Objectives The aims of this study were to evaluate the feasibility of quantitative synthetic magnetic resonance imaging (SyMRI) for characterizing bone lesions in prostate cancer and to discriminate viable progressive osteoblastic bone metastasis from nonviable bone metastases with treatment-induced sclerosis during the treatment course. Materials and Methods This institutional review board-approved prospective study included 96 consecutive prostate cancer patients who underwent whole-body MRI including diffusion-weighted imaging at the time of staging at diagnosis or starting a new line of anticancer treatment. Additional synthetic MRI of the lumbosacral spine, pelvis, and proximal femurs was performed. A region of interest of 1.0 cm in diameter was set in each bone lesion by 2 independent readers who were blinded to bone lesions' diagnosis. Differences in SyMRI variables between the different bone lesions were compared with the Wilcoxon rank sum test, and associations of SyMRI variables with active disease were analyzed with logistic regression analysis. Performance of T1, T2, and proton density (PD) for diagnosing active disease was assessed using the area under the receiver operating characteristic curve. Results Ninety-three bone lesions were eligible for analysis. The PD values of active (viable) bone metastatic lesions were significantly higher than those of inactive (nonviable) bone metastatic lesions without sclerosis and those of red bone marrow (P <0.001 for both readers). The PD values of inactive bone metastatic lesions with sclerosis were significantly lower than those of inactive bone metastatic lesions without sclerosis and red bone marrow (P <0.001 for both readers). The PD value proved to be an independent significant indicator (P <0.001) for differentiating bone lesions. The areas under the curve of T1/T2/PD for identifying active disease were 0.81/0.69/0.93 for reader 1 and 0.78/0.70/0.92 for reader 2, respectively. Conclusions Signal quantification on SyMRI provides objective assessment of bone lesions in the lower trunk. The PD value can be useful to determine the viability of bone metastases in prostate cancer.