Clinical Application and Research Progress of Fluorine-18-sodium Fluoride PET/CT in Benign Bone Lesions: A Review

At present, two imaging modalities are widely used for imaging bone metabolism function. Bone scanning is performed with 99mTclabeled methylene diphosphate (99mTc-MDP) Single Photon Emission Computed Tomography/Computed Tomography (SPECT/CT) and [18F] sodium fluoride (NaF) Positron Emission Tomography/ Computed Tomography (PET/CT) [1]. 18F-NaF is a positron emitter that was first applied to bone scans by Blau et al. [2] in 1962. PET/ CT is a molecular imaging modality that combines the structural evaluation and function of the lesion for diagnosis [3]. 18F-NaF PET/ CT is a molecular imaging modality that is increasingly used in human bone diseases [4-7]. The value of 18F-NaF PET/CT in bone metastases imaging of malignant tumor has been widely recognized. Given its involvement in skeletal calcium salt metabolism [2], 18F-NaF PET/CT may play an important role in assessing various benign bone diseases in the future. Although 99mTc-MDP remains the most commonly used radionuclide imaging agent for diagnosing benign bone diseases in general hospitals, 18F-NaF PET/CT has attracted increasing attention given its advantages, such as high image quality, short inspection time, high spatial resolution, CT attenuation correction, and threedimensional imaging [8].


The theory of 18 F-NaF PET/CT bone imaging
Bone tissue is composed of organic matter and inorganic salt, and inorganic salt is mainly hydroxyapatite crystals. 18 F-NaF bone uptake depends on the exchange of fluoride ions with hydroxyl ions in hydroxyapatite crystals, thus forming fluorapatite [9]. The uptake of 18 F in bone is dependent on blood flow, and almost all of the transmitted 18F is retained by the bone after a single passage of blood [10]. 18 F is mostly transported by red blood cells directly in the blood, so it has the advantages of low protein binding rate and rapid plasma clearance. Furthermore, 18 F has a high affinity for bone, so it has become a superior imaging agent compared with the 99m Tc-labeled phosphonate compounds [11]. After intravenous injection of 18 F-NaF, the absorption rate of the imaging agent differs between different bone types. Compared with the level of cortical bone, the degree of 18F-NaF absorption in the bone marrow can be neglected [11]. The SNM practice guidelines of 18 F-NaF PET/CT12 indicate that the activity in adults ranges from 185 to 370 MBq (5-10 mCi). Higher activity (370 MBq [10 mCi]) can be used in obese patients. Paediatric activities should be based on body weight (2.22 MBq/kg [0.06 mCi/kg]), and the range of use should be 18.5-185 MBq (0.5-5 mCi).
replace the damaged joints, and surgically replace the prosthesis to solve the patient's dysfunction. Currently, the arthroplasty infection rate is less than 1%. However, once the infection occurs, treatment is extremely difficult. This condition was once known as a catastrophic joint replacement complication [17]. X-ray is the most commonly used examination modality for orthopedic doctors. However, Duff et al. [18] suggest that X-ray film is neither sensitive nor specific to the diagnosis of infection and its main function is to exclude aseptic loosening after joint replacement. Because PET/CT has distinctive features that combine the function and fine anatomy of lesions, some scholars have used 18 F-NaF PET/CT to evaluate aseptic loosening and infection after joint replacement. Hans Creutzig et al. [19] confirmed the importance of 18 F-NaF PET/CT in joint prosthesis infection for the first time. Olu Adesanya et al. [20] reviewed the literature and summarized that the sensitivity of 18 F-NaF-PET for the identification of prosthesis infection was 97.04%. In 2011, Kobayashi et al. [21] conducted a prospective study to identify aseptic loosening and sepsis. Images were obtained after injection of 185 MBq 18F fluoride for 40 minutes. By measuring the degree of uptake of 18 F in the tissue surrounding the prosthesis (SUVmax), she distinguished normal, aseptically loose and infected prostheses. The mean values of normal, aseptic loosening and infected prostheses were estimated as 4.9±2.5, 8.1±2.9, and 10.5±3.4, respectively.

Arthritis
In addition to the high uptake of bone lesions associated with skeletal structural remodelling, the most common cause of increased fluoride absorption in the bones may be arthroplasty. The term refers broadly to inflammatory diseases that occur in the human joints and their surrounding tissues caused by inflammation, infection, degeneration, trauma, or other factors, including osteoarthritis, ankylosing spondylitis and the like. Studies have demonstrated that US, MRI, and HR-pQCT imaging modalities can help clinicians diagnose arthritis early in the early stage [22]. However, Jiang Yue et al. [22] noted that these imaging modalities are still flawed, and their clinical application in improving diagnostic accuracy and guiding treatment decisions remains unclear. Radionuclide imaging is often used as a diagnostic method for this type of disease, but the diagnosis of arthritis often needs to be combined with clinical manifestations and specific laboratory tests.
Osteoarthritis (OA) is a chronic joint disease characterized by articular cartilage degeneration and secondary hyperosteogeny. Osteoarthritis often occurs in large joints, such as knees and hips, as well as the vertebral facet joints [23]. 18 F-NaF PET/CT revealed that fluoride absorption in joints increased, making it a sensitive tool to detect osteoarthritis in bones. Assessment of planar bone scanning or radiographs may be limited in areas with complex anatomical structures, such as feet, whereas PET/CT has significant advantages. Yasuhide Hirata et al. [24] studied 17 patients with hip pain and used a three-dimensional pelvic femoral model to calculate the equivalent stress distribution by finite element analysis and to analyze the correlation between the calculated stress distribution and the degree of 18 F-fluoro-PET intake. The results revealed that the Spearman's correlation coefficient between the maximum normalized uptake value (SUVmax) and the maximum equivalent pressure were 0.752. Kobayashi et al. [6] studied 48 patients with hip arthritis. They performed radiographic evaluations based on Kellgren and Lawrence grade and minimum joint space, assessed the severity of pain, and measured the SUVmax of each joint to assess the correlation of SUVmax with imaging or clinical manifestations. The results revealed a statistically significant difference (P<0.0001) between the SUV values of significant pain and minor pain in the early stage of 18 F-NaF is rapidly cleared from the plasma and excreted by the renal system due to glomerular filtration and renal tubular secretion. The clearance rate of 18 F in the renal system is related to the urinary flow rate, and the clearance rate is 60 to 90% of the Glomerular Filtration Rate (GFR) during high urinary flow and 5% of GFR during low urine flow [12]. The SNM practice guidelines [13] indicate that patients should be hydrated sufficiently to promote the rapid excretion of radiopharmaceuticals, thus reducing radiation dose and improving image quality. Patients without contraindications should be encouraged to drink more water and empty their bladders before image acquisition.

Benign bone disease
Benign bone disease indications of 18 F-NaF PET/CT include the following: 1) early diagnosis of infectious bone diseases, such as osteomyelitis; 2) diagnosis of arthritis; 3) diagnosis of trauma and occult fracture; 4) evaluation of bone activity; 5) diagnosis of metabolic bone disease; 6) diagnosis of osteoarthritis; and 7) early diagnosis of osteonecrosis, etc. In general, the degree of uptake of 18 F-NaF alone cannot be used to distinguish between benign and malignant bone diseases. Therefore, combined judgments with CT signs in PET/CT are crucial for diagnosis. Any degree of uptake of 18 F-NaF, as long as it is significantly higher or lower than the adjacent bone tissue or the corresponding bone tissue of the contralateral side, suggests abnormal bone metabolism.

Infection
The most common infectious bone diseases examined by nuclear medicine include osteomyelitis and surgical site infection. Most osteomyelitis cases have typical clinical and imaging findings. However, the pathogenesis and development of osteomyelitis can be affected by numerous factors, including the widespread application of antibiotics and changes in bacterial virulence. Osteomyelitis cases presenting atypical clinical and radiological manifestations have gradually increased, making its imaging diagnosis and differential diagnosis more difficult. He most commonly used nuclear medicine test for the detection of osteomyelitis is three-phase imaging of bone scintigraphy, which includes blood flow, blood pool and delayed imaging. The blood flow phase is obtained immediately after the injection of the radioactive tracer ( 99m Tc-MDP) for 1 minute followed by obtaining the blood pool image, and the delayed image is performed after 2-4 hours [14]. Given the similar pharmacological behaviors of 18 F-NaF and 99mTc-MDP and the rapid plasma clearance of 18 F, the same information revealed by perfusion and blood pool phase in 99mTc-MDP three-phase bone scan can be obtained within 10 minutes after 18F injection. Freesmeyer et al. [15] analyzed the relationship between early radioactive tracer distribution and chronic osteomyelitis in response to this characteristic of 18 F-NaF. They collected 4 images in 1 frame/15 s and 4 images in 1 frame/60 s, separately, for 5 minutes for 11 patients and then plotted the ROI to obtain the SUVmax and SUVmean values. The maximal value (edSUVmax) and average value (edSUVmean) of early dynamic SUV (ed-SUV) were acquired 31 to 45 seconds after the imaging agent injection. The difference between the lesion area and the contralateral normal area was statistically significant (P<0.05), indicating that the quantitative analysis of the early phase of dynamic bone imaging had important value for the diagnosis of chronic osteomyelitis. Studies have demonstrated that 18 F-NaF PET/CT with early scanning features can replace three-phase bone scans [15,16].
The surgical site infection often occurs after joint replacement surgery. Artificial joint replacement surgery as an orthopaedic surgery involves the use of engineering methods to simulate human joints, the X-ray examination without hip gap clearance. Fischer et al. [25] performed 18 F-NaF PET/CT to evaluate 28 patients with foot pain, and most of these patients underwent routine CT or MRI but did not have a definitive diagnosis. The results revealed that 18 F-NaF PET/ CT identified abnormalities, such as osteoarthritis, painful accessory bone, or inflammatory lesions. The treatment management of the abovementioned 46% of patients has changed, reflecting the important value of 18 F-NaF PET/CT in clinical treatment management.
Ankylosing spondylitis (AS) is a disease characterized by inflammation of sacroiliac joints and spinal attachment points and is strongly associated with HLA-b. The main symptom of this disease is inflammatory backache. Although MRI is considered the preferred imaging method to diagnose early inflammation in AS [26,27], it only exhibits high specificity in the inflammatory phase, and many patients' diagnoses were delayed for greater than seven years due to some practical application limitations [28]. Given that 18 F-NaF PET/CT can detect the anabolic repair process of new bone formation, it not only reveals a high uptake of the lesion during the inflammatory phase but also inflammatory repair phase. Fischer et al. [29] studied 10 patients with active AS and evaluated the difference between 18 F-NaF PET/CT and MRI in diagnosing sacroiliac joint and spinal cord edema using a double-blind method. The results revealed that 18 F-NaF PET/CT can provide patients with additional MRI evaluation information. For example, when spinal cord edema is mild, bone metabolism in adjacent vertebral bodies can be abnormal.

Trauma
At present, conventional radiography is the preferred imaging method for the detection of fractures, especially limb fractures. Because of the rapidity and wide availability of CT imaging, occult fractures that involve complex joint fractures or are not visible on standard radiographs are typically imaged with CT [30]. However, if the result of the trauma is only slight fracture of the cortex or trabecular bone, it is difficult to make a diagnosis using traditional x-ray and CT [31]. Early diagnosis of occult fractures is very important for clinical management because delayed treatment can lead to serious complications, such as osteonecrosis, non-union, and impaired function [32]. Studies have demonstrated that MRI is a very sensitive imaging technique for describing the trabecular bone and its surrounding lesions [33], and MRI has a high diagnostic value for stress fractures and avulsion fractures, especially occult fractures [34]. Although MRI has a good ability to discriminate between cortical fractures and bone marrow edema, the examination site is limited, and occult fractures without obvious symptoms may be neglected. Numerous contraindications are noted, such as pacemakers and other metal devices. 99m Tc-MDP bone imaging is a specific functional and molecular imaging with high sensitivity, and 18 F-NaF PET/CT can detect more lesions compared with conventional radionuclide imaging. Bone damage is common in abused children, but infants have high bone organic matter and high plasticity. Conventional X-ray and CT may not be able to detect signs of fracture. Therefore, it may be challenging to quickly determine the full range of injury during initial assessment [35,36]. Laura et al. [37] performed 18 F-NaF PET/CT and bone examination on 22 abused children under 2 years of age to assess their bone damage. PET identified a total of 200 fractures, whereas bone examination only identified 156 fractures. Among them, the sensitivity of PET for rib fractures is the highest compared with bone examination. These results indicate that 18 F-NaF PET/CT can be used as a global bone assessment technique for children of abuse older than 1 year of age.

Bone grafts
In various bone tumors of the limbs, allograft bone grafts are used to replace the resected bone to maintain stability and functional integrity. These grafts include cancellous bone transplantation and total bone transplantation, and bone transplantation is prone to infection, non-healing and other complications. Imaging methods, such as X-ray, CT, MRI, or bone scintigraphy, are not standardized in assessing bone grafts, making imaging assessment of bone graft controversial [38]. Winfried Brenner et al. [39] performed an 18 F-NaF PET/CT quantitative assessment of the postoperative healing time of limb allograft bone grafts. They performed a total of 52 18 F-NaF PET/ CT scans in 34 cases of cancellous bone and total bone grafts. The results revealed that the bone metabolism of cancellous bone grafts decreased by 25% between 6 and 12 months postoperatively and that SUV, KPat, and KNLR total decreased by 60-65% after two years. Total bone transplantation exhibited a 20% increase in fluoride metabolism during the first 6-12 months and decreased to 70% of the initial activity after two years. 18 F-NaF PET/CT is a promising tool to evaluate bone metabolism and normal healing of limb bone grafts. Gösta Ullmark et al. [40] used 18 F-NaF PET/CT to analyze the healing of small allograft bone grafts in 7 patients undergoing acetabular bone graft. SUV was increased by 77%, 91%, and 20% compared with the contralateral one-week, four-months and 12-months postoperatively, respectively, confirming that 18 F-NaF PET/CT is a sensitive and effective imaging technology to monitor the survival condition of implanted bone. 18 F-NaF PET/CT is the most sensitive imaging modality for the detection of malignant bone lesions [41] however; its evaluation of benign bone tumors is limited. Benign bone tumors and osteomatoid lesions are relatively common bone diseases. Benign tumor of bone includes osteogenic and chondrogenic tumors, whereas osteomatoid diseases include tendon sheath cyst, eosinophilic granulation swelling, and bone infarction. Traditional imaging examinations deduce benign and malignant tumors through morphological features, but no imaging studies are available that can confirm the diagnosis of benign bone tumors and osteomatoid lesions. These diseases still need to be excluded through the pathological examination of malignant diseases. Studies have demonstrated that 18 F-NaF bone scans exhibit increased diagnostic sensitivity and accuracy compared with 99mTc-MDP bone scans in evaluating benign and malignant lesions in bones, although many comparisons are performed with planar single photon acquisitions [42][43][44]. 18 F-NaF PET/CT is of great value in diagnosing atypical osteoid osteoma and osteomatoid lesions, such as bone infarcts.

Benign tumor and osteomatoid lesions
Osteoid osteoma is a common benign osteogenic bone tumor with unknown etiology and high incidence in young men. In 35% of cases, the precise location of osteoid osteoma may be difficult to detect because it is easily hidden by edema in the surrounding tissue. In 50% of cases, osteoid osteoma has atypical imaging findings, which may lead to misdiagnosis [45]. More difficulties are encounter when locating the tumor nest of osteoid osteoma using conventional X-ray and CT examinations. In contrast, 18 F-NaF PET/CT bone imaging with molecular imaging technology can clearly demonstrate high imaging agent uptake with the highest SUV value noted in the tumor nest, and this information in combination with anatomical effects can accurately locate the tumor nest [46]. or hardened edges at borders and is often located at the backbone and metaphysis. Infarction can be mistaken for chondroid tumors (such as enchondroma, etc.). Cystic bone infarction involves the formation of cystic changes in the segment of the long bone or the flat stem, and its imaging findings can be similar to intraosseous lipomas or chondrosarcoma. It is often difficult to make a clear early diagnosis of the disease using X-ray and CT examinations; thus, this condition is easily missed and misdiagnosed. MRI exhibits increased sensitivity and specificity, typically exhibiting a map-like change in the edge of the lesion. Due to the lack of blood supply, the lesion imaging agent exhibits no or low radionuclide uptake, and reports of 18 F-NaF PET/ CT-based diagnosis of this disease are rare given that only one case has been reported [47].

Metabolic bone disease
Metabolic bone disease refers to bone disease caused by congenital or acquired factors that destroy or interfere with normal bone metabolism and biochemical state, resulting in bone biochemical metabolic disorders. Its pathogenesis includes abnormalities in bone resorption, bone growth and mineral deposition. Imaging features, such as X-ray or CT, of metabolic bone disease represent abnormal bone mineral density, which may be due to increased bone production, increased reabsorption, and abnormal mineralization. Morand Piert et al. [48] used 18 F-NaF PET/CT to measure the local bone blood flow in healthy pigs and performed correlation analysis with static and dynamic indicators of bone metabolism. The results showed that 18 F can quantitatively evaluate bone tissue blood flow and metabolic activity in healthy pigs and concluded that 18 F-NaF PET/CT are beneficial for the follow-up of patients with metabolic bone disease.
Renal osteodystrophy is a condition characterized by decreased bone formation and/or impaired mineralization.
Clinicians recommend that patients with renal osteodystrophy undergo a bone metabolic activity measurement at least once a year to monitor the level of bone metabolism in kidney osteodystrophy and evaluate the efficacy [49]. Cristina and his colleagues performed 18 F-NaF PET in 11 patients with renal osteodystrophy to evaluate bone metabolic activity, and 11 healthy adults were used as controls. The results showed that 18 F-NaF PET/CT quantifies metabolic bone activity in patients with renal osteodystrophy and distinguish the specific form of the disease [49].
Paget disease of the bone is a chronic osteoma similar to degeneration that can cause bone swelling, deformity, and weakened strength, which subsequently cause bone pain, arthritis, deformities, and fractures. Its pathological features include accelerated bone turnover involving bone resorption and formation. At present, bisphosphate has been used in the treatment of Paget's disease and clinicians often evaluate the therapeutic effect by measuring blood or urine markers of bone resorption or formation, such as alkaline phosphatase. Installe J et al. [50] studied the therapeutic effect of bisphosphonates in 14 patients with Paget's disease using 18F-NaF PET/CT. The 18F uptake of diseased bone was significantly increased compared normal bone, and the 18F uptake of patients after 1~6 months of treatment with bisphosphonates was significantly reduced, demonstrating that 18 F-NaF PET/ CT can be used to non-invasively and accurately detect the therapeutic effect of bisphosphonates on Paget disease. Cook GJ et al. [51] used a dynamic 18 F-NaF PET/CT technique to quantify bone metabolic markers in 7 patients with Paget's disease of the spine. The dynamic 18 F-NaF PET/ CT technique exhibits value in the determination of regional metabolic parameters of focal bone disease. Chakraborty et al. [52] reported a case of a 65-year-old male patient with bladder transitional cell carcinoma with Paget's disease. 99mTc-MDP bone scan revealed only strong skull uptake, whereas 18 F-NaF PET/CT revealed that the right superior pubic ramus and left ilium near sacroiliac joint also showed high uptake in addition to the skull, suggesting suspicious metastatic lesions.
Osteoporosis is a common systemic metabolic bone disease characterized by decreased bone mass per unit volume and altered bone microarchitecture, and this condition more commonly occurs in postmenopausal women and older men [53]. A serious consequence of osteoporosis is the occurrence of osteoporotic fractures, which are fractures that can occur during mild trauma or daily activities. 18 F-NaF PET/CT is a convenient and non-invasive technique for studying bone formation in important osteoporotic fractures, such as the spine and pure cortical bone or trabecular bone. The diagnosis of traditional osteoporosis relies on bone biopsy and biochemical markers of blood or urine [54]. 18 F-NaF PET/CT can be used as a complementary technique for routine bone turnover measurement and a monitoring tool to evaluate the efficacy of treatment in clinical trials. Siddikque and colleagues studied 20 women who used diphosphate and 18 women who used tripeptide to treat postmenopausal osteoporosis. 18 F-NaF PET/CT could be used to simply diagnose diseases, analyze the curative effect and prognosis, and assist in the development of new drugs [55].

Conclusion
Radionuclide bone scans are widely used in clinic because of their high sensitivity and early detection of bone tumors from a metabolic perspective. At present, 18 F-NaF PET/CT exhibits great potential value in the diagnosis of benign bone disease and evaluation of treatment effects. 18 F-NaF PET/CT has a good diagnostic effect on common bone infectious diseases, such as osteomyelitis and surgical site infections, due to dynamic bone imaging early quantitative analysis technology, and it has the potential characteristics to replace the three-phase bone scan. When used in combination with information regarding clinical manifestations and specific laboratory tests, 18 F-NaF PET/ CT can accurately locate complex anatomic sites and provide high fluorine uptake information during the inflammatory phase and the inflammatory repair phase of arthritis. This imaging modality is of great value in diagnosing traumatic injuries, especially occult fractures, with only a slight fracture of the cortical bone or trabecular bone, providing accurate information for the assessment of the extent of injury in abused children. 18 F-NaF PET/CT is also a sensitive and effective imaging technology that can monitor the survival of bone grafts. Bone benign tumors and osteomatoid lesions can be differentiated from malignant bone tumors by measuring SUV values or delaying imaging. 18 F-NaF PET/CT can be used as a supplementary technique for routine bone turnover measurement and is beneficial in the follow-up of patients with metabolic bone diseases. Although 18 F-NaF PET/CT has been widely used in the diagnosis and monitoring of various benign bone diseases, numerous benign bone diseases still lack experimental data, and the studies described in this paper used small samples. In the future, further comparative studies of larger patient groups are needed. In addition to benign bone disease described above, 18 F-NaF PET/CT technology may have the potential for further research in monitoring the early efficacy of new drugs, myositis ossificans, joint disorders syndrome, and evaluating unexplained bone pain. 18 F-NaF has the potential to become a gold standard for the imaging of bone function. The normal bone uptake of 18F-NaF was more than twice that of 99m Tc-MDP, and the relative uptake of 18 F-NaF was higher when the bone turnover was increased, and 18 F-NaF was more rapidly cleared from the blood pool. Within 20 minutes of the injection, the peak of radiopharmaceutical imaging is reached and a clear contrast between bone and background is formed. Therefore, compared with conventional SPECT/CT, 18 F-NaF PET/CT images have a higher target/primary ratio, and can detect lesions with a slight increase in bone turnover that cannot be detected by the former. However, there are some undeniable limitations to this technology. For example, due to the degenerative changes in the bones of the elderly, there are often concentrated areas after imaging, which brings certain difficulties for differential diagnosis. The radiation exposure of 18F-NaF is approximately 70% higher than that of 99m Tc-MDP, which may be a practical obstacle to its wider clinical application. Therefore, the development of more sensitive PET systems for solving radiation exposure problems is worth further investigation. Moreover, the current high cost of 18 F-NaF PET/CT examination is one of the main reasons for limiting its use in benign skeletal diseases. The actual clinical application in China is limited, and it is only limited to general hospitals with PET/CT technology and 18F-NaF cyclotrons, while it is relatively widely used in Europe and the United States. Despite these limitations, this technology with great potential still has important research significance.