Comparative risk of osteopenia, osteoporosis, and pathological fractures in breast cancer patients treated with steroidal versus non-steroidal aromatase inhibitors: A large-scale real-world data analysis.

e12683 Background: Aromatase inhibitors (AIs) are widely used in hormone positive breast cancer. They are classified as either steroidal or non-steroidal. While both classes are associated with accelerated bone loss and increased risk of osteopenia, osteoporosis, and fractures, direct comparative data on bone outcomes between these classes remains limited. To address this gap, we conducted a large-scale real word analysis to clarify differential bone risks in breast cancer patients treated with different aromatase inhibitors. Methods: This TriNetX analysis utilized 157 healthcare organizations in the Global Collaborative Network. Two cohorts of breast cancer patients initiating non-steroidal (anastrozole/exemestane) versus steroidal (letrozole/fadrozole) aromatase inhibitors were identified. Index events were defined by AI initiation after cancer diagnosis, with outcomes measured from one year post-index onward. Osteopenia, osteoporosis, and pathological fracture diagnoses were analyzed using risk ratios, odds ratios, and survival analyses. Propensity score matching balanced demographics and baseline characteristics, producing 128,276 matched patients in each cohort. Outcomes were analyzed using association measures and Kaplan–Meier survival functions, including all patients irrespective of prior outcomes. Results: After matching, non-steroidal AI users showed higher osteopenia risk (26.1% vs. 23.5%; OR 1.15, p < 0.001) and osteoporosis risk (18.1% vs. 16.4%; OR 1.13, p < 0.001) compared with steroidal AI users. Survival analyses revealed minimal differences (HR ≈ 1.0). Conversely, pathological fractures were slightly less frequent among non-steroidal users (2.5% vs. 2.7%; OR 0.95, p = 0.038; HR 0.84, p < 0.001). Median survival durations for bone outcomes were broadly similar between cohorts. These data suggest non-steroidal AIs may confer slightly greater risks for bone density loss, while steroidal AIs may slightly increase pathological fracture likelihood, though absolute differences appear clinically limited. Conclusions: In this large real-world cohort, non-steroidal aromatase inhibitor users exhibited modestly higher rates of osteopenia (26.1% vs 23.5%, OR ≈ 1.15) and osteoporosis (18.1% vs 16.4%, OR ≈ 1.13) compared with steroidal AI users, while time-to-event differences were minimal. Surprisingly, pathological fractures were slightly less frequent among non-steroidal users (OR 0.95, HR 0.84). These findings are broadly compatible with literature suggesting exemestane (a steroidal AI) may be somewhat less deleterious to bone than non-steroidal agents, though the paradoxical fracture result merits cautious interpretation in light of possible confounding.