Neuroendocrine and neural control of bone mass in health and disease

Bone is a highly dynamic and purposefully organized structure that remodels constantly throughout adult life. Disordered bone remodeling, in which resorption of old bone by osteoclasts exceeds new bone formation by osteoblasts, results in bone loss, which, in turn, is associated with debilitating conditions, including osteoporosis and metastatic bone disease. The past decade has revealed vital new insights into the role of the central nervous system in skeletal regulation. These studies have led to a better understanding of physiologic circuitry, enabled us to revisit disease pathophysiology, and in doing so, prompted the creation of candidate therapeutics. The central neural control of bone is exerted through two arms - an amplitude-modulated (AM) neurohormonal arm that relies on changes in circulating levels of anterior and posterior pituitary hormones, which act on bone directly, and a frequency-modulated (FM) arm that arises from changes in the firing frequency of sympathetic, parasympathetic, and sensory nerves that innervate bone. Here, we review the medical consequences arising from the dysfunction of the AM and FM arms, as well as studies that have unmasked promising therapeutic targets.