Bisphosphonate-associated scleritis: a case report and review.

Abstract: An 86-year-old female was treated for osteoporosis with alendronate, an aminobisphosphonate. Six weeks after alendronate therapy began, scleritis developed in the patient's right eye. The alendronate was discontinued, and, with the administration of prednisone, the symptoms of scleritis fully resolved. Rechallenge resulted in recurrence of the symptoms. Bisphosphonates are commonly used in the management of osteoporosis and are generally safe agents. Rarely, they have been linked with ocular inflammation. This case report reviews the literature on the ocular effects of bisphosphonates and discusses a possible mechanism for the association.

Key Words: alendronate, bisphosphonate, scleritis, uveitis 

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Aminobisphosphonates are potent and specific antiresorptive agents used for the treatment of osteoporosis. They work by limiting osteoclast activity, thus inhibiting bone resorption. (1) Nitrogen-containing bisphosphonates have no detrimental effect on bone growth or mineralization. (1) Formerly, only intravenous agents such as pamidronate were available. In the last two decades, newer oral bisphosphonates, such as alendronate and risedronate, have shown efficacy in the management of osteoporosis and are often used as first-line agents. (2,3) To date, gastrointestinal side effects, including esophagitis, esophageal reflux, and dyspepsia, have been the main reported side effects, albeit not commonly. (4)

Pamidronate, a nitrogen-containing bisphosphonate, has been linked to several types of ocular inflammation, such as anterior uveitis, scleritis, episcleritis, and nonspecific conjunctivitis, and even more rarely, optic neuropathy, peripapillary atrophy, cataracts, and corneal opacities. (5-8) Studies on ocular inflammation associated with pamidronate have most often documented positive dechallenge and rechallenge data for scleritis, a potentially serious clinical manifestation. (7,8) More recently, alendronate and risedronate have rarely been associated with similar episodes of ocular inflammation. (9-12)

Case Report

An 86-year-old female with a history of osteoporosis presented with the sudden-onset of pain above her right eye. The pain was described as sharp, waxing and waning in intensity, and debilitating at times. Shortly after the pain began, she noticed redness of the eye, prompting her to call her ophthalmologist, who treated her with antibacterial eyedrops. The discomfort and redness did not improve despite treatment with nonsteroidals and topical medications, so she sought a second opinion.

Her medical history was notable for hypertension, osteoarthritis, bilateral cataracts (status post extractions 5 years earlier), and recently diagnosed osteoporosis. She had started 70 mg of alendronate sodium once weekly about 6 weeks before this presentation. Her other medications included lisinopril, bisoprolol/hydrochlorothiazide, and ibuprofen as needed. Her review of symptoms was negative for fevers, chills, jaw claudication, change in vision, tinnitus, or dizziness.

On physical examination, she had diffuse, mild, conjunctival injection in both eyes with a prominent area of nodular scleritis and adjacent hyperemia temporally in the right eye. This area was tender to palpation. On ophthalmoscopy, the discs appeared flat, sharp, and pink, with a cup-to-disc ratio of 0.2 in both eyes. The vessels appeared normal. An area of posterior scleritis inferior to the disc in the right eye was noted. Her laboratory evaluation revealed normal chemistries and complete blood counts. Her sedimentation rate was 31 mm/hr.

Given the temporal relation with initiation of alendronate therapy, the medication was discontinued, and the patient was started on prednisone at 60 mg per day. Her symptoms resolved completely within 1 week of the institution of steroid therapy, and her prednisone dosage was rapidly tapered. Six months later, after discussion with the patient, a rechallenge with once-weekly alendronate was attempted due to the severity of her osteoporosis and the lack of definitive evidence associating oral bisphosphonates with scleritis. Four weeks later, the discomfort above the right eye reappeared, so the patient discontinued use of the medication. She did not require treatment with steroids for this recurrence. She has remained free of symptoms since that time.

Discussion

Over the last 10 years, bisphosphonates have become the mainstay for the treatment of osteoporosis. They are both efficacious and well tolerated. (13) Pamidronate, one of the early intravenous bisphosphonates, has been associated with adverse ocular events in several case reports. (5-8) In a comprehensive report consisting of data on ocular adverse drug reactions, Ciba-Geigy Central Epidemiology and Drug Safety Center in Basel, Switzerland, had recorded 23 cases of suspected inflammatory eye reactions associated with the use of this agent as of 1993. (7) Three groups of ocular inflammation were found among the 23 patients: anterior uveitis, episcleritis and scleritis, and nonspecific conjunctivitis. (7) Doses of pamidronate ranged from 30 to 120 mg intravenously daily. Seven patients had anterior uveitis, expressed bilaterally in six patients and unilaterally in one. (7,14) Most of the reactions were treated with topical corticosteroids and resolved within several days to 1 month. Two of the three patients who had severe uveitis were hospitalized. A second group of patients, consisting of three people, developed either unilateral episcleritis or scleritis between 1 and 6 days after intravenous pamidronate treatment. Full recovery occurred in all patients after the cessation of pamidronate therapy. The remaining 13 patients in this series of reports responded with nonspecific conjunctivitis. Ocular inflammatory symptoms also subsided with discontinuation of the bisphosphonate. (7)

More recently, Fraunfelder et al (8) performed a comprehensive review of specific cases of scleritis (similar diagnosis as in our patient) associated with pamidronate disodium collected from reports submitted to the World Health Organization (Uppsala, Sweden), the Food and Drug Administration (Bethesda, MD), and the National Registry of Drug-Induced Ocular Side Effects (Casey Eye Institute, Portland, OR). Unilateral scleritis associated with pamidronate therapy (doses of 30 to 60 mg intravenously) was found in 17 reports, occurring anteriorly in 16 of those cases, and with one case of bilateral scleritis. Positive rechallenge data were noted in six cases, with scleritis recurring in the same eye as the initial inflammation. All cases of scleritis required the discontinuation of pamidronate therapy before the inflammatory symptoms would fully subside. (8)

To our knowledge, although alendronate has been associated with ocular inflammation as well, only four cases implicating alendronate as causative of scleritis have been reported in the literature. (9,10,12) In a series of three patients by Mbekeani et al, (9) two had development of posterior scleritis and one was found to have anterior nodular scleritis. The three patients had no history of ocular symptoms or connective tissue disorders. Withdrawal of alendronate, followed by administration of steroids, resulted in resolution of the scleritis. None were rechallenged. (9) A fourth case of acute nongranulomatous anterior uveitis possibly associated with alendronate has recently been reported. (10) Only one case of risedronate-associated iritis (at doses of 30 mg orally per day) has been reported. (11)

Beyond their well-recognized inhibition of osteoclasts, bisphosphonates exert myriad effects on the immune system. In particular, pamidronate stimulates the production of a T-cell subset that specifically inhibits bone resorption and may activate the production of antigenic receptor T-cells, which leads to the release of cytokines. (7,8) Other effects include the increased production of interleukin-1, interleukin-6, and C-reactive proteins. (7-9,14) An inflammatory response is the composite end result of these actions. Clinically, patients may have low-grade pyrexia and influenza-like symptoms with the administration of intravenous pamidronate. (15,16) In the published reports of ocular adverse events, patients often had such constitutional symptoms before the development of ocular inflammation, suggesting that an underlying inflammatory, acute-phase response may be driving the scleritis. (5,7-9,14) It is reasonable to postulate that other bisphosphonates may invoke similar inflammatory responses, (17) given the comparable mechanisms of actions of drugs in this class.

Also in support of a class effect linking aminobisphosphonates to ocular inflammation is the fact that the onset of symptoms and description of symptoms in reported cases with alendronate and risedronate were similar to those of pamidronate-associated cases. Furthermore, the risedronate-treated patient's ocular inflammation recurred when treated with pamidronate, a different bisphosphonate, suggesting a class effect. (11) These commonalities suggest that the association of bisphosphonate use with scleritis may share a comparable pathophysiology for pamidronate, alendronate, risedronate, and others. The nitrogen component appears to be important in this process, as no cases of ocular inflammation have been reported with bisphosphonates lacking such an amine group. Whether the route of administration, dose, potency of the bisphosphonate, or underlying patient diagnosis is related to the development of scleritis remains unclear. Certainly, the dose of 70 mg per week of alendronate in our case is smaller than the doses of pamidronate and risedronate reported in other cases (doses of alendronate in prior cases were not reported), but the potencies of the individual drugs differ, and no conclusions can be drawn. Importantly, no cases resolved without discontinuation of the bisphosphonate.

Our case is the fifth known documentation of a probable association of scleritis with alendronate and subsequent resolution upon discontinuing the drug and administering prednisone. As in prior reported cases, the timing of the onset and clinical manifestations of ocular inflammation in this patient is similar to those previously described and supports a probable but not definitive causal link. Our case further adds to the literature by being the first to document recurrence of symptoms with rechallenge with alendronate. Such rechallenge is crucial in establishing causality.

Conclusion

Alendronate and other aminobisphosphonates may be associated with ocular inflammation, albeit very uncommonly. Episcleritis and scleritis, if untreated, can result in serious, permanent eye damage. Appropriate treatment of the scleritis would include immediate discontinuation of the bisphosphonate and referral to an ophthalmologist. Given the potential reversibility of bisphosphonate-associated scleritis, it is essential for all clinicians to recognize this uncommon but important side effect.

References

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2. Liberman UA, Weiss SR, Broll J, et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N Engl J Med 1995;333:1437-1496.

3. Harris ST, Watts NB, Genant HK, et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis. JAMA 1999;282:1344-1352.

4. De Groen PC, Lubbe DF, Hirsch LJ, et al. Esophagitis associated with the use of alendronate. N Engl J Med 1996; 335:1016-1021.

5. Ghose K, Waterworth R, Trolove P, et al. Uveitis associated with pamidronate. Aust N Z J Med 1994;24:320.

6. O'Donnell NP, Rao GP, Aguis-Fernandez A. Paget's disease: ocular complications of disodium pamidronate treatment. Br J Clin Pract 1995;49:272-273.

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

8. Fraunfelder FT, Fraunfelder FW, Jensvold B. Scleritis and other ocular side effects associated with pamidronate disodium. Am J Ophthalmol 2003;135:219-222.

9. Mbekeani JN, Slamovits TL, Schwartz BH, et al. Ocular inflammation associated with alendronate therapy. Arch Ophthalmol 1999;117:837-838.

10. Salmen S, Berrueta L, Sanchez N, et al. Nongranulomatous anterior uveitis associated with alendronate therapy. Invest Clin 2002;43:49-52.

11. Siris ES. Bisphosphonates and iritis. Lancet 1993;341:436-437.

12. Fraunfelder FW, Fraunfelder FT. Bisphosphonates and ocular inflammation (letter to the editor). N Engl J Med 2003;348:1187-8.

13. Watts NB. Bisphosphonate treatment of osteoporosis. Clin Geriatr Med 2003;19:395-414.

14. Moorthy RS, Valluri S, Jampol L. Drug-induced uveitis. Surv Ophthalmol 1998;42:557-570.

15. Thiebaud D, Burckhardt P, Melchior J, et al. Two years' effectiveness of intravenous pamidronate (APD) versus oral fluoride for osteoporosis occurring in the postmenopause. Osteoporos Int 1994;4:76-83.

16. Boutsen Y, Jamart J, Esselinckx W, et al. Primary prevention of glucocorticoid-induced osteoporosis with intravenous pamidronate and calcium: a prospective controlled 1-year study comparing a single infusion, an infusion given once every 3 months, and calcium alone. J Bone Miner Res 2001;16:104-112.

17. Adami S, Bhalla AK, Dorizzi R, et al. The acute-phase response after bisphosphonate administration. Calcif Tissue Int 1987;41:326-331.

It is difficult to say what is impossible, for the dream of yesterday is
the hope of today and the reality of tomorrow.
--Robert H. Goddard

Sophia Leung, BS, Bimal H. Ashar, MD, and Redonda G. Miller, MD

From the Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD.

Reprint requests to Dr. Redonda G. Miller, Johns Hopkins Outpatient Center, Room 7143, 601 N. Caroline St., Baltimore, MD 21287. Email: [e-mail]

Accepted October 5, 2004.

RELATED ARTICLE: Key Points

* Aminobisphosphonates are common and highly effective agents used for the prevention and treatment of osteoporosis.

* Adverse ocular events, including uveitis, scleritis, and conjunctivitis, have been reported with aminobisphosphonate use, particularly pamidronate.

* Resolution of ocular findings usually occurs with with-drawal of the agent; occasionally systemic steroids are also required.