Glucocorticoids have profound effects on bone leading to glucocorticoid-induced osteoporosis observed at long term steroid therapy. The glucocorticoid receptor (GR) is a hormone-induced transcription factor controlling gene expression as a monomer or dimeric molecule. We demonstrated- in contrast to the prevailing view - that the induction of genes by dimeric GR molecules suppresses inflammation in disease models. In contrast the monomer GR mediates inhibition of bone formation and bone loss. Using high content screen analysis, we identified novel modulators that abrogate the deleterious effects of glucocorticoids on bone. Our mechanistic studies provide new drug targets and rationales for improved steroid therapy with lesser side effects.