We hypothesize that a rising follicle-stimulating hormone (FSH) level during the menopausal transition, even in the face of a normal estrogen level, contributes to increased bone resorption and profound bone loss that is accompanied by trabecular perforation and diminished bone strength. FSH has been shown to directly stimulate osteoclast formation and bone resorption, and our murine genetic studies indicate that the absence of FSH can, in part, protect against hypogonadal hyperresorption that causes bone loss. Furthermore, carefully conducted human studies, such as the Study of Women Across Nations (SWAN), indicate strong correlations between serum FSH levels and bone loss. Potential therapeutic implications include the development of antagonists to circulating FSH and its osteoclastic receptor.