Role of bone regeneration and turnover modulators in control of fracture.

Although most fractures heal in accordance with a highly regulated and well-known multistep process, 5%-10% of fractures result in delayed union or nonunion, causing morbidity, prolonged hospitalization, and economic cost for the individual and society. Ongoing research has improved our understanding of genes and molecules that are expressed during fracture healing. This knowledge has been translated into preclinical/clinical trials. Unfortunately, the success of most promising agents, and therefore most preclinically/clinically tested factors, is controversial and frequently disappointing. Taking advantage of our knowledge concerning the temporal events contributing to fracture healing, and as a result of our studies, we suggest that the application of several factors in sequence will intervene in different, crucial crossroads, accelerate remodeling, and result in an improved outcome. These factors will encompass stimulated recruitment and proliferation of stem cells to enlarge the progenitor pool, facilitate its differentiation into mature chondrocytes and osteoblasts, and stimulate cartilage resorption and its remodeling into bone by endochondral ossification--a process in which blood vessels, metalloproteinases, and osteoclasts work in concert to remodel immature bone into mature bone. The aim of this article is to highlight events that contribute to and drive the dynamic healing process in order to help clinicians to find successful, novel treatment protocols.