Glucocorticoid (GC) use results in rapid bone loss and an elevated risk of fracture. The excess bone fragility from GC treatment is multifactorial. GCs increase bone remodeling through reductions in gonadal hormones, elevations in PTH from negative calcium balance, early stimulation of osteoclast maturation and activity, and delayed, sustained reduction in osteogenesis and osteoblast activity. GCs also alter the metabolism of osteocytes so that increased osteocyte lacunae size, with demineralization around the osteocyte and reduced elastic modulus, is observed in a mouse model of GC-induced bone loss. In summary, GC effects on bone fragility are multifactorial, and additional studies are now under way to clarify how GCs alter osteocyte metabolism and result in reduction in localized bone strength.