Bone complications in patients with Cushing's syndrome: looking for clinical, biochemical, and genetic determinants

This is the first study examining the impact of both clinical, biochemical, and genetic determinants in the occurrence of bone complications in patients with overt Cushing's syndrome (CS). It demonstrates that the degree and duration of hypercortisolism seem to play a major role in bone loss and fractures development in these patients. Bone loss and fractures are a common complication of CS. We investigate the role of gender, disease etiology, duration, and degree of hypercortisolism as well as the impact of glucocorticoid receptor (GR) polymorphisms on the development of bone complications in CS. Fifty-two patients with active CS (38 Cushing's disease and 14 with cortisol-secreting adrenal adenoma) were genotyped for GR polymorphisms (BclI, N363S, ER22/23EK, and A3669G). In all patients, clinical, hormonal, and biochemical markers of bone turnover, densitometric parameters [lumbar spine and left femur bone mineral density (BMD), T-score, Z-score] as well as the prevalence of bone demineralization and both vertebral and peripheral fractures were assessed. No differences were found in bone complications according to gender, disease etiology, and genetic variants distribution. Fractured patients compared to non-fractured ones showed increased levels of urinary free cortisol (UFC) and a more compromised densitometric profile. UFC levels correlated with the occurrence of vertebral fractures (r = 0.43, p = 0.009) while midnight serum cortisol correlated with L1-L4 BMD values (r = -0.35, p = 0.04). Disease duration correlated with the presence of peripheral fractures (r = 0.36, p = 0.04). While GR gene variants as well as gender and disease etiology seem not to play a role, the degree and duration of hypercortisolism seem to be the major determinants of bone loss and fractures in this group of patients. More investigations are needed to understand the real impact of these determinants on the development of bone complications in patients with hypercortisolism.