Numerous humoral factors are involved in the development of renal osteodystrophy, causing perturbations in bone mineral density (BMD) in patients with end-stage renal disease (ESRD). The RANKL/OPG cytokine system appears to mediate the effects of many of these factors on bone turnover, contributing to the pathogenesis of renal bone disease. The aim of this study was to evaluate the clinical and biochemical correlations of BMD measurements in patients on chronic hemodialysis. Fifty-four hemodialysis patients underwent measurement of BMD at the proximal femur and the lumbar spine (L2-L4). Intact parathyroid hormone (PTH), osteoprotegerin (OPG), sRANKL, and main bone biochemical markers were also measured in serum samples of all patients. BMD of the femoral neck was negatively correlated with OPG levels (r = 0.333, P = 0.014). OPG levels were significantly different among normal, osteopenic, and osteoporotic tertiles defined according to BMD of the femoral neck. The highest OPG levels were measured in the lowest T-score (osteoporotic) tertile and were higher than in the osteopenic and normal tertiles (P < 0.05). A threshold level for OPG at 21.5 pmol/l enabled the detection of osteoporotic patients with 76.5% sensitivity and 62.2% specificity. BMD values of trabecular bone-rich sites of the skeleton such as lumbar spine (L2-L4), trochanter, and Ward' s triangle were inversely correlated with total ALP levels (P < 0.05). Hemodialysis patients with low BMD of the femoral neck demonstrated higher OPG levels than patients with normal BMD. Those with lumbar spine (L2-L4), trochanteric, and Ward's triangle BMDs below the normal range presented higher total ALP levels. These results suggest that OPG and total ALP may be clinically useful markers in the detection of significant femoral neck and trabecular bone mineral deficit in hemodialysis patients, warranting further investigations.