NLRP3 Activation With Bisphosphonate Use and the Risk of Incident Age-Related Macular Degeneration

To determine whether bisphosphonate use increases the risk of age-related macular degeneration (AMD), thereby providing evidence for the involvement of the NLRP3 inflammasome in AMD pathogenesis.

Retrospective cohort study among US veterans who had undergone dual-energy x-ray absorptiometry (DEXA) scans. Time-dependent Cox models were used to assess the association between cumulative bisphosphonate exposure and AMD incidence. Propensity score matching was applied to balance characteristics between bisphosphonate users and nonusers. A secondary analysis examined the impact of NLRP3 inhibitors (fluoxetine and fluvoxamine) on AMD risk among bisphosphonate users.

After propensity score matching, each additional year of bisphosphonate use was associated with a 4.7% increased hazard of AMD (hazard ratio [HR], 1.047; 95% confidence interval [CI], 1.020-1.074). In the secondary analysis, fluoxetine or fluvoxamine use among bisphosphonate users was linked to a reduced hazard of incident AMD (HR, 0.814; 95% CI, 0.676-0.98) in the matched sample.

Bisphosphonate use increases AMD risk, while NLRP3 inhibitors mitigate this effect. These findings support the hypothesis that the NLRP3 inflammasome is involved in AMD pathogenesis and represents a potential therapeutic target.