Our data do not support these Protease Inhibitor Library observations of a threshold effect of bioE2 on cortical bone. The current view is that testosterone acts on bone primarily via aromatisation to estrogens. There is some evidence, at least in rats, that T may increase periosteal

apposition (and thereby increase total area), and certainly in adolescents T increases periosteal growth. Szulc et al. using data from DXA, suggested an increase in periosteal apposition with age though not via an action of T [15, 31]. In contrast, Khosla et al. found an inverse association in men with higher levels of T linked with reduced bone area [14]. Our results (both centres) showed no significant change in bone area with increasing testosterone at the 50% site though there was a positive association at the 4% site among the older NVP-BGJ398 Leuven men. One of the intriguing findings was the differences in the absolute pQCT parameters between the two centres and the relationships with sex steroids. Subjects in both centres were recruited using the same methods and were from a similar socioeconomic background. Removing subjects (n = 18) who were taking medications

known to influence sex steroid levels did not change the results. Further adjustment for smoking and physical activity had no effect on these relationships. The lower total BMD and larger bone area in Leuven at the 4% site may in part be related to the slightly different and more distal slice location used at the two centres. It is unlikely, however, that this difference in protocol explains centre differences at the 50% site due to the more homogenous structure of the radius at this anatomical site. It is therefore likely that other explanations, including genetic and environmental factors, play a role in these Manchester–Leuven skeletal and hormone differences. Genetic factors are known to influence both bone mass and structure at the radius. Data from family and twin studies suggest that genetic factors explain about 50% of the variation in the radius total and trabecular vBMD, and up to 40% of cortical vBMD [32, 33]. In addition, a large proportion of the variation in geometric parameters such Vildagliptin as radius cross-sectional

area (27%) and cortical thickness (51%) are also attributable to genetic factors [33]. Variations in other skeletal parameters across Europe have previously been reported [34]; however, to the best of our knowledge, there are no data concerning pQCT parameters. We cannot explain the variation in findings in relation to the associations between bone parameters and sex hormones, other than the slight difference in protocol using pQCT which we feel would be unlikely to explain the variation. The similarity in rate of change with age for the skeletal parameters in both centres provides some construct validity to these measures. The strength of our study was that it was population based and used pQCT measurements to obtain information not only on bone density but also bone morphology.