The complexity of skeletal fragility in overt endogenous Cushing’s syndrome: how much do we know?

Skeletal fragility is a major, yet still under-recognized, complication of endogenous Cushing’s syndrome, with a prevalence of densitometric osteoporosis of approximately 30-50% and fragility fractures reported in 11-76% of patients across published series. Chronic cortisol excess impairs bone strength through a complex network of direct and indirect mechanisms that collectively produce a deterioration of bone quality extending well beyond what is captured by standard densitometry. Therefore, fragility fractures occur in a substantial proportion of patients at bone mineral density values in the osteopenic or even normal range, underscoring the central role of bone microarchitectural impairment. Emerging tools, including the Trabecular Bone Score, high-resolution peripheral quantitative computed tomography, and bone marrow fat assessment by MRI, provide complementary information on bone quality and fracture risk. Following successful treatment of hypercortisolism, spontaneous skeletal recovery occurs but is slow, site-specific, and incomplete, with fracture risk remaining elevated for years after remission. Despite the clinical relevance of these complications, no CS-skeletal specific guidelines exist for their management, the evidence base for bone-active agents in endogenous CS is extremely limited, and real-world data confirm that bone health is systematically under-assessed in routine practice. This review provides a comprehensive and updated overview of the epidemiology, pathophysiology, risk assessment, and treatment of skeletal fragility in endogenous CS, with the aim of raising awareness and highlighting the urgent need for dedicated diagnostic and therapeutic strategies in this high-risk population.