2016;75(Suppl 2):90–91.
   Google Scholar
• Persson MSM, Sarmanova A, Doherty M, et al. Conventional and biologic disease-modifying anti-rheumatic drugs for osteoarthritis: a meta-analysis of randomized controlled trials. Rheumatology ( Oxford). 2018 Jun 16;57(10):1830–1837.
   Google Scholar
• Palmer RMJ, Hickery MS, Charles IG, et al. Induction of nitric oxide synthase in human chondrocytes. Biochem Biophys Res Commun. 1993 May 28;193(1):398–405.
   PubMed Web of Science ®Google Scholar
• Jarvinen K, Vuolteenaho K, Nieminen R, et al. Selective iNOS inhibitor 1400W enhances anti-catabolic IL-10 and reduces destructive MMP-10 in OA cartilage. Survey of the effects of 1400W on inflammatory mediators produced by OA cartilage as detected by protein antibody array. Clin Exp Rheumatol. 2008 Mar–Apr;26(2):275–282.
   PubMed Web of Science ®Google Scholar
• Hellio le Graverand MP, Clemmer R, 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 Feb;72(2):187–195.
   PubMed Web of Science ®Google Scholar
• Bar-Yehuda S, Rath-Wolfson L, Del Valle L, et al. Induction of an antiinflammatory effect and prevention of cartilage damage in rat knee osteoarthritis by CF101 treatment. Arthritis Rheum. 2009 Oct;60(10):3061–3071.
   PubMedGoogle Scholar
• Alvaro-Gracia JM. Licofelone–clinical update on a novel LOX/COX inhibitor for the treatment of osteoarthritis. Rheumatology (Oxford). 2004 Feb;43 Suppl 1:i21–i25.
   PubMed Web of Science ®Google Scholar
• Pelletier J-P, Boileau C, Boily M, et al. The protective effect of licofelone on experimental osteoarthritis is correlated with the downregulation of gene expression and protein synthesis of several major cartilage catabolic factors: MMP-13, cathepsin K and aggrecanases. Arthritis Res Ther. 2005;7(5):R1091–R1102.
   PubMed Web of Science ®Google Scholar
• Raynauld JP, Martel-Pelletier J, Bias 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. 2009 Jun;68(6):938–947.
   PubMed Web of Science ®Google Scholar
• Wildi LM, Raynauld JP, Martel-Pelletier J, et al. Relationship between bone marrow lesions, cartilage loss and pain in knee osteoarthritis: results from a randomised controlled clinical trial using MRI. Ann Rheum Dis. 2010 Dec;69(12):2118–2124.
   PubMed Web of Science ®Google Scholar
• Emrani PS, Katz JN, Kessler CL, et al. Joint space narrowing and Kellgren-Lawrence progression in knee osteoarthritis: an analytic literature synthesis [Research support, N.I.H., Extramural review]. Osteoarthritis Cartilage. 2008 Aug;16(8):873–882.
   PubMed Web of Science ®Google Scholar
• Hunter DJ. Pharmacologic therapy for osteoarthritis–the era of disease modification. Nat Rev Rheumatol. 2011 Jan;7(1):13–22.
   PubMed Web of Science ®Google Scholar
• Eckstein F, Le Graverand MP. Plain radiography or magnetic resonance imaging (MRI): which is better in assessing outcome in clinical trials of disease-modifying osteoarthritis drugs? Summary of a debate held at the World Congress of Osteoarthritis 2014 [Review]. Semin Arthritis Rheum. 2015 Dec;45(3):251–256.
   PubMed Web of Science ®Google Scholar
• Hellio Le Graverand-Gastineau M. Disease modifying osteoarthritis drugs: facing development challenges and choosing molecular targets [Review]. Curr Drug Targets. 2010 May;11(5):528–535.
   PubMed Web of Science ®Google Scholar
• Roemer FW, Kwoh CK, Hayashi D, et al. The role of radiography and MRI for eligibility assessment in DMOAD trials of knee OA. Nat Rev Rheumatol. 2018 Jun;14(6):372–380.
   PubMed Web of Science ®Google Scholar
• Cooper C, Adachi JD, Bardin T, et al. How to define responders in osteoarthritis. Curr Med Res Opin. 2013 april 17;29(6):719–729.
   PubMed Web of Science ®Google Scholar
• Guermazi A, Niu J, Hayashi D, et al. Prevalence of abnormalities in knees detected by MRI in adults without knee osteoarthritis: population based observational study (Framingham Osteoarthritis Study). BMJ. 2012;345:e5339.
   PubMedGoogle Scholar
• Hannan MT, Felson DT, Pincus T. Analysis of the discordance between radiographic changes and knee pain in osteoarthritis of the knee. J Rheumatol. 2000 Jun;27(6):1513–1517.
   PubMed Web of Science ®Google Scholar
• Hunter DJ, Hellio Le Graverand-Gastineau MP. How close are we to having structure-modifying drugs available? [Review]. Med Clin North Am. 2009 Jan;93(1):223–234, xiii.
   PubMed Web of Science ®Google Scholar
• Mazzuca SA, Brandt KD. Is knee radiography useful for studying the efficacy of a disease-modifying osteoarthritis drug in humans? Rheum Dis Clin North Am. 2003 Nov;29(4):819–830.
   PubMed Web of Science ®Google Scholar
• Yuqing Z, Michael N, Jingbo N, et al. Fluctuation of knee pain and changes in bone marrow lesions, effusions, and synovitis on magnetic resonance imaging. Arthritis Rheum. 2011;63(3):691–699.
   PubMedGoogle Scholar
• Hunter DJ, Zhang W, Conaghan PG, et al. Responsiveness and reliability of MRI in knee osteoarthritis: a meta-analysis of published evidence. Osteoarthritis Cartilage. 2011 may 01;19(5):589–605.
   PubMed Web of Science ®Google Scholar
• Bijlsma JW, Berenbaum F, Lafeber FP. Osteoarthritis: an update with relevance for clinical practice. Lancet. 2011 Jun 18;377(9783):2115–2126.
   PubMed Web of Science ®Google Scholar
• Oo WM, Linklater JM, Hunter DJ. Imaging in knee osteoarthritis. Curr Opin Rheumatol. 2017 Jan;29(1):86–95.
   PubMed Web of Science ®Google Scholar
• Migliore A, Scire CA, Carmona L, et al. The challenge of the definition of early symptomatic knee osteoarthritis: a proposal of criteria and red flags from an international initiative promoted by the Italian Society for Rheumatology. Rheumatol Int. 2017 Aug;37(8):1227–1236.
   PubMed Web of Science ®Google Scholar
• Felson D, Niu J, Sack B, et al. Progression of osteoarthritis as a state of inertia. Ann Rheum Dis. 2012. DOI:10.1136/annrheumdis-2012-201575.
   Google Scholar
• Bruyere O, Cooper C, Arden N, et al. Can we identify patients with high risk of osteoarthritis progression who will respond to treatment? A focus on epidemiology and phenotype of osteoarthritis. Drugs Aging. 2015 Mar;32(3):179–187.
   PubMed Web of Science ®Google Scholar
• Tonge DP, Pearson MJ, Jones SW. The hallmarks of osteoarthritis and the potential to develop personalised disease-modifying pharmacological therapeutics. Osteoarthritis Cartilage. 2014 May;22(5):609–621.
   PubMed Web of Science ®Google Scholar
• Mobasheri A. The future of osteoarthritis therapeutics: targeted pharmacological therapy. Curr Rheumatol Rep. 2013 Oct;15(10):364.
   PubMed Web of Science ®Google Scholar
• Kellgren JH, Lawrence JS. Radiological assessment of osteo-arthrosis. Ann Rheum Dis. 1957 Dec;16(4):494–502.
   PubMed Web of Science ®Google Scholar
• Guermazi A, Niu J, Hayashi D, et al. Prevalence of abnormalities in knees detected by MRI in adults without knee osteoarthritis: population based observational study (Framingham Osteoarthritis Study). BMJ (Clin Res Ed). 2012;345:e5339. .
   PubMed Web of Science ®Google Scholar
• Mazzuca SA, Brandt KD. Plain radiography as an outcome measure in clinical trials involving patients with knee osteoarthritis. Rheum Dis Clin North Am. 1999 May;25(2):467–480, ix.
   PubMed Web of Science ®Google Scholar
• Eckstein F, Le Graverand MP. Plain radiography or magnetic resonance imaging (MRI): which is better in assessing outcome in clinical trials of disease-modifying osteoarthritis drugs? Summary of a debate held at the World Congress of Osteoarthritis 2014. Semin Arthritis Rheum. 2015 Dec;45(3):251–256.
   PubMed Web of Science ®Google Scholar
• Oei EHG, Wick MC, Muller-Lutz A, et al. Cartilage imaging: techniques and developments. Semin Musculoskelet Radiol. 2018 Apr;22(2):245–260.
   PubMed Web of Science ®Google Scholar
• Hayashi D, Roemer FW, Guermazi A. Recent advances in research imaging of osteoarthritis with focus on MRI, ultrasound and hybrid imaging. Clin Exp Rheumatol. 2018 Sep–Oct;36 Suppl 114(5):43–52.
   PubMed Web of Science ®Google Scholar
• Keen HI, Wakefield RJ, Conaghan PG. A systematic review of ultrasonography in osteoarthritis. Ann Rheum Dis. 2009 May;68(5):611–619.
   PubMed Web of Science ®Google Scholar
• Oo WM, Linklater JM, Daniel M, et al. Clinimetrics of ultrasound pathologies in osteoarthritis: systematic literature review and meta-analysis. Osteoarthritis Cartilage. 2018 May;26(5):601–611.
   PubMed Web of Science ®Google Scholar
• Bay-Jensen AC, Thudium CS, Gualillo O, et al. Biochemical marker discovery, testing and evaluation for facilitating OA drug discovery and development. Drug Discov Today. 2018 Feb;23(2):349–358.
   PubMed Web of Science ®Google Scholar
• Abramson S, Krasnokutsky S. Biomarkers in osteoarthritis. Bull NYU Hosp Jt Dis. 2006;64(1–2):77–81.
   PubMedGoogle Scholar
• Attur M, Krasnokutsky-Samuels S, Samuels J, et al. Prognostic biomarkers in osteoarthritis. Curr Opin Rheumatol. 2013 Jan;25(1):136–144.
   PubMed Web of Science ®Google Scholar
• Bay-Jensen AC, Thudium CS, Mobasheri A. Development and use of biochemical markers in osteoarthritis: current update. Curr Opin Rheumatol. 2018 Jan;30(1):121–128.
   PubMed Web of Science ®Google Scholar
• Roman-Blas JA, Bizzi E, Largo R, et al. An update on the up and coming therapies to treat osteoarthritis, a multifaceted disease. Expert Opin Pharmacother. 2016 Sep 01;17(13):1745–1756.
   PubMed Web of Science ®Google Scholar
• Rosen J, Sancheti P, Fierlinger A, et al. Cost-effectiveness of different forms of intra-articular injections for the treatment of osteoarthritis of the knee. Adv Ther. 2016 Jun;33(6):998–1011.
   PubMed Web of Science ®Google Scholar
• Strand V, McIntyre LF, Beach WR, et al. Safety and efficacy of US-approved viscosupplements for knee osteoarthritis: a systematic review and meta-analysis of randomized, saline-controlled trials. J Pain Res. 2015;8:217–228.
   PubMed Web of Science ®Google Scholar
• Nguyen C, Rannou F. The safety of intra-articular injections for the treatment of knee osteoarthritis: a critical narrative review. Expert Opin Drug Saf. 2017 Aug;16(8):897–902. PubMed PMID: 28627937; eng.
   PubMed Web of Science ®Google Scholar
• Wehling P, Evans C, Wehling J, et al. Effectiveness of intra-articular therapies in osteoarthritis: a literature review. Ther Adv Musculoskelet Dis. 2017 Aug;9(8):183–196.
   PubMed Web of Science ®Google Scholar
• Bannuru RR, Schmid CH, Kent DM, et al. Comparative effectiveness of pharmacologic interventions for knee osteoarthritis: a systematic review and network meta-analysis. Ann Intern Med. 2015 Jan 6;162(1):46–54.
   PubMed Web of Science ®Google Scholar
• Yang X, Du H, Zhai G. Progress in intra-articular drug deliv-ery systems for osteoarthritis. Curr Drug Targets. 2014;15(9):888–900.
   PubMed Web of Science ®Google Scholar
• Evans CH, Kraus VB, Setton LA. Progress in intra-articular therapy. Nat Rev Rheumatol. 2014 Jan;10(1):11–22.
   PubMed Web of Science ®Google Scholar
• Maudens P, Jordan O, Allemann E. Recent advances in intra-articular drug delivery systems for osteoarthritis therapy. Drug Discov Today. 2018 Oct;23(10):1761–1775.
   PubMed Web of Science ®Google Scholar