The incidence of cancer and its related bone breakdown have increased in recent years the prescription of bisphosphonates, particularly zoledronate. To date, a few cases of zoledronate-related orbital inflammation have been reported in the literature. 12,17–27
Orbital inflammation is relatively uncommon and is often accompanied by an APR, which usually presents with fever, chills, fatigue, myalgia, and arthralgia within 72 hours of administration. Our patient experienced very short intervals (approximately 8 hours) between infusion and the presentation of inflammatory symptoms. APR occurs in approximately 40–50% of cases. This acute response is self-limiting and is managed conservatively. It mostly occurs after the first infusion and decreases with subsequent injections. Some physicians have applied rechallenge combined with prophylactic steroids in a few patients to prevent the development of APR, particularly orbital or ocular inflammation. 3,5–10,15,28 The exact risk factors for this rare but serious side effect of zoledronic acid are not clear. Some suggest that γδ T cells play a role in triggering the inflammatory cascade by releasing interleukin-1 and interleukin-6. 29,30 The role of previous allergic or anaphylactic reactions is not understood.
In special cases of cancer-induced osteoporosis, because of the immunodeficiency state, the most important differential diagnosis of orbital inflammation is infectious cellulitis, particularly invasive fungal infection. Hence, orbital and PNS imaging are mandatory for these patients.
Interestingly, most cases of zoledronate-induced orbital inflammation are unilateral, and bilateral involvement occurs in 29% of patients. 31
In almost all the reported cases, orbital inflammation was completely resolved with systemic corticosteroids. In our case, incomplete and abrupt discontinuation of systemic corticosteroids led to relapse of orbital inflammation. This may indicate the necessity of an adequate dosage, duration, and tapering manner for corticosteroids.
Although APR may have a self-limiting effect, in the presence of severe orbital inflammation, the prescription of systemic corticosteroids is reasonable. In these patients, severe proptosis and orbital congestion may be sight-threatening due to compressive optic neuropathy or exposure keratopathy.21 Watching and follow-up may be options only for patients with mild inflammation or for patients with contraindications for corticosteroid therapy.
In summary, zoledronate-induced orbital inflammation is a side effect that should be addressed after ruling out infectious causes, particularly bacterial and fungal causes. Severe cases require a sufficient dose and duration of systemic corticosteroid treatment in a tapered manner. All physicians, especially those at chemical centers, ophthalmologists, and infectious disease specialists, should be aware of this rare but important side effect of zoledronate administration and pay special attention to the patient’s drug history. Future studies could focus on risk factors and prevent this side effect.