Drug Safety

, Volume 29, Issue 2, pp 151–160 | Cite as

Ophthalmological Events in Patients Receiving Risedronate

Summary of Information Gained Through Follow-Up in a Prescription-Event Monitoring Study in England
  • Beate Aurich-Barrera
  • Lynda Wilton
  • Scott Harris
  • Saad A.W. Shakir
Original Research Article

Abstract

Background: In the UK, the nitrogen bisphosphonate risedronate is licensed for the prevention and treatment of osteoporosis and corticosteroid-induced osteoporosis in postmenopausal women. It is also licensed for the treatment of Paget’s disease. During a prescription-event monitoring (PEM) study on risedronate we noted a number of ophthalmological events. Recently, case reports of ophthalmological adverse drug reactions in patients taking bisphosphonates were published in the medical literature. The aim of this study was to further evaluate the association of ophthalmological events reported in relation to risedronate treatment during a PEM study on the drug.

Methods: An observational cohort study (PEM study) was conducted in England between September 2000 and June 2002. General practitioners (GPs) were asked for follow-up information on selected events. Events followed up were classified as either ‘probably’, ‘possibly’ or ‘unlikely’ to be related to risedronate, using a modified WHO classification. If insufficient information was obtained on the follow-up questionnaire, the cases were categorised as ‘unassessable’.

Results: Of the total PEM study cohort of 13 643 patients, 11 156 (82%) were females and 2398 (18%) were males. We received 359 reports of ophthalmological events in 313 patients during the entire study period. Of these we followed up 178 events in 178 patients. Nineteen events in 19 patients were assessed as possibly or probably related to risedronate. The age range for these patients was 50–92 years and the time to onset ranged from 7 days to 5 months. Dry eye (six reports), sore eye (five reports) and conjunctivitis (three reports) were the most frequently reported ophthalmological events assessed as probably or possibly related to risedronate therapy. GPs also reported several other inflammatory conditions of the eye, amongst them two events each of iritis and episcleritis as well as one of keratitis. However, the information received on follow up of these events was insufficient to make causality assessments.

Conclusion: Patients receiving risedronate can present with a variety of signs and symptoms affecting the eye with different degrees of severity. Patients may present after the first month of treatment. Doctors should have an increased awareness of possible ophthalmological adverse drug reactions in patients receiving this drug, which may affect the eyesight in a population at increased risk of fracture if they fall.

Keywords

Risedronate Causality Assessment Green Form Ocular Adverse Effect Risedronate Treatment 

Notes

Acknowledgements

We would like to thank all the general practitioners who have kindly participated in this study without payment and those that completed the follow-up questionnaires. We also thank the Prescription Pricing Authority for their continuing support. Further, we would like to thank Mr Shayne Freemantle, Data Analysis Manager, the entire Drug Safety Research Unit (DSRU) team that worked on this study and Mrs Lesley Flowers for preparing this manuscript.

Funding: The DSRU is a medical charity receiving unconditional grants from pharmaceutical companies, including the manufacturers of risedronate and alendronate, and other products in osteoporosis. However, these companies have no control over our decision to conduct a study, the study protocol or the reporting of any results.

Conflicts of interest: Professor Saad Shakir has received consultancy and lecturing fees from the manufacturers of products used for the treatment of osteoporosis. Beate Aurich-Barrera, Lynda Wilton and Scott Harris have no conflicts of interest that are directly relevant to this study.

WHO statement: The WHO Collaborating Centre in Uppsala, Sweden states that, with respect to data released from the centre, “the information is not homogenous at least with respect to origin or likelihood that the pharmaceutical product caused the adverse reaction” and that “the information does not represent the opinion of the WHO”.

References

  1. 1.
    Actonel 5mg [summary of product characteristics]. Egham: Procter and Gamble Pharmaceuticals UK Ltd, 2002Google Scholar
  2. 2.
    Actonel 30mg [summary of product characteristics]. Egham: Procter and Gamble Pharmaceuticals UK Ltd, 2002Google Scholar
  3. 3.
    Actonel once a week 35mg [summary of product characteristics]. Egham: Procter and Gamble Pharmaceuticals UK Ltd, 2003Google Scholar
  4. 4.
    Reginster J, Minne HW, Sorensen OH, et al. Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Osteoporos Int 2000; 11(1): 83–91PubMedCrossRefGoogle Scholar
  5. 5.
    Brown JP, Chines AA, Myers WR, et al. Improvement of pagetic bone lesions with risedronate treatment: a radiologic study. Bone 2000 Mar; 26(3): 263–7PubMedCrossRefGoogle Scholar
  6. 6.
    Reszka AA, Rodan GA. Bisphosphonate mechanism of action. Curr Rheumatol Rep 2003 Feb; 5(1): 65–74PubMedCrossRefGoogle Scholar
  7. 7.
    Reszka AA, Rodan GA. Nitrogen-containing bisphosphonate mechanism of action. Mini Rev Med Chem 2004; 4(7): 711–9PubMedGoogle Scholar
  8. 8.
    Fisher JE, Rodan GA, Reszka AA. In vivo effects of bisphosphonates on the osteoclast mevalonate pathway. Endocrinology 2000 Dec; 141(12): 4793–6PubMedCrossRefGoogle Scholar
  9. 9.
    Rogers HL, Marshall D, Rogers MJ. Effects of Bisphosphonates on osteoclasts in vitro, studies by scanning electron microscopy. Bone 2002; 30: 435Google Scholar
  10. 10.
    Zhang D, Udagawa N, Nakamura I, et al. The small GTP-binding protein Rho p21, is involved in bone resorption by regulating cytoskeletal organization in osteoclasts. J Cell Sci 1995; 108: 2285–92PubMedGoogle Scholar
  11. 11.
    Reszka AA, Halasy-Nagy JM, Masarachia PJ, et al. Bisphosphonates act directly on the osteoclast to induce caspase cleavage of mst1 kinase during apoptosis: a link between inhibition of the mevalonate pathway and regulation of an apoptosis-promoting kinase. J Biol Chem 1999 Dec 3; 274(49): 34967–73PubMedCrossRefGoogle Scholar
  12. 12.
    Sanders JM, Ghosh S, Chan JM, et al. Quantative structure-activity relationships for gammadelta T cell activation by biphosphonates. J Med Chem 2004; 47(2): 375–84PubMedCrossRefGoogle Scholar
  13. 13.
    Siris ES. Bisphosphonates and iritis. Lancet 1993; 341: 436–7PubMedCrossRefGoogle Scholar
  14. 14.
    Fraunfelder FW, Fraunfelder FT, Jensvold B. Scleritis and other ocular side effects associated with pamidronate disodium. Am J Ophthalmol 2003; 135(2): 219–22PubMedCrossRefGoogle Scholar
  15. 15.
    Fraunfelder FW, Fraunfelder FT. Bisphosphonates and ocular inflammation. N Engl J Med 2003 Mar 20; 348(12): 1187–8PubMedCrossRefGoogle Scholar
  16. 16.
    Macarol V, Fraunfelder FT. Pamidronate disodium and possible ocular adverse drug reactions. Am J Ophthalmol 1994; 118(2): 220–4PubMedGoogle Scholar
  17. 17.
    De S, Meyer P, Crisp AJ. Pamidronate and Uveitis. Br J Rheumatol 1995; 34(5): 479PubMedCrossRefGoogle Scholar
  18. 18.
    Mbekeani JN, Slamovits TL, Schwartz BH, et al. Ocular inflammation associated with alendronate therapy. Arch Ophthalmol 1999 Jun; 117(6): 837–8PubMedGoogle Scholar
  19. 19.
    O’Donnell N, Rao GP, Aguis-Fernandez A. Paget’s disease: ocular complications of disodium pamidronate treatment. Br J Clin Pract 1995; 49(5): 272–3PubMedGoogle Scholar
  20. 20.
    Rey J, Daumen-Legre V, Pham T, et al. Uveitis, an under-recognized adverse effect of pamidronate: case report and literature review. Joint Bone Spine 2000; 67(4): 337–40PubMedGoogle Scholar
  21. 21.
    Salmen S, Berrueta L, Sanchez N, et al. Nongranulomatous anterior uveitis associated with alendronate therapy. Invest Clin 2002; 43(1): 49–52PubMedGoogle Scholar
  22. 22.
    Asensio Sanchez VM, Botella Oltra G, Carrasco E. Bifosfonatos e inflamacion intraocular. Arch Soc Esp Oftalmol 2004; 2: 2–4Google Scholar
  23. 23.
    Malik AR, Campbell SH, Toma NM. Bilateral acute anterior uveitis after alendronate [letter]. Br J Ophthalmol 2002; 86(12): 1443PubMedCrossRefGoogle Scholar
  24. 24.
    Leung S, Ashar BII, Miller RG. Bisphosphonate-associated scleritis: a case report and review. South Med J 2005; 98(7): 733–5PubMedCrossRefGoogle Scholar
  25. 25.
    Fietta P, Manganelli P, Lodigiani L. Clodronate induced uveitis [letter]. Ann Rheum Dis 2003; 62(4): 378PubMedCrossRefGoogle Scholar
  26. 26.
    Durnian JM, Olujohungbe A, Kyle G. Bilateral acute uveitis and conjunctivitis after zoledronic acid therapy. Eye 2005; 19(2): 221–2PubMedCrossRefGoogle Scholar
  27. 27.
    Haverbeke G, Pertile G, Claes C, et al. Posterior uveitis: an under-recognized adverse effect of pamidronate: 2 case reports. Bull Soc Belge Ophtamol 2003; (290): 71–6Google Scholar
  28. 28.
    Ghose K, Waterworth R, Trolove P, et al. Uveitis associated with pamidronate. Aust N Z J Med 1994; 24(3): 320PubMedCrossRefGoogle Scholar
  29. 29.
    Stewart GO, Stuckey BG, Ward LC, et al. Iritis following intravenous pamidronate. Aust N Z J Med 1996; 26(3): 414–5PubMedCrossRefGoogle Scholar
  30. 30.
    Vinas G, Olive A, Holgado S, et al. Episcleritis secondary to risedronate. Med Clin (Barc) 2002 Apr 27; 118(15): 598–9Google Scholar
  31. 31.
    Barrera BA, Wilton L, Harris S, Shakir SA. Prescription-event monitoring study on 13,164 patients prescribed risedronate in primary care in England. Osteoporos Int 2005: Epub ahead of printGoogle Scholar
  32. 32.
    Shakir SAW. Prescription-event monitoring. In: BL Strom, editor. Pharmacoepidemiology. 4th ed. Chichester: John Wiley & Sons Ltd, 2005: 203–16Google Scholar
  33. 33.
    Shakir SA. Causality and correlation in pharmacovigilance. In: Talbot PW, editor. Stephens’ detection of new adverse drug reactions. 5th ed. Chichester: John Wiley & Sons Ltd, 2004: 329–43Google Scholar
  34. 34.
    CIOMS.WHO. International Guidelines for Biomedical Research Involving Human Subjects. Geneva: CIOMS WHO, 1993Google Scholar
  35. 35.
    Multi-Centre Research Ethics Committee Guidance Notes. Examples of enquiries and surveys in the public interest where no reference to a Research Ethics Committee is necessary. UK, MREC, 2000; Appendix C:21Google Scholar
  36. 36.
    Guidelines on practice of ethical committees in medical research involving human subjects. Royal College of Physicians of London. August 1996Google Scholar
  37. 37.
    Heeley E, Riley J, Layton D, et al. Prescription-event monitoring and reporting of adverse drug reactions. Lancet 2001 Dec 1; 358(9296): 1872–3PubMedCrossRefGoogle Scholar
  38. 38.
    McAvoy BR, Kramer EF. General practice postal surveys: a questionnaire too far? BMJ 1996 Sep 21; 313(7059): 732–3PubMedCrossRefGoogle Scholar
  39. 39.
    Biswas PN, Wilton LV, Shakir SA. Pharmacovigilance study of alendronate in England. Osteoporos Int 2003; 14(6): 507–14PubMedCrossRefGoogle Scholar
  40. 40.
    Springuel P, McMorran M. Biphosphonates and ocular disorders; Canadian Adverse Drug Reaction Newsletter. Canada: Health Canada, 2003: 1–2Google Scholar
  41. 41.
    Topliss D, Isaacs D, Lander C, et al. Bisphosphonates and ocular inflammation. Aust Adv Drug Reactions Bull 2004; 23(2): 7–8Google Scholar
  42. 42.
    Reszka AA, Halasy-Nagy J, Rodan GA. Nitrogen-bisphosphonates block retinoblastoma phosphorylation and cell growth by inhibiting the cholesterol biosynthetic pathway in a keratinocyte model for oesophageal irritation. Mol Pharmacol 2001 Feb; 59(2): 193–202PubMedGoogle Scholar
  43. 43.
    Santini D, Fratto ME, Vincenzi B, et al. Bisphosphonate effects in cancer and inflammatory diseases: in vitro and in vivo modulation of cyutokine activities. BioDrugs 2004; 18(4): 269–78PubMedCrossRefGoogle Scholar
  44. 44.
    Nelson JD, Helms H, Fiscella R, et al. A new look at dry eye disease and its treatment. Adv Ther 2000; 17(2): 84–93PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2006

Authors and Affiliations

  • Beate Aurich-Barrera
    • 1
    • 2
  • Lynda Wilton
    • 1
    • 2
  • Scott Harris
    • 1
    • 3
  • Saad A.W. Shakir
    • 1
    • 2
  1. 1.Drug Safety Research UnitBursledon HallSouthamptonUK
  2. 2.University of PortsmouthPortsmouthUK
  3. 3.University of SouthamptonSouthamptonUK

Personalised recommendations