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Objectives and questions: Glucocorticoids play a key role in bone metabolism. Prolonged exposure to synthetic glucocorticoids is known to contribute to bone loss and osteoporosis. While systemic endogenous glucocorticoid (eGC) levels are well studied, little is known about concentrations in bone and their potential role in bone homeostasis. The enzyme 11β-hydroxysteroid dehydrogenase type 1(11β-HSD1), encoded by HSD11B1, regulates local cortisol availability. Its expression in osteoblasts has been shown to increase with age. Beyond age related changes in gene regulation, genetic polymorphisms of HSD11B1 have been linked with alterations in bone quality. This pilot study aimed to establish a method for quantifying eGCs in human bone and to examine their correlation with systemic levels, age, sex, genotypes, and skeletal site.

Material and methods: Peripheral blood (preoperative) and local bone marrow (BM, intraoperative) were collected from 52 patients undergoing primary total hip arthroplasty (THA) or periacetabular osteotomy (PAO). The median age was 53.8 years (22.2–75.7). Bone samples were derived from the os femoris in THA and the os ilium in PAO patients. Following organic solvent extraction, eGCs were quantified using LC-MS/MS. Genotyping of HSD11B1 was performed with the rhAmp SNP genotyping system. Correlation between systemic and local eGC levels was analyzed using Spearman’s rank correlation. Differences between cortisol-to-cortisone ratios were assessed using Wilcoxon test and group comparisons with the Mann-Whitney-U test.

Results: Cortisone and cortisol were reliably quantified in bone for the first time. Median local cortisone was 9.5 ng/g BM (IQR 5.3–16.8) and cortisol 32.7 ng/g BM (14.7–55.3), while systemic cortisone was 19.95 ng/ml (16.8–24.7) and cortisol 108.5 ng/ml (69.9–147.0). No correlation was observed between systemic and local levels. The cortisol-to-cortisone ratios showed significant differences between systemic and local concentrations (p<0.001). Group comparisons showed higher local cortisone levels in females than males (10.5 vs. 6.69 ng/g BM, p=0.0262) and in PAO than THA patients (19.31 vs. 6.78 ng/g BM, p<0.001). THA patients had a higher local cortisol-to-cortisone ratio than PAO patients (3.74 vs. 3.37, p=0.0441). No significant differences in eGC levels were observed across age or genotype.

Discussion and conclusions: This pilot study demonstrates the feasibility of quantifying eGCs in human bone. The absence of correlation between systemic and local eGC levels along with significant differences in cortisol-to-cortisone ratios, suggests an independent regulatory mechanism within bone. Notably, local cortisone was higher in females and PAO patients than in males and THA patients, suggesting sex- and site-specific influences on local glucocorticoid metabolism, potentially affecting bone homeostasis. Further studies with larger cohorts and multivariate analyses that control for age, sex, genotype, and location, are needed to validate and extend these findings.