br Although cortical bone structural outcomes at proximal sk
Although cortical bone structural outcomes at proximal skeletal sites did not differ in ADT-treated men compared to controls in our study, an unexpected finding was that ADT-treated men had higher total bone area of the distal tibia but lower vBMD. Previous research has reported that periosteal bone apposition may occur during aging to partially offset endocortical bone resorption to maintain cortical thickness and bone strength . Thus, the higher total area in ADT-treated men in this study may therefore represent a compensatory re-sponse to the lower total vBMD to maintain bone strength. Indeed, a small increase in the size or outer diameter of the bone can lead to large increases in bone strength because the resistance of bone to bending or torsional forces is related exponentially (to the 4th power) to its dia-meter . In contrast to these findings, distal radius total bone area did not differ between the groups, despite both total and trabecular vBMD being lower in ADT-treated men compared to controls. These contrasting results may be due to the fact that the distal radius is a non-weight-bearing site. It is well established that mechanical loading is a potent stimuli for skeletal Pirinixic Acid , and that the tibia is sub-jected to regular loading. However, despite the greater total bone area, distal tibia bone strength was still lower in ADT-treated men compared to healthy controls, suggesting that the greater bone size did not compensate for the lower vBMD in this study. Additionally, sex steroids may influence the sensitivity of bone to mechanical loading . Mouse models suggest that estrogen deficiency may decrease the sen-sitivity, whereas androgen deficiency does not impair and may even
increase the skeletal response to mechanical loading . Prospective studies are required to further investigate changes in vBMD, bone structure and strength during ADT and to confirm the results of the current study. An additional novel aspect of this study was the assessment of cortical bone density distribution at proximal sites to evaluate whether ADT was associated with regional-specific changes in cortical bone density. This is important because previous research has reported that cortical bone mass and density are not uniform throughout the cortex [21,22] and change with age [22,23]. For example, a study in-vestigating mid-tibia cortical bone vBMD in young compared to older men reported that despite equivalent whole bone cortical bone vBMD, older men had lower endocortical vBMD and higher pericortical vBMD compared to young men . Any variations in cortical density are likely to be related to changes in intracortical remodelling that alters the porosity and/or mineralization of bone . In this study, we found that cortical bone density distribution across the cortex of both the proximal tibia and radius did not differ in ADT-treated men compared to controls. Given that it has been reported that about 70% of the age-related reduction in cortical vBMD is due to increased porosity , these findings suggests ADT does not appear to adversely affect cortical porosity. However, further studies using more advanced high resolution imaging techniques such as HR-pQCT are needed to address this question.
Although previous cross-sectional studies investigating DXA aBMD in ADT-treated men compared to control groups have reported mixed results [9–14], we found that lumbar aBMD was ~7–8% lower in the ADT-treated men compared to PCa and healthy controls. This is con-sistent with the findings from several studies which also observed that lumbar spine aBMD in ADT-treated men was 8% to 23% lower com-pared to PCa controls [9,11,12] or healthy controls . In contrast, we observed no significant differences in aBMD at proximal femur sites, which is consistent with a number of studies reporting no differences in total hip [9,11,13], femoral neck [10,13,14], or trochanter aBMD [10,13] in ADT-treated men compared to PCa and/or healthy controls. Although some previous studies have reported 7% to 12% lower total hip [10,12] and femoral neck aBMD  in ADT-treated men compared to PCa controls, the contrasting results with regard to DXA aBMD may be related to a number of factors, including differences in the duration of ADT use and sample sizes used which may have limited the statistical power to detect any significant between group differences. For instance, Stoch et al.  included 19 ADT-treated men and reported no sig-nificant differences in lumbar spine and femoral neck BMD, despite being 6.5% and 8.3% lower respectively compared to PCa controls. The lower aBMD of the lumbar spine but not of the femoral neck observed in ADT-treated men compared to controls supports our pQCT results that suggest ADT may primarily affect trabecular bone, given that the lumbar spine contains a higher proportion of trabecular bone than the proximal femur.