Heterogeneity in long bone metabolism with limb laterality and normal aging: 18F-NaF-PET/CT study

Introduction: ¹⁸F-sodium fluoride (NaF)-positron emission tomography/computed tomography (PET/CT) is a molecular imaging modality that has been gaining traction in the literature for the potential early diagnoses and treatment of various metabolic, inflammatory, and arthropathic bone disorders. Specifically, the radiolabeled fluoride ion exchanges with hydroxyapatite of the remodeling bone, reflecting increased osteoblastic activity and/or blood flow. While NaF-PET has been widely used for the assessment of joints and axial bone such as the lumbar spine, its use in studying long bone remains relatively limited. In this study, we investigated the heterogeneity and effect of limb laterality and aging on long bone metabolism in a healthy population using NaF-PET/CT.

Methods: Analysis was performed retrospectively and blindly in randomized healthy subjects from the Cardiovascular Molecular Calcification Assessed by 18FNaF PET/CT (CAMONA) study including 35 females and 35 males with a mean age of 44.5 years. Regions of the interest in tibia, femur, fibula, and humerus were generated in fused PET/CT image, and the global mean standardized uptake value (global SUVmean) reflecting NaF uptake was calculated using a Hounsfield unit (HU) threshold-based segmentation algorithm on the OsiriX software version 12.0 (Pixmeo, Bernex, Switzerland). Upper and lower thresholds were set at 150 HU and 1500 HU, respectively, to segment cortical bone, and a morphological closing algorithm was applied to extend the ROI to the trabecular space. All statistical tests and graphs were performed and plotted using GraphPad Prism 8 (San Diego, CA, USA).

Results: The right tibia had significantly greater NaF SUVmean than the left tibia in both females (right: 1.15 ± 0.39, left: 0.69 ± 0.30; p < 0.0001) and males (right 1.17 ± 0.34, left: 0.71 ± 0.30; p < 0.0001). The results were similar for the femur in females (right: 1.35 ± 0.42, left: 1.28 ± 0.40; p = 0.002) and males (right: 1.15 ± 0.29, left: 1.10 ± 0.34; p = 0.01). In contrast, there was no laterality difference in the fibula for both sexes (females – right: 0.98 ± 0.44, left: 0.95 ± 0.31; p = 0.72; males – right: 0.86 ± 0.31, left: 0.85 ± 0.28; p = 0.70). Interestingly, for the humerus, the left side exhibited higher NaF SUVmean for females (left: 1.07 ± 0.47, right: 0.99 ± 0.41; p = 0.02), while no significant difference was found for males (left: 1.09 ± 0.38, right: 1.15 ± 0.44; p = 0.09). With respect to aging, there was a significant, positive correlation between NaF SUVmean and aging in the left tibia (p = 0.004, r = 0.48), left fibula (p = 0.03, r = 0.36), and right humerus (p = 0.04, r = 0.35) of females only. None of the NaF SUVmean of long bones in males correlated with age.

Conclusions: We observed heterogeneity in the NaF uptake and bone metabolism of long bones including the tibia, femur, fibula, and humerus with respect to laterality and aging. Specifically, the tibia exhibited the strongest limb laterality difference with the right side having greater NaF uptake than the left, which could reflect the greater use of the right-sided lower limb and increased bone turnover in our study cohort. On the other hand, laterality differences were less straightforward in the femur, fibula, and humerus. Additionally, NaF uptakes in the long bones investigated did not exhibit a consistent correlation with age exhibiting in both right and left limbs of females and males, suggesting that long bones may not be suitable regions to monitor the effects of normal, age-dependent changes in bone metabolism. Further studies should instead focus on studying the effect of direct pathological conditions such as osteoporosis or rheumatoid arthritis on long bone metabolism.