Recent advances in glucocorticoid regulation of bone and the bone marrow niche: Genetic and pharmacological approaches to understand and prevent bone loss.

Glucocorticoids are essential steroid hormones whose excess - whether from therapeutic use or endogenous overproduction - causes significant bone loss and fracture risk. In bone, glucocorticoids act directly on osteoblasts, osteocytes, and osteoclasts via the glucocorticoid receptor and indirectly through bone marrow adipose tissue and shared mesenchymal progenitors. An important mechanism involves suppression of canonical Wnt/β-catenin signaling, which reduces osteogenesis and increases marrow adiposity. Several pharmacological and plant-derived compounds with therapeutic promise target Wnt and other glucocorticoid-regulated signaling pathways. Emerging evidence highlights intermediary and potential therapeutic roles for niche-derived extracellular vesicles in bone loss associated with glucocorticoids. Comparing results between studies is complicated by underreporting of environmental and biological variables that may interact with glucocorticoids to affect bone or the marrow niche, which underscores the need for greater methodological rigor in preclinical studies.