The Impact of Mild Autonomous Cortisol Secretion on Bone Turnover Markers

Context Several studies have reported increased risk of fragility fractures in patients with mild autonomous cortisol secretion (MACS), discordant to the degree of bone density deterioration. Objective To evaluate the effect of MACS on bone metabolism in patients with adrenal adenomas. Design Cross-sectional study with prospective enrollment, 2014-2019 Setting Referral center. Patients 213 patients with adrenal adenomas: 22 Cushing syndrome (CS), 92 MACS and 99 nonfunctioning adrenal tumors (NFAT). Main Outcome Measures Osteocalcin, procollagen I intact N-terminal (PINP), C-terminal telopeptide (CTX), sclerostin. Results Patients with CS demonstrated lower markers of bone formation compared with patients with MACS and NFAT (CS vs MACS vs NFAT: mean osteocalcin 14.8 vs 20.1 vs 21.3 ng/mL [P < 0.0001]; mean PINP 34.8 vs 48.7 vs 48.5 µg/L [P = 0.003]). Severity of cortisol excess was inversely associated with sclerostin (CS vs MACS vs NFAT: mean sclerostin 419 vs 538 vs 624 ng/L, [P < 0.0001]). In a multivariable model of age, sex, body mass index, cortisol, and bone turnover markers, sclerostin was a significant predictor of low bone mass in patients with MACS (OR 0.63 [CI 95%, 0.40–0.98] for each 100 ng/L of sclerostin increase). After adrenalectomy, osteocalcin, CTX, and sclerostin increased by a mean difference of 6.3 ng/mL, 0.12 ng/mL, and 171 pg/mL (P = 0.02 for all), respectively. Conclusions Lower sclerostin level in patients with MACS reflects a reduction in osteocyte function or number associated with exposure to chronic cortisol excess. Increase in bone turnover markers after adrenalectomy suggests restoration of favorable bone metabolism.