OBJECTIVE To review new discoveries that revisit our current thinking on the genesis of osteoporosis using hypogonadal and thyrotoxic bone loss as examples. METHODS We focus on cell biologic, mouse genetic, and human studies that have established a direct action of the interior pituitary hormones follicle-stimulating hormone and thyrotropin on the skeleton and discuss emerging clinical evidence for a novel pituitary-bone axis in humans that bypasses master endocrine organs, namely the ovaries and thyroid gland. RESULTS The cataloguing of human mutations, the use of genetically modified mice that recapitulate human disease, and the rapid growth of genomic sciences have together had a profound impact on how basic research is translated into clinical practice. The skeleton has become a paradigm for the application of such advances to an extent that hitherto unrecognized physiologic and pathophysiologic findings have emerged. We propose that hypogonadal and thyrotoxic bone loss are not solely due to changes in the level of master hormones, but instead also arise from the direct action of anterior pituitary hormones on the skeleton. CONCLUSIONS We predict a pituitary-bone axis in which pituitary hormones bypass traditional endocrine targets to affect the skeleton directly with remarkable sensitivity. New therapeutic targets thus become a likely possibility.