Introduction: A major determinant of osteoporotic fracture is peak bone mineral density (BMD). In women peak BMD is highly heritable and several quantitative trait loci (QTL) have been reported. There are few comparable data in men. This study in men aimed to establish the heritability of peak BMD, identify QTL contributing to normal variation in BMD, and determine which QTL might be sex-specific.

Methods: BMD at the spine and hip were measured in 323 pairs of brothers age 18-61 (264 white pairs; 59 black pairs). Heritability was calculated and linkage analysis performed with spine and hip BMD phenotypes.

Results: Heritability estimates ranged from 0.61 to 0.87 and were not significantly different between white and black men. A 9 cM genome wide scan followed by genotyping with more closely spaced markers identified suggestive QTL (LOD>2.2) for BMD on chromosomes 1q (spine), 2p (spine), 2q (hip), 14p (spine), 18 (hip), and on 21 (hip). Comparison with published data in 774 pairs of premenopausal sisters suggested that the QTL on 1q (spine), 2q (hip), 14p (spine), and 21q (hip) were male-specific whereas those on 2p (spine) and 18 (hip) were not sex-specific.

Conclusions: This study demonstrates that BMD in healthy men is highly heritable with similar estimates of the genetic contribution to BMD in both whites and blacks. Of the 6 QTL identified, 3 were specific for spine BMD and 3 were specific for hip BMD. When compared with published QTL for peak BMD in women from the same geographical region, 4 of the QTL appeared to be male-specific. The occurrence of sex-specific genes in humans for BMD has potentially important implications for the pathogenesis and treatment of osteoporosis.