Neuropeptides and the puzzle of bone remodeling. State of the art.

Bone metabolism is dependent on cells of the osteoblast and osteoclast lineage. These cells play a major role in the synthesis and degradation of osteoid and in its mineralization and demineralization. Bone cells are under the influence of various systemic and local auto/paracrine factors. One further regulatory element that can play both a sensory/ afferent and a regulatory/efferent role, consists of neuropeptide-containing nerves. In particular, the calcitonin gene-related peptide (CGRP) and vasoactive intestinal peptide (VIP) have been implicated; their distribution in bone and their molecular biology are discussed in some detail. Bone neuropeptides can function as direct bone cell regulators, with additional amplifying indirect effects mediated by vascular endothelial cells, monocyte/macrophages and mast cells and their mediators. Recent experimental and clinical work has implicated bone nerves in processes varying from normal remodelling to fracture healing and non-union. Apart from systemic endocrine influences on bone stock and osteoclast/ osteoblast coupling (activation-resorption-formation cycle) mediated by local auto/paracrine factors, bone nerves/neuropeptides may explain why various inputs/outputs are transformed in a meaningful way to altered mass and quality of bone.