Background: Nitric oxide regulates bone turnover by osteoblasts and
osteoclasts. Nitric oxide production is impaired by the T-786C eNOS single
nucleotide polymorphism, with a substitution of the nucleotide thymine by
cytosine at a locus 786 base pairs upstream of the eNOS gene. This leads to
vasoconstriction, platelet aggregation, reduced angiogenesis, and reduced bone
formation, all of which may be associated with osteonecrosis of the hip. We
studied relationships between the T-786C eNOS polymorphism and idiopathic and
secondary necrosis of the head of the femur in order to better understand the
pathophysiology of osteonecrosis.
Methods: With use of polymerase chain reaction methodology, the
T-786C eNOS polymorphism was compared in ninety-five patients with femoral
head necrosis (including thirty-six nonsmokers with idiopathic necrosis and
fifty-nine patients with secondary necrosis) and seventy-two healthy normal
Results: Homozygosity for the mutant eNOS allele (TT) was present in
eight (22%) of thirty-six patients with idiopathic osteonecrosis as compared
with one (3%) of thirty-six race, gender, and age-matched controls;
heterozygosity (TC) was present in nineteen patients (53%) as compared with
ten controls (28%); and the wild-type normal genotype (CC) was present in nine
patients (25%) as compared with twenty-five controls (69%) (p = 0.0004).
Logistic regression revealed that the T-786C eNOS mutant allele was positively
associated with idiopathic osteonecrosis of the femoral head (odds ratio, 6.0;
95% confidence interval, 2.51 to 14.4). The fifty-nine patients with secondary
osteonecrosis did not differ from fifty-two race, gender, and age-matched
controls in terms of the distribution of the T-786C eNOS polymorphism (p =
0.19) or in terms of mutant allele frequency (30% compared with 21%; p =
0.15). The thirty-six patients with idiopathic osteonecrosis differed from the
fifty-nine patients with secondary osteonecrosis in that they were more likely
to have mutant eNOS genotypes (p = 0.033) and to have a higher mutant T allele
frequency (49% compared with 30%; p = 0.009).
Conclusions: The T-786C eNOS polymorphism and resultant reduction of
nitric oxide production is associated with, and may contribute to, the
pathogenesis of idiopathic osteonecrosis of the femoral head.
Level of Evidence: Prognostic Level III. See Instructions
to Authors for a complete description of levels of evidence.