Adiposity Excess and Vertebral Fractures in Patients With Breast Cancer Taking Aromatase Inhibitors

Importance: Aromatase inhibitors (AIs) profoundly suppress estrogen synthesis and accelerate bone loss in postmenopausal women with early breast cancer (EBC). Although body mass index (BMI)-defined obesity has been considered protective for skeletal health, emerging evidence suggests a paradoxical association with fracture risk. Objective: To evaluate whether fat mass percentage (FM%) greater than 40.8%, measured by dual-energy x-ray absorptiometry (DXA), is associated with vertebral fracture (VF) progression in patients with EBC receiving AIs. Design, Settings, and Participants: This retrospective cohort study included consecutive postmenopausal women with EBC (stages I-III) recruited in a single referral center between September 2014 and June 2024. All patients received adjuvant endocrine therapy and underwent serial DXA assessments. Patients treated with tamoxifen or with major comorbidities affecting skeletal fragility were excluded. Exposures: Body composition and bone fragility parameters evaluated by DXA at baseline and at 18, 24, and 30 months. Main Outcomes and Measures: Adiposity excess was defined as FM% greater than 40.8%, and VF progression was defined as new incident fractures and/or worsening by at least 1 Genant grade at a previously fractured vertebral level. Their association was evaluated using a joint model; time-dependent associations were evaluated using extended Cox regression. Secondary analyses explored associations with bone mineral density, trabecular bone score (TBS), appendicular lean mass index (ALMI), and traditional fracture risk factors. Results: A total of 769 White women (median [range] age, 63 [30-87] years; median [range] BMI, 24.6 [15.6-46.1]) entered the study. During follow-up, 69 patients (9.0%) experienced VF progression. FM% greater than 40.8% was independently associated with increased VF progression (adjusted hazard ratio [HR], 2.00; 95% CI, 1.44-2.82; P < .001). Higher ALMI (HR, 0.38; 95% CI, 0.22-0.65; P < .001) and BMD (HR, 0.79; 95% CI, 0.66-0.94; P = .01) were associated with lower risk of VF progression. Conclusions and Relevance: In this retrospective cohort study of patients with EBC receiving AIs, adiposity excess was identified as a novel fracture risk factor, whereas higher muscle mass was protective. These findings support incorporating body-composition assessment into fracture-risk evaluation and preventive strategies for patients undergoing AI therapy.