Despite advances in targeted therapies, treatment with glucocorticoids remains a mainstay in the management of various immune-mediated diseases. High cumulative doses of exogenous glucocorticoids lead to a spectrum of side-effects, in particular increased fracture risk. Fragility fractures might result in immobility, frequent admission to hospitals, and loss of quality of life. Glucocorticoid excess impairs bone microarchitecture and bone strength and can cause multiple vertebral fractures. Fracture risk at other skeletal sites is also enhanced and triggered by an increased risk for falls. Glucocorticoid-induced osteoporosis results from direct suppression of osteoblast and osteocyte function, a transient stimulation of osteoclast formation and activity, catabolic effects on bone matrix and muscle protein, and metabolic alterations. Assessment of fracture risk using the Fracture Risk Assessment Tool (FRAX) with dual-energy X-ray absorptiometry represents the first diagnostic step; its predictive value can be improved by applying specific adjustments such as the trabecular bone score. This Review highlights how the bone microenvironment responds to supraphysiological glucocorticoid concentrations, and discusses the basis for skeletal fragility and fractures. We review the use and limitations of current and emerging imaging technologies and prediction tools, and discuss bone-forming and antiresorptive treatment strategies and their use to prevent and treat glucocorticoid-induced osteoporosis.