Skeletal metastases are a significant problem in prostate cancer (PC). The patients are also exposed to treatment-related skeletal changes. This cross-sectional study evaluated a marker of bone resorption, TRACP 5b in relation to the standard analyte total alkaline phosphatase (tALP) as a marker of skeletal changes. Serum levels of TRACP 5b, tALP and PSA were measured in 130 prostate cancer patients. Comparison was made between patients with (BM+, n = 25) and without (BM-, n = 105) skeletal metastases, and between those treated with (n = 64) or without (n = 66) androgen deprivation (AD). Sensitivities and specificities were calculated for each marker and diagnostic accuracy was evaluated by ROC curve analysis. ROC curves indicated the superior accuracy of tALP, whereas TRACP 5b and PSA were comparable. With tALP the best combination of sensitivity (96%) and specificity of (91%) was reached at a cut-off point 224 U/L, the corresponding values were for TRACP 5b sensitivity (76%), specificity (89%) with a cut-off point 4.89 U/L, and for PSA sensitivity (65%), specificity (81%) at 23 ng/L for skeletal metastases. Patients treated with AD showed with increasing duration an increase in TRACP 5b values. TRACP 5b was less specific than tALP as a marker of skeletal metastases. TRACP 5b may have a role in the diagnostics of skeletal changes in PC with a focus on treatment-related skeletal changes.