T786C Mutation in the Endothelial Nitric Oxide Synthase Gene in Patients With Primary Osteonecrosis

Mutations in the T786C endothelial nitric oxide synthase gene (eNOS) are associated with osteonecrosis and Prinzmetal's angina. Nitric oxide is necessary for bone health and ameliorates Prinzmetal's angina. This study compared mutations of T786C eNOS in 146 patients with primary osteonecrosis, 114 patients with Prinzmetal's angina, and 83 normal control subjects. Patients with osteonecrosis had more mutant eNOS alleles than control subjects (42% vs 22%, respectively; P<.0001) but had the same number of mutant alleles as patients with Prinzmetal's angina (42% vs 41%, respectively; P=.7), who in turn had more mutant eNOS alleles than control subjects (41% vs 22%, respectively; P=.0001). Of 146 patients with primary osteonecrosis, 65 (45%) had none of the 5 thrombophilias (Factor V Leiden heterozygosity, high levels of Factors VIII and XI, anticardiolipin antibody immunoglobulin M, and homocysteine) that otherwise distinguished patients with osteonecrosis from control subjects (P<.05). No associations were found between eNOS hetero-homozygosity and the 5 major thrombophilias in primary osteonecrosis. Of the 65 patients who had osteonecrosis but no major thrombophilias, for 41 (28% of the total sample of 146), eNOS hetero-homozygosity was the only abnormality. Normalization of nitric oxide levels with l-arginine 9 g/d or l-citrulline 800 mg/d, both of which relieve vasospastic angina in Prinzmetal's angina, which has the same eNOS genotype as primary osteonecrosis, may slow or stop the progression of osteonecrosis. Placebo-controlled trials of patients with primary osteonecrosis who are hetero-homozygous for the T786C eNOS mutation and have no major thrombophilias are needed to assess the safety and efficacy of this treatment. [Orthopedics. 2017; 40(5):e898-e903.].