In this study, we found that [18F]NaF uptake was significantly higher in the right iliac bone compared to the left in both males and females and in the combined-gender analysis. Additionally, our findings demonstrated an age-dependent decline in [18F]NaF uptake in both genders, suggesting a reduction in bone metabolic activity with aging. We also identified a significant positive correlation between SUVmean and BMI across all groups, indicating a potential link between body composition and bone metabolic activity. A negative correlation was observed between SUVmean and physical activity in the left iliac bone of females and the combined-group, whereas no significant correlation was found in males.

The observed higher [18F]NaF uptake in the right iliac bone compared to the left suggests potential functional variations between the two sides. While no studies have specifically investigated laterality in iliac bones, bilateral asymmetry in pelvic bones has been previously reported, arising from both external factors like biomechanical loading and internal factors such as genetics [19]. However, directional asymmetries are generally considered adaptive responses to loading. Mechanical loading plays a critical role in regulating bone mass and morphology by inducing dynamic strains in bone tissue, with peak strain amplitude and strain rate being key predictors of the osteogenic response [20, 21]. Although the pelvis exhibits less directional asymmetry than the limbs, its close association with the lower limbs and role in locomotion suggest that its asymmetries may resemble those found in the lower limbs [22]. Evidence supports right limb dominance in our study cohort, as demonstrated by greater [18F]NaF uptake in the right tibia than the left in both male and female subjects in a study by Park et al. [23]. Limb dominance may also be associated with the side of the body where injury occurs [24, 25]. Previous [18F]NaF studies assessing bone turnover at the sacroiliac and hip joints suggest that laterality may be associated with increased osteoblastic activity in right-sided weight-bearing bones and joints compared to the left in this cohort [26, 27]. However, the absence of data related to limb preference in the examined subjects limits definitive conclusions for lateral differences in [18F]NaF uptake in iliac bone.

Our results revealed an age-dependent decline in iliac bone [18F]NaF uptake on PET/CT imaging in both genders, with females showing a stronger negative correlation with age compared to males. This pattern aligns with the pathogenesis and epidemiology of osteoporosis, characterized by an imbalance in bone remodeling where resorption exceeds formation, leading to net bone loss that affects women more than men [28]. Osteoporosis develops through a variety of factors, including genetic predisposition (variants in genes such as vitamin D receptor, collagen type I, and estrogen receptor), hormonal changes (declining levels of estrogen and testosterone), and environmental factors (inadequate calcium intake, vitamin D deficiency, and physical inactivity) [29]. These factors disrupt the tightly regulated bone remodeling process, which involves osteoclastic resorption of old bone followed by osteoblastic formation of new bone [30]. In osteoporosis, excessive osteoclastic activity or inadequate osteoblastic response leads to incomplete refilling of resorption cavities, deteriorating bone mass and microarchitecture [28]. Peak bone mass, typically attained by the third decade of life, significantly influences osteoporosis risk [31], and this maximum bone density depends on genetic factors and modifiable lifestyle elements during development [32]. After reaching peak bone mass, both genders experience age-associated bone loss, but females face accelerated decline. In postmenopausal women, estrogen deficiency upregulates osteoclastogenesis while impairing osteoblastic function [33, 34]. In contrast, males undergo a more gradual decline attributed to decreased testosterone, vitamin D insufficiency, and other comorbidities [35]. Other contributors to excessive bone resorption include glucocorticoid exposure, alcohol consumption, smoking, sedentary lifestyle, and certain metabolic disorders [36]. Our findings align with previous [18F]NaF PET/CT studies demonstrating an age-dependent decrease in bone metabolic activity at other skeletal sites typically involved in osteoporosis. Utilizing the same cohort of individuals with or at risk for osteoporosis as previously analyzed by Rhodes et al. in their study of the femoral neck, we applied our novel ROI approach to the iliac bone and observed a similar trend between [18F]NaF uptake and age. This suggests that our method yields comparable insights into age-related changes in bone metabolism at a different skeletal site; however, it does not independently validate the findings of Rhodes et al. [16]. Frost et al. found significantly lower vertebral bone plasma clearance values by [18F]NaF PET in a cohort of postmenopausal women with osteoporosis compared to osteopenic and normal subjects [17]. In agreement with this existing evidence from established osteoporosis-prone regions like the spine and hip, our data expands the utility of [18F]NaF PET/CT to interrogate molecular signatures of aging bone metabolism in the iliac bones.

A significant positive correlation was observed between SUVmean and BMI in males, females, and the combined-group. A weak negative correlation was found between SUVmean and physical activity in the left iliac bone of females and in the combined-group but there was no significant correlation in males. While the relationship between increased BMI and bone formation is relatively well-documented, particularly in the glenohumeral joint [37], the precise underlying mechanisms remain an area of ongoing investigation. Elevated BMI influences bone health through alterations in bone cell metabolism, fluctuations in bone-regulating hormones, and increased oxidative stress and inflammation [38]. Although excessive adipose tissue has been hypothesized to exert a bone-protective effect through mechanical loading and hence stimulating bone formation via increased osteoblast and osteocyte activity, studies that account for overall body weight often fail to support a positive association between fat mass and bone mass [39]. Moreover, excessive fat mass, particularly in individuals with a BMI exceeding 35, has been demonstrated to negatively impact bone mineral density and mechanical strength. Conversely, lean body mass, which is closely associated with physical activity and mechanical loading, has been strongly linked to improved bone mineral density, as muscle activity plays a critical role in promoting bone growth [40]. Therefore, incorporating a detailed analysis of fat mass versus lean body mass on bone formation, and hence [18F]NaF uptake, could provide a more comprehensive understanding of these relationships in future studies.

On the other hand, when both genders were analyzed together, a significant negative correlation was observed between mean [18F]NaF uptake and physical activity levels. This finding contrasts with established literature, which generally supports a positive relationship between physical activity and bone metabolism, as mechanical loading is known to enhance osteogenesis. However, this discrepancy may be attributed to the specific nature of the physical activity performed, as certain weight-bearing exercises, such as resistance training, are more effective in stimulating osteogenic activity. In contrast, non-weight-bearing exercises do not provide sufficient mechanical loading to promote bone formation. The mechanical load applied during weight-bearing exercises must exceed those experienced during routine daily activities to effectively stimulate new bone formation [41, 42]. Notably, our study did not categorize participants’ physical activity types, and it is plausible that individuals with high physical activity levels predominantly engaged in non-weight-bearing exercises, thereby failing to induce adequate bone formation and resulting in decreased [18F]NaF uptake.

To our knowledge, this is the first study evaluating [18F]NaF uptake in iliac bones and analyze the variation based on laterality, age, gender, BMI, and physical activity level. This region is an intriguing site for studying systemic metabolic bone disease for several reasons. First, the iliac bones are large, making measurements convenient and potentially reproducible. Second, as part of the pelvic ring, a central weight-bearing structure, the iliac bones are susceptible to fragility fractures, which can lead to significant morbidity and mortality in the aging and osteoporotic population [43]. While the spine and hip are classic sites for bone mineral density measurements during osteoporosis screening, they have limitations. Osteoarthritis can affect these areas, potentially leading to artificially elevated bone mineral density [44]. Additionally, surgeries in the spine and hips are common, making measurements in these sites unreliable due to post-surgical changes [45, 46]. Currently, transiliac bone biopsy sampling of the iliac crest is the only direct method to assess bone remodeling dynamics at the tissue level through quantitative histomorphometric analysis [14]. Previous histomorphometric studies on iliac crest biopsy samples have shown age-related microstructural deterioration of trabecular bone, including decreased trabecular thickness, increased trabecular separation, compromised bone formation rates, and elevated erosion surfaces. These findings are consistent with the profile of exaggerated bone turnover and remodeling imbalance characterizing osteoporosis [14, 47]. However, these invasive transiliac procedures are limited by sampling errors and are rarely performed outside of research settings due to their invasive nature. These limitations highlight the significant implications of our study. [18F]NaF PET/CT imaging of iliac bones could serve as a non-invasive alternative for assessing bone metabolism, offering a new modality for how we diagnose, monitor, and treat metabolic bone diseases like osteoporosis in both research and clinical settings.

Our retrospective analysis of an otherwise healthy cohort from the CAMONA study had several strengths, including comprehensive clinical phenotyping and quantitative assessment of [18F]NaF uptake within the iliac bones on a per-subject basis. However, the study lacked correlative measurements of bone mineral density, clinical history of fractures, and other potential risk factors for metabolic bone disease. Future studies should incorporate this data to relate [18F]NaF uptake patterns to clinically relevant osteoporosis outcomes and assess diagnostic performance against gold-standard measures of skeletal fragility. Additionally, establishing age-, sex-, and BMI-matched reference ranges for quantitative [18F]NaF uptake parameters in the iliac bones through larger normative databases will be necessary to enhance diagnostic performance for identifying individuals with metabolic bone disease. Exploring the influence of factors like physical activity levels on iliac bone metabolism and conducting longitudinal evaluations to track changes in iliac [18F]NaF uptake over time will further clarify the relationship between molecular bone activity and structural deficits that increase fracture risk, ultimately defining imaging biomarker thresholds for initiating clinical interventions.