Acute blepharitis: an unusual complication of zoledronic acid

Dear Editor, Millions of patients are now taking medications for the treatment of osteoporosis, which represents actually a major health care issue. The most frequently prescribed drugs are the bisphosphonates, powerful inhibitors of osteoclastic activity. Randomized controlled trials have documented their efficacy in the prevention of bone loss and in the reduction of fractures in postmenopausal women and men with established osteoporosis.1 However, multiple rare safety issues that were not observed in clinical trials have now emerged with post-marketing surveillance and increasing clinical experience,2 such as inflammatory eye reactions. We will report a case of a 62-year-old osteoporotic woman who presented for management of a recurrent swollen left eye that followed the introduction of the zoledronic acid. We will also present a mini-review of the available data on bisphosphonate-reported ocular side effects. A 62-year-old White woman with a history of postmenopausal osteoporosis presented for management of a swollen left eye (Fig. 1). She first noticed this symptom after the introduction of the zoledronic acid 3 years ago. She reported that it was initially painless, and appeared 48 h after each infusion, with spontaneous and complete resolution 5 days later. The first episode occurred after an acute-phase reaction. Lately, the recurrent swollen eye lasted longer and was more expanded. It was associated with burning, dryness and photophobia with no diplopia. She did not develop any symptoms in the right eye. Her past medical history was positive for peptic ulcer disease and negative for eye problems. Ophthalmologic exam including a slit-lamp showed edema and redness of the left upper lid, with no exophthalmos and no elevated intraocular pressure. The vision was unaffected. The right eye was completely normal. A swabbing of the eyelid secretions was negative for bacteria and fungi. In the absence of gravity signs, no radiologic evaluation was requested. A topical treatment was administered, including steroid eye drops and ointment as well as artificial tears, and lid hygiene was recommended. Two weeks later, the woman had completely recovered. The patient was worried about continuing the intravenous bisphosphonate. The zoledronic acid was stopped. No oral bisphosphonate was tried because of her ulcer disease. A new class of medications was offered, the subcutaneously administered denosumab, the first RANKL (receptor activator of nuclear factor-κB ligand) inhibitor approved by the Food and Drug Administration for osteoporosis. The patient was also advised to continue supplemental calcium and vitamin D. She received two doses of denosumab, without any recurrence. Ocular inflammatory reactions in patients on bisphosphonate treatment have been reported in the literature since the early 1990s. Although rare, cases have been shown to occur with nitrogen and non-nitrogen containing bisphosphonates, as well as oral and intravenous preparations.3, 4 The most common ocular side effect is non-specific conjunctivitis, which usually is self-limiting. Other rare conditions include uveitis, episcleritis, scleritis, keratitis and orbital inflammation. Cranial nerve palsy, optic or retrobulbar neuritis, and orbital or periorbital edema have occasionally been reported. Of those, uveitis, scleritis, keratitis and global orbital inflammation are associated with major morbidity and require the discontinuation of bisphosphonate treatment.5 More than one ocular side effect can occur simultaneously. Presentation may be unilateral or bilateral.6, 7 Symptoms often occur after an acute-phase reaction, and thus, may represent a localized manifestation of a systemic adverse reaction to the drug. However, they can occur weeks, months or even years after bisphosphonate initiation. Ocular inflammation tended to appear earlier with intravenous compared to oral bisphosphonates.8 The incidence rate of bisphosphonate-associated ocular inflammation was reported through one clinical trial and three large post-marketing surveys. Reid et al.9 analyzed the adverse events occurring within 3 days of zoledronic acid infusion from the HORIZON (Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly)-Pivotal Fracture Trial, the largest trial in the phase 3 osteoporosis program for zoledronic acid. Eye symptoms occurred in 0.6% of the zoledronic acid group and 0.1% of the placebo group (P < 0.0001). The large population-based cohort studies have shown conflicting results, but overall they reported a low incidence of orbital inflammation associated with bisphosphonates treatment for osteoporosis. A large US veteran cohort8 showed that the 6-month rate of inflammatory eye reactions after exposure to bisphosphonates was 7.9 new cases per 10 000 individuals, with a relative risk of 1.23 (95% confidence interval [CI] 0.85–1.79) compared with veterans not exposed to bisphosphonates. A large pharmaco-epidemiological cohort study from Canada10 exposed an incidence rate among first-time bisphosphonates users of 29 per 10 000 person-years for uveitis and 63 per 10 000 person-years for scleritis. In contrast, the incidence among people who did not use oral bisphosphonates was 20 per 10 000 person-years for uveitis and 36 per 10 000 for scleritis (number needed to harm: 1100 and 370, respectively). First-time users had an elevated risk of both uveitis (adjusted relative risk [RR] 1.45, 95% CI 1.25–1.68) and scleritis (adjusted RR 1.51, 95% CI 1.34–1.68). A third post-approval study using a national registry in Denmark11 reported that the eye steroid treatment rates in the first year of osteoporosis treatment were 44 per 1000 patient-years (95% CI 42–46) for alendronate, 40 per 1000 (95% CI 38–43) for etidronate, 45 per 1000 (95% CI 35–57) for risedronate. The incidence of hospital-treated uveitis was very low, occurring in 0.07% of users of alendronate or risedronate and in 0.04% of etidronate users. However, no difference was found with bisphosphonate users compared with non-users after adjustment for underlying diseases and age. Patients with a rheumatic or pulmonary disease were at increased risk. There are no clear pathogenic mechanisms for how bisphosphonates could potentially cause ocular inflammation. It may be explained by the fact that the bisphosphonates cause elevated levels of proinflammatory cytokines, including interleukin 6 and tumor necrosis factor α, similar to the acute-phase reaction typically seen after bisphosphonates infusion.11, 12 This is why the risk of ocular side effects could be greater with intravenous than oral formulations. Our patient developed a unilateral and acute inflammatory blepharitis following the introduction of an intravenous bisphosphonate, which is by itself a risk factor for ocular complications. To assess the imputability of zoledronate, the WHO Causality Guide of Suspected Adverse Reactions was used.13 This case of periorbital inflammation may be classified as a ‘certain’ adverse effect of zoledronic acid because it satisfied the following criteria: plausible time relationship to the bisphosphonate intake; plausible response to the unintentional rechallenge, and dechallenge; and absence of concurrent disease or other drugs predisposing to the complication. No new treatments have recently been initiated. There were no indicators of any other diagnosis with the patient: no previous ocular diseases, no clinical signs of seborrheic dermatitis or rosacea, no history of new allergen introduction, no evidence of infection. Since it is a benign condition, the reintroduction of the zoledronic acid could be safe if prophylactic regimens are used. We could switch to a different bisphosphonate with close monitoring of the patient since the last episode of blepharitis was more severe. A case of a severe scleritis complicating zoledronic acid infusion was progressively resolved after replacing it by a different drug of the same class, pamidronate, indicating the possibility of immunologic tolerance.14 Because of the ulcer disease reported by our patient, oral bisphosphonates were contraindicated. The injectable ibandronate might be a good option. However, the zoledronic acid was withdrawn and the patient shifted to a novel anti-osteoporotic drug, denosumab, without any recurrence. Several anti-osteoporotic medications could be offered to our patient, such as selective estrogen-receptor modulators (raloxifene), teriparatide and denosumab. Raloxifene has not been shown to reduce non-vertebral fractures, including hip fractures, and has to be taken orally every day. Teriparatide and denosumab, although expensive medications, reduce the risk of vertebral and non-vertebral fractures comparable to zoledronic acid.1 Also, teriparatide is administered subcutaneously every day, and denosumab is administered every 6 months, maintaining therefore our patient's compliance, who was receiving an injectable treatment once yearly. Bisphosphonates are associated with several ocular complications, some of which may be potentially devastating, and others may be annoying, can affect adherence, without causing permanent injury. Given the large and growing number of patients receiving bisphosphonates, it is likely that physicians may encounter some patients with these side effects. Healthcare providers must be aware of bisphosphonate-related ocular complications and should inform their patients, so that they can seek immediate assessment. Early reporting of any signs of eye inflammation is advised to prevent further complications. In serious ocular conditions, urgent ophthalmologic referral is required, as well as drug discontinuation. Physicians must probably prescribe bisphosphonates with close monitoring for patients with a history of inflammatory ocular disease or mild ocular symptoms following use of a bisphosphonate. Other anti-osteoporotic agents may also be used. We would like to thank Doctor Nazek Saadallah for her valuable input to the manuscript. The authors declare that they have no conflicts of interest.

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