Subchondral Bone Metabolic Responses to Acute Mechanical Loading in Unilateral Knee Pain: A Quantitative NaF PET/MRI Study

Objective To characterize regional subchondral bone metabolism before and after acute mechanical loading in individuals with unilateral knee pain using dynamic [18F]sodium fluoride ([18F]NaF) positron emission tomography (PET)/magnetic resonance imaging (MRI), and to investigate relationships with cartilage composition and pain severity. Design Twenty-two individuals with unilateral knee pain and 22 age- and sex-matched healthy controls underwent bilateral dynamic [18F]NaF PET/MRI before and after a standardized stair-climbing protocol in this prospective feasibility study. Automated MRI-based segmentations were used to quantify regional PET standardized uptake values (SUVmean, SUVmax) and pharmacokinetic parameters (K1: bone perfusion, Ki: bone mineralization, extraction fraction) across subchondral bone regions. Quantitative cartilage T2 mapping was performed using qDESS MRI. Painful knees were compared with contralateral asymptomatic knees and healthy control knees using regional effect sizes and regression analyses. Exploratory analyses evaluated associations between PET metrics, cartilage T2, and pain severity. Results Painful knees demonstrated consistently higher baseline subchondral bone metabolic activity than healthy controls, with the largest differences in the medial tibial and medial femoral subchondral bone (Cohen's d=0.51-0.90). Following mechanical loading, exercise-induced increases in bone metabolism were more widespread and demonstrated predominantly moderate-to-large effect sizes (d=0.62-1.15), particularly within the medial and lateral femoral and medial tibial subchondral bone. In contrast, comparisons between painful and contralateral knees showed only localized metabolic differences with predominantly negligible-to-small effect sizes (d=0.16-0.55). Sensitivity analyses adjusting for age and BMI produced similar regional patterns. Exploratory analyses demonstrated generally weak associations between PET-derived metabolic measures, cartilage T2, and pain severity, with only isolated moderate regional correlations. Conclusions Dynamic [18F]NaF PET/MRI demonstrates increased baseline subchondral bone metabolic activity and an exaggerated metabolic response to mechanical loading in symptomatic knees compared with healthy controls. The modest differences between painful and contralateral knees suggest that the asymptomatic limb may not represent a truly unaffected reference. Dynamic [18F]NaF PET provides complementary information beyond cartilage MRI and patient-reported pain and shows promise for investigating subchondral bone metabolism in knee pain, early joint degeneration, and treatment response.