Bone loss is an inevitable result of getting older in both sexes. This loss is accelerated in women in the early years following menopause and in both sexes with drugs and diseases, prominently hyperthyroidism. Postmenopausal osteoporosis and hyperthyroid osteoporosis, both of which are widely recognized clinical entities, have been thought to arise from low estrogen levels and high thyroid hormone levels, respectively. However, when estrogen declines, follicle-stimulating hormone, an anterior pituitary hormone, rises. Likewise, when thyroid hormone levels rise in hyperthyroidism, thyroid-stimulating hormone levels fall. We have used a complement of mouse genetic, pharmacological, and cell biological approaches to unravel a direct action of follicle-stimulating hormone and thyroid-stimulating hormone on bone remodeling and bone mass. Apart from establishing a novel pituitary-bone axis of physiological significance, our studies challenge the existing 1-hormone, 1-disease paradigm in endocrinology and suggest that a plurality of hormonal disturbances involving pituitary hormones cause postmenopausal and hyperthyroid osteoporoses. New therapeutic targets thus emerge from these studies. Mt Sinai J Med 76:474-483, 2009. (c) 2009 Mount Sinai School of Medicine.