18F-Sodium Fluoride PET as a Diagnostic Modality for Metabolic, Autoimmune, and Osteogenic Bone Disorders: Cellular Mechanisms and Clinical Applications.

In a healthy body, homeostatic actions of osteoclasts and osteoblasts maintain the integrity of the skeletal system. When cellular activities of osteoclasts and osteoblasts become abnormal, pathological bone conditions, such as osteoporosis, can occur. Traditional imaging modalities, such as radiographs, are insensitive to the early cellular changes that precede gross pathological findings, often leading to delayed disease diagnoses and suboptimal therapeutic strategies. 18F-sodium fluoride (18F-NaF)-positron emission tomography (PET) is an emerging imaging modality with the potential for early diagnosis and monitoring of bone diseases through the detection of subtle metabolic changes. Specifically, the dissociated 18F- is incorporated into hydroxyapatite, and its uptake reflects osteoblastic activity and bone perfusion, allowing for the quantification of bone turnover. While 18F-NaF-PET has traditionally been used to detect metastatic bone disease, recent literature corroborates the use of 18F-NaF-PET in benign osseous conditions as well. In this review, we discuss the cellular mechanisms of 18F-NaF-PET and examine recent findings on its clinical application in diverse metabolic, autoimmune, and osteogenic bone disorders.

Imaging of Rotator Cuff Calcific Tendinopathy Using 18 F-NaF and 18 F-FDG PET/CT.

ABSTRACT: Calcific tendinopathy is a common condition of the shoulder caused by the inflammation and deposition of hydroxyapatite crystals in the rotator cuff tendons. PET tracers capturing the molecular changes associated with the crystal deposition of calcific tendinopathy remain underinvestigated. In this report, we present calcified tendinopathy of the infraspinatus tendon demonstrating both 18 F-NaF and 18 F-FDG focal uptake in a 61-year-old woman.

Monitoring the Progression of a Calcifying Uterine Leiomyoma: Detection Using 18 F-NaF-PET/CT.

ABSTRACT: Uterine leiomyomas (fibroids) are common and benign hormone-dependent tumors of the uterus, often coinciding with atypical menstrual bleeding, urinary incontinence, and lower abdominal pain. The PET tracer 18 F-NaF has been used to study metastatic and benign bone disorders, but its potential use in investigating the molecular alterations of extraosseous tissues and tumors has not been fully investigated. In this report, we present a calcifying uterine leiomyoma incidentally detected on 18 F-NaF PET/CT scans in a postmenopausal 61-year-old woman and follow-up image 2 years after, highlighting the potential of 18 F-NaF in monitoring both the molecular and structural progression of uterine leiomyomas.

Simultaneous Uptake of 18 F-NaF and 18 F-FDG by Bladder and Prostate Calculi.

ABSTRACT: Calcification and formation of calculi in the genitourinary system such as the bladder, kidney, and prostate are common processes of aging. Despite being in different parts of the body, these calculi can share risk factors; for instance, bladder and prostate calculi are seen in older men with benign prostatic hyperplasia. There have been increasing reports of detection of calculi using PET tracers such as 18 F-NaF and 18 F-FDG, suggesting their role for detection of extraosseous calcification. In this report, we present simultaneous detection of bladder and prostate calculi with both 18 F-NaF and 18 F-FDG avidity in a 74-year-old man with multiple myeloma.

The Utility of 18 F-NaF-Positron Emission Tomography/Computed Tomography in Measuring the Metabolic Activity of the Aging Spine : Implications for Osteoporosis.

STUDY DESIGN: Cross-sectional; observational. OBJECTIVES: To determine whether sodium fluoride (NaF) positron emission tomography/computed tomography (PET/CT) can be used to monitor decreased bone turnover with aging in the spine. BACKGROUND: Osteoporosis is characterized by structural changes in the bone such as decreased bone mineral density leading to an increased risk for fractures. An imaging modality capable of identifying molecular changes that precede these structural changes could be critical for the early diagnosis and monitoring of osteoporosis and other metabolic bone disorders. MATERIALS AND METHODS: The potential of 18 F-sodium fluoride (NaF)-PET/CT in detecting changes in bone turnover associated with aging was examined in the lumbar spine of 88 healthy volunteers (43 females, 45 males; mean age 44.6 yr). Regions of interest equal to the trabecular body of the L1 to L4 vertebrae were used to calculate the mean standardized uptake value (SUVmean) and average Hounsfield unit (HU) values. Receiver-operating characteristic curve analysis with an area under the curve using the Wilson/Brown method was generated to assess the value of NaF uptake (SUVmean) in predicting osteoporosis as defined by HU-threshold values. To determine the correlation among global SUVmean, mean HU values, and age, the Spearman correlation test was performed on images acquired at 90 minutes postinjection. RESULTS: There was a significant negative correlation between NaF SUVmean and age in females ( P < 0.0001, r = -0.59), and a weaker, but also significant correlation in males ( P = 0.03, r = -0.32). In females only, there was a significant correlation between NaF uptake and age at all acquisition time points. Measured NaF uptake increased by 10% to 15% with acquisition time in both sexes, from 45 to 90 minutes and from 90 to 180 minutes. CONCLUSIONS: NaF-PET/CT detects decreased vertebral bone turnover with aging, particularly in females. Measured NaF uptake increased with PET acquisition time after tracer injection, which must be considered in follow-up studies monitoring disease development and treatment effects.

The role of 18F-FDG PET/CT in primary cutaneous lymphoma: an educational review.

INTRODUCTION: Primary cutaneous lymphoma (PCL) is a cutaneous non-Hodgkin's lymphoma that originates in the skin and lacks extracutaneous spread upon initial diagnosis. The clinical management of secondary cutaneous lymphomas is different from that of PCLs, and earlier detection is associated with better prognosis. Accurate staging is necessary to determine the extent of disease and to choose the appropriate treatment. The aim of this review is to investigate the current and potential roles of 18F- fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET/CT) in the diagnosis, staging, and monitoring of PCLs. METHODS: A focused review of the scientific literature was performed using inclusion criteria to filter results pertaining to human clinical studies performed between 2015 and 2021 that analyzed cutaneous PCL lesions on 18F PET/CT imaging. RESULTS & CONCLUSION: A review of 9 clinical studies published after 2015 concluded that 18F-FDG PET/CT is highly sensitive and specific for aggressive PCLs and proved valuable for identifying extracutaneous disease. These studies found 18F-FDG PET/CT highly useful for guiding lymph node biopsy and that imaging results influenced therapeutic decision in many cases. These studies also predominantly concluded that 18F-FDG PET/CT is more sensitive than computed tomography (CT) alone for detection of subcutaneous PCL lesions. Routine revision of nonattenuation-corrected (NAC) PET images may improve the sensitivity of 18F-FDG PET/CT for detection of indolent cutaneous lesions and may expand the potential uses of 18F-FDG PET/CT in the clinic. Furthermore, calculating a global disease score from 18F-FDG PET/CT at every follow-up visit may simplify assessment of disease progression in the early clinical stages, as well as predict the prognosis of disease in patients with PCL.

State of the Art Imaging of Osteoporosis.

Osteoporosis is a common disease, particularly prevalent in geriatric populations, which causes significant worldwide morbidity due to increased bone fragility and fracture risk. Currently, the gold-standard modality for diagnosis and evaluation of osteoporosis progression and treatment relies on dual-energy x-ray absorptiometry (DXA), which measures bone mineral density (BMD) and calculates a score based upon standard deviation of measured BMD from the mean. However, other imaging modalities can also be used to evaluate osteoporosis. Here, we review historical as well as current research into development of new imaging modalities that can provide more nuanced or opportunistic analyses of bone quality, turnover, and density that can be helpful in triaging severity and determining treatment success in osteoporosis. We discuss the use of opportunistic computed tomography (CT) scans, as well as the use of quantitative CT to help determine fracture risk and perform more detailed bone quality analysis than would be allowed by DXA . Within magnetic resonance imaging (MRI), new developments include the use of advanced MRI techniques such as quantitative susceptibility mapping (QSM), magnetic resonance spectroscopy, and chemical shift encoding-based water-fat MRI (CSE-MRI) to enable clinicians improved assessment of nonmineralized bone compartments as well as a way to longitudinally assess bone quality without the repeated exposure to ionizing radiation. Within ultrasound, development of quantitative ultrasound shows promise particularly in future low-cost, broadly available screening tools. We focus primarily on historical and recent developments within radiotracer use as applicable to osteoporosis, particularly in the use of hybrid methods such as NaF-PET/CT, wherein patients with osteoporosis show reduced uptake of radiotracers such as NaF. Use of radiotracers may provide clinicians with even earlier detection windows for osteoporosis than would traditional biomarkers. Given the metabolic nature of this disease, current investigation into the role molecular imaging can play in the prediction of this disease as well as in replacing invasive diagnostic procedures shows particular promise.

Novel technique of detecting inflammatory and osseous changes in the glenohumeral joint associated with patient age and weight using FDG- and NaF-PET imaging.

OBJECTIVE: The glenohumeral (GH) joint is a classic ball-and-socket joint of the shoulder subject to various pathologies including osteoarthritis (OA). Degenerative changes of the OA evident on traditional imaging are proceeded by molecular changes, which if detected early could enhance disease prevention and treatment. In this study, we use 18F-FluoroDeoxyGlucose (FDG) and 18F-sodium-fluoride (NaF)-PET/CT to investigate the effects limb laterality, age, and BMI on the inflammation and bone turnover of the GH shoulder joint. METHODS: FDG and NaF-PET/CT scans of 41 females (mean age of 43.9 ± 14.2 years) and 45 males (mean age of 44.5 ± 13.8 years) were analyzed with a semi-quantitative technique based on predefined region of interest. RESULTS: There was greater FDG uptake in the left side of the GH joint compared to the right in both females (left: 0.79 ± 0.17, right: 0.71 ± 0.2; P < 0.0001) and males (left: 0.76 ± 0.19, right: 0.57 ± 0.18; P < 0.0001). We also observed a strong positive association between BMI and FDG uptakes in females (left: P < 0.0001, r = 0.71, right: P < 0.0001, r = 0.58) and males (left: P < 0.0001, r = 0.56, right: P < 0.0001, r = 0.64). Association between BMI and NaF uptake were found in males as well (left: P = 0.004, r = 0.42, right: P = 0.02, r = 0.35). CONCLUSION: Our study demonstrates the varying effect of limb laterality and BMI on FDG and NaF uptake at the GH joint. Adoption of molecular imaging will require future studies that correlate tracer uptake with relevant medical and illness history as well as degenerative change evident on traditional imaging.

Coupling of Inflammation and Microcalcification in the Pathogenesis of Prostate Calculi: Detection Using 18 F-NaF and 18 F-FDG PET/CT.

ABSTRACT: Prostatic calculi are common and usually asymptomatic calcified stones frequently found incidentally in imaging or during the evaluation of benign prostatic hyperplasia. Those associated with chronic prostatitis can lead to bacterial colonization, inflammation, and blockage of secretory ducts, resulting in pelvic pain and lower urinary tract symptoms. Although PET tracers such as 18 F-NaF and 18 F-FDG have been used to assess metastatic and benign bone disorders, their comparative avidity in the domain of extraosseous and prostate calcification remains to be fully explored. We present incidentally detected bilateral prostatic calcification in an asymptomatic 42-year-old man exhibiting coavidity of 18 F-NaF and 18 F-FDG, highlighting the molecular coupling of inflammation and microcalcification in the pathogenesis of prostate calculi.

Representation of Asian American Populations in Medical School Curricula.

Importance: Despite being one of the fastest-growing populations in the US, the Asian American population is often misrepresented in and omitted from health research and policy debate. There is a current lack of understanding of how Asian American populations are portrayed in medical school curricula. Objective: To assess how Asian American populations and their subgroups are represented in medical school curricula. Design, Setting, and Participants: In this qualitative study, the content of 632 lectures from all 19 courses of the preclinical curriculum at a single US institution from the academic year 2020 to 2021 was analyzed to identify and characterize unique mentions of race and ethnicity as well as granular ethnicity. Among the 632 lectures, we identified 256 nonrepetitive, unique mentions of race and ethnicity or granular ethnicity. These unique mentions were coded and analyzed for emerging patterns of use. Main Outcomes and Measures: Study outcomes included (1) the frequency of specific racial and ethnic categories mentioned in the curriculum, (2) the relative proportion of mentions of race and ethnicity that involved or included Asian American data by courses and context, and (3) key themes representing emerging patterns found from qualitative analysis of curriculum content for mentions of Asian American populations or lack thereof. Results: Among the 632 lectures, 256 nonrepetitive mentions of race and ethnicity or granular ethnicity were identified; of these, Asian American populations and/or their subgroups were mentioned in 79 of the instances (30.9%). The most common terms used to denote Asian American populations were Asian, with 36 mentions (45.6%); followed by Japanese, with 10 mentions (12.7%); and Chinese, with 8 mentions (10.1%). Overall, there were 26 mentions (10.2%) of American Indian or Alaska Native populations, 12 mentions (4.7%) of Asian and Pacific Islander or Asian American and Pacific Islander populations, 67 mentions (26.2%) of Asian or Asian American populations, 143 mentions (55.9%) of Black or African American populations, 62 mentions (24.2%) of Hispanic or Latino populations, 4 mentions (1.6%) of Native Hawaiian or Pacific Islander populations, and 154 mentions (60.2%) of White populations. During the analysis of the curriculum for representation of Asian American populations, the following 5 key themes emerged from the data: (1) omission, (2) aggregation, (3) inconsistent categorization, (4) misidentification of granular ethnicity, and (5) association of race and ethnicity with disease. Conclusions and Relevance: This qualitative study suggests that the curriculum from a single US medical school largely mirrors the inappropriate use of race and ethnicity found in published health literature and clinical guidelines. Solutions with long-term results will require collaboration among diverse groups of interest to adopt inclusive research programs and design. Such solutions could better equip students in combating race-based medicine and could promote community outreach programs built based on trust.

The effects of limb laterality and age on the inflammation and bone turnover of the acromioclavicular shoulder joint: 18 F-fluorodeoxyglucose and 18 F-sodium-fluoride-PET/computed tomography study.

PURPOSE: The acromioclavicular (AC) joint is a common site of injury and degenerative changes such as osteoarthritis (OA) of the shoulder. Physical manifestations of OA are preceded by molecular changes, detection of which may enhance early prophylaxis and monitoring of disease progression. In this study, we investigate the use of 18 F-FDG and 18 F-NaF-PET/CT to assess the effects of limb laterality and age on the inflammation and bone turnover of the AC shoulder joint. METHODS: We analyzed FDG and NaF-PET/CT scans of 41 females (mean age of 43.9 ± 14.2 years) and 45 males (mean age of 44.5 ± 13.8 years) using a semiquantitative technique based on predefined ROI. RESULTS: There was a greater NaF uptake in the right side of the AC joint compared with the left in both females (left: 2.22 ± 1.00; right: 3.08 ± 1.18; P < 0.0001) and males (left: 2.57 ± 1.49; right: 2.99 ± 1.40; P = 0.003). No consistent correlation between age and NaF or FDG uptakes were found in both females and males. There was also a positive correlation between FDG and NaF uptakes in both left ( P = 0.01; r = 0.37) and right ( P = 0.0006; r = 0.53) AC joints of male subjects. CONCLUSION: Our study is the first to reveal the varying effect of right-left limb laterality and aging on FDG and NaF uptake at the AC joint. Future studies correlating the history of shoulder trauma, pain, and degenerative change with FDG and NaF-PET/CT findings will be critical in the adoption of molecular imaging in the clinical setting.

Application of 18F-NaF-PET/CT in assessing age-related changes in the cervical spine.

Background: Cervical spondylosis is the degeneration of cervical spine often associated with aging and neck pain. As the degenerative changes are coupled with altered osteoblastic activity, imaging modalities sensitive to such molecular changes could be valuable for clinical assessment, disease prophylaxis, and monitoring early therapy response. In this study, we examined the role of 18F-sodium fluoride-positron emission tomography/computed tomography (18F-NaF-PET/CT) in detecting age-associated changes in the cervical spine of an adult population with broad age spectrum. Methods: In this retrospective cross-sectional study, we analyzed 18F-NaF-PET/CT scans of 88 control volunteers (43 females, 45 males) with age ranging from 21 to 75 years (mean =44.6, standard deviation, 14.0) divided into younger (21-45 years) and older (46-75 years) age groups. A semi-automated global assessment technique was used to measure 18F-NaF uptake in C2-C4 and C5-C7 vertebrae of the subjects. Furthermore, a CT-based scoring system was devised to measure the degree of structural degeneration. Results: There was a significant difference in 18F-NaF uptake of the younger and older groups at the C5-C7 vertebrae for both females (younger: mean =4.13, 95% CI: 3.72-4.55; older: mean = 4.80, 95% CI: 4.40-5.20; P=0.005) and males (younger: mean =3.66, 95% CI: 3.24-4.09; older: mean =4.22, 95% CI: 3.80-4.64; P=0.009), but not at the C2-C4 vertebrae. Furthermore, there was a positive correlation between the degree of degeneration and 18F-NaF uptake at both C2-C4 and C5-C7 spinal segments of both sexes. Conclusions: Aging is associated with increased 18F-NaF uptake in the cervical spine, which may be associated with osteoblastic activity coupled with degeneration. Our study alludes to the potential role of 18F-NaF-PET/CT in evaluating age-related degeneration and osteoarthritis of the spine.

The crosstalk between MYC and mTORC1 during osteoclastogenesis.

Osteoclasts are bone-resorbing cells that undergo extensive changes in morphology throughout their differentiation. Altered osteoclast differentiation and activity lead to changes in pathological bone resorption. The mammalian target of rapamycin (mTOR) is a kinase, and aberrant mTOR complex 1 (mTORC1) signaling is associated with altered bone homeostasis. The activation of mTORC1 is biphasically regulated during osteoclastogenesis; however, the mechanism behind mTORC1-mediated regulation of osteoclastogenesis and bone resorption is incompletely understood. Here, we found that MYC coordinates the dynamic regulation of mTORC1 activation during osteoclastogenesis. MYC-deficiency blocked the early activation of mTORC1 and also reversed the decreased activity of mTORC1 at the late stage of osteoclastogenesis. The suppression of mTORC1 activity by rapamycin in mature osteoclasts enhances bone resorption activity despite the indispensable role of high mTORC1 activation in osteoclast formation in both mouse and human cells. Mechanistically, MYC induces Growth arrest and DNA damage-inducible protein (GADD34) expression and suppresses mTORC1 activity at the late phase of osteoclastogenesis. Taken together, our findings identify a MYC-GADD34 axis as an upstream regulator of dynamic mTORC1 activation in osteoclastogenesis and highlight the interplay between MYC and mTORC1 pathways in determining osteoclast activity.

Feasibility of Global Assessment of Bone Metastases in Prostate Cancer with 18F-Sodium Fluoride-PET/Computed Tomography.

18F-sodium fluoride (NaF) PET/computed tomography (CT) allows detection of bone metastases in patients with prostate cancer (PCa). The aim of this study was to test the feasibility of assessing global metastatic bone disease in patients with PCa by using a threshold-based PET segmentation technique. This retrospective analysis was performed in 32 patients with PCa with known bone metastases who underwent NaF-PET/CT imaging. An adaptive contrast-oriented thresholding technique was used to segment NaF avid lesions. The mean metabolic volumetric product (MVPmean), partial volume-corrected MVPmean (cMVPmean), and metabolically active volume (MAV) were calculated. Lesional values were summed within each patient to obtain the global PET disease burden. Pearson correlation analysis was used to assess the associations between global NaF-PET/CT metrics and clinical biomarkers of metastatic disease activity. Global MVPmean, cMVPmean, and MAV were significantly correlated with alkaline phosphatase (ALP) levels (p < 0.05). No correlation was observed between global NaF-PET/CT measures and prostate-specific antigen (PSA) levels. Global assessment is a feasible method to quantify metastatic bone disease activity in patients with PCa. Convergent validity was supported by demonstrating a significant correlation between NaF-PET/CT parameters and blood ALP levels.

MYC-mediated early glycolysis negatively regulates proinflammatory responses by controlling IRF4 in inflammatory macrophages.

MYC activates different metabolic programs in a cell-type- and cell-status-dependent manner. However, the role of MYC in inflammatory macrophages has not yet been determined. Metabolic and molecular analyses reveal that MYC, but not hypoxia inducible factor 1 (HIF1), is involved in enhancing early glycolytic flux during inflammatory macrophage polarization. Ablation of MYC decreases lactate production by regulating lactate dehydrogenase (LDH) activity and causes increased inflammatory cytokines by regulating interferon regulatory factor 4 (IRF4) in response to lipopolysaccharide. Moreover, myeloid-specific deletion of MYC and pharmacological inhibition of the MYC/LDH axis enhance inflammation and the bacterial clearance in vivo. These results elucidate the potential role of the MYC/LDH/IRF4 axis in inflammatory macrophages by connecting early glycolysis with inflammatory responses and suggest that modulating early glycolytic flux mediated by the MYC/LDH axis can be used to open avenues for the therapeutic modulation of macrophage polarization to fight against bacterial infection.

PET-Based Imaging with 18F-FDG and 18F-NaF to Assess Inflammation and Microcalcification in Atherosclerosis and Other Vascular and Thrombotic Disorders.

Positron emission tomography (PET) imaging with 18F-fluorodeoxyglucose (FDG) represents a method of detecting and characterizing arterial wall inflammation, with potential applications in the early assessment of vascular disorders such as atherosclerosis. By portraying early-stage molecular changes, FDG-PET findings have previously been shown to correlate with atherosclerosis progression. In addition, recent studies have suggested that microcalcification revealed by 18F-sodium fluoride (NaF) may be more sensitive at detecting atherogenic changes compared to FDG-PET. In this review, we summarize the roles of FDG and NaF in the assessment of atherosclerosis and discuss the role of global assessment in quantification of the vascular disease burden. Furthermore, we will review the emerging applications of FDG-PET in various vascular disorders, including pulmonary embolism, as well as inflammatory and infectious vascular diseases.

The M-CSF receptor in osteoclasts and beyond.

Colony-stimulating factor 1 receptor (CSF1R, also known as c-FMS) is a receptor tyrosine kinase. Macrophage colony-stimulating factor (M-CSF) and IL-34 are ligands of CSF1R. CSF1R-mediated signaling is crucial for the survival, function, proliferation, and differentiation of myeloid lineage cells, including osteoclasts, monocytes/macrophages, microglia, Langerhans cells in the skin, and Paneth cells in the intestine. CSF1R also plays an important role in oocytes and trophoblastic cells in the female reproductive tract and in the maintenance and maturation of neural progenitor cells. Given that CSF1R is expressed in a wide range of myeloid cells, altered CSF1R signaling is implicated in inflammatory, neoplastic, and neurodegenerative diseases. Inhibiting CSF1R signaling through an inhibitory anti-CSF1R antibody or small molecule inhibitors that target the kinase activity of CSF1R has thus been a promising therapeutic strategy for those diseases. In this review, we cover the recent progress in our understanding of the various roles of CSF1R in osteoclasts and other myeloid cells, highlighting the therapeutic applications of CSF1R inhibitors in disease conditions.

NRF2 Is an Upstream Regulator of MYC-Mediated Osteoclastogenesis and Pathological Bone Erosion.

Osteoclasts are the sole bone-resorbing cells that play an essential role in homeostatic bone remodeling and pathogenic bone destruction such as inflammatory arthritis. Pharmacologically targeting osteoclasts has been a promising approach to alleviating bone disease, but there remains room for improvement in mitigating drug side effects and enhancing cell specificity. Recently, we demonstrated the crucial role of MYC and its downstream effectors in driving osteoclast differentiation. Despite these advances, upstream regulators of MYC have not been well defined. In this study, we identify nuclear factor erythroid 2-related factor 2 (NRF2), a transcription factor known to regulate the expression of phase II antioxidant enzymes, as a novel upstream regulator of MYC. NRF2 negatively regulates receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis through the ERK and p38 signaling-mediated suppression of MYC transcription. Furthermore, the ablation of MYC in osteoclasts reverses the enhanced osteoclast differentiation and activity in NRF2 deficiency in vivo and in vitro in addition to protecting NRF2-deficient mice from pathological bone loss in a murine model of inflammatory arthritis. Our findings indicate that this novel NRF2-MYC axis could be instrumental for the fine-tuning of osteoclast formation and provides additional ways in which osteoclasts could be therapeutically targeted to prevent pathological bone erosion.