Clinical Rheumatology

, Volume 36, Issue 10, pp 2343–2350 | Cite as

Intramuscular clodronate in erosive osteoarthritis of the hand is effective on pain and reduces serum COMP: a randomized pilot trial—The ER.O.D.E. study (ERosive Osteoarthritis and Disodium-clodronate Evaluation)

  • Gianantonio Saviola
  • Lul Abdi-Ali
  • Maria Rosaria Povino
  • Lorella Campostrini
  • Silvano Sacco
  • Luca Dalle Carbonare
Original Article


We evaluated the efficacy and safety of intramuscular clodronate (CLO) for the treatment of active erosive osteoarthritis of the hand (EOA). Forty outpatients treated with anti-inflammatory (NSAIDs) or analgesic drugs since at least 6 months, for at least 3 days a week, were randomly divided into two groups. Group A: 24 patients treated for 6 months with intramuscular (i.m.) CLO added to usual NSAIDs or analgesic drugs. The attack dose was 200 mg/day i.m. for 10 days followed by a maintenance dose of CLO i.m. 200 mg/day for 6 days after 3 and 6 months. Group B: 16 patients who continued the usual treatment with anti-inflammatory or analgesic drugs. Patients in both groups reported in a diary, day by day, the consumption of symptomatic drugs. In group A, the consumption of anti-inflammatory or analgesic drugs (p < 0.0001), pain (p < 0.0001), number of tender joints (p = 0.0097), number of swollen joints (p = 0.0251), Dreiser score (p = 0.0119), and patient’s and physician’s global assessment of disease activity significantly decreased (both p < 0.001). At 6 months, serum COMP also significantly decreased (p < 0.0029). Strength of right (p = 0.0465) and left hand (+38%, p = ns) significantly increased. In group B, there was no significant change in all parameters considered. Intramuscular CLO in EOA of the hand is effective and safe on pain with a significant reduction in the consumption of anti-inflammatory or analgesic drugs, increasing the functionality of the hands. Serum COMP reduction suggests that CLO could play a role as a disease-modifying drug (EudraCT number 2013–000832-85).


Bisphosphonates Cartilage oligomeric matrix protein Clodronate Comp Erosive osteoarthritis of the hand 



The authors thank Dr. Laura Comini for the critical revision and editing of the manuscript.

Author’s contribution

Recruitment of patients and assessment: Gianantonio Saviola, Lul Abdi-Ali, Maria Rosaria Povino and Luca Dalle Carbonare.

Clinical analysis: Lorella Campostrini and Silvano Sacco.

Statistics: Silvano Sacco.

Protocol development: Gianantonio Saviola.

Manuscript preparation: Gianantonio Saviola, Luca Dalle Carbonare, and Silvano Sacco.

Compliance with ethical standards




No funding source.


  1. 1.
    Punzi L, Favero M, Frallonardo P, Ramonda R (2015) Time to redefine erosive osteoarthrtitis. RMD Open 1(1):e000105. doi: 10.1136/rmdopen-2015-000105 CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Funck-Brentano T, Cohen-Solal M (2015) Subchondral bone and osteoarthritis. Curr Opin Rheumatol 27(4):420–426. doi: 10.1097/BOR.0000000000000181 Review
  3. 3.
    Zhen G, Wen C, Jia X et al (2013) Inhibition of TGF-β signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritis. Nat Med 19(6):704–712. doi: 10.1038/nm.3143 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Zhang W, Doherty M, Leeb BF et al (2009) EULAR evidence-based recommendations for the diagnosis of hand osteoarthritis: report of a task force of ESCISIT. Ann Rheum Dis 68:8–17CrossRefPubMedGoogle Scholar
  5. 5.
    Mancarella L, Magnani M, Addimanda O, Pignotti E, Galletti S, Meliconi R (2010) Ultrasound-detected synovitis with power Doppler signal is associated with severe radiographic damage and reduced cartilage thickness in hand osteoarthritis. Osteoarthr Cartil 18(10):1263–1268. doi: 10.1016/j.joca.2010.06.006 CrossRefPubMedGoogle Scholar
  6. 6.
    Maheu E (2012) Erosive hand osteoarthritis. Rev Prat 62(5):635–641 Review Google Scholar
  7. 7.
    Haugen IK, Mathiessen A, Slatkowsky-Christensen B et al (2016) Synovitis and radiographic progression in non-erosive and erosive hand osteoarthritis: is erosive hand osteoarthritis a separate inflammatory phenotype? Osteoarthr Cartil 24(4):647–654. doi: 10.1016/j.joca.2015.11.014 CrossRefPubMedGoogle Scholar
  8. 8.
    Marshall M, Nicholls E, Kwok WY et al (2015) Erosive osteoarthritis: a more severe form of radiographic hand osteoarthritis rather than a distinct entity? Ann Rheum Dis 74(1):136–141. doi: 10.1136/annrheumdis-2013-203948 CrossRefPubMedGoogle Scholar
  9. 9.
    Cavasin F, Punzi L, Ramonda R et al (2004) Prevalence of erosive osteoarthritis of the hands in a population from venetian area. Reumatismo 56(1):46–50PubMedGoogle Scholar
  10. 10.
    Altman R, Alarcon G, Appelrouth D et al (1990) The American College of Rheumatology criteria for the classification and reporting of osteoarthritis of the hand. Arthritis Rheum 33:1601–1610CrossRefPubMedGoogle Scholar
  11. 11.
    Hochberg MC, Martel-Pelletier J, Monfort J et al (2016) MOVES investigation group. Combined chondroitin sulfate and glucosamine for painful knee osteoarthritis: a multicentre, randomised, double-blind, non-inferiority trial versus celecoxib. Ann Rheum Dis 75(1):37–44. doi: 10.1136/annrheumdis-2014-206792 CrossRefPubMedGoogle Scholar
  12. 12.
    Roman-Blas JA, Castañeda S, Sánchez-Pernaute O, Largo R, Herrero-Beaumont G, CS/GS Combined Therapy Study Group (2017) 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 69(1):77–85. doi: 10.1002/art.39819 CrossRefPubMedGoogle Scholar
  13. 13.
    Bryant LR, des Rosier KF, Carpenter MT (1995) Hydroxychloroquine in the treatment of erosive osteoarthritis. J Rheumatol 22:1527–1531PubMedGoogle Scholar
  14. 14.
    Punzi L, Bertazzolo N, Pianon M, Michelotto M, Todesco S (1996) Soluble interleukin-2 receptors and the treatment with hydroxychloroquine in erosive osteoarthritis. J Rheumatol 23:1477PubMedGoogle Scholar
  15. 15.
    Saviola G, Abdi-Ali L, Campostrini L et al (2012) Clodronate and hydroxychloroquine in erosive osteoarthritis: a 24-month open randomized pilot study. Mod Rheumatol 22(2):256–263. doi: 10.1007/s10165-011-0506-8 CrossRefPubMedGoogle Scholar
  16. 16.
    Verbruggen G, Wittoek R, Vander Cruyssen B, Elewaut D (2012) 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 71(6):891–898. doi: 10.1136/ard.2011.149849 CrossRefPubMedGoogle Scholar
  17. 17.
    Bacconier L, Jorgensen C, Fabre S (2009) Erosive osteoarthritis of the hand: clinical experience with anakinra. Ann Rheum Dis 68(6):1078–1079CrossRefGoogle Scholar
  18. 18.
    Fioravanti A, Fabbroni M, Cerase A, Galeazzi M (2009) Treatment of erosive osteoarthritis of the hands by intra-articular infliximab injections: a pilot study. Rheumatol Int 29:961–965CrossRefPubMedGoogle Scholar
  19. 19.
    Saviola G, Santoro L (2000) Clodronate in erosive osteoarthritis of the hand: efficacy for pain and function recovery. G Ital Med Lav Ergon 22:328–331PubMedGoogle Scholar
  20. 20.
    Lehenkari PP, Kellinsalmi M, Näpänkangas JP et al (2002) Further insight into mechanism of action of clodronate: inhibition of mitochondrial ADP/ATP translocase by a nonhydrolyzable, adenine-containing metabolite. Mol Pharmacol 61(5):1255–1262CrossRefPubMedGoogle Scholar
  21. 21.
    Frith JC, Monkkonen J, Auriola S, Monkkonen H, Rogers MJ (2001) The molecular mechanism of action of the antiresorptive ad antinflammatory drug clodronate: evidence for the formation in vivo of a metabolite that inhibits bone resorption and cause osteoclast and macrophage apopotosis. Arthritis Rheum 44:2201–2210CrossRefPubMedGoogle Scholar
  22. 22.
    Tseng S, Reddi AH, Di Cesare PE (2009) Cartilage oligomeric matrix protein (COMP): a biomarker of arthritis. Biomark Insights 4:33–44PubMedPubMedCentralGoogle Scholar
  23. 23.
    Halász K, Kassner A, Mörgelin M, Heinegård D (2007) COMP acts as a catalyst in collagen fibrillogenesis. J Biol Chem 282(43):31166–31173CrossRefPubMedGoogle Scholar
  24. 24.
    Dreiser RL, Maheu E, Guillou GB, Caspard H, Grouin JM (1995) Validation of an algofunctional index for osteoarthrtitis of the hand. Rev Rheum Engl Ed 62(6 Suppl 1):43S–53SGoogle Scholar
  25. 25.
    Kloppenburg M, Bøyesen P, Visser AW et al (2015) Report from the OMERACT hand osteoarthritis working group: set of core domains and preliminary set of instruments for use in clinical trials and observational studies. J Rheumatol 42(11):2190–2197CrossRefPubMedGoogle Scholar
  26. 26.
    Cantatore FP, Corrado A, Grano M, Quarta L, Colucci S, Melillo N (2004)Osteocalcin synthesis by human osteoblasts from normal and osteoarthrtic bone after vitamin D3 stimulation. Clin Rheumatol 23(6):490–495CrossRefPubMedGoogle Scholar
  27. 27.
    Chan TF, Couchourel D, Abed E, Delalendre A, Duval N, Lajeunesse D (2011) Elevated Dickkopf-2 levels contribute to the abnormal phenotype of human osteoarthritic osteoblasts. J Bone Miner Res 26:1399–1410CrossRefPubMedGoogle Scholar
  28. 28.
    Goldring MB, Goldring SR (2010) Articular cartilage and subchondral bone in the pathogenesis of osteoarthritis. Ann N Y Acad Sci 1192:230–237CrossRefPubMedGoogle Scholar
  29. 29.
    Xing RL, Zhao LR, Wang PM (2016) Bisphosphonates therapy for osteoarthritis: a meta-analysis of randomized controlled trials. Spring 5(1):1704 eCollection 2016 Google Scholar
  30. 30.
    Corrado A, Neve A, Maruotti N, Gaudio A, Marucci A, Cantatore FP (2010) Dose-dependent metabolic effect of zoledronate on primary human osteoblastic cell cultures. Clin Exp Rheumatol 28(6):873–879PubMedGoogle Scholar
  31. 31.
    Corrado A, Cantatore FP, Grano M, Colucci S (2005) Neridronate and human osteoblasts in normal, osteoporotic and osteoarthritic subjects. Clin Rheumatol 24(5):527–534CrossRefPubMedGoogle Scholar
  32. 32.
    Frediani B, Spreafico A, Capperucci C et al (2004) Long term effects of neridronate on human cell coltures. Bone 35(4):859–869CrossRefPubMedGoogle Scholar
  33. 33.
    Frediani B, Bertoldi I (2015) Clodronate: new directions of use. Clin Cases Miner Bone Metab 12(2):97–108. doi: 10.11138/ccmbm/2015.12.2.097 Review
  34. 34.
    Liu L, Igarashi K, Kanzaki H et al (2006) Clodronate inhibits PGE2 production in compressed periodontal ligament cells. J Dent Res 85(8):757–760CrossRefPubMedGoogle Scholar
  35. 35.
    Teronen O, Konttinen YT, Lindqvist C et al (1997) Inhibition of matrix metalloproteinase-1 by dichloromethylene bisphosphonate (clodronate). Calcif Tissue Int 61:59–61CrossRefPubMedGoogle Scholar
  36. 36.
    Barrera P, Blom A, van Lent PL et al (2000) Synovial macrophage depletion with clodronate-containing liposomes in rheumatoid arthritis. Arthritis Rheum 43(9):1951–1959CrossRefPubMedGoogle Scholar
  37. 37.
    Bonabello A, Galmozzi MR, Canaparo R, Serpe L, Zara GP (2003) Long-term analgesic effect of clodronate in rodents. Bone 33(4):567–574CrossRefPubMedGoogle Scholar
  38. 38.
    Kim S, Seiryu M, Okada S et al (2013) Analgesic effects of the non-nitrogen-containing bisphosphonates etidronate and clodronate, independent of anti-resorptive effects on bone. Eur J Pharmacol 699(1–3):14–22. doi: 10.1016/j.ejphar.2012.11.031 CrossRefPubMedGoogle Scholar
  39. 39.
    Shima K, Nemoto W, Tsuchiya M et al (2016) Bisphosphonates clodronate and etidronate exert analgesic effects by acting on glutamate and/or ATP-related pain transmission pathways. Biol Pharm Bull 39(5):770–777. doi: 10.1248/bpb.b15-00882 CrossRefPubMedGoogle Scholar
  40. 40.
    Rossini M, Viapiana O, Ramonda R et al (2009) Intraarticular clodronate for the treatment of knee osteoarthrtitis: dose ranging study vs hyaluronic acid. Rheumatology 48:773–778CrossRefPubMedGoogle Scholar
  41. 41.
    Rossini M, Adami S, Fracassi E et al (2015) Effects of intra-articular clodronate in the treatment of knee osteoarthritis: results of a double-blind, randomized placebo-controlled trial. Rheumatol Int 35(2):255–263. doi: 10.1007/s00296-014-3100-5 CrossRefPubMedGoogle Scholar
  42. 42.
    Saviola G, Abdi-Ali L, Povino MR (2015) Clodronate: old drug, new uses. J Biol Regul Homeost Agents 29(3):719–722 Review Google Scholar
  43. 43.
    Rosa RG, Collavino K, Lakhani A et al (2014) Clodronate exerts an anabolic effect on articular chondrocytes mediated through the purinergic receptor pathway. Osteoarthr Cartil 22(9):1327–1336. doi: 10.1016/j.joca.2014.07.009 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Ribatti D, Maruotti N, Nico B et al (2008) Clodronate inhibits angiogenesis in vitro and in vivo. Oncol Rep 19(5):1109–1112PubMedGoogle Scholar
  45. 45.
    Vilim V, Vitasek R, Olejarova M, Machacek S et al (2001) Serum cartilage oligomeric matrix protein reflects the presence of clinically diagnosed synovitis in patients with knee osteoarthritis. Osteoarthr Cart 9:612–616CrossRefGoogle Scholar
  46. 46.
    Bleasel JF, Poole AR, Heinegard D et al (1999) Changes in serum cartilage marker level indicate altered cartilage metabolism in families with the osteoarthritis-related type II collagen gene COL2A1 mutation. Arthritis Rheum 42:39–45CrossRefPubMedGoogle Scholar
  47. 47.
    Conrozier T, Saxne T, Fan CS et al (1998) Serum concentration of cartilage oligomeric matrix protein and bone sialoprotein in hip osteoarthritis: a one year prospective study. Ann Rheum Dis 57:527–532CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Vilim V, Olejarova M, Machacek S, Gatterova J, Kraus VB, Pavelka K (2002) Serum levels of cartilage oligomeric matrix protein (COMP) correlate with radiographic progression of knee osteoarthritis. Osteoarthr Cart 10:707–713CrossRefGoogle Scholar
  49. 49.
    Petersson IF, Boegard T, Svensson B, Heinegard D, Saxne T (1998) Changes in cartilage and bone metabolism identified by serum markers in early osteoarthritis of the knee joint. Br J Rheumatol 37:44–56CrossRefGoogle Scholar
  50. 50.
    Aslam I, Perjar I, Shi XA, Renner JB, Kraus WB, Golightly YM, Jordan JM, Nelson AE (2014) Association between biomarkers of joint metabolism, hand osteoarthrtitis and hand pain and function: the Johnston County osteoarthritis project. J Rheumatol 41(5):938–944CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International League of Associations for Rheumatology (ILAR) 2017

Authors and Affiliations

  • Gianantonio Saviola
    • 1
  • Lul Abdi-Ali
    • 1
  • Maria Rosaria Povino
    • 1
  • Lorella Campostrini
    • 2
  • Silvano Sacco
    • 2
  • Luca Dalle Carbonare
    • 3
  1. 1.Rheumatology and Rehabilitation UnitMaugeri Clinical Scientific Institutes—IRCCS of Castel GoffredoCastel GoffredoItaly
  2. 2.Laboratory and Clinical Biochemistry UnitMaugeri Clinical Scientific Institutes—IRCCS of Castel GoffredoMantuaItaly
  3. 3.Department of MedicineUniversity of VeronaVeronaItaly

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