Glucocorticoid Effects on Bone Metabolism

Glucocorticoids are steroid hormones widely used for their anti-inflammatory and immunosuppressive properties, but prolonged or high-dose exposure disrupts bone remodelling. At the cellular level, glucocorticoids inhibit osteoblast proliferation and differentiation, promote osteoblast and osteocyte apoptosis, and prolong osteoclast lifespan, leading to a net increase in bone resorption and a decrease in bone formation. These actions are mediated through the glucocorticoid receptor, which alters gene transcription in bone-forming and bone-resorbing cells. Chronic exposure also impairs the bone marrow microenvironment, shifting mesenchymal progenitor cells towards adipogenesis at the expense of osteogenesis, and suppresses key signalling pathways such as Wnt/β-catenin. In the growing skeleton, glucocorticoids fracture the coupling between angiogenesis and osteogenesis, further compromising skeletal integrity. Clinically, these mechanisms culminate in glucocorticoid-induced osteoporosis, characterised by reduced bone mass, weakened microarchitecture and elevated fracture risk. Understanding these multifaceted effects has spurred efforts to preserve anti-inflammatory efficacy while mitigating skeletal damage.

Research from Nature Portfolio

Proof-of-concept clinical studies have evaluated selective inhibition of 11β-hydroxysteroid dehydrogenase type 1 to limit tissue-specific activation of glucocorticoids. Co-administration of a small-molecule 11β-HSD1 inhibitor with prednisolone preserved markers of bone formation and reduced bone turnover detritus without compromising systemic anti-inflammatory action, suggesting a viable strategy to decouple skeletal toxicity from therapeutic benefit. In parallel, experimental work in juvenile models has revealed that glucocorticoid treatment induces senescence of metaphyseal endothelial cells by suppressing osteoclast-derived angiogenin. Restoration of the angiogenin/plexin-B2 axis prevented vascular ageing in bone, re-established local angiogenesis and coupled osteogenesis, highlighting a critical vascular component in glucocorticoid-induced skeletal pathology.

Glucocorticoid Effects on Bone Metabolism publication trend

The graph below shows the total number of articles in glucocorticoid effects on bone metabolism across all publications each year (not limited to Nature Index journals).

Technical terms

Glucocorticoids (GCs): Endogenous or synthetic steroid hormones with potent anti-inflammatory effects that regulate gene expression in bone cells.

Osteoblast: Bone-forming cell responsible for synthesising and mineralising bone matrix.

Osteoclast: Multinucleated cell that degrades bone matrix during remodelling.

Osteocyte: Mature bone cell embedded within mineralised matrix, crucial for mechanosensation and orchestration of remodelling.

11β-HSD1: Enzyme that regenerates active glucocorticoids from inactive forms within peripheral tissues.

Wnt/β-catenin signalling: Molecular pathway essential for osteoblast proliferation, differentiation and survival.

Angiogenin/PLXNB2 axis: Signalling interaction by which osteoclast-derived angiogenin supports endothelial cell rRNA transcription and vascular integrity in bone.

References

1. 11β-HSD1 inhibition in men mitigates prednisolone-induced adverse effects in a proof-of-concept randomised double-blind placebo-controlled trial. Nature Communications (2023).
2. Excess glucocorticoids inhibit murine bone turnover via modulating the immunometabolism of the skeletal microenvironment. Journal of Clinical Investigation (2024).
3. Protein kinase G2 activation restores Wnt signaling and bone mass in glucocorticoid-induced osteoporosis in mice. JCI Insight (2024).
4. Osteoclasts protect bone blood vessels against senescence through the angiogenin/plexin-B2 axis. Nature Communications (2021).
5. The shift in the balance between osteoblastogenesis and adipogenesis of mesenchymal stem cells mediated by glucocorticoid receptor. Stem Cell Research & Therapy (2019).