Fracture healing requires intact nitric oxide production

Fracture healing gone awry can result in delayed or nonunion with significant morbidity. Useful research just published in the journal Bone shows that reduced nitric oxide production impairs fracture healing. The authors note:

"Between 5% and 10% of all fractures fail to heal adequately resulting in nonunion of the fracture fragments. This can significantly decrease a patient's quality of life and create associated psychosocial and socio-economic problems."

Nitric oxide synthase and fracture healing

Nitric oxide is known to be crucial for respiration, cardiovascular health, immune health and numerous other functions, and known to be involved in fracture healing. The authors take this a step further:

"Nitric oxide (NO) and nitric oxide synthases (NOS) have been found to be involved in fracture healing, but until now it is not known if disturbances in these mechanisms play a role in nonunion and delayed union development. In this study, we explored the role of endothelial and inducible NOS deficiency in a delayed union model in mice."

They used femur osteotomy with periosteal damage for their model of fracture to observe the healing response in both normal ('wild') and NOS knockout (Nos2^−/− and Nos3^−/−) mice 'engineered' to not produce nitric oxide synthase and generate nitric oxide. Fracture healing completely stalled in the latter:

"With μCT [micro-computed tomography], delayed union was observed in wild type animals, whereas in both Nos2^−/− and Nos3^−/− mice nonunion development was evident. Both knock-out strains also showed a significantly increased influx of MPO [myeloperoxidase] when compared with wild type mice. Concentrations of amino acids and expression of enzymes related to the arginine-NO metabolism were aberrant in NOS deficient mice when compared to contralateral control femurs and wild type samples."

Clinical note

Testing and for nitric oxide sufficiency and replenishment in the context of impaired NOS function is now very practical (see Neogenis Medical in Useful Links) and should be standard of care in fracture management, especially when there is a history of hypertension or other cardiovascular disorders. The authors conclude:

"In the present study we show for the first time that the absence of nitric oxide synthases results in a disturbed arginine-NO metabolism and inadequate fracture healing with the transition of delayed union into a nonunion in mice after a femur osteotomy. Based on these data we suggest that the arginine-NO metabolism may play a role in the prevention of delayed unions and nonunions."