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Department of Internal Medicine (L.G., L.M., L.P., A.F., A.T., C.M., F.D.M., M.L.B.), University of Florence, 50139 Florence, Italy; and Institute of Internal Medicine (D.M., S.G., B.L., C.G.), University of Siena, 53100 Siena, Italy
Address all correspondence and requests for reprints to: Maria Luisa Brandi, M.D., Ph.D., Department of Internal Medicine, University of Florence, Viale Pieraccini 18, 50139 Florence, Italy. E-mail: m.brandi{at}dmi.unifi.it.
Current evidence suggests that estrogen plays a dominant role in determining bone mineral density (BMD) in men, and inactivating mutations in the aromatase CYP19 gene have been associated with low bone mass in young males. We previously reported an association between a TTTA repeat polymorphism in intron 4 of the CYP19 gene and osteoporotic risk in postmenopausal females. Here we explore the role of this polymorphism as a genetic determinant of BMD in a sample of elderly males who were recruited by direct mailing and followed longitudinally for 2 (n = 300) and 4 (n = 200) yr. Six different allelic variants, containing seven, eight, nine, 10, 11, and 12 TTTA repeats, were detected. There was a bimodal distribution of alleles, with two major peaks at seven and 11 repeats and a very low distribution of the nine-repeat allele. Men with a high-repeat genotype (>nine repeats) showed higher lumbar BMD values, lower bone turnover markers, higher estradiol levels, and a lower rate of BMD change than men with a low-repeat genotype (<nine repeats). The association with BMD was not significant in the subgroup of patients with high body mass index (>25), suggesting that the effect of CYP19 genotypes on bone may be masked by the increase in fat mass. Moreover, the high-repeat genotype was less represented, although not significantly, in the vertebral fracture group with respect to the nonvertebral fracture group. Functional in vitro analysis after incubation with [3H]-androstenedione showed a higher aromatase activity in fibroblasts from subjects with a high-repeat genotype than in fibroblasts from subjects with a low-repeat genotype. In conclusion, differences in estrogen levels due to polymorphism at the aromatase CYP19 gene may predispose men to increased age-related bone loss and fracture risk.
This work was supported by grants from Ministero dell’Università e della Ricerca Scientifica e Tecnologica (60% and 40%) and from the National Health System Projects (to M.L.B.).
L.G. and L.M. contributed equally to this work.
Abbreviations: ANCOVA, Analysis of covariance; BMD, bone mineral density; BMI, body mass index; BUA, broadband ultrasound attenuation; c-bioE2, calculated bioavailable estradiol; c-bioT, calculated bioavailable testosterone; CI, confidence interval; CV, coefficient of variation; DXA, dual-energy x-ray absorptiometry; E2, estradiol; FAI, free androgen index; FEI, free estrogen index; SOS, speed of sound; T, testosterone.
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