Bone metastases are common in prostate cancer (PCa). Fluorocholine-18 (FCH) and sodium fluoride-18 (NaF) have been used to assess PCa associated skeletal disease in thousands of patients by demonstrating different mechanism of uptake-cell membrane (lipid) synthesis and bone mineralization. Here, this difference is characterized quantitatively in detail. Our study cohort consisted of 12 patients with advanced disease (> 5 lesions) (M) and of five PCa patients with no skeletal disease (N). They had routine PET/CT with FCH and NaF on consecutive days. Skeletal regions in CT were used to co-register the two PET/CT scans. Bone 3-D volume of interest (VOI) was defined on the CT of PET with a threshold of HU > 150, and sclerotic/dense bone as HU > 600, respectively. Additional VOIs were defined on PET uptake with the threshold values on both FCH (SUV > 3.5) and NaF (SUV > 10). The pathologic skeletal volumes for each technique (CT, HU > 600), NaF (SUV > 10) and FCH (SUV > 3.5) were developed and analyzed. The skeletal VOIs varied from 5.03 L to 7.31 L, whereas sclerotic bone VOIs were from 0.88 L to 2.99 L. Total choline kinase (cell membrane synthesis) activity for FCH (TCA) varied from 0.008 to 4.85 [kg] in M group and from 0.0006 to 0.085 [kg] in N group. Total accelerated osteoblastic (bone demineralization) activity for NaF (TBA varied from 0.25 to 13.6 [kg] in M group and varied from 0.000 to 1.09 [kg] in N group. The sclerotic bone volume represented only 1.86 ± 1.71% of the pathologic FCH volume and 4.07 ± 3.21% of the pathologic NaF volume in M group, and only 0.08 ± 0.09% and 0.18 ± 0.19% in N group, respectively. Our results suggest that CT alone cannot be used for the assessment of the extent of active metastatic skeletal disease in PCa. NaF and FCH give complementary information about the activity of the skeletal disease, improving diagnosis and disease staging.