A number of studies suggest that progestagens may have beneficial effects on bone metabolism. C(21) Progestin medroxyprogesterone acetate (MPA) is one of the most commonly prescribed progestins for hormone replacement therapy and in gynecologic practice. However, it appears that MPA with significant glucocorticoid (GC) activity may decrease bone density. In this review, we argue that bone loss associated with MPA administration is caused by decreased osteoblast differentiation as a result of MPA occupying the GC receptor, since increasing GC receptor occupancy beyond that reached at normal (= optimal) GC concentrations attenuates osteoblast differentiation. We propose that progestins with no GC activity may be a better choice for progestagen therapy to achieve more beneficial effects on bone metabolism.