Fragilità ossea nella sindrome di Cushing endogena: caratteristiche cliniche, fattori prognostici ed evoluzione

Endogenous Cushing’s syndrome (CS) is characterized by chronic cortisol excess, leading to profound metabolic and skeletal derangements. Bone damage results from a biphasic effect on bone formation and turnover, causing reduced BMD and increased fracture risk. Additional mechanisms include impaired bone quality and altered vitamin D metabolism. However, data remain limited and conflicting. This PhD project investigated the interplay between vitamin D status, body fat distribution, bone quality, and fracture risk, and evaluated long-term skeletal recovery after biochemical remission. Materials and methods: The project integrated cross-sectional and prospective analyses from a single tertiary referral cohort. Aim 1: 51 patients with overt CS (43 Cushing’s disease, 6 ACS, 2 EAS) were compared with 52 matched controls to assess 25(OH)D, 1,25(OH)₂D, calcium-phosphate metabolism, bone turnover markers and body composition by DXA, including VAT. Hypovitaminosis D was defined as 25(OH)D <50 nmol/L. Aims 2–3: 51 CS patients were evaluated for prevalence and predictors of fragility fractures; vertebral morphometry, DXA/TBS, carotid ultrasound and vascular history were included. Logistic regression models tested associations. Aim 4: 58 patients with Cushing’s disease achieving sustained remission (36 surgical, 22 medical) were followed for up to 5 years to assess longitudinal changes in BMD, bone markers and fractures. Results: Aim 1: Median disease duration was 24 months. Compared with controls, CS patients had lower 25(OH)D (38 vs 49 nmol/L, p<0.001) and higher hypovitaminosis D prevalence (84.3% vs 51.9%, p<0.001). They showed greater central adiposity (waist 95 vs 86 cm, p<0.001; trunk fat 14,062 vs 10,924 g, p=0.008) and higher VAT (1,527 vs 1,033 g, p=0.016). Within CS, hypovitaminosis D was linked to older age and adverse metabolic profile (higher glucose, triglycerides, LDL) and greater trunk fat/VAT. 25(OH)D correlated inversely with BMI, waist, trunk fat% and VAT, and positively with HDL. In multivariate models, VAT% remained an independent inverse predictor of 25(OH)D, while BMI lost significance. Aims 2–3: At diagnosis, 32/51 patients (62.7%) had fragility fractures (25 vertebral). Fractured patients had longer disease duration (36 vs 12 months, p=0.025), larger waist (107.6 vs 94.5 cm, p=0.006), higher uric acid (0.35 vs 0.25 mmol/l, p=0.001), and more frequent VTE (31.3% vs 5.3%, p=0.037) and carotid plaques (47% vs 5.3%, p=0.002). Lumbar spine T-score was lower in fractured patients (−2.12 vs −1.04, p=0.030), while TBS was uniformly reduced (median 1.26) without differences by fracture status. Multivariable models identified atherosclerotic plaques (adjusted OR 13.4, p=0.038) and densitometric osteoporosis (adjusted OR 11.3, p=0.017) as independent predictors of fractures. Aim 4: Over 5 years post-remission, lumbar spine BMD improved (0.830 → 0.960 g/cm², p=0.001), with greater gains in surgical remission. Baseline BMD was the strongest predictor of follow-up BMD. Despite improvements, new fractures occurred, highlighting persistent skeletal vulnerability. Conclusions: Endogenous CS shows a very high prevalence of hypovitaminosis D, strongly linked to visceral adiposity independent of BMI. Bone fragility is frequent and reflects cumulative disease burden, bone status and, unexpectedly, vascular disease. After remission, lumbar BMD improves, especially after surgery, but recovery is incomplete and fracture risk persists. These findings support systematic evaluation of vitamin D and fat distribution, integration of cardio-metabolic care, and long-term skeletal monitoring in CS.