The Impact of Mild Autonomous Cortisol Secretion on Bone Turnover Markers

J Clin Endocrinol Metab. 2020 May 1;105(5):1469-1477. doi: 10.1210/clinem/dgaa120.


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.

Keywords: Cushing syndrome; MACS; bone turnover markers; nonfunctioning adrenal tumors; osteopenia; osteoporosis; sclerostin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / blood
  • Adenoma / metabolism
  • Adenoma / pathology
  • Adolescent
  • Adrenal Gland Neoplasms / metabolism
  • Adrenal Gland Neoplasms / pathology
  • Adult
  • Biomarkers / analysis
  • Biomarkers / blood*
  • Bone Remodeling / physiology
  • Bone and Bones / metabolism*
  • Collagen Type I / blood
  • Cross-Sectional Studies
  • Cushing Syndrome / metabolism
  • Female
  • Humans
  • Hydrocortisone / blood
  • Hydrocortisone / metabolism*
  • Male
  • Middle Aged
  • Minnesota
  • Osteocalcin / blood
  • Paraneoplastic Endocrine Syndromes / metabolism*
  • Peptides / blood
  • Procollagen / blood
  • Severity of Illness Index
  • Young Adult


  • Adaptor Proteins, Signal Transducing
  • Biomarkers
  • Collagen Type I
  • Peptides
  • Procollagen
  • SOST protein, human
  • collagen type I trimeric cross-linked peptide
  • Osteocalcin
  • Hydrocortisone