Skip to main content

Advertisement

SpringerLink
Log in

A systematic review and meta-analysis of oxaceprol in the management of osteoarthritis: An evidence from randomized parallel-group controlled trials

  • Review article
  • Published:
Pharmacological Reports Aims and scope Submit manuscript

Abstract

Oxaceprol, a derivative of l-proline, is an established drug for managing osteoarthritis (OA) with better safety profile than non-steroidal anti-inflammatory drugs (NSAIDs). This systematic review and meta-analysis, following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, evaluated the efficacy, safety and tolerability of oxaceprol in OA. Electronic databases for published and grey (unpublished) literature were searched to identify parallel-group randomized controlled trials (RCTs) evaluating the impact of oxaceprol in patients with OA. Risk of bias was assessed using the Cochrane collaboration’s tool. A total of seven parallel-group RCTs involving 1087 participants were included in the systematic review. Meta-analysis, in Review Manager, demonstrated numerically greater/significant improvements compared to active control [diclofenac/ibuprofen]/placebo in pain and function of joint; similar improvement vs. active control in global treatment efficacy; no difference/significant difference vs. active control/placebo in NSAIDs as rescue medication. Treatment with oxaceprol showed numerically less adverse events (AEs) than active control (diclofenac: risk ratio [RR], 0.71; 95% confidence interval [CI], 0.45 to 1.11; p = 0.14: ibuprofen: RR, 0.73; 95% CI, 0.30 to 1.78; p = 0.49) and significantly fewer AEs compared to placebo (RR, 0.76; 95% CI, 0.63 to 0.92; p = 0.004). Given the nature of small-to-moderate sample size and short duration of eligible studies, the available clinical evidence of oxaceprol in the management of OA is modest — though looks promising. New and better RCTs with larger sample size and longer follow-up are warranted to strengthen the use of oxaceprol in clinical setting for managing OA.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. WHO Chronic rheumatic conditions. WHO n.d. https://doi.org/www.who.int/chp/topics/rheumatic/en/ (accessed June 2, 2018).

  2. Arthritis by the Numbers | Scientific Research | Arthritis Foundation. ArthritisOrg n.d. https://doi.org/www.arthritis.org/arthritis-cure/scientific-facts/(accessed June 2, 2018).

  3. Johnson VL, Hunter DJ. The epidemiology of osteoarthritis. Best Pract Res Clin Rheumatol 2014;28:5–15, doi:https://doi.org/10.1016/j.berh.2014.01.004.

    Article  PubMed  Google Scholar 

  4. Nüesch E, Dieppe P, Reichenbach S, Williams S, Iff S, Jüni P. All cause and disease specific mortality in patients with knee or hip osteoarthritis: population based cohort study. BMJ 2011;342:d1165, doi:https://doi.org/10.1136/bmj.d1165.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Maiese K. Picking a bone with WISP1 (CCN4): new strategies against degenerative joint disease. J Transl Sci 2016;1:83–5.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Sinusas K. Osteoarthritis: diagnosis and treatment. Am Fam Phys 2012;85:49–56.

    Google Scholar 

  7. Yusuf E. Pharmacologic and non-pharmacologic treatment of osteoarthritis. Curr Treat Options Rheum 2016;2:111–25, doi:https://doi.org/10.1007/s40674-016-0042-y.

    Article  Google Scholar 

  8. Gore M, Tai K-S, Sadosky A, Leslie D, Stacey BR. Use and costs of prescription medications and alternative treatments in patients with osteoarthritis and chronic low back pain in community-based settings. Pain Pract 2012;12:550–60, doi:https://doi.org/10.1111/j.1533-2500.2012.00532.x.

    Article  PubMed  Google Scholar 

  9. Jüni P, Reichenbach S, Dieppe P. Osteoarthritis: rational approach to treating the individual. Best Pract Res Clin Rheumatol 2006;20:721–40, doi:https://doi.org/10.1016/j.berh.2006.05.002.

    Article  PubMed  Google Scholar 

  10. da Costa BR, Reichenbach S, Keller N, Nartey L, Wandel S, Jüni P, et al. Effectiveness of non-steroidal anti-inflammatory drugs for the treatment of pain in knee and hip osteoarthritis: a network meta-analysis. Lancet 2017;390: e21–33, doi:https://doi.org/10.1016/S0140-6736(17)31744-0.

    Article  PubMed  Google Scholar 

  11. Alacqua M, Trifirò G, Cavagna L, Caporali R, Montecucco CM, Moretti S, et al. Prescribing pattern of drugs in the treatment of osteoarthritis in Italian general practice: the effect of rofecoxib withdrawal. Arthritis Rheum 2008;59:568–74, doi:https://doi.org/10.1002/art.23526.

    Article  PubMed  Google Scholar 

  12. Lapane KL, Liu S-H, Dubé CE, Driban JB, McAlindon TE, Eaton CB. Factors associated with the use of hyaluronic acid and corticosteroid injections among patients with radiographically confirmed knee osteoarthritis: a retrospective data analysis. Clin Ther 2017;39:347–58, doi:https://doi.org/10.1016/j.clinthera.2017.01.006.

    Article  CAS  PubMed  Google Scholar 

  13. Park H-R, Cho S-K, Im SG, Jung S-Y, Kim D, Jang EJ, et al. Treatment patterns of knee osteoarthritis patients in Korea. Korean J Intern Med 2018, doi:https://doi.org/10.3904/kjim.2017.304.

    Article  PubMed  Google Scholar 

  14. Ullal SD, Sanji N, Kamath RK, Pai M, Kamath SU, Savur AD. Prescribing pattern for osteoarthritis in a tertiary care hospital. J Clin Diagn Res 2010;4:2421–6.

    CAS  Google Scholar 

  15. Wilson N, Sanchez-Riera L, Morros R, Diez-Perez A, Javaid MK, Cooper C, et al. Drug utilization in patients with OA: a population-based study. Rheumatology (Oxford) 2015;54:860–7, doi:https://doi.org/10.1093/rheumatology/keu403.

    Article  CAS  Google Scholar 

  16. Bally M, Dendukuri N, Rich B, Nadeau L, Helin-Salmivaara A, Garbe E, et al. Risk of acute myocardial infarction with NSAIDs in real world use: bayesian meta-analysis of individual patient data. BMJ 2017;357:, doi:https://doi.org/10.1136/bmj.j1909.

  17. Dib RA, Chinzon D, de S Fontes LH, de Sá Teixeira AC, Navarro-Rodriguez T. Ulcer and bleeding complications and their relationship with dyspeptic symptoms in NSAIDs users: a transversal multicenter study. Scand J Gastroenterol 2014;49:785–9, doi:https://doi.org/10.3109/00365521.2014.919016.

    Article  CAS  PubMed  Google Scholar 

  18. García Rodríguez LA, Tacconelli S, Patrignani P. Role of dose potency in the prediction of risk of myocardial infarction associated with nonsteroidal anti-inflammatory drugs in the general population. J Am Coll Cardiol 2008;52:1628–36, doi:https://doi.org/10.1016/j.jacc.2008.08.041.

    Article  PubMed  CAS  Google Scholar 

  19. Lanas A, Garcia-Tell G, Armada B, Oteo-Alvaro A. Prescription patterns and appropriateness of NSAID therapy according to gastrointestinal risk and cardiovascular history in patients with diagnoses of osteoarthritis. BMC Med 2011;9:38, doi:https://doi.org/10.1186/1741-7015-9-38.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Reicin AS, Shapiro D, Sperling RS, Barr E, Yu Q. Comparison of cardiovascular thrombotic events in patients with osteoarthritis treated with rofecoxib versus nonselective nonsteroidal anti-inflammatory drugs (ibuprofen, diclofenac, and nabumetone). Am J Cardiol 2002;89:204–9, doi:https://doi.org/10.1016/S0002-9149(01)02201-9.

    Article  CAS  PubMed  Google Scholar 

  21. Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T, Whelton A, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA 2000;284:1247–55, doi:https://doi.org/10.1001/jama.284.10.1247.

    Article  CAS  PubMed  Google Scholar 

  22. Sowers JR, White WB, Pitt B, Whelton A, Simon LS, Winer N, et al. The Effects of cyclooxygenase-2 inhibitors and nonsteroidal anti-inflammatory therapy on 24-hour blood pressure in patients with hypertension, osteoarthritis, and type 2 diabetes mellitus. Arch Intern Med 2005;165:161–8, doi:https://doi.org/10.1001/archinte.165.2.161.

    Article  CAS  PubMed  Google Scholar 

  23. Trelle S, Reichenbach S, Wandel S, Hildebrand P, Tschannen B, Villiger PM, et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ 2011;342:c7086, doi:https://doi.org/10.1136/bmj.c7086.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Walter RB, Milano F, Brasky TM, White E. Long-term use of acetaminophen, aspirin, and other nonsteroidal anti-inflammatory drugs and risk of hematologic malignancies: results from the prospective Vitamins and Lifestyle (VITAL) study. J Clin Oncol 2011;29:2424–31, doi:https://doi.org/10.1200/JCO.2011.34.6346.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Parnham MJ. Antirheumatic agents and leukocyte recruitment. New light on the mechanism of action of oxaceprol. Biochem Pharmacol 1999;58:209–15, doi:https://doi.org/10.1016/S0006-2952(99)00056-8.

    Article  CAS  PubMed  Google Scholar 

  26. Ionac M, Parnham MJ, Plauchithiu M, Brune K. Oxaceprol, an atypical inhibitor of inflammation and joint damage. Pharmacol Res 1996;33:367–73, doi:https://doi.org/10.1006/phrs.1996.0051.

    Article  CAS  PubMed  Google Scholar 

  27. Cashman JN. The mechanisms of action of NSAIDs in analgesia. Drugs 1996;52(Suppl. 5):13–23, doi:https://doi.org/10.2165/00003495-199600525-00004.

    Article  CAS  PubMed  Google Scholar 

  28. Bauer HW, Klasser M, von Hanstein KL, Rolinger H, Schladitz G, Henke HD, et al. Oxaceprol is as effective as diclofenac in the therapy of osteoarthritis of the knee and hip. Clin Rheumatol 1999;18:4–9, doi:https://doi.org/10.1007/s100670050043.

    Article  CAS  PubMed  Google Scholar 

  29. Herrmann G, Steeger D, Klasser M, Wirbitzky J, Fürst M, Venbrocks R, et al. Oxaceprol is a well-tolerated therapy for osteoarthritis with efficacy equivalent to diclofenac. Clin Rheumatol 2000;19:99–104, doi:https://doi.org/10.1007/s100670050025.

    Article  CAS  PubMed  Google Scholar 

  30. Hildebrandt H. Therapie von gon- und coxarthrosen. Klinischer vergleich von oxaceprol und ibuprofen [Therapy of gonarthrosis and coxarthrosis. Clinical comparison of oxaceprol and ibuprofen]. Zeitschrift Fur Allgemeinmedizin 1995;71: 1742–1744+1747–1748.

    Google Scholar 

  31. Steinbach K, Bauer HW. Klinischer Vergleich von Oxaceprol und Diclofenac bei Gon-und Koxarthrosen [Clinical comparison of oxaceprol and diclofenac in gonarthrosis and coxarthrosis]. Extracta Orthop 1995;18:18–21.

    Article  Google Scholar 

  32. Vagt CW, Kaiser T, Leineweber G. Wirksamkeitsvergleich der oralen Therapie mit Oxazeprol versus Ibuprofen bei Gonarthrose und Coxarthrose [Efficacy comparison of oral therapy with oxaceprol versus ibuprofen in gonarthrosis and coxarthrosis]. Rheuma 1990;10:263–7.

    Google Scholar 

  33. Pawar HS, Francis NK, Hota T, Peter N, Mitra A. Comparative evaluation of therapeutic efficacy of intra-articular oxaceprol with conventional modalities in osteoarthritis animal model. Clin Rheumatol 2018;37:2195–201, doi:https://doi.org/10.1007/s10067-018-4087-1.

    Article  PubMed  Google Scholar 

  34. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med 2009;6:e1000100, doi:https://doi.org/10.1371/journal.pmed.1000100.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Higgins JPT, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 2011;343:d5928, doi:https://doi.org/10.1136/bmj.d5928.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Higgins JPT, Green S. Cochrane handbook for systematic reviews of interventions. Wiley Online Library; 2008, doi:https://doi.org/10.1002/9780470712184.

    Google Scholar 

  37. Michael B, Larry VH, Julian H, Hannah RW. Introduction to meta-analysis. UK: A John Wiley and Sons Ltd; 2009, doi:https://doi.org/10.1002/9780470743386.

    Google Scholar 

  38. Feldman S, Bergal S, Nores JM, Dalayeun JF, Remy J. Traitement par la N-acétyl-hydroxyproline des arthropathies dégénératives: analyse et synthèse de 7 essais cliniques [Treatment of degenerative osteoarticular disease with N-acetyl-hydroxyproline. Analysis and synthesis of 7 clinical trials]. Rhumatologie 1994;46: 281–281.

    Google Scholar 

  39. Juvin E. Essai pragmatique de l’oxacéprol 200 mg dans le traitement au long cours de l’arthrose des membres inférieurs [A pragmatic trial of oxaceprol 200 mg in the long-term treatment of lower limb osteoarthritis]. Semaine Des Hopitaux de Paris 1998;74:47–54.

    Google Scholar 

  40. Krüger K, Klasser M, Mössinger J, Becker U. Oxaceprol-a randomised, placebo-controlled clinical study in osteoarthritis with a non-conventional nonsteroidal anti-inflammatory drug. Clin Exp Rheumatol 2007;25:29–34.

    PubMed  Google Scholar 

  41. A phase III, multicentric, single blind, randomized, comparative study to assess the efficacy and safety of Oxaceprol capsule with Diclofenac tablet in patients with osteoarthritis [CTRI/2009/091/000798]. n.d. https://doi.org/www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=968 (accessed June 12, 2018).

  42. Oxaceprol versus tramadol in knee osteoarthritis: a randomized controlled trial [CTRI/2014/08/004821]. n.d. https://doi.org/www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=7458 (accessed June 12, 2018).

  43. Diehl K, Fallot-Burghardt W, Frie A. Die Therapie der Gonarthrose mit Oxaceprol [The Therapy of gonarthrosis with Oxaceprol] 1985;35:. p. 51–7.

    Google Scholar 

  44. Diehl K, Fallot-Burghardt W, Frie A. Treatment of patella chondropathy with oxaceprol. Therapiewoche 1985;35:3388–92.

    Google Scholar 

  45. Finkbeiner G. Konservative Behandlung der Gonarthrose mit oxaceprol. Therapiewoche 1986;36:116–9.

    Google Scholar 

  46. Franz M. Die Behandlung degenerativer Gelenkerkrankungen mit Oxaceprol. Rheuma 1992;12:137–41.

    Google Scholar 

  47. Laborie G, Arramon JY. [The acetyl-hydroxyproline, metabolic harmonizator of connective tissue (100 cases in rheumatologic practice)]. Bord Med 1970;3:3059–60 passim.

    CAS  PubMed  Google Scholar 

  48. Michael J. Die Therapie von Koxarthrosen und Gonarthrosen mit Oxaceprol [Therapy of coxarthrosis and gonarthrosis with Oxaceprol]. Therapiewoche 1986;36:3076–81.

    Google Scholar 

  49. Schubotz R, Hausmann L. Behandlung degenerative Gelenkerkrankungen mit N-Acetyl-Hydroxyprolin [Treatment of degenerative joint disease with N-acetyl-hydroxyproline]. Therapiewoche 1977;27:4248–52.

    Google Scholar 

  50. NDI 176 — N-Acetyl-L-Hydroxyproline — Supporting & Related Materials n.d. https://doi.org/www.regulations.gov/document?D=FDA-2004-S-0571-0026 (accessed November 10, 2018).

  51. Sites BD, Masaracchia MM, Davis M. Distinguishing between efficacy and real-world effectiveness: the case for thinking beyond classic randomized controlled trial design. Reg Anesth Pain Med 2017;42:131–2, doi:https://doi.org/10.1097/AAP.0000000000000563.

    Article  PubMed  Google Scholar 

  52. Gurevitch J, Koricheva J, Nakagawa S, Stewart G. Meta-analysis and the science of research synthesis. Nature 2018;555:175–82, doi:https://doi.org/10.1038/nature25753.

    Article  CAS  PubMed  Google Scholar 

  53. Barton S. Which clinical studies provide the best evidence? The best RCT still trumps the best observational study. BMJ 2000;321:255–6, doi:https://doi.org/10.1136/bmj.321.7256.255.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Oxford Centre for Evidence-based Medicine — Levels of Evidence (March 2009). CEBM 2009. https://doi.org/www.cebm.net/2009/06/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/ (accessed July 19, 2018).

  55. Witte S, Lasek R, Victor N. Wirksamkeit von Ademetionin und Oxaceprol für die Behandlung von Arthrosen [Meta-analysis of the efficacy of adenosylmethionine and oxaceprol in the treatment of osteoarthritis]. Orthopade 2002;31:1058–65, doi:https://doi.org/10.1007/s00132-002-0366-1.

    Article  CAS  PubMed  Google Scholar 

  56. Brune K, Graf P, Glatt M. Inhibition of prostaglandin synthesis in vivo by nonsteroid anti-inflammatory drugs: evidence for the importance of pharmacokinetics. Agents Actions 1976;6:159–64, doi:https://doi.org/10.1007/BF01972201.

    Article  CAS  PubMed  Google Scholar 

  57. Flower RJ. Drugs which inhibit prostaglandin biosynthesis. Pharmacol Rev 1974;26:33–67.

    CAS  PubMed  Google Scholar 

  58. Clayton JJ. Nutraceuticals in the management of osteoarthritis. Orthopedics 2007;30:624–9, doi:https://doi.org/10.3928/01477447-20070801-13 quiz 630-1.

    Article  PubMed  Google Scholar 

  59. Ragle RL, Sawitzke AD. Nutraceuticals in the management of osteoarthritis: a critical review. Drugs Aging 2012;29:717–31, doi:https://doi.org/10.1007/s40266-012-0006-3.

    Article  CAS  PubMed  Google Scholar 

  60. Veihelmann A, Hofbauer A, Refior HJ, Messmer K. Oxaceprol, an atypical inhibitor of inflammation, reduces leukocyte adherence in mouse antigen-induced arthritis. Acta Orthop Scand 2001;72:293–8, doi:https://doi.org/10.1080/00016470152846655.

    Article  CAS  PubMed  Google Scholar 

  61. Harris A, Schropp A, Messmer K. Effects of oxaceprol on the microcirculation in ischemia/reperfusion injury. Eur J Med Res 1998;3:182–8.

    CAS  PubMed  Google Scholar 

  62. Walker-Bone K, Javaid K, Arden N, Cooper C. Regular review: medical management of osteoarthritis. BMJ 2000;321:936–40, doi:https://doi.org/10.1136/bmj.321.7266.936.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Samant AP, Samant PD, Nayak UV. Comparative study of therapeutic efficacy and safety of oxaceprol and oral glucosamine in patients with osteoarthritis of knee. Indian J Pharmacol 2013;45: S111–S111.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Real World Evidence, Molecular Connections (P) Ltd., Basavanagudi, Bengaluru, India

    Sharanbasappa Durg, Melita Lobo, Lakshmi Venkatachalam, Guruprasad Rao & Jignesh Bhate

Authors
  1. Sharanbasappa Durg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Melita Lobo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lakshmi Venkatachalam
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Guruprasad Rao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jignesh Bhate
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sharanbasappa Durg.

Supplementary data

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Durg, S., Lobo, M., Venkatachalam, L. et al. A systematic review and meta-analysis of oxaceprol in the management of osteoarthritis: An evidence from randomized parallel-group controlled trials. Pharmacol. Rep 71, 374–383 (2019). https://doi.org/10.1016/j.pharep.2018.12.010

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1016/j.pharep.2018.12.010

Keywords

Search

Navigation