There is increasing evidence from animal models that bone, in addition to its traditional function of providing structural support for the organism, has a rich network of interactions with multiple other tissues. This perspective focuses on evidence from human studies demonstrating that bone is an endocrine organ regulating energy metabolism, with the specific examples being osteocalcin, lipocalin 2, RANKL, and sclerostin. Conversely, animal studies have also demonstrated that a key hormone regulating energy metabolism, leptin, regulates bone metabolism via the sympathetic nervous system. Studies in humans have established a role for the sympathetic nervous system in regulating bone turnover; indeed, the potential therapeutic benefit of targeting this pathway in humans to prevent postmenopausal bone loss is currently being evaluated.