IMPACT OF MILD AUTONOMOUS CORTISOL SECRETION ONVERTEBRAL FRACTURE RISK

Mild autonomous cortisol secretion (MACS) represents the most frequent hormonal alteration in patients with adrenal incidentalomas (20-50% prevalence) and has been increasingly associated with cardiometabolic and skeletal complications, including fragility fractures, even in the absence of overt Cushing's syndrome. However, the impact of MACS on vertebral fracture (VFx) risk and the potential benefit of adrenalectomy on skeletal outcomes remain incompletely defined. This thesis aimed to: (1) evaluate the prevalence and incidence of VFx in patients with adrenal incidentalomas according to cortisol secretion status, and (2) assess whether surgical correction of MACS through adrenalectomy reduces vertebral fracture risk. Study 1 analyzed a retrospective cohort of 444 patients with adrenal incidentalomas, stratified as MACS (n=210) or non-functioning adrenal incidentalomas (NFAI; n=234) per current guidelines. In the cross-sectional arm, MACS was independently associated with higher VFx prevalence (40% vs 18%; OR 5.3, 95% CI 3.4-8.2) and osteoporosis (28% vs 14%), despite modest BMD reductions (LS T-score difference -0.3 SD), indicating impaired bone quality. In the longitudinal arm (126 patients, ≥24 months follow-up), MACS independently predicted incident VFx (25% vs 8%; adjusted HR 3.0, 95% CI 1.6-5.6), even with normal baseline BMD. Study 2 combined retrospective (n=53 MACS patients: 31 surgical vs 22 conservative) and prospective randomized arms (n=49: 21 surgical vs 28 conservative). Adrenalectomy achieved biochemical remission in >90% and reduced incident VFx over 3-5 years median follow-up. BMD remained stable in both groups. Conclusions: MACS increases VFx risk independently of BMD, with adrenalectomy providing fracture protection. These findings advocate systematic VFx screening in MACS and incorporating skeletal risk into surgical decision-making.