Orbital Inflammation Caused by Aminobisphosphonates


The aim of this review was to describe orbital inflammation secondary to aminobisphosphonates by analyzing demographic data, clinical presentation, and treatment of the disease. This is a narrative literature review. The search was performed using databases such as Ovid/MEDLINE and COCHRANE. The searches were limited to papers in the English language. We found 43 cases of orbital inflammation due to aminobisphosphonates. Zoledronate was the drug most associated with orbital side effects. Clinical presentation was evident by unilateral involvement (89%), palpebral edema (88%), conjunctival congestion (81%), chemosis (79%), ocular pain (77%), ocular motility impairment (65%), proptosis (56%), and blurred vision (39%). It can affect both eyes (11%) and is accompanied by anterior uveitis (23%). Orbital inflammation secondary to aminobisphosphonates is a severe side effect. Clinically, it cannot be distinguished from idiopathic inflammation of the orbit. Therefore, it is important to rule out previous drug exposure. Timely treatment is vital to expect a favorable outcome, with systemic corticosteroids being the treatment of choice.


Alendronate, Bisphosphonates, Dacryoadenitis, Myositis, Pamidronate, Zoledronate

1. Olson K, Van Poznak C. Significance and impact of bisphosphonate-induced acute phase responses. J Oncol Pharm Pract 2007;13:223–229.

2. Thiébaud D, Sauty A, Burckhardt P, Leuenberger P, Sitzler L, Green JR, et al. An in vitro and in vivo study of cytokines in the acute-phase response associated with bisphosphonates. Calcif Tissue Int 1997;61:386–392.

3. Buckler HM, Mercer SJ, Davison, Hollis S, Richardson P, Anderson D. Evaluation of adverse experiences related to pamidronate infusion in Paget’s disease of bone. Ann Rheum Dis 1998:57;572–572.

4. Dicuonzo G, Vincenzi B, Santini D, Avvisati G, Rocci L, Battistoni F, et al. Fever after zoledronic acid administration is due to increase in TNF-α and IL-6. J Interferon Cytokine Res 2003;23:649–654.

5. Reid IR, Gamble GD, Mesenbrink P, Lakatos P, Black DM. Characterization of and risk factors for the acute-phase response after zoledronic acid. J Clin Endocrinol Metab 2010;95:4380–4387.

6. Macarol V, Fraunfelder FT. Pamidronate disodium and possible ocular adverse drug reactions. Am J Ophthalmol 1994;118:220–224.

7. Mbekeani JN, Slamovits TL, Schwartz BH, Sauer HL. Ocular inflammation associated with alendronate therapy. Arch Ophthalmol 1999;117:837–838.

8. Ryan PJ, Sampath R. Idiopathic orbital inflammation following intravenous pamidronate. Rheumatology 2001;40:956–957.

9. Subramanian PS, Kerrison JB, Calvert PC, Miller NR. Orbital inflammatory disease after pamidronate treatment for metastatic prostate cancer. Arch Ophthalmol 2003;121:1335–1336.

10. Benderson D, Karakunnel J, Kathuria S, Badros A. Scleritis complicating zoledronic acid infusion. Clin Lymphoma Myeloma 2006;7:145–147.

11. Phillips PM, Newman SA. Orbital inflammatory disease after intravenous infusion of zoledronate for treatment of metastatic renal cell carcinoma. Arch Ophthalmol 2008;126:137–139.

12. Sharma NS, Ooi J-L, Masselos K, Hooper MJ, Francis IC. Zoledronic acid infusion and orbital inflammatory disease. N Engl J Med 2008;359:1410–1411.

13. Seth A, Anderson DP, Albiani DA, Barton JJS. Orbital inflammation and optic neuropathy with zoledronic acid for metastatic prostate cancer. Can J Ophthalmol 2009;44:467–468.

14. Procianoy F, Procianoy E. Orbital inflammatory disease secondary to a single-dose administration of zoledronic acid for treatment of postmenopausal osteoporosis. Osteoporos Int 2010;21:1057–1058.

15. Yang EB, Birkholz ES, Lee AG. Another case of bisphosphonate-induced orbital inflammation. J Neuroophthalmol 2010:30:94–95.

16. Missotten G, Verheezen Y. Orbital inflammation after use of zoledronic acid for metastasized prostate carcinoma. Bull Soc Belge Ophtalmol 2010;315:23–24.

17. Yeo J, Jafer AK. Zolendronate associated inflammatory orbital disease. NZ Med J 2010;1323:50–52.

18. Kaur H, Uy C, Kelly J, Moses AM. Orbital inflammatory disease in a patient treated with zoledronate. Endocr Pract 2011;17:e101–e103.

19. Ortiz-Perez S, Fernandez E, Molina JJ, Sanchez-Dalmau B, Navarro M, Corretger X, et al. Two cases of drug-induced orbital inflammatory disease. Orbit 2011;30:37–39.

20. Peterson JD, Bedrossian EH. Bisphosphonate-associated orbital inflammation—a case report and review. Orbit 2012;31:119–123.

21. Rahimy E, Law SK. Orbital inflammation after zoledronate infusion: an emerging complication. Can J Ophthalmol 2013;48;e11–e12.

22. Schwab P, Harmon D, Bruno R, Fraunfelder FW, Kim DH. A 55-year-old woman with orbital inflammation. Arthritis Care Res 2012;64:1776–1782.

23. Böni C, Kordic H, Chaloupka K. Bisphosphonateassociated orbital inflammatory disease and uveitis anterior - a case report and review. Klin Monbl Augenheilkd 2013;230:367–369.

24. Lefebvre DR, Mandeville JT, Yonekawa Y, Arroyo JG, Torun N, Freitag SK. A case series and review of bisphosphonate-associated orbital inflammation. Ocul Immunol Inflamm 2014;25:1–6.

25. Vora MM, Rodgers IR, Uretsky S. Nitrogen bisphosphonate-induced orbital inflammatory disease. Ophthalmic Plast Reconstr Surg 2014;30:e84–e85.

26. Pirbhai A, Rajak SN, Goold LA, Cunneen TS, Wilcsek G, Martin P, et al. Bisphosphonate-induced orbital inflammation: a case series and review. Orbit 2015;34:331–335.

27. Gonzalez Barlatay J, Hernandez Gauna G, Premoli J, Luis VR, Jorge PE. Orbital inflammation caused by bisphosphonates case report and literature review. IJOO 2016;2:148–151.

28. Muruganandam M, Sandhu H. Orbital inflammation secondary to zoledronic acid, a rare presentation. J Clin Rheumatol 2016;22:384.

29. Umunakwe OC, Herren D, Kim SJ, Kohanim S. Diffuse ocular and orbital inflammation after zoledronate infusioncase report and review of the literature. Digit J Ophthalmol 2017;23:18–21.

30. Tan M, Kalin-Hajdu E, Narayan R, Wong SW, Martin TG. Zoledronic acid-induced orbital inflammation in a patient with multiple myeloma. J Oncol Pharm Pract 2019;25:1253–1257.

31. Chehade LK, Curragh D, Selva D. Bisphosphonateinduced orbital inflammation: more common than once thought? Osteoporos Int 2019;30:1117–1120.

32. Herrera I, Kam Y, Whittaker TJ, Champion M, Ajlan RS. Bisphosphonate-induced orbital inflammation in a patient on chronic immunosuppressive therapy. BMC Ophthalmol 2019;19:51.

33. Keren S, Leibovitch I, Ben Cnaan R, Neudorfer M, Fogel O, Greenman Y, et al. Aminobisphosphonate-associated orbital and ocular inflammatory disease. Acta Ophthalmol 2019;97:e792–e799.

34. Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007;356:1809–1822.

35. Kunzmann V, Bauer E, Feurle J, Weissinger F, Tony HP, Wilhelm M. Stimulation of γδ T cells by aminobisphosphonates and induction of antiplasma cell activity in multiple myeloma. Blood 2000;96:384–392.

36. Gober H-J, Kistowska M, Angman L, Jenö P, Mori L, De Libero G. Human T cell receptor γδ cells recognize endogenous mevalonate metabolites in tumor cells. J Exp Med 2003;197:163–168.

37. Roelofs AJ, Jauhiainen M, Mönkkönen H, Rogers MJ, Mönkkönen J, Thompson K. Peripheral blood monocytes are responsible for γδ T cell activation induced by zoledronic acid through accumulation of IPP/DMAPP. Br J Haematology 2009;144:245–250.

38. Thompson K, Keech F, McLernon DJ, Vinod K, May RJ, Simpson WG, et al. Fluvastatin does not prevent the acutephase response to intravenous zoledronic acid in postmenopausal women. Bone 2011;49:140–145.

39. Kunzmann V, Bauer E, Wilhelm M. γ/δ T-cell stimulation by pamidronate. N Engl J Med 1999;340:737–738.