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Effects of intra-articular clodronate in the treatment of knee osteoarthritis: results of a double-blind, randomized placebo-controlled trial

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Abstract

Aim of this study was to evaluate the efficacy and tolerability of intra-articular (IA) clodronate, compared to saline solution, in patients with symptomatic knee osteoarthritis (KOA). In this double-blind phase 3 randomized clinical trial, patients were randomized to receive once weekly IA injection of 2 mg clodronate or placebo for 4 weeks with 12 weeks of follow-up. The primary objective was the sum of spontaneous, on passive movement, and at digital pressing pain relief assessed by visual analogue score (VAS) of 0–100 at 5 weeks after the final injection. Improving in Western Ontario MacMaster (WOMAC) scale, Lequesne index, consumption of acetaminophen, and physician or patient overall judgment were secondary objectives. Study population included 80 patients, 67 women and 13 men aged 66 ± 6 (SD) years. A significant improvement for all efficacy parameters was observed at all-time points in both groups. A significant difference in favor to clodronate in VAS for pain was observed 5 weeks after the last injection (−114.6 vs. −87.2 for clodronate and placebo group, respectively; p < 0.05). The improvements in Lequesne index, global KOA evaluation from both patients and investigators, and the WOMAC pain subscale were significantly greater in the clodronate group. The proportion of patients that did not require acetaminophen was significantly greater in the clodronate group (about 10 vs. 30 % for clodronate and placebo group, respectively; p < 0.05). IA 2 mg clodronate is associated with small and transient symptomatic and functional benefits and it is safe in KOA patients.

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References

  1. Herrero-Beaumont G, Roman-Blas JA, Castañeda S, Jimenez SA (2009) Primary osteoarthritis no longer primary: three subsets with distinct etiological, clinical, and therapeutic characteristics. Semin Arthritis Rheum 39:71–80

    Article  PubMed  Google Scholar 

  2. Peat G, McCarney R, Croft P (2001) Knee pain and osteoarthritis in older adults: a review of community burden and current use of primary health care. Ann Rheum Dis 60:91–97

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Hochberg MC, Altman RD, April KT et al (2012) 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 64:465–474

    Article  CAS  Google Scholar 

  4. Zhang W, Nuki G, Moskowitz RW et al (2010) 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 18:476–499

    Article  CAS  PubMed  Google Scholar 

  5. Herrero-Beaumont G, Roman-Blas JA, Largo R, Berenbaum F, Castaneda S (2011) Bone mineral density and joint cartilage: four clinical settings of a complex relationship in osteoarthritis. Ann Rheum Dis 70:1523–1525

    Article  PubMed  Google Scholar 

  6. Bush PG, Hall AC (2003) The volume and morphology of chondrocytes within non-degenerate and degenerate human articular cartilage. Osteoarthritis Cartilage 11:242–251

    Article  CAS  PubMed  Google Scholar 

  7. Goldring MB, Goldring SR (2010) Articular cartilage and subchondral bone in the pathogenesis of osteoarthritis. Ann NY Acad Sci 1192:230–237

    Article  CAS  PubMed  Google Scholar 

  8. Zhang ZM, Li ZC, Jiang LS, Jiang SD, Dai LY (2010) Micro-CT and mechanical evaluation of subchondral trabecular bone structure between postmenopausal women with osteoarthritis and osteoporosis. Osteoporos Int 21:1383–1390

    Article  PubMed  Google Scholar 

  9. Karvonen RL, Miller PR, Nelson DA, Granda JL, Fernandez-Madrid F (1998) Periarticular osteoporosis in osteoarthritis of the knee. J Rheumatol 25:2187–2194

    CAS  PubMed  Google Scholar 

  10. Messent EA, Ward RJ, Tonkin CJ, Buckland-Wright C (2005) Cancellous bone differences between knees with early, definite and advanced joint space loss: a comparative quantitative macroradiographic study. Osteoarthritis Cartilage 13:39–47

    Article  PubMed  Google Scholar 

  11. Davies-Tuck ML, Wluka AE, Wang Y et al (2009) The natural history of bone marrow lesions in community-based adults with no clinical knee osteoarthritis. Ann Rheum Dis 68:904–908

    Article  CAS  PubMed  Google Scholar 

  12. Dore D, Quinn S, Ding C et al (2010) Subchondral bone and cartilage damage: a prospective study in older adults. Arthritis Rheum 62:1967–1973

    PubMed  Google Scholar 

  13. Bergman AG, Willen HK, Lindstrand AL, Pettersson HAT (1994) Osteoarthritis of the knee: correlation of subchondral MR signal abnormalities with histopathologic and radiographic features. Skeletal Radiol 23:445–448

    Article  CAS  PubMed  Google Scholar 

  14. Zanetti M, Bruder E, Romero J, Hodler J (2000) Bone marrow edema pattern in osteoarthritic knees: correlation between MR imaging and histologic findings. Radiology 215:835–840

    Article  CAS  PubMed  Google Scholar 

  15. Hernandez-Molina G, Guermazi A, Niu J et al (2008) Central bone marrow lesions in symptomatic knee osteoarthritis and their relationship to anterior cruciate ligament tears and cartilage loss. Arthritis Rheum 58:130–136

    Article  PubMed Central  PubMed  Google Scholar 

  16. Yusuf E, Kortekaas MC, Watt I, Huizinga TW, Kloppenburg M (2011) Do knee abnormalities visualised on MRI explain knee pain in knee osteoarthritis? A systematic review. Ann Rheum Dis 70:60–67

    Article  PubMed  Google Scholar 

  17. Karsdal MA, BayJensen AC, Lories RJ et al (2014) The coupling of bone and cartilage turnover in osteoarthritis: opportunities for bone antiresorptives and anabolics as potential treatments ? Ann Rheum Dis 73:336–348

    Article  CAS  PubMed  Google Scholar 

  18. Carbone LD, Nevitt MC, Wildy K et al (2004) The relationship of antiresorptive drug use to structural findings and symptoms of knee osteoarthritis. Arthritis Rheum 50:3516–3525

    Article  PubMed  Google Scholar 

  19. Muehleman C, Green J, Williams JM et al (2002) The effect of bone remodeling inhibition by zoledronic acid in an animal model of cartilage matrix damage. Osteoarthritis Cartilage 10:226–233

    Article  CAS  PubMed  Google Scholar 

  20. Hayami T, Pickarski M, Wesolowski GA et al (2004) The role of subchondral bone remodeling in osteoarthritis: reduction of cartilage degeneration and prevention of osteophyte formation by alendronate in the rat anterior cruciate ligament transection model. Arthritis Rheum 50:1193–1206

    Article  CAS  PubMed  Google Scholar 

  21. Funck-Brentano T, Lin H, Hay E et al (2012) Targeting bone alleviates osteoarthritis in osteopenic mice and modulates cartilage catabolism. PLoS One 7:e33543

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Panahifar A, Maksymowych WP, Doschak MR (2012) Potential mechanism of alendronate inhibition of osteophyte formation in the rat model of post-traumatic osteoarthritis: evaluation of elemental strontium as a molecular tracer of bone formation. Osteoarthritis Cartilage 20:694–702

    Article  CAS  PubMed  Google Scholar 

  23. Teronen O, Heikkila P, Konttinen YT et al (1999) MMP inhibition and downregulation by bisphosphonates. Ann NY Acad Sci 878:453–465

    Article  CAS  PubMed  Google Scholar 

  24. Fujita T, Fujii Y, Okada SF, Miyauchi A, Takagi Y (2001) Analgesic effect of etidronate on degenerative joint disease. J Bone Miner Metab 19:251–256

    Article  CAS  PubMed  Google Scholar 

  25. Neogi T, Nevitt MC, Ensrud KE, Bauer D, Felson DT (2008) The effect of alendronate on progression of spinal osteophytes and disc space narrowing. Ann Rheum Dis 67:1427–1430

    Article  CAS  PubMed  Google Scholar 

  26. Spector TD, Conaghan PG, Buckland-Wright JC et al (2005) Effect of risedronate on joint structure and symptoms of knee osteoarthritis: results of the BRISK randomized, controlled trial. Arthritis Res Ther 7:R625–R633

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Bingham CO, Buckland-Wright JC, Garnero P et al (2006) 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 54:3494–3507

    Article  CAS  PubMed  Google Scholar 

  28. Laslett LL, Dore DA, Quinn SJ et al (2012) Zoledronic acid reduces knee pain and bone marrow lesions over 1 year: a randomised controlled trial. Ann Rheum Dis 71:1322–1328

    Article  CAS  PubMed  Google Scholar 

  29. Laslett LL, Kingsbury SR, Hensor EM, Bowes MA, Conaghan PG (2014) Effect of bisphosphonate use in patients with symptomatic and radiographic knee osteoarthritis: data from the Osteoarthritis Initiative. Ann Rheum Dis 73:824–830

    Article  CAS  PubMed  Google Scholar 

  30. Abrahamsen B (2010) Adverse effects of bisphosphonates. Calcif Tissue Int 86:421–435

    Article  CAS  PubMed  Google Scholar 

  31. Rossini M, Viapiana O, Ramonda R et al (2009) Intra-articular clodronate for the treatment of knee osteoarthritis: dose ranging study vs hyaluronic acid. Rheumatology 48:773–778

    Article  CAS  PubMed  Google Scholar 

  32. Jordan KM, Arden NK, Doherty M et al (2003) 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 62:1145–1155

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Rutijes AWS, Juni P, da Costa BR et al (2012) Viscosupplementation for Ostearthritis of the knee: a systematic review and meta-analysis. Ann Int Med 157:180–191

    Article  Google Scholar 

  34. Bellamy N, Campbell J, Robinson V et al (2006) Intraarticular corticosteroid for treatment of osteoarthritis of the knee. Cochrane Database Syst Rev 2:CD005328

  35. Jørgensen A, Stengaard-Pedersen K, Simonsen O et al (2010) Intra-articular hyaluronan is without clinical effect in knee osteoarthritis: a multicentre, randomised, placebo-controlled, double-blind study of 337 patients followed for 1 year. Ann Rheum Dis 69:1097–1102

    Article  PubMed  Google Scholar 

  36. Lundsgaard C, Dufour N, Fallentin E, Winkel P, Gluud C (2008) Intra-articular sodium hyaluronate 2 mL versus physiological saline 20 mL versus physiological saline 2 mL for painful knee osteoarthritis: a randomized clinical trial. Scand J Rheumatol 37:142–150

    Article  CAS  PubMed  Google Scholar 

  37. Zhang W, Robertson J, Jones AC, Dieppe PA, Doherty M (2008) The placebo effect and its determinants in osteoarthritis: meta-analysis of randomised controlled trials. Ann Rheum Dis 67:1716–1723

    Article  CAS  PubMed  Google Scholar 

  38. Altman R, Asch E, Bloch D et al (1986) Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association. Arthritis Rheum 29:1039–1049

    Article  CAS  PubMed  Google Scholar 

  39. Kellgren MJ (1963) The epidemiology of chronic rheumatism: atlas of standard radiographs, 2nd edn. Blackwell Scientific, Oxford, UK

    Google Scholar 

  40. Wolfe F, Smythe HA, Yunus MB et al (1990) The American College of Rheumatology 1990 criteria for the classification of fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum 33:160–172

    Article  CAS  PubMed  Google Scholar 

  41. Bellamy N, Buchanan WW, Goldsmith CH et al (1998) Validation Study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol 15:1833–1840

    Google Scholar 

  42. Lequesne M, Méry C, Samson M et al (1987) Indexes of severity for osteoarthritis of the hip and knee. Scand J Rheumatol 65(Suppl):85–89

    Article  CAS  Google Scholar 

  43. Ranstam J, Turkiewicz A, Boonen S et al (2012) Alternative analyses for handling incomplete follow-up in the intention-to-treat analysis: the randomized controlled trial of balloon kyphoplasty versus non-surgical care for vertebral compression fracture (FREE). BMC Med Res Methodol 24(12):35

    Article  Google Scholar 

  44. Wang CT, Lin J, Chang CJ, Lin YT, Hou SM (2004) Therapeutic effects of hyaluronic acid on osteoarthritis of the knee. A meta-analysis of randomized controlled trials. J Bone Joint Surg Am 86-A:538–545

    PubMed  Google Scholar 

  45. Bellamy N, Campbell J, Robinson V et al (2006) Viscosupplementation for the treatment of osteoarthritis of the knee. Cochrane Database Syst Rev 2:CD005321

  46. Reichenbach S, Blank S, Rutjes AW et al (2007) Hylan versus hyaluronic acid for osteoarthritis of the knee: a systematic review and meta-analysis. Arthritis Rheum 57:1410–1418

    Article  PubMed  Google Scholar 

  47. Bannuru RR, Natov NS, Dasi UR, Schmid CH, McAlindon TE (2011) Therapeutic trajectory following intra-articular hyaluronic acid injection in knee osteoarthritis—meta-analysis. Osteoarthritis Cartilage 19:611–619

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed Central  PubMed  Google Scholar 

  49. Medina JM, Thomas A, Denegar CR (2006) Knee osteoarthritis: should your patient opt for hyaluronic acid injection? J Fam Pract 55:669–675

    PubMed  Google Scholar 

  50. Lo GH, LaValley M, McAlindon T, Felson DT (2003) Intra-articular hyaluronic acid in treatment of knee osteoarthritis: a meta-analysis. JAMA 290:3115–3121

    Article  CAS  PubMed  Google Scholar 

  51. Zhen G, Wen C, Jia X et al (2013) Inhibition of TGF-β signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritis. Nature Med 19(6):704–712. doi:10.1038/nm.3143

  52. Frith JC, Mönkkönen J, Auriola S, Mönkkönen H, Rogers MJ (2001) The molecular mechanism of action of the antiresorptive and antiinflammatory drug clodronate: evidence for the formation in vivo of a metabolite that inhibits bone resorption and causes osteoclast and macrophage apoptosis. Arthritis Rheum 44:2201–2210

    Article  CAS  PubMed  Google Scholar 

  53. Rossini M, Adami S, Viapiana O et al (2012) Long-term effects of amino-bisphosphonates on circulating γδ T cells. Calcif Tissue Int 91:395–399

    Article  CAS  PubMed  Google Scholar 

  54. Rossini M, Adami S, Viapiana O et al (2013) Acute phase response after zoledronic acid is associated with long-term effects on white blood cells. Calcif Tissue Int 93:249–252

    Article  CAS  PubMed  Google Scholar 

  55. Barrera P, Blom A, Van Lent PL et al (2000) TI: synovial macrophage depletion with clodronate-containing liposomes in rheumatoid arthritis. Arthritis Rheum 43:1951–1959

    Article  CAS  PubMed  Google Scholar 

  56. Cinar BM, Ozkoc G, Bolat F et al (2014) Intra articular zoledronic acid in rat osteoarthritis model: significant reduced synovitis may indicate chondroprotective effect. Knee Surg Sports Traumatol Arthrosc [Epub ahead of print]

  57. Sagar DR, Ashraf S, Xu L et al (2013) Osteoprotegerin reduces the development of pain behaviour and joint pathology in a model of osteoarthritis. Ann Rheum Dis [Epub ahead of print]

  58. Varenna M, Adami S, Rossini M et al (2013) Treatment of complex regional pain syndrome type I with neridronate: a randomized, double-blind, placebo-controlled study. Rheumatology 52:534–542

    Article  CAS  PubMed  Google Scholar 

  59. Yanow J, Pappagallo M, Pillai L (2008) Complex regional pain syndrome (CRPS/RSD) and neuropathic pain: role of intravenous bisphosphonates as analgesics. ScientificWorldJournal 8:229–236

    Article  PubMed  Google Scholar 

  60. Dehghani F, Conrad A, Kohl A, Korf HW, Hailer NP (2004) Clodronate inhibits the secretion of proinflammatory cytokines and NO by isolated microglial cells and reduces the number of proliferating glial cells in excitotoxically injured organotypic hippocampa slice cultures. Exp Neurol 189:241–251

    Article  CAS  PubMed  Google Scholar 

  61. Reginster JY, Badurski J, Bellamy N et al (2013) Efficacy and safety of strontium ranelate in the treatment of knee osteoarthritis: results of a double-blind, randomised placebo-controlled trial. Ann Rheum Dis 72:179–186

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  62. Fleisch H (2007) Introduction to bisphosphonates, History and functional mechanisms. Orthopade 36:103–109

    Article  CAS  PubMed  Google Scholar 

  63. Rose K, Finger IE, Ferenz KB (2011) Interaction of clodronate with fibroblast growth factor 2 reduces FGF2-activity in endothelial cells. Biomed Pharmacother 65:46–51

    Article  CAS  PubMed  Google Scholar 

  64. Gomez-Barrena E, Lindroos L, Ceponis A et al (2006) Cartilage oligomeric matrix protein (COMP) is modified by intra-articular liposomal clodronate in an experimental model of arthritis. Clin Exp Rheumatol 24:622–628

    CAS  PubMed  Google Scholar 

  65. Nancollas GH, Tang R, Phipps RJ et al (2006) Novel insights into actions of bisphosphonates on bone: differences in interactions with hydroxyapatite. Bone 38:617–627

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Abiogen Pharma provided, free of charge, all medications. The study was independently designed by three of the investigators (SA-MR-DG) and Abiogen Pharma provided administrative assistance in order to have the protocol written in accordance with the current national and international requirements.

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None.

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Authors and Affiliations

  1. Rheumatology Section, Department of Medicine, University of Verona, Verona, Italy

    Maurizio Rossini, Silvano Adami, Elena Fracassi, Ombretta Viapiana, Giovanni Orsolini, Maria Rosaria Povino, Luca Idolazzi & Davide Gatti

  2. Rheumatology Unit, Policlinico Borgo Roma, University of Verona, Piazzale Scuro, 10, 37134, Verona, Italy

    Maurizio Rossini

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  1. Maurizio Rossini
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  2. Silvano Adami
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  3. Elena Fracassi
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  4. Ombretta Viapiana
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Correspondence to Maurizio Rossini.

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Trial registration number: EUDRACT 2009-012956-26.

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Rossini, M., Adami, S., Fracassi, E. et al. Effects of intra-articular clodronate in the treatment of knee osteoarthritis: results of a double-blind, randomized placebo-controlled trial. Rheumatol Int 35, 255–263 (2015). https://doi.org/10.1007/s00296-014-3100-5

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