Glucocorticoids (GCs) are in general used to treat chronic inflammatory diseases, such as rheumatoid arthritis. The therapy is hampered by severe side effects in particular by effects on the integrity of the bone leading to GC-induced osteoporosis (GIO). Dissociating ligands for the GC receptor (GR) had been developed to avoid dimerization of the GR but to maintain protein-protein interaction by the monomeric GR protein. These compounds are supposed to ameliorate side effects but to keep anti-inflammatory efficacy. Using conditional and function selective mice we showed however that GR dimerization and GR monomer activities contribute in various degrees for immunosuppression and GIO. For GIO the presence of the GR monomer in osteoblasts is sufficient for inhibition of bone formation, osteoblast differentiation, and consequently bone loss. Interaction of the GR monomer with AP-1, but not NF-κB is decisive for suppression of osteoblast differentiation via inhibition of the osteoblastogenesis promoting factor IL-11. With the use of Compound A we describe a dissociating ligands for the GR that does not affect AP-1 driven IL-11 expression and does not inhibit osteoblast differentiation. Suppression of pro-inflammatory cytokine expression is still maintained by CpdA triggered GR activation. Thus, by elucidating the mechanism how the GR affects bone integrity we defined criteria for novel selective GR ligands that help to avoid GIO while acting anti-inflammatory.