(B-286) Bisphosphonate Use and the Risk of Inflammatory Eye Reactions: A Case-Crossover Study

Background: Case reports suggest a potential acute risk of inflammatory eye reactions (IERs) with bisphosphonate use, but population-based cohort studies yield inconsistent findings and cannot account for genetic influence.

Objectives: This study used a case-crossover design to assess whether bisphosphonate use increases the risk of IERs.

Methods: We identified incident cases of IERs—including uveitis, scleritis, and cystoid macular edema (CME)—between 2011 and 2021 from Taiwan’s National Health Insurance Research Database. In the primary analysis, we defined the 30-day period before the event date as the hazard window, preceded by a 90-day washout. Before the washout period, one of four consecutive 30-day intervals was randomly selected as the reference window. Exposure to bisphosphonates in the hazard and reference windows was determined based on prescription records. Conditional logistic regression was used to estimate the odds ratio (OR) of bisphosphonate exposure in the hazard versus reference window, controlling for within-person time-invariant confounders. We examined exposure to any bisphosphonate, intravenous (IV) or oral bisphosphonates, and individual bisphosphonates. Sensitivity analyses were conducted by varying the hazard and reference window lengths (15, 60, and 90 days).

Results: We identified 269,545 uveitis, 132,585 scleritis, and 115,914 CME cases, corresponding to annual incidence rates of 11.8, 6.6, and 5.2 per 10,000 population, respectively. Among uveitis cases, any bisphosphonate exposure was associated with an increased risk (OR 1.25, 95% CI: 1.07–1.46). The risk was particularly elevated for IV bisphosphonates (OR 1.82, 95% CI: 1.43–2.31), especially zoledronic acid (OR 2.58, 95% CI: 1.89–3.53). In contrast, exposure to oral bisphosphonates and other individual agents yielded neutral or inconclusive results. Sensitivity analyses confirmed these findings. For scleritis, a similar but milder increasing trend was observed, though the association was not statistically significant (OR 1.18, 95% CI: 0.87–1.60 for any bisphosphonate, OR 1.00, 95% CI: 0.62–1.61 for IV bisphosphonates, and OR 1.67, 95% CI: 0.88–3.16 for zoledronic acid). No significant association was found for CME, except for a potential increased risk with clodronic acid (OR 2.67, 95% CI: 0.71–10.05).

Conclusions: Our findings suggest that bisphosphonate use, particularly IV formulations such as zoledronic acid, may be associated with an increased risk of uveitis and potentially scleritis. However, no clear association was observed for CME. These results highlight the need for further investigation into the inflammatory ocular effects of bisphosphonates, especially in high-risk populations.