Conversion of C(19) steroids to estrogens is catalyzed by the aromatase enzyme. Inactivating mutations of the aromatase gene are associated with decreased bone mineral density in both men and women. Genetic studies suggest that several genes contribute to the regulation of bone mass via interaction with the modeling and remodeling processes. Among these genes, the aromatase gene is a potential candidate to be evaluated for segregation with bone metabolism and bone mass. A tetranucleotide simple tandem repeat polymorphism in intron 4 at the human aromatase cytochrome P-450 gene has been recently described. In the present study we evaluated the distribution of this polymorphism in a cohort of Italian postmenopausal women, both normal and osteoporotic. We observed that the NN genotype was significantly more frequent in nonosteoporotic women than in osteoporotic women (72.7% vs. 27.2%), whereas the DN genotype was significantly more represented in osteoporotic women (90.48% vs. 9.5%; Pearson's chi(2) test = 42.8; df = 10; P = or < 0.01). The allele containing the longer TTTA repeats was statistically more represented in nonosteoporotic women (Pearson's chi(2) test = 19.14; df = 2; P = 0.00007). In addition, women with a high number of TTTA repeats had a significantly higher lumbar bone mineral density than women with alleles containing 8-11 TTTA repeats (P = 0.03). Finally, considering the spine fractures, a significantly higher incidence was observed in women with shorter TTTA repeats than in those with longer TTTA repeats (Pearson's chi(2) test = 7.3; df = 2; P = 0.02), equivalent to a relative risk of 4.1 (95% confidence interval, 1.19-13.87). In conclusion, the aromatase gene can be one of the several genes potentially involved in the maintenance of bone mass and in the regulation of bone mass loss.