Fig. 3.

As the target organ of the nervous system, the bone is innervated by the sympathetic nervous system. Specifically, the brainstem and hypothalamus integrate internal and external signals, and noradrenergic fibers are present in the periosteum, bone, and bone marrow. The extension of sympathetic nerve axons to osteoblasts and osteoclasts is the anatomical basis for the dynamic neuroregulation of bone metabolism. After fracture, the enhancement of sympathetic tone, caused by fracture pain, increases the level of norepinephrine, which will bind to specific receptors (such as β₂R) on osteoblasts or pre-osteoclast. The osteoblasts differentiation and osteoclasts maturation were regulated though specific signaling pathways to achieve the balance between bone resorption and bone reconstruction.