This study was conducted to determine the role of computed tomography (CT)-based segmentation methodology to semi-quantify the degree of inflammation and reactive bone formation in the 18 18 knee joints by fluorine-18-fluorodeoxyglucose (F-FDG) and F-sodium fluoride positron emission tomo-18 graphy/CT (F-NaF PET/CT) imaging, respectively. Furthermore, we assessed the impact of aging and body mass index (BMI) on these biological responses. In this retrospective study, we 18 18 examined a total of 97 subjects who had undergone both F-FDG and F-NaF PET/CT scanning. The mean age was 49.3±14.9 (21-75) and the mean BMI was 26.7±4.3 (17.7-42.0). Whole joint compartments and osseous compartments were segmented on fused PET/CT images using a 3D-growing algorithm with an adjustable upper/lower Hounsfield Units (HU) thresholds and manual tools. The metabolic activity and volume of each compartment was measured, values from the osseous compartment were subtracted from the whole joint to get the volume and metabolic activity of the soft tissue. The metabolic activity was correlated with age and BMI. Fluorine-18-FDG uptake in the soft tissues surrounding the joint was 18 0.35±0.07 while 0.19±0.04 in the osseous structures (P< 0.0001). Aging positively correlated with F-FDG 18 uptake in the soft tissue (r= 0.37, P= 0.0001). Body mass index positively correlated with F-FDG uptake in 18 the soft tissue (r= 0.53, P< 0.0001), osseous compartment (r= 0.58, P< 0.0001) and F-NaF uptake in the joint (r= 0.37, P= 0.0001). A positive association was noted between the degree of new bone formation and the inflammatory reaction (P< 0.01). The PET-based molecular imaging probes along with the CT-based segmentation techniques revealed an association between aging and the inflammatory activity of the soft tissue compartment. Similarly, a positive correlation was noted between BMI and inflammation and reactive bone formation of the knee joint compartments.