Med Oncol (2008) 25:238–240 DOI 10.1007/s12032-007-9006-2
CASE
A case report: zoledronic acid-induced anterior uveitis Saadettin Kilickap Æ Yasemin Ozdamar Æ M. Kadri Altundag Æ Omer Dizdar
Received: 16 July 2007 / Accepted: 17 August 2007 / Published online: 8 September 2007 Ó Humana Press Inc. 2007
Abstract Background Bisphosphonates prevent bone loss by binding on active sites of bone remodeling and inhibiting osteoclast-mediated bone resorption. Zoledronic acid is recommended for patients with bone metastases from breast, prostate, and lung cancers. Objective To report a case of anterior uveitis after the infusion of zoledronic acid. Case Summary A breast cancer patient with bone metastasis was admitted with pain, visual loss, hyperemia, and periorbital swelling in her right eye 24 h after the first dose of zoledronic acid. Biomicroscopic anterior segment examination of the right eye showed corneal keratic precipitates, ciliary injection, and moderate amount of cells in anterior chamber. With the diagnosis of right anterior uveitis, topical prednisolone acetate (1%) was started, and her symptoms completely resolved within 1 week. Use of the Naranjo probability scale indicated a probable relationship between uveitis and zoledronic acid therapy in our patient. Discussion Uveitis is a rare complication of zoledronic acid. The mechanism is unclear. Proinflammatory cytokines such as TNF-a and IL-6 may also play a role in pathogenesis of zoledronic acid-related uveitis. Conclusion Zoledronic acid may be associated with inflammatory eye diseases and result in serious ocular damage. Keywords Zoledronic acid Cancer Uveitis Side effect Pathogenesis S. Kilickap (&) M. K. Altundag O. Dizdar Department of Oncology, Hacettepe University Institute of Oncology, 06100-Sıhhiye, Ankara, Turkey e-mail:
[email protected] Y. Ozdamar Department of Retina, Ankara Ulucanlar Eye Research Hospital, Ankara, Turkey
Introduction Bisphosphonates are synthetic pyrophosphate analogs. They are effective inhibitors of osteoclast-mediated bone resorption and significantly reduce the incidence of skeletal complications in patients with benign skeletal disease such as osteoporosis and Paget’s disease. It is because of their potent antiresorptive activity, that they are also used for malignancy-induced hypercalcemia [1] and prevention of skeletal-related events in patients having metastatic bone disease. Zoledronic acid is the most potent bisphosphonate. Currently, zoledronic acid is recommended for patients with bone metastases from breast, prostate and lung cancer. It is generally well tolerated. Hypocalcemia is the most common side effect of zoledronic acid. The other frequently reported adverse events include bone pain, emesis, constipation, headache, fluctuations in serum electrolyte (magnesium, calcium, and phosphorus) levels, elevation in serum creatinine, osteonecrosis of the jaw (ONJ), and transient flu-like symptoms such as nausea, myalgia, arthralgia, and low-grade fever. In English literature, serious ocular side effects after the administration of zoledronic acid have been reported in only a few articles [4, 5]. Herein, we present a patient with metastatic breast cancer who developed anterior uveitis after zoledronic acid infusion.
Case A 48-year-old woman was admitted to our hospital with pain, decreased vision, periorbital swelling, and hyperemia in her right eye. In her medical history, she had been diagnosed with breast carcinoma in 1989. She was treated with modified radical mastectomy, adjuvant chemotherapy
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and radiotherapy. In 2005, bilateral lung metastases were diagnosed. The patient received 6 cycles of docetaxel and adriamycin with partial response, followed by anastrozole. On March 2007, bone metastases were detected in L1-4 vertebrae, and pelvic bones with intractable pain. Palliative radiotherapy was given on L1-4 vertebrae and zoledronic acid was commenced (4 mg iv, 100 cc normal saline given over 15 min). After 24 h of the first dose of zoledronic acid, her symptoms started. She did not use any concomitant drugs. On ocular examination, the best-corrected visual acuities with Snellen charts was 2/10 in the right eye and 10/10 in the left eye. Intraocular pressures were bilaterally normal. Biomicroscopic anterior segment examination of the right eye showed corneal keratic precipitates, ciliary injection and moderate amount of cells in anterior chamber (Fig. 1). The ocular examination of the left eye was normal. Dilated retinal examination was bilaterally normal. Laboratory evaluation including serum chemistries and complete blood counts was unremarkable. With the diagnosis of right anterior uveitis, topical prednisolone acetate (1%) was started every 6 h. Her symptoms resolved completely within 1 week after steroid therapy.
Discussion Till to date, a number of ocular side effects including conjunctivitis, ocular pain, scleritis, photophobia, episcleritis, blurred vision, and uveitis have been reported for different bisphosphonates including alendronate, pamidronate, etidronate, and risedronate [7]. Severe anterior uveitis has been reported in patients who received alendronate and pamidronate [8–11]. However, only two cases who developed bilateral and unilateral anterior uveitis after the
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infusion of zoledronic acid have been reported [12, 13]. One patient was treated with topical steroid (prednisone) and atropine, but the other received only topical steroid (1% cyclopentolate). In both cases, the symptoms resolved after the therapy. Non-infectious uveitis is usually initiated by an inflammatory stimulus in which cytokines play a central role. Inflammatory ocular diseases including uveitis are thought to have an imbalance among proinflammatory cytokines such as tumor necrosis factor-a (TNF-a), interferon-c (IFN-c), interleukin-1 (IL-1), and interleukin-6 (IL-6), which regulate the immune system to maintain inflammatory response [14]. Uveitis has also been characterized by a CD4(+) T-helper 1 cells-mediated inflammation with elevations in IL-2, IFN-a, and lymphotoxin, and has a distinctive cytokine pattern of IL-6, IL-8, IL-13, TNF-a, and IL-2 in aqueous humor [15]. The mechanism of zoledronic acid-related uveitis is unclear. Symptoms such as nausea, myalgia, arthralgia, low-grade fever and increased bone pain usually result from an inflammatory reaction which develops after zoledronic acid administration and they are usually transient. The onset of these symptoms is typically within 24 h after the first infusion, and symptoms generally persist for less than 48 h. Dicuonzo et al reported that circulating levels of TNF-a and IL-6 increased after zoledronic acid infusion, and that, this increase was higher in patients who experienced fever than those without fever [16]. These cytokines, which are also the mediators of inflammatory uveitis, may be included in zoledronic acid-related uveitis. In this report, we presented a case of unilateral anterior uveitis after the infusion of zoledronic acid. We did not evaluate the serum and aqueous humor levels of TNF-a and IL-6. But, use of the Naranjo probability scale indicated a probable relationship between uveitis and zoledronic acid therapy in our patient [17]. In conclusion, zoledronic acid may be associated with inflammatory eye diseases and result in serious ocular damage, which can be successfully treated with topical steroids. We suggest that clinicians should be aware of this important side effect, and refer these patients to an ophtalmologist.
References
Fig. 1 Appearance of the ciliary injection and moderate inflammatory reaction in the right eye
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