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Novel Musculoskeletal and Orthopedic Applications of 18F-Sodium Fluoride PET

Open AccessPublished:February 12, 2021DOI:https://doi.org/10.1016/j.cpet.2020.12.006

      Keywords

      Key points

      • 18F-sodium fluoride (NaF) PET can detect causes of bone pain and traumatic injuries that cannot be successfully visualized by other modalities such as radiography, bone scintigraphy, computed tomography, and magnetic resonance. Thus, NaF-PET may contribute to the assessment of occult fractures, child abuse, and stress-related injuries.
      • NaF-PET is an excellent modality to assess osteoarthritis, ankylosing spondylitis, and temporomandibular joint dysfunction. More studies are needed to determine its potential role in inflammatory arthropathies such as rheumatoid arthritis and psoriatic arthritis.
      • Complications of orthopedic surgery such as hardware loosening and infection are readily visualized by NaF-PET. Heterotopic ossification after surgery is another possible imaging target that requires further exploration.
      • Metabolic bone diseases such as osteoporosis and Paget disease can be evaluated over time with NaF-PET to determine effects of pharmacologic interventions such as bisphosphonates and teriparatide.
      • NaF-PET may have a role in assessing primary bone tumors such as osteosarcoma, helping to determine response to treatment and guiding patient management decisions.

      Introduction

      The bone-seeking properties of 18F-sodium fluoride (NaF) were first described in 1962 by Blau and colleagues,
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      Fluorine-18: a new isotope for bone scanning.
      who used this positron-emitting radiotracer in skeletal scintigraphy. Both high uptake by bone and rapid plasma clearance of NaF were determined to be advantages in imaging skeletal metabolism.
      • Blau M.
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      • Bender M.A.
      18 F-fluoride for bone imaging.
      The mechanism of NaF uptake relies on the exchange of OH for 18F, converting hydroxyapatite on the surface of the bone matrix to fluorapatite.
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      18 F-fluoride for bone imaging.
      ,
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      Evolving role of molecular imaging with (18)F-sodium fluoride PET as a biomarker for calcium metabolism.
      One hour after NaF is administered intravenously, only 10% remains in the plasma compartment because of a first-pass extraction rate of 100%, allowing excellent contrast resolution.
      • Beheshti M.
      (18)F-Sodium Fluoride PET/CT and PET/MR imaging of bone and joint disorders.
      However, the use of NaF was largely abandoned after the introduction of phosphate-based tracers labeled with 99mTc.
      • Beheshti M.
      (18)F-Sodium Fluoride PET/CT and PET/MR imaging of bone and joint disorders.
      The first of these was 99mTc-polyphosphate, which was described in 1971,
      • Subramanian G.
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      A new complex of 99mTc for skeletal imaging.
      followed by 99mTc-methylene diphosphonate in 1975.
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      Technetium-99m-methylene diphosphonate--a superior agent for skeletal imaging: comparison with other technetium complexes.
      Compared with NaF, bone scintigraphy (BS) with 99mTc-labeled agents had the advantage of a longer half-life (6.0 hours vs 110 minutes) and photons with lower energy (140-keV vs 511-keV), allowing easier detection by conventional gamma cameras.
      • Beheshti M.
      (18)F-Sodium Fluoride PET/CT and PET/MR imaging of bone and joint disorders.
      ,

      Blake GM, Fogelman I. Bone radionuclide imaging, quantitation and bone densitometry. In: McCready R, Gnanasegaran G, Bomanji JB, editors. A history of radionuclide studies in the UK: 50th Anniversary of the British Nuclear Medicine Society; Springer. Cham (CH): 2016. p. 111–20.

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      Skeletal PET with 18F-fluoride: applying new technology to an old tracer.
      Over the next 4 decades, developments in PET scanners allowed the detection of high-energy photons, resulting in the widespread adoption of many 18F-based tracers.
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      • Gholami S.
      • et al.
      Evolving role of molecular imaging with (18)F-sodium fluoride PET as a biomarker for calcium metabolism.
      ,
      • Beheshti M.
      (18)F-Sodium Fluoride PET/CT and PET/MR imaging of bone and joint disorders.
      As PET imaging with 2-deoxy-2-[18F]fluoro-d-glucose (FDG) continues to expand, increased efficiency in the production and delivery of 18F-labeled tracers has resulted in greater NaF availability.
      • Grant F.D.
      • Fahey F.H.
      • Packard A.B.
      • et al.
      Skeletal PET with 18F-fluoride: applying new technology to an old tracer.
      Several properties of NaF, such as lower protein binding and higher plasma clearance, justify its superiority to 99mTc-labeled tracers.
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      • Bhargava P.
      • Behnia F.
      • et al.
      Newer PET application with an old tracer: role of 18F-NaF skeletal PET/CT in oncologic practice.
      In addition, the increased spatial resolution of PET compared with gamma cameras presents a significant advantage.

      Blake GM, Fogelman I. Bone radionuclide imaging, quantitation and bone densitometry. In: McCready R, Gnanasegaran G, Bomanji JB, editors. A history of radionuclide studies in the UK: 50th Anniversary of the British Nuclear Medicine Society; Springer. Cham (CH): 2016. p. 111–20.

      Consequently, the promise of high-resolution skeletal imaging has sparked a growing interest in assessing musculoskeletal disorders by NaF-PET.
      Quantitative PET parameters used to measure new bone formation include bone plasma clearance expressed as Ki and bone uptake expressed as a standardized uptake value (SUV).
      • Austin A.G.
      • Raynor W.Y.
      • Reilly C.C.
      • et al.
      Evolving role of MR imaging and PET in assessing osteoporosis.
      Calculation of plasma clearance is based on rate constants that describe the movement of NaF between plasma, bone extracellular fluid, and bone mineral compartments. To obtain these data, the Hawkins method represents the standard protocol, requiring 60-minute dynamic imaging and arterial or venous sampling and only allowing the assessment of a single skeletal site at a time.
      • Blake G.M.
      • Puri T.
      • Siddique M.
      • et al.
      Site specific measurements of bone formation using [(18)F] sodium fluoride PET/CT.
      More recently, simplified methods of estimating Ki have been developed, such as that proposed by Siddique and colleagues,
      • Siddique M.
      • Blake G.M.
      • Frost M.L.
      • et al.
      Estimation of regional bone metabolism from whole-body 18F-fluoride PET static images.
      which nonetheless requires 4 venous blood samples taken at 10-minute intervals starting 30 minutes after tracer administration. Alternatively, NaF uptake can be measured throughout the skeleton with a single static scan and no need for blood sampling. SUV represents the detected activity concentration in an area, normalized to the administered activity and the patient’s body weight or lean body mass.
      • Austin A.G.
      • Raynor W.Y.
      • Reilly C.C.
      • et al.
      Evolving role of MR imaging and PET in assessing osteoporosis.
      A major focus of NaF-PET imaging has been the assessment of skeletal metastases from prostate and breast cancer.
      • Bastawrous S.
      • Bhargava P.
      • Behnia F.
      • et al.
      Newer PET application with an old tracer: role of 18F-NaF skeletal PET/CT in oncologic practice.
      Although NaF-PET represents a sensitive method of detecting osteoblastic changes, other PET tracers are available that are more appropriate in this domain. Because bone metastases start with seeding of the red marrow by malignant cells, PET imaging with FDG, 18F-fluciclovine (FACBC), radiolabeled choline, or prostate-specific membrane antigen ligands constitutes a more direct approach and has the advantage of detecting intramedullary lesions that have not resulted in reactive bone remodeling.
      • Walker S.M.
      • Lim I.
      • Lindenberg L.
      • et al.
      Positron emission tomography (PET) radiotracers for prostate cancer imaging.
      ,
      • Aydin A.
      • Yu J.Q.
      • Zhuang H.
      • et al.
      Detection of bone marrow metastases by FDG-PET and missed by bone scintigraphy in widespread melanoma.
      By contrast, indirect evidence of metastasis provided by bone imaging modalities is not appropriate for detecting cancer cell activity, unless malignant cells themselves express osteoblastic activity, as in osteosarcoma.
      • Raynor W.Y.
      • Al-Zaghal A.
      • Zadeh M.Z.
      • et al.
      Metastatic seeding attacks bone marrow, not bone: rectifying ongoing misconceptions.
      Rather, NaF-PET, combined with computed tomography (CT) or magnetic resonance (MR) for anatomic correlation, has a promising role in the imaging of benign musculoskeletal disorders that cause direct changes in osteoblastic activity. This article discusses the novel applications and utility of NaF in the assessment of musculoskeletal trauma, arthropathies, back pain, orthopedic complications, metabolic bone disease, and other osseous and soft tissue disorders.

      Musculoskeletal trauma

      The first-line imaging modality to assess for traumatic fracture is conventional radiography, and CT can be used to detect and characterize occult and complex fractures with high sensitivity.
      • Jarraya M.
      • Hayashi D.
      • Roemer F.W.
      • et al.
      Radiographically occult and subtle fractures: a pictorial review.
      Recent investigations have suggested the superiority of NaF-PET/CT to conventional modalities in the detection of pathologic fractures, fatigue fractures, and occult fractures.
      • Usmani S.
      • Marafi F.
      • Al Kandari F.
      • et al.
      Adductor insertion avulsion syndrome with stress fracture in morbidly obese patient diagnosed on (18)f-sodium fluoride positron emission tomography-computed tomography.
      • Seifert P.
      • Konig V.
      • Hofmann G.O.
      • et al.
      Devitalized bone in a multi-fragment femoral shaft fracture detected by (18)F-NaF PET-CT.
      • Dua S.G.
      • Purandare N.C.
      • Shah S.
      • et al.
      F-18 fluoride PET/CT in the detection of radiation-induced pelvic insufficiency fractures.
      • Drubach L.A.
      • Johnston P.R.
      • Newton A.W.
      • et al.
      Skeletal trauma in child abuse: detection with 18F-NaF PET.
      • Hsu W.K.
      • Feeley B.T.
      • Krenek L.
      • et al.
      The use of 18F-fluoride and 18F-FDG PET scans to assess fracture healing in a rat femur model.
      Jeon and colleagues
      • Jeon T.J.
      • Kim S.
      • Park J.
      • et al.
      Use of (18)F-sodium fluoride bone PET for disability evaluation in ankle trauma: a pilot study.
      retrospectively analyzed NaF-PET/CT images obtained a median of 290 days after ankle injury in a study that included 95 patients with fracture, 12 with Achilles tendon rupture, 12 with ligament injury, and 2 with complex regional pain syndrome. All patients with fractures were found to have NaF-avid lesions, and only 8 in the nonfracture group had negative NaF-PET/CT findings. Further, various PET parameters, including maximum SUV (SUVmax), mean SUV (SUVmean), metabolic target volume (MTV), and total lesion activity (TLA = SUVmean × MTV) were all inversely correlated with ankle range of motion. The feasibility of imaging stress fractures with NaF-PET/MR was investigated in 20 patients with foot pain by Crönlein and colleagues.
      • Cronlein M.
      • Rauscher I.
      • Beer A.J.
      • et al.
      Visualization of stress fractures of the foot using PET-MRI: a feasibility study.
      Despite negative findings on radiography, 4 stress fractures and 7 stress reactions involving the foot and ankle were identified by PET/MR. A comparative study between PET/CT and PET/MR by the same group found that both hybrid modalities identified the same 42 lesions across 22 subjects with foot pain of unclear cause.
      • Rauscher I.
      • Beer A.J.
      • Schaeffeler C.
      • et al.
      Evaluation of 18F-fluoride PET/MR and PET/CT in patients with foot pain of unclear cause.
      They reported that NaF uptake expressed as SUVmax and SUVmean was highly correlated between PET/CT and PET/MR. Although PET/CT was noted as being superior for the diagnosis of osteoarthritis, the ability to assess bone marrow resulted in PET/MR being favored in the diagnosis of stress fractures and bone marrow edema. Spriet and colleagues
      • Spriet M.
      • Espinosa-Mur P.
      • Cissell D.D.
      • et al.
      (18) F-sodium fluoride positron emission tomography of the racing Thoroughbred fetlock: validation and comparison with other imaging modalities in nine horses.
      reported a study of 9 racehorses, in which NaF-PET/CT imaging was performed on 16 forelimbs and 4 hindlimbs. The investigators found that NaF-PET/CT detected lesions that were not present on BS, CT, or MR, and they concluded that early detection of stress injuries by PET could play a role in preventing catastrophic fractures in horseracing.
      Indications for NaF-PET/CT in children and young adults have primarily been for benign disorders.
      • Grant F.D.
      (1)(8)F-fluoride PET and PET/CT in children and young adults.
      The bones of the thorax and extremities have been observed to have increased NaF avidity in cases of fracture and stress injury.
      • Drubach L.A.
      • Johnston P.R.
      • Newton A.W.
      • et al.
      Skeletal trauma in child abuse: detection with 18F-NaF PET.
      As with BS, NaF uptake may be present at the pubic synchondrosis as part of normal development.
      • Hardoff R.
      • Gips S.
      Ischiopubic synchondrosis. Normal finding, increased pubic uptake on bone scintigraphy.
      ,
      • Cawley K.A.
      • Dvorak A.D.
      • Wilmot M.D.
      Normal anatomic variant: scintigraphy of the ischiopubic synchondrosis.
      One application of NaF-PET/CT that has been proposed is in the evaluation of child abuse. In a study of 22 pediatric patients with suspicion of having been abused, Drubach and colleagues
      • Drubach L.A.
      • Johnston P.R.
      • Newton A.W.
      • et al.
      Skeletal trauma in child abuse: detection with 18F-NaF PET.
      found that although high-detail skeletal survey detected 156 fractures, imaging with NaF-PET detected 200 fractures (Fig. 1). The investigators calculated the sensitivities of NaF-PET and skeletal survey by comparing baseline imaging studies with follow-up skeletal survey imaging performed 10 to 24 days later. The results suggested that NaF-PET was superior to baseline skeletal survey in detecting fractures involving bones of the thorax, such as the ribs, sternum, scapulae, and clavicles, with a sensitivity of 92%. The sensitivity of NaF-PET in detecting posterior rib fractures was determined to be 93%. At the same time, NaF-PET was found to be inferior in the detection of classic metaphyseal fractures, with a sensitivity of 67%, whereas skeletal survey had a sensitivity of 80%. Overall for all lesions, NaF-PET was found to have a sensitivity of 85%, whereas skeletal survey had a sensitivity of 72%, and the investigators concluded that, in addition to initial radiographic evaluation to assess for metaphyseal fractures, further imaging with NaF-PET may warrant consideration in order to uncover injuries that would otherwise not be evident until follow-up imaging.
      Figure thumbnail gr1
      Fig. 1Maximum intensity projection NaF-PET in a 2-month-old boy. Multiple posterior rib fractures (arrows) and left lateral anterior rib fractures (arrowheads) are visualized bilaterally.
      (From Drubach LA, Johnston PR, Newton AW, Perez-Rossello JM, Grant FD, Kleinman PK. Skeletal trauma in child abuse: detection with 18F-NaF PET. Radiology. 2010;255(1):173-181; with permission.)
      In general, the preliminary investigations into the assessment of traumatic injury by NaF-PET/CT and NaF-PET/MR show great promise. To gain a better understanding of how this technology can best be used in a variety of clinical scenarios, larger prospective trials are urgently needed.

      Arthropathies

      NaF has shown success in visualizing changes associated with joint degeneration such as in osteoarthritis (OA) and temporomandibular disorder (TMD).
      • Khaw T.H.
      • Raynor W.Y.
      • Borja A.J.
      • et al.
      Assessing the effects of body weight on subchondral bone formation with quantitative (18)F-sodium fluoride PET.
      • Tibrewala R.
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      [(18) F]-Sodium fluoride PET/MR imaging for bone-cartilage interactions in hip osteoarthritis: a feasibility study.
      • Suh M.S.
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      • Kim Y.K.
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      (18)F-NaF PET/CT for the evaluation of temporomandibular joint disorder.
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      Applications of PET imaging in the evaluation of musculoskeletal diseases among the geriatric population.
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      PET/MRI of metabolic activity in osteoarthritis: a feasibility study.
      • Savic D.
      • Pedoia V.
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      Imaging bone-cartilage interactions in osteoarthritis using [(18)F]-NaF PET-MRI.
      • Kobayashi N.
      • Inaba Y.
      • Yukizawa Y.
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      Use of 18F-fluoride positron emission tomography as a predictor of the hip osteoarthritis progression.
      • Hirata Y.
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      • Kobayashi N.
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      Correlation between mechanical stress by finite element analysis and 18F-fluoride PET uptake in hip osteoarthritis patients.
      • Lee J.W.
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      • Kim S.J.
      • et al.
      Clinical utility of fluoride-18 positron emission tomography/CT in temporomandibular disorder with osteoarthritis: comparisons with 99mTc-MDP bone scan.
      • Temmerman O.P.
      • Raijmakers P.G.
      • Kloet R.
      • et al.
      In vivo measurements of blood flow and bone metabolism in osteoarthritis.
      Both FDG and NaF activities at the knee were assessed in 97 subjects in a study by Al-Zaghal and colleagues,
      • Al-Zaghal A.
      • Yellanki D.P.
      • Ayubcha C.
      • et al.
      CT-based tissue segmentation to assess knee joint inflammation and reactive bone formation assessed by (18)F-FDG and (18)F-NaF PET/CT: effects of age and BMI.
      who found uptake of both tracers was correlated with body mass index. Studies from the same group have similarly found associations between body mass index and NaF uptake at the sacroiliac and hip joints, which are often involved in OA.
      • Al-Zaghal A.
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      • Kothekar E.
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      Sacroiliac joint asymmetry regarding inflammation and bone turnover: assessment by FDG and NaF PET/CT.
      ,
      • Yellanki D.P.
      • Kothekar E.
      • Al-Zaghal A.
      • et al.
      Efficacy of (18)F-FDG and (18)F-NaF PET/CT imaging: a novel semi-quantitative assessment of the effects of age and obesity on hip joint inflammation and bone degeneration.
      A retrospective study in 34 subjects by Khaw and colleagues
      • Khaw T.H.
      • Raynor W.Y.
      • Borja A.J.
      • et al.
      Assessing the effects of body weight on subchondral bone formation with quantitative (18)F-sodium fluoride PET.
      showed increased NaF uptake measured at the joints of the elbows, hands, knees, and feet with higher subject body weight, which is a major factor in degenerative joint disease. The interaction between cartilage and bone at the knee in patients with early signs of OA has been successfully imaged by NaF-PET/MR, and an association between NaF activity and pain was described in cases without morphologic abnormalities.
      • Savic D.
      • Pedoia V.
      • Seo Y.
      • et al.
      Imaging bone-cartilage interactions in osteoarthritis using [(18)F]-NaF PET-MRI.
      This finding suggests that NaF activity can explain underlying pathophysiology before changes are evident on conventional modalities, a notion that is supported by a study that found, in 172 NaF-avid lesions associated with knee pain or injury, that 63 appeared normal on MR.
      • Kogan F.
      • Fan A.P.
      • McWalter E.J.
      • et al.
      PET/MRI of metabolic activity in osteoarthritis: a feasibility study.
      In addition to the potential for early diagnosis, the predictive power of NaF-PET was shown in a study of 57 hip joints by Kobayashi and colleagues,
      • Kobayashi N.
      • Inaba Y.
      • Yukizawa Y.
      • et al.
      Use of 18F-fluoride positron emission tomography as a predictor of the hip osteoarthritis progression.
      who showed that SUVmax predicted pain worsening and minimum joint space narrowing. Regarding the assessment of TMD, NaF-PET/CT seems feasible in diagnosis and determining the response to treatment.
      • Suh M.S.
      • Park S.H.
      • Kim Y.K.
      • et al.
      (18)F-NaF PET/CT for the evaluation of temporomandibular joint disorder.
      ,
      • Lee J.W.
      • Lee S.M.
      • Kim S.J.
      • et al.
      Clinical utility of fluoride-18 positron emission tomography/CT in temporomandibular disorder with osteoarthritis: comparisons with 99mTc-MDP bone scan.
      Conventional BS is commonly used in joint diseases such as rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA). In a meta-analysis of 25 studies, the sensitivity of BS in detecting AS in 361 patients was 51.8%, with a sensitivity of 49.4% for detecting sacroiliitis in 255 patients.
      • Song I.H.
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      • Rudwaleit M.
      • et al.
      The diagnostic value of scintigraphy in assessing sacroiliitis in ankylosing spondylitis: a systematic literature research.
      In contrast, the higher sensitivity of MR has resulted in its replacement of BS as the first-line modality for spondyloarthropathies at some institutions.
      • Beheshti M.
      (18)F-Sodium Fluoride PET/CT and PET/MR imaging of bone and joint disorders.
      A major limitation of MR is the limited field of view obtained by whole-body MR, which often does not include distal extremities. As investigators continue to assess its validity, NaF-PET/CT may represent a useful modality in assessing various inflammatory joint diseases.
      Although visualization of inflammation with FDG is suitable for imaging RA and PsA,
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      • Kaneko H.
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      Fluorodeoxyglucose PET/CT of arthritis in rheumatic diseases: a pictorial review.
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      Comparison of methods of quantifying global synovial metabolic activity with FDG-PET/CT in rheumatoid arthritis.
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      • et al.
      (18)F- FDG PET/CT joint assessment of early therapeutic response in rheumatoid arthritis patients treated with rituximab.
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      Diagnostic value of 18F-fluorodeoxyglucose uptake parameters to differentiate rheumatoid arthritis from other types of arthritis.
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      • et al.
      F-18 FDG uptake in a patient with psoriatic arthritis: imaging correlation with patient symptoms.
      several studies have reported the utility of NaF in imaging AS.
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      PET/MR imaging in musculoskeletal precision imaging - third wave after X-ray and MR.
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      • Choi Y.Y.
      • et al.
      Predictive value of semi-quantitative index from F-18-fluoride PET/CT for treatment response in patients with ankylosing spondylitis.
      • Kim K.
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      • Goh T.S.
      • et al.
      Prediction of response to tumor necrosis value-alpha blocker is suggested by (18)F-NaF SUVmax but not by quantitative pharmacokinetic analysis in patients with ankylosing spondylitis.
      • Son S.M.
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      Evaluation of the diagnostic performance of (18)F-NaF positron emission tomography/computed tomography in patients with suspected ankylosing spondylitis according to the Assessment of SpondyloArthritis International Society criteria.
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      Dual-phase hybrid (18) F-Fluoride Positron emission tomography/MRI in ankylosing spondylitis: investigating the link between MRI bone changes, regional hyperaemia and increased osteoblastic activity.
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      Baseline increased 18F-fluoride uptake lesions at vertebral corners on positron emission tomography predict new syndesmophyte development in ankylosing spondylitis: a 2-year longitudinal study.
      • Idolazzi L.
      • Salgarello M.
      • Gatti D.
      • et al.
      18F-fluoride PET/CT for detection of axial involvement in ankylosing spondylitis: correlation with disease activity.
      • Buchbender C.
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      • Ruhlmann V.
      • et al.
      Hybrid 18F-labeled Fluoride Positron Emission Tomography/Magnetic Resonance (MR) imaging of the sacroiliac joints and the spine in patients with axial spondyloarthritis: a pilot study exploring the link of MR bone pathologies and increased osteoblastic activity.
      • Lee S.G.
      • Kim I.J.
      • Kim K.Y.
      • et al.
      Assessment of bone synthetic activity in inflammatory lesions and syndesmophytes in patients with ankylosing spondylitis: the potential role of 18F-fluoride positron emission tomography-magnetic resonance imaging.
      • Bruijnen S.T.
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      Bone formation rather than inflammation reflects ankylosing spondylitis activity on PET-CT: a pilot study.
      Son and colleagues
      • Son S.M.
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      Evaluation of the diagnostic performance of (18)F-NaF positron emission tomography/computed tomography in patients with suspected ankylosing spondylitis according to the Assessment of SpondyloArthritis International Society criteria.
      examined 49 patients with AS and 19 patients without AS, all of whom had inflammatory low back pain for at least 3 months. Enthesopathy, syndesmophytes, and sacroiliitis were identified on NaF-PET/CT. Overall, NaF-PET/CT was found to have a sensitivity of 79.6% and a specificity of 84.2% in the diagnosis of AS. A study by Strobel and colleagues
      • Strobel K.
      • Fischer D.R.
      • Tamborrini G.
      • et al.
      18F-fluoride PET/CT for detection of sacroiliitis in ankylosing spondylitis.
      used NaF-PET/CT to evaluate sacroiliitis in 15 patients with AS and 13 patients with mechanical back pain. By calculating the ratio of NaF uptake in the sacroiliac joint to the uptake in the sacrum, the investigators used a cutoff of 1.3 as indicating sacroiliitis. Using this method, the sensitivity of NaF-PET/CT in sacroiliitis was found to be 80% with a specificity of 77%. To compare modalities in AS, whole-body MR and NaF-PET/CT were used to image 10 patients with AS.
      • Fischer D.R.
      • Pfirrmann C.W.
      • Zubler V.
      • et al.
      High bone turnover assessed by 18F-fluoride PET/CT in the spine and sacroiliac joints of patients with ankylosing spondylitis: comparison with inflammatory lesions detected by whole body MRI.
      At the sacroiliac joint, NaF uptake was found to correlate with bone marrow edema on MR, and there was a modest correlation at the spine. The investigators explained that the correlation was weaker than expected, possibly because of NaF-PET/CT portraying bone remodeling that occurs independently from inflammation. In a study of 12 patients with AS imaged by NaF-PET/MR, Park and colleagues
      • Park E.K.
      • Pak K.
      • Park J.H.
      • et al.
      Baseline increased 18F-fluoride uptake lesions at vertebral corners on positron emission tomography predict new syndesmophyte development in ankylosing spondylitis: a 2-year longitudinal study.
      found that baseline NaF uptake was independently associated with syndesmophyte formation on radiography at 2-year follow-up. These findings may indicate utility for NaF-PET combined with both CT and MR in the evaluation of AS and a need for further investigation into this field of study.
      Using NaF-PET/CT to assess the effects of treatment regimens, Bruijnen and colleagues
      • Bruijnen S.T.G.
      • Verweij N.J.F.
      • van Duivenvoorde L.M.
      • et al.
      Bone formation in ankylosing spondylitis during anti-tumour necrosis factor therapy imaged by 18F-fluoride positron emission tomography.
      studied 12 patients with active AS receiving anti–tumor necrosis factor therapy (Fig. 2). Imaging was performed at baseline and 12 weeks after initiation of treatment. In patients who responded to treatment after 24 weeks, NaF uptake was found to decrease at the costovertebral and sacroiliac joints after 12 weeks, whereas no significant changes were observed in nonresponders. Although NaF uptake at 12 weeks correlated with clinical evaluation at 24 weeks, clinical evaluation at 12 weeks did not correlate with later clinical evaluation. This finding suggests that NaF-PET/CT can predict eventual treatment efficacy, even when PET findings contradict early clinical evidence. Other studies examining patients with AS treated with anti–tumor necrosis factor therapy have found success in predicting treatment response from NaF uptake measured from baseline NaF-PET/CT images.
      • Lee S.J.
      • Kim J.Y.
      • Choi Y.Y.
      • et al.
      Predictive value of semi-quantitative index from F-18-fluoride PET/CT for treatment response in patients with ankylosing spondylitis.
      ,
      • Kim K.
      • Son S.M.
      • Goh T.S.
      • et al.
      Prediction of response to tumor necrosis value-alpha blocker is suggested by (18)F-NaF SUVmax but not by quantitative pharmacokinetic analysis in patients with ankylosing spondylitis.
      Figure thumbnail gr2
      Fig. 2Baseline (A) and 12-week follow-up (B) NaF-PET images of an patient with AS starting anti–tumor necrosis factor therapy. Although NaF activity in some AS lesions decreased (solid arrows), activity in other lesions increased (dashed arrows). Uptake at the facet joints was considered to be a result of osteoarthritis (arrowheads).
      (From Bruijnen STG, Verweij NJF, van Duivenvoorde LM, et al. Bone formation in ankylosing spondylitis during anti-tumour necrosis factor therapy imaged by 18F-fluoride positron emission tomography. Rheumatology (Oxford). 2018;57(4):631-638; with permission.)
      A limited number of studies have examined NaF activity at the joints in RA and PsA. In a preclinical trial using mice with glucose-6-phosphate isomerase–induced arthritis, NaF-PET/CT was found to correlate with the degree of bone destruction.
      • Irmler I.M.
      • Gebhardt P.
      • Hoffmann B.
      • et al.
      18 F-Fluoride positron emission tomography/computed tomography for noninvasive in vivo quantification of pathophysiological bone metabolism in experimental murine arthritis.
      Another trial using a murine model found that anti–tumor necrosis factor therapy resulted in increased NaF activity at growth plates and was associated with increased osteoblasts, osteoid formation, and trabecular bone mass.
      • Hayer S.
      • Zeilinger M.
      • Weiss V.
      • et al.
      Multimodal [(18) F]FDG PET/CT is a direct readout for inflammatory bone repair: a longitudinal study in TNFalpha transgenic mice.
      Watanabe and colleagues
      • Watanabe T.
      • Takase-Minegishi K.
      • Ihata A.
      • et al.
      18)F-FDG and (18)F-NaF PET/CT demonstrate coupling of inflammation and accelerated bone turnover in rheumatoid arthritis.
      assessed the hands of 12 patients with RA by FDG-PET/CT and NaF-PET/CT to compare the utility of the 2 tracers. SUVmax of both tracers as measured in the joints were found to correlate with one another. The NaF-PET parameter calculated by summing SUVmax from the metacarpophalangeal joints, proximal interphalangeal joints, and regions of the wrists was associated with the disease activity score in 28 joints, the modified health assessment questionnaire (mHAQ), radiographic progression, and the presence of erosions. Jonnakuti and colleagues
      • Jonnakuti V.S.
      • Raynor W.Y.
      • Taratuta E.
      • et al.
      A novel method to assess subchondral bone formation using [18F]NaF-PET in the evaluation of knee degeneration.
      reported that NaF uptake in the knees of patients with RA was associated with Kellgren-Lawrence grading, suggesting that NaF-PET/CT can track bone changes associated with RA over time. Tan and colleagues
      • Tan A.L.
      • Tanner S.F.
      • Waller M.L.
      • et al.
      High-resolution [18F]fluoride positron emission tomography of the distal interphalangeal joint in psoriatic arthritis--a bone-enthesis-nail complex.
      imaged 234 distal interphalangeal joints from 10 patients with PsA, 10 patients with OA, and 10 healthy controls. Compared with that of OA, NaF uptake in PsA involved the distal phalanges more diffusely, with increased uptake at the tufts, periosteum, and entheses. As imaging with NaF-PET is applied to new areas, it is imperative that, in addition to OA and AS, its potential role to portray bone involvement in other arthropathies is considered and investigated on a large scale.

      Back pain

      Analogous to previous studies that used BS and single-photon emission CT (SPECT),
      • Strobel K.
      • Burger C.
      • Seifert B.
      • et al.
      Characterization of focal bone lesions in the axial skeleton: performance of planar bone scintigraphy compared with SPECT and SPECT fused with CT.
      • Takemitsu M.
      • El Rassi G.
      • Woratanarat P.
      • et al.
      Low back pain in pediatric athletes with unilateral tracer uptake at the pars interarticularis on single photon emission computed tomography.
      • Reinartz P.
      • Schaffeldt J.
      • Sabri O.
      • et al.
      Benign versus malignant osseous lesions in the lumbar vertebrae: differentiation by means of bone SPET.
      • De Maeseneer M.
      • Lenchik L.
      • Everaert H.
      • et al.
      Evaluation of lower back pain with bone scintigraphy and SPECT.
      • Bellah R.D.
      • Summerville D.A.
      • Treves S.T.
      • et al.
      Low-back pain in adolescent athletes: detection of stress injury to the pars interarticularis with SPECT.
      • Collier B.D.
      • Johnson R.P.
      • Carrera G.F.
      • et al.
      Painful spondylolysis or spondylolisthesis studied by radiography and single-photon emission computed tomography.
      NaF-PET/CT has been used to assess benign causes of back pain.
      • Drubach L.A.
      • Connolly S.A.
      • Palmer 3rd, E.L.
      Skeletal scintigraphy with 18F-NaF PET for the evaluation of bone pain in children.
      • Lim R.
      • Fahey F.H.
      • Drubach L.A.
      • et al.
      Early experience with fluorine-18 sodium fluoride bone PET in young patients with back pain.
      • Ovadia D.
      • Metser U.
      • Lievshitz G.
      • et al.
      Back pain in adolescents: assessment with integrated 18F-fluoride positron-emission tomography-computed tomography.
      Athletes are particularly at risk of injuries resulting from repetitive hyperextension (Fig. 3).
      • Goetzinger S.
      • Courtney S.
      • Yee K.
      • et al.
      Spondylolysis in young athletes: an overview emphasizing nonoperative management.
      A common cause of low back pain in young athletes is spondylolysis, defined as a defect or stress fracture involving the pars interarticularis that commonly affects the lumbar spine. Pars fractures show increased bone turnover until the bone is finished healing.
      • Ovadia D.
      • Metser U.
      • Lievshitz G.
      • et al.
      Back pain in adolescents: assessment with integrated 18F-fluoride positron-emission tomography-computed tomography.
      ,
      • Zukotynski K.
      • Curtis C.
      • Grant F.D.
      • et al.
      The value of SPECT in the detection of stress injury to the pars interarticularis in patients with low back pain.
      Grant and colleagues
      • Grant F.D.
      • Fahey F.H.
      • Packard A.B.
      • et al.
      Skeletal PET with 18F-fluoride: applying new technology to an old tracer.
      report that, in their experience, correlation with CT confirms pars fracture in about half of cases with abnormal NaF uptake, with the other half likely representing patients with pars stress without spondylolysis. The investigators also reported that, generally, normal NaF uptake corresponds to normal anatomy of the pars interarticularis on CT, except in cases of long-standing spondylolysis where bone turnover is at baseline.
      Figure thumbnail gr3
      Fig. 3NaF-PET maximum intensity projection (A), transaxial (B), and fused PET/CT (D) images in an 18-year-old female dancer with extension-based low back pain show significant activity at the sacroiliac joints, whereas minimal abnormality is apparent on CT (C).
      (From Grant FD. 18F-fluoride PET and PET/CT in children and young adults. PET Clin. 2014;9(3):287-297; with permission.)
      Not only does NaF-PET/CT facilitate the diagnosis of pars stress but it can also help diagnose other potential causes of back pain, such as facet arthropathy.
      • Jenkins N.W.
      • Talbott J.F.
      • Shah V.
      • et al.
      [(18)F]-Sodium fluoride PET MR-based localization and quantification of bone turnover as a biomarker for facet joint-induced disability.
      • Mabray M.C.
      • Brus-Ramer M.
      • Behr S.C.
      • et al.
      (18)F-Sodium Fluoride PET-CT hybrid imaging of the lumbar facet joints: tracer uptake and degree of correlation to CT-graded arthropathy.
      • Gamie S.
      • El-Maghraby T.
      The role of PET/CT in evaluation of Facet and Disc abnormalities in patients with low back pain using (18)F-Fluoride.
      The observation that NaF uptake at the cervical, thoracic, and lumbar spine is associated with increased body weight in healthy individuals suggests that NaF-PET/CT can detect early changes in the spine related to degeneration.
      • Ayubcha C.
      • Zirakchian Zadeh M.
      • Stochkendahl M.J.
      • et al.
      Quantitative evaluation of normal spinal osseous metabolism with 18F-NaF PET/CT.
      In 42 adult patients with back pain and no history of spine surgery, NaF-PET/CT scans identified the cause of pain in 37 (88%) of the patients.
      • Gamie S.
      • El-Maghraby T.
      The role of PET/CT in evaluation of Facet and Disc abnormalities in patients with low back pain using (18)F-Fluoride.
      Furthermore, NaF activity at lumbar facet joints has been found to correlate with both MR findings and clinical disability.
      • Jenkins N.W.
      • Talbott J.F.
      • Shah V.
      • et al.
      [(18)F]-Sodium fluoride PET MR-based localization and quantification of bone turnover as a biomarker for facet joint-induced disability.
      Mabray and colleagues
      • Mabray M.C.
      • Brus-Ramer M.
      • Behr S.C.
      • et al.
      (18)F-Sodium Fluoride PET-CT hybrid imaging of the lumbar facet joints: tracer uptake and degree of correlation to CT-graded arthropathy.
      observed that, in 30 adult patients who underwent imaging by NaF-PET/CT, uptake of NaF was only weakly correlated with CT Pathria grade of facet osteoarthropathy. Thereby, the investigators reasoned that the assessment of bone turnover with NaF provided new information that can be used to supplement structural data provided by CT.
      Although many causes of back pain are related to muscular injuries or abnormalities associated with intervertebral discs, osseous involvement is common. Therefore, NaF-PET should be considered as the imaging modality of choice in these cases even when malignancy is not suspected. In a study of 15 adolescent patients with back pain, Ovadia and colleagues
      • Ovadia D.
      • Metser U.
      • Lievshitz G.
      • et al.
      Back pain in adolescents: assessment with integrated 18F-fluoride positron-emission tomography-computed tomography.
      found that NaF-PET/CT revealed positive findings in 10 patients, which included spondylolysis, frank fracture, osteoid osteoma, osteitis pubis, sacroiliitis, and disc herniation. Pseudoarthrosis associated with lumbosacral transitional vertebrae is another cause of back pain that can be evaluated by NaF-PET/CT.
      • Grant F.D.
      (1)(8)F-fluoride PET and PET/CT in children and young adults.
      Lim and colleagues
      • Lim R.
      • Fahey F.H.
      • Drubach L.A.
      • et al.
      Early experience with fluorine-18 sodium fluoride bone PET in young patients with back pain.
      identified back pain caused by vertebral body ring apophyseal injury and stress or injury at the spinous process, pars interarticularis, pedicle, sacroiliac joint, and transitional vertebra-sacral articulation. Usmani and colleagues
      • Usmani S.
      • Ahmed N.
      • Marafi F.
      • et al.
      Bertolotti syndrome demonstrated on 18F-NaF PET/CT.
      reported the case of a 34-year-old woman with severe low back pain, whose L5 vertebra contained a hemisacralized left transverse process. The transverse-sacral articulation showed NaF avidity, consistent with Bertolotti syndrome. A study in 55 patients with lumbosacral transitional vertebrae by the same investigators showed a strong correlation between NaF uptake and the presence of symptoms.
      • Usmani S.
      • Ahmed N.
      • Marafi F.
      • et al.
      18)F-sodium fluoride bone PET-CT in symptomatic lumbosacral transitional vertebra.
      These early studies and case reports show the significant utility of NaF-PET in the evaluation of musculoskeletal back pain, warranting further investigation into the potential role PET may play in the diagnosis, management, and follow-up of this serious cause of disability.

      Orthopedic complications

      Faced with an aging population, the prevalence of OA is increasing, and joint replacement surgery is becoming more common.
      • Koh Y.G.
      • Jung K.H.
      • Hong H.T.
      • et al.
      Optimal design of patient-specific total knee arthroplasty for improvement in wear performance.
      ,
      • Tzatzairis T.
      • Fiska A.
      • Ververidis A.
      • et al.
      Minimally invasive versus conventional approaches in total knee replacement/arthroplasty: a review of the literature.
      Postsurgical complications include instability, infection, fracture, and loosening, and the ability to discriminate between infection and aseptic loosening has important implications for patient management.
      • Markes A.R.
      • Cheung E.
      • Ma C.B.
      Failed reverse shoulder arthroplasty and recommendations for revision.
      • Kwak J.M.
      • Koh K.H.
      • Jeon I.H.
      Total elbow arthroplasty: clinical outcomes, complications, and revision surgery.
      • Chalmers P.N.
      • Boileau P.
      • Romeo A.A.
      • et al.
      Revision reverse shoulder arthroplasty.
      • Deshmukh S.
      • Omar I.M.
      Imaging of hip arthroplasties: normal findings and hardware complications.
      The first-line modality after hip or knee arthroplasty is radiography, which can show subsequent fractures and dislocations. Although the high sensitivity of 3-phase BS can be used to rule out postsurgical loosening and infection,
      • Niccoli G.
      • Mercurio D.
      • Cortese F.
      Bone scan in painful knee arthroplasty: obsolete or actual examination?.
      the addition of anatomic information in SPECT/CT can improve the otherwise low specificity.
      • Van den Wyngaert T.
      • Paycha F.
      • Strobel K.
      • et al.
      SPECT/CT in postoperative painful hip arthroplasty.
      Scintigraphy with gallium-67 (Ga67) and indium-111 (111In)–labeled white blood cells represent other methods of increasing the specificity of 3-phase BS.
      • Thelu-Vanysacker M.
      • Frederic P.
      • Charles-Edouard T.
      • et al.
      SPECT/CT in postoperative shoulder pain.
      • Palestro C.J.
      • Love C.
      Role of nuclear medicine for diagnosing infection of recently implanted lower extremity arthroplasties.
      • Yue B.
      • Tang T.
      The use of nuclear imaging for the diagnosis of periprosthetic infection after knee and hip arthroplasties.
      Several studies have indicated that NaF-PET has utility in assessing complications related to hip arthroplasty.
      • Ullmark G.
      • Sorensen J.
      • Nilsson O.
      • et al.
      Bone mineralisation adjacent to cemented and uncemented acetabular cups: analysis by [18F]-fluoride-PET in a randomised clinical trial.
      • Tezuka T.
      • Kobayashi N.
      • Hyonmin C.
      • et al.
      Influence of hydroxyapatite coating for the prevention of bone mineral density loss and bone metabolism after total hip arthroplasty: assessment using (18)F-fluoride positron emission tomography and dual-energy X-ray absorptiometry by randomized controlled trial.
      • Ullmark G.
      Occult hip prosthetic loosening diagnosed by [18F] Fluoride-PET/CT.
      • Nyström A.
      • Kiritopoulos D.
      • Ullmark G.
      • et al.
      Denosumab prevents early periprosthetic bone loss after uncemented total hip arthroplasty: results from a randomized placebo-controlled clinical trial.
      • Ullmark G.
      • Sorensen J.
      • Maripuu E.
      • et al.
      Fingerprint pattern of bone mineralisation on cemented and uncemented femoral stems: analysis by [18F]-fluoride-PET in a randomised clinical trial.
      • Kumar R.
      • Kumar R.
      • Kumar V.
      • et al.
      Potential clinical implication of (18) F-FDG PET/CT in diagnosis of periprosthetic infection and its comparison with (18) F-Fluoride PET/CT.
      • Kumar R.
      • Kumar R.
      • Kumar V.
      • et al.
      Comparative analysis of dual-phase 18F-fluoride PET/CT and three phase bone scintigraphy in the evaluation of septic (or painful) hip prostheses: a prospective study.
      • Bernstein P.
      • Beuthien-Baumann B.
      • Kotzerke J.
      • et al.
      Periacetabular bone metabolism following hip revision surgery. PET-based evaluation of allograft osteointegration.
      • Ullmark G.
      • Nilsson O.
      • Maripuu E.
      • et al.
      Analysis of bone mineralization on uncemented femoral stems by [18F]-fluoride-PET: a randomized clinical study of 16 hips in 8 patients.
      • Ullmark G.
      • Sorensen J.
      • Nilsson O.
      Analysis of bone formation on porous and calcium phosphate-coated acetabular cups: a randomised clinical [18F]fluoride PET study.
      • Ullmark G.
      • Sundgren K.
      • Milbrink J.
      • et al.
      Metabolic development of necrotic bone in the femoral head following resurfacing arthroplasty. A clinical [18F]fluoride-PET study in 11 asymptomatic hips.
      • Choe H.
      • Inaba Y.
      • Kobayashi N.
      • et al.
      Use of 18F-fluoride PET to determine the appropriate tissue sampling region for improved sensitivity of tissue examinations in cases of suspected periprosthetic infection after total hip arthroplasty.
      • Kobayashi N.
      • Inaba Y.
      • Choe H.
      • et al.
      Use of F-18 fluoride PET to differentiate septic from aseptic loosening in total hip arthroplasty patients.
      • Ullmark G.
      • Sundgren K.
      • Milbrink J.
      • et al.
      Femoral head viability following resurfacing arthroplasty. A clinical positron emission tomography study.
      • Kuo J.
      • Foster C.
      • Shelton D.
      Particle disease on fluoride-18 (NaF) PET/CT imaging.
      • Zoccali C.
      • Teori G.
      • Salducca N.
      The role of FDG-PET in distinguishing between septic and aseptic loosening in hip prosthesis: a review of literature.
      • Ullmark G.
      • Sorensen J.
      • Nilsson O.
      Bone healing of severe acetabular defects after revision arthroplasty.
      • Ullmark G.
      • Sundgren K.
      • Milbrink J.
      • et al.
      Osteonecrosis following resurfacing arthroplasty.
      • Temmerman O.P.
      • Raijmakers P.G.
      • Heyligers I.C.
      • et al.
      Bone metabolism after total hip revision surgery with impacted grafting: evaluation using H2 15O and [18F]fluoride PET; a pilot study.
      • Ullmark G.
      • Sorensen J.
      • Langstrom B.
      • et al.
      Bone regeneration 6 years after impaction bone grafting: a PET analysis.
      • Forrest N.
      • Welch A.
      • Murray A.D.
      • et al.
      Femoral head viability after Birmingham resurfacing hip arthroplasty: assessment with use of [18F] fluoride positron emission tomography.
      • Sorensen J.
      • Ullmark G.
      • Langstrom B.
      • et al.
      Rapid bone and blood flow formation in impacted morselized allografts: positron emission tomography (PET) studies on allografts in 5 femoral component revisions of total hip arthroplasty.
      • Piert M.
      • Winter E.
      • Becker G.A.
      • et al.
      Allogenic bone graft viability after hip revision arthroplasty assessed by dynamic [18F]fluoride ion positron emission tomography.
      Increased NaF activity can indicate stem loosening in patients experiencing pain but with equivocal radiograph findings.
      • Ullmark G.
      Occult hip prosthetic loosening diagnosed by [18F] Fluoride-PET/CT.
      To determine the efficacy of denosumab in preventing periprosthetic bone loss, which contributes to loosening, Nyström and colleagues
      • Nyström A.
      • Kiritopoulos D.
      • Ullmark G.
      • et al.
      Denosumab prevents early periprosthetic bone loss after uncemented total hip arthroplasty: results from a randomized placebo-controlled clinical trial.
      quantified bone turnover with NaF-PET. They noted that, in patients treated with denosumab, the increase in uptake after surgery was not as great as the increase in the patients receiving placebo. Even higher uptake in septic loosening is observed compared with aseptic loosening. By visually assessing the proportion of the bone-implant interface that showed NaF avidity, Kobayashi and colleagues
      • Kobayashi N.
      • Inaba Y.
      • Choe H.
      • et al.
      Use of F-18 fluoride PET to differentiate septic from aseptic loosening in total hip arthroplasty patients.
      diagnosed infection in 65 hip prostheses by NaF-PET/CT with a sensitivity of 95% and a specificity of 98%. In a comparative study between NaF-PET/CT and FDG-PET/CT, 42 patients with painful hip prostheses suspected of loosening underwent imaging before revision arthroplasty to determine whether or not infection was present.
      • Kumar R.
      • Kumar R.
      • Kumar V.
      • et al.
      Potential clinical implication of (18) F-FDG PET/CT in diagnosis of periprosthetic infection and its comparison with (18) F-Fluoride PET/CT.
      The sensitivity and specificity of NaF-PET/CT were 75% and 96%, respectively, whereas the sensitivity and specificity of FDG-PET/CT were 94% and 92%, respectively. Although imaging with NaF resulted in higher specificity, the investigators argued that the overall diagnostic performance with FDG was more suitable for routine clinical practice. As an analog to 3-phase BS, multiphase NaF-PET has been proposed to assess for infection. In a demonstration of early-phase imaging in a patient with cellulitis, Li and colleagues
      • Li Y.
      • Schiepers C.
      • Lake R.
      • et al.
      Clinical utility of (18)F-fluoride PET/CT in benign and malignant bone diseases.
      suggested that NaF-PET images acquired 2 minutes after tracer administration can be used to visualize increased regional blood flow at infected areas. Although future investigations may assess the feasibility of this method in a larger number of patients, there is currently limited evidence regarding early-phase NaF-PET in infection. Choe and colleagues
      • Choe H.
      • Inaba Y.
      • Kobayashi N.
      • et al.
      Use of 18F-fluoride PET to determine the appropriate tissue sampling region for improved sensitivity of tissue examinations in cases of suspected periprosthetic infection after total hip arthroplasty.
      found that, by using NaF-PET to identify active lesions in total hip arthroplasty patients, they achieved a higher accuracy of tissue sampling in the diagnosis of periprosthetic infection. Besides hip arthroplasty, NaF-PET has been used to image knee, ankle, and shoulder arthroplasties.
      • Hochreiter J.
      • Mattiassich G.
      • Hitzl W.
      • et al.
      Quantitative in vivo assessment of bone allograft viability using (18)F-fluoride PET/CT after glenoid augmentation in reverse shoulder arthroplasty: a pilot study.
      • Dyke J.P.
      • Garfinkel J.H.
      • Volpert L.
      • et al.
      Imaging of bone perfusion and metabolism in subjects Undergoing total ankle arthroplasty using (18)F-fluoride positron emission tomography.
      • Koob S.
      • Gaertner F.C.
      • Jansen T.R.
      • et al.
      Diagnosis of peri-prosthetic loosening of total hip and knee arthroplasty using (18)F-Fluoride PET/CT.
      • Son H.J.
      • Jeong Y.J.
      • Yoon H.J.
      • et al.
      Visual pattern and serial quantitation of (18)F-Sodium Fluoride PET/CT in asymptomatic patients after hip and knee arthroplasty.
      • Sterner T.
      • Pink R.
      • Freudenberg L.
      • et al.
      The role of [18F]fluoride positron emission tomography in the early detection of aseptic loosening of total knee arthroplasty.
      A study that included 24 hip and 13 knee prostheses found that NaF-PET/CT had a sensitivity of 95% and a specificity of 87% in diagnosing periprosthetic loosening (Fig. 4).
      • Koob S.
      • Gaertner F.C.
      • Jansen T.R.
      • et al.
      Diagnosis of peri-prosthetic loosening of total hip and knee arthroplasty using (18)F-Fluoride PET/CT.
      The viability and fusion of femoral allografts in 7 patients who underwent reverse total shoulder arthroplasty was assessed by NaF-PET/CT, which showed a similar amount of uptake in the allografts as in reference vertebrae.
      • Hochreiter J.
      • Mattiassich G.
      • Hitzl W.
      • et al.
      Quantitative in vivo assessment of bone allograft viability using (18)F-fluoride PET/CT after glenoid augmentation in reverse shoulder arthroplasty: a pilot study.
      Figure thumbnail gr4
      Fig. 4NaF-PET and PET/CT images of a 72-year-old woman who underwent total hip arthroplasty 12 years earlier. High NaF uptake involving the right acetabular component suggests loosening. No loosening is suspected in the right femoral component or in either components of the left arthroplasty.
      (From Koob S, Gaertner FC, Jansen TR, et al. Diagnosis of peri-prosthetic loosening of total hip and knee arthroplasty using (18)F-Fluoride PET/CT. Oncotarget. 2019;10(22):2203-2211; with permission.)
      Spinal orthopedics is another area that may benefit from NaF-PET, which may have a role in predicting healing and identifying complications such as nonunion, pseudarthrosis, infection, and hardware loosening.
      • Constantinescu C.M.
      • Jacobsen M.K.
      • Gerke O.
      • et al.
      Fusion and healing prediction in posterolateral spinal fusion using (18)F-Sodium Fluoride-PET/CT.
      • Pouldar D.
      • Bakshian S.
      • Matthews R.
      • et al.
      Utility of 18F sodium fluoride PET/CT imaging in the evaluation of postoperative pain following surgical spine fusion.
      • Seifen T.
      • Rodrigues M.
      • Rettenbacher L.
      • et al.
      The value of (18)F-fluoride PET/CT in the assessment of screw loosening in patients after intervertebral fusion stabilization.
      • Peters M.
      • Willems P.
      • Weijers R.
      • et al.
      Pseudarthrosis after lumbar spinal fusion: the role of (1)(8)F-fluoride PET/CT.
      • Peters M.J.
      • Wierts R.
      • Jutten E.M.
      • et al.
      Evaluation of a short dynamic 18F-fluoride PET/CT scanning method to assess bone metabolic activity in spinal orthopedics.
      • Quon A.
      • Dodd R.
      • Iagaru A.
      • et al.
      Initial investigation of (1)(8)F-NaF PET/CT for identification of vertebral sites amenable to surgical revision after spinal fusion surgery.
      In pediatrics, Grant
      • Grant F.D.
      (1)(8)F-fluoride PET and PET/CT in children and young adults.
      reported utility in determining the cause of pain in children who underwent spinal fusion surgery for scoliosis. Fischer and colleagues
      • Fischer D.R.
      • Zweifel K.
      • Treyer V.
      • et al.
      Assessment of successful incorporation of cages after cervical or lumbar intercorporal fusion with [(18)F]fluoride positron-emission tomography/computed tomography.
      studied 20 patients who underwent cervical or lumbar intercorporal fusion and found that increased NaF activity could be visualized in cervical cages for up to 8 years after intervention and up to 10 years in lumbar cages (Fig. 5). The investigators suggested that this may represent unsuccessful fusion, which could be a result of stress or microinstability. In a comparison between NaF-PET/CT, plain radiography, and CT, fusion was assessed in 8 patients after en bloc spondylectomy.
      • Pumberger M.
      • Prasad V.
      • Druschel C.
      • et al.
      Quantitative in vivo fusion assessment by (18)F-fluoride PET/CT following en bloc spondylectomy.
      Although radiographs and CT showed successful fusion in all patients, NaF-PET/CT findings indicated nonunion in each case, showing a large discrepancy in findings between these modalities.
      Figure thumbnail gr5
      Fig. 5Low-dose CT (left), fused NaF-PET/CT (middle), and NaF-PET (right) images of a 52-year-old male patient who underwent 2 adjacent intercorporal fusions (C3/4, C4/5). At 79 months postoperatively, both cervical cages still show increased NaF activity.
      (From Fischer DR, Zweifel K, Treyer V, et al. Assessment of successful incorporation of cages after cervical or lumbar intercorporal fusion with [(18)F]fluoride positron-emission tomography/computed tomography. Eur Spine J. 2011;20(4):640-648; with permission.)
      Although more studies are needed, other orthopedic applications of NaF-PET include assessing the effects of Taylor Spatial Frame treatment,
      • Sanchez-Crespo A.
      • Christiansson F.
      • Thur C.K.
      • et al.
      Predictive value of [(18)F]-fluoride PET for monitoring bone remodeling in patients with orthopedic conditions treated with a Taylor spatial frame.
      as well as determining the progression of graft incorporation after anterior cruciate ligament reconstruction.
      • Sorensen J.
      • Michaelsson K.
      • Strand H.
      • et al.
      Long-standing increased bone turnover at the fixation points after anterior cruciate ligament reconstruction: a positron emission tomography (PET) study of 8 patients.
      NaF activity can also be informative for surgical planning. In patients with hip fractures, decreased NaF activity was predictive of future need for joint replacement surgery.
      • Schiepers C.
      • Broos P.
      • Miserez M.
      • et al.
      Measurement of skeletal flow with positron emission tomography and 18F-fluoride in femoral head osteonecrosis.
      In a study of patients with osteonecrosis, 9 out of 17 hips had NaF avidity in the absence of findings on BS, SPECT, and MR, which shows the importance of this modality.
      • Dasa V.
      • Adbel-Nabi H.
      • Anders M.J.
      • et al.
      F-18 fluoride positron emission tomography of the hip for osteonecrosis.
      Patients with posttraumatic and postsurgical chronic osteomyelitis after unsuccessful surgical intervention were imaged by both FDG-PET/CT and NaF-PET/CT in a study by Christersson and colleagues.
      • Christersson A.
      • Larsson S.
      • Sorensen J.
      Presurgical localization of infected avascular bone segments in chronic complicated posttraumatic osteomyelitis in the lower extremity using dual-tracer PET/CT.
      In all 8 patients assessed, PET determined the culprit sequestrum, and, in 4 patients, an additional sequestrum with no clinical signs was identified. Follow-up revealed no clinical indications of recurrence and negative PET findings in all patients. Because both the disorder and the treatment often directly affect bone activity in orthopedics, it is logical that imaging with NaF-PET has a large role to play in managing patients before and after surgical procedures. Preliminary studies in this area are very promising, and future studies should focus on surgical planning as well as using NaF-PET to investigate the healing process or associated complications after treatment, which could be overlooked by conventional modalities.

      Metabolic bone diseases

      Osteoporosis is a systemic disease of bone, in which reduced bone mass results in greater fragility and risk of fracture. Because osteoporosis mostly occurs in elderly men and postmenopausal women, its prevalence is expected to increase with current demographic trends.
      • Akkawi I.
      • Zmerly H.
      Osteoporosis: current concepts.
      Osteoporotic fractures often involve the vertebrae, hip, distal forearm, or shoulder.
      • Sozen T.
      • Ozisik L.
      • Basaran N.C.
      An overview and management of osteoporosis.
      To assess for osteoporosis, bone mineral density (BMD) determined by dual x-ray absorptiometry (DXA) and expressed as a T score is the current standard of care. Representing the number of standard deviations from average BMD in a young healthy population, a T score between −1.0 and −2.5 is diagnostic for osteopenia, whereas a T score less than −2.5 is considered osteoporosis.
      • Akkawi I.
      • Zmerly H.
      Osteoporosis: current concepts.
      However, some investigators have questioned the accuracy of DXA-derived BMD,
      • Pennington Z.
      • Ehresman J.
      • Lubelski D.
      • et al.
      Assessing underlying bone quality in spine surgery patients: a narrative review of dual-energy X-ray absorptiometry (DXA) and alternatives.
      • Albano D.
      • Agnollitto P.M.
      • Petrini M.
      • et al.
      Operator-Related Errors and Pitfalls in Dual Energy X-ray absorptiometry: how to recognize and avoid them.
      • Choksi P.
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      The challenges of diagnosing osteoporosis and the limitations of currently available tools.
      and 1 study found that most women with hip fracture had T scores more than −2.5, showing the low sensitivity of this technique.
      • Kinoshita H.
      • Tamaki T.
      • Hashimoto T.
      • et al.
      Factors influencing lumbar spine bone mineral density assessment by dual-energy X-ray absorptiometry: comparison with lumbar spinal radiogram.
      Rather than BMD, bone turnover can be used to evaluate patients for osteoporosis. However, established methods face certain limitations.
      • Frost M.L.
      • Blake G.M.
      • Fogelman I.
      (18)F-Fluoride PET in osteoporosis.
      Bone turnover markers can be used to evaluate overall metabolic activity but suffer from low sensitivity and cannot assess individual skeletal sites. Alternatively, transiliac biopsy after double labeling with tetracycline is invasive and limited to 1 area of the skeleton.
      Bone imaging with functional modalities such as PET is a sensitive method that can overcome the limitations associated with other bone turnover assessments.
      • Zhang V.
      • Koa B.
      • Borja A.J.
      • et al.
      Diagnosis and monitoring of osteoporosis with total-body (18)F-sodium fluoride-PET/CT.
      ,
      • Reilly C.C.
      • Raynor W.Y.
      • Hong A.L.
      • et al.
      Diagnosis and monitoring of osteoporosis with (18)F-Sodium Fluoride PET: an unavoidable path for the foreseeable future.
      A study by Piert and colleagues
      • Piert M.
      • Zittel T.T.
      • Becker G.A.
      • et al.
      Assessment of porcine bone metabolism by dynamic.
      used NaF-PET to assess bone turnover at the vertebrae of healthy pigs and compared their findings with histomorphometric data derived from iliac crest biopsies. The influx rate and volume flux of NaF were found to correlate with the mineral apposition rate, and the investigators concluded that NaF-PET may represent a noninvasive method of following metabolic bone diseases over time, decreasing the need for invasive bone biopsies. NaF-PET has had success in detecting both postmenopausal and glucocorticoid-induced osteoporosis.
      • Jassel I.S.
      • Siddique M.
      • Frost M.L.
      • et al.
      The influence of CT and dual-energy X-ray absorptiometry (DXA) bone density on quantitative [(18)F] sodium fluoride PET.
      • Frost M.L.
      • Blake G.M.
      • Park-Holohan S.J.
      • et al.
      Long-term precision of 18F-fluoride PET skeletal kinetic studies in the assessment of bone metabolism.
      • Uchida K.
      • Nakajima H.
      • Miyazaki T.
      • et al.
      Effects of alendronate on bone metabolism in glucocorticoid-induced osteoporosis measured by 18F-fluoride PET: a prospective study.
      • Frost M.L.
      • Fogelman I.
      • Blake G.M.
      • et al.
      Dissociation between global markers of bone formation and direct measurement of spinal bone formation in osteoporosis.
      • Berding G.
      • Kirchhoff T.D.
      • Burchert W.
      • et al.
      [18F]fluoride PET indicates reduced bone formation in severe glucocorticoid-induced osteoporosis.
      A study of 71 male and 68 female subjects observed a decrease in NaF uptake at the femoral neck with age, correlating with BMD from CT.
      • Rhodes S.
      • Batzdorf A.
      • Sorci O.
      • et al.
      Assessment of femoral neck bone metabolism using (18)F-sodium fluoride PET/CT imaging.
      In patients diagnosed with osteoporosis by DXA, NaF activity at the lumbar spine is significantly lower than in healthy persons and in patients with osteopenia.
      • Uchida K.
      • Nakajima H.
      • Miyazaki T.
      • et al.
      Effects of alendronate on bone metabolism in glucocorticoid-induced osteoporosis measured by 18F-fluoride PET: a prospective study.
      • Frost M.L.
      • Fogelman I.
      • Blake G.M.
      • et al.
      Dissociation between global markers of bone formation and direct measurement of spinal bone formation in osteoporosis.
      • Berding G.
      • Kirchhoff T.D.
      • Burchert W.
      • et al.
      [18F]fluoride PET indicates reduced bone formation in severe glucocorticoid-induced osteoporosis.
      Bone formation at other skeletal sites as determined by NaF-PET include the pelvis, tibia, parietal bone, humerus, and sternum.
      • Win A.Z.
      • Aparici C.M.
      Normal SUV values measured from NaF18- PET/CT bone scan studies.
      ,
      • Frost M.L.
      • Moore A.E.
      • Siddique M.
      • et al.
      (1)(8)F-fluoride PET as a noninvasive imaging biomarker for determining treatment efficacy of bone active agents at the hip: a prospective, randomized, controlled clinical study.
      The effects of antiresorptive therapy with bisphosphonates result in a rapid decrease in osteoclast activity, followed by a gradual decrease in osteoblast metabolism. Several studies have observed this expected decrease in bone formation after treatment with risedronate and alendronate.
      • Uchida K.
      • Nakajima H.
      • Miyazaki T.
      • et al.
      Effects of alendronate on bone metabolism in glucocorticoid-induced osteoporosis measured by 18F-fluoride PET: a prospective study.
      ,
      • Frost M.L.
      • Blake G.M.
      • Cook G.J.
      • et al.
      Differences in regional bone perfusion and turnover between lumbar spine and distal humerus: (18)F-fluoride PET study of treatment-naive and treated postmenopausal women.
      • Frost M.L.
      • Cook G.J.
      • Blake G.M.
      • et al.
      The relationship between regional bone turnover measured using 18F-fluoride positron emission tomography and changes in BMD is equivalent to that seen for biochemical markers of bone turnover.
      • Frost M.L.
      • Cook G.J.
      • Blake G.M.
      • et al.
      A prospective study of risedronate on regional bone metabolism and blood flow at the lumbar spine measured by 18F-fluoride positron emission tomography.
      Uchida and colleagues
      • Uchida K.
      • Nakajima H.
      • Miyazaki T.
      • et al.
      Effects of alendronate on bone metabolism in glucocorticoid-induced osteoporosis measured by 18F-fluoride PET: a prospective study.
      observed a significant decrease in SUV at the lumbar spine after 3 months of treatment with alendronate, whereas no significant changes in serum bone-specific alkaline phosphate were observed until 6 months, and DXA did not show a significant change until 12 months. In 11 postmenopausal women treated with alendronate and 9 treated with risedronate, Frost and colleagues
      • Frost M.L.
      • Siddique M.
      • Blake G.M.
      • et al.
      Regional bone metabolism at the lumbar spine and hip following discontinuation of alendronate and risedronate treatment in postmenopausal women.
      found that NaF activity remained suppressed in the spine in both groups 12 months after discontinuation of therapy. However, after 12 months of discontinuation in the alendronate group, an increase in NaF uptake at the hip and femoral shaft was seen.
      In contrast, teriparatide therapy causes increased activity in both osteoblasts and osteoclasts. As expected, increased bone turnover at the spine, femoral shaft, and pelvis portrayed by NaF-PET was described in a study of 18 postmenopausal women after 6 months of teriparatide therapy.
      • Frost M.L.
      • Siddique M.
      • Blake G.M.
      • et al.
      Differential effects of teriparatide on regional bone formation using (18)F-fluoride positron emission tomography.
      A study by the same group saw significantly greater NaF clearance at the hip, femoral neck, lumbar spine, and pelvis in patients after 12 weeks of taking teriparatide, whereas no changes were observed in a control group taking calcium and vitamin D only.
      • Frost M.L.
      • Moore A.E.
      • Siddique M.
      • et al.
      (1)(8)F-fluoride PET as a noninvasive imaging biomarker for determining treatment efficacy of bone active agents at the hip: a prospective, randomized, controlled clinical study.
      Paget disease, characterized by increased osteoclast activity followed by increased osteoblast activity, and renal osteodystrophy, in which chronic kidney disease results in abnormally low or high bone turnover, are other disorders that may benefit from NaF-PET assessment.
      • Aaltonen L.
      • Koivuviita N.
      • Seppanen M.
      • et al.
      Correlation between (18)F-Sodium Fluoride positron emission tomography and bone histomorphometry in dialysis patients.
      • Cucchi F.
      • Simonsen L.
      • Abild-Nielsen A.G.
      • et al.
      18F-Sodium fluoride PET/CT in paget disease.
      • Derlin T.
      • Weiberg D.
      • Sohns J.M.
      Multitracer molecular imaging of paget disease targeting bone remodeling, fatty acid metabolism, and PSMA expression on PET/CT.
      • Frost M.L.
      • Compston J.E.
      • Goldsmith D.
      • et al.
      (18)F-fluoride positron emission tomography measurements of regional bone formation in hemodialysis patients with suspected adynamic bone disease.
      • Installe J.
      • Nzeusseu A.
      • Bol A.
      • et al.
      (18)F-fluoride PET for monitoring therapeutic response in Paget's disease of bone.
      • Messa C.
      • Goodman W.G.
      • Hoh C.K.
      • et al.
      Bone metabolic activity measured with positron emission tomography and [18F]fluoride ion in renal osteodystrophy: correlation with bone histomorphometry.
      NaF activity is higher in pagetic bones and has been found to decrease after 1 month of treatment with bisphosphonates, followed by a further decrease after 6 months.
      • Installe J.
      • Nzeusseu A.
      • Bol A.
      • et al.
      (18)F-fluoride PET for monitoring therapeutic response in Paget's disease of bone.
      Despite normal biomarkers, increased NaF activity was observed in most patients. In 11 patients with renal osteodystrophy, Messa and colleagues
      • Messa C.
      • Goodman W.G.
      • Hoh C.K.
      • et al.
      Bone metabolic activity measured with positron emission tomography and [18F]fluoride ion in renal osteodystrophy: correlation with bone histomorphometry.
      determined that clearance of NaF could differentiate between high bone turnover in secondary hyperparathyroidism and low-turnover bone disease. Further, NaF clearance correlated with serum alkaline phosphatase and parathyroid hormone levels as well as with histomorphometric data. After parathyroidectomy and medical therapy in 2 patients, NaF clearance was found to decrease by approximately 30% to 40%. These studies imply that NaF-PET is much more sensitive than the existing approaches for assessing the involvement of bones throughout the body in a variety of metabolic disorders. Although the implementation of routine PET imaging may present challenges in terms of cost and radiation exposure, NaF-PET could play a key role in therapy development, in which sensitive tests are needed to evaluate early biological effects in vivo.

      Other osseous and soft tissue disorders

      Aside from the aforementioned major applications of NaF-PET in bone and joint disorders, an array of other potential areas of investigation have been suggested by preliminary observations. Osteonecrosis, including medication-related osteonecrosis of the jaw, seems to be a promising area in need of further study,
      • Kim Y.
      • Lee H.Y.
      • Yoon H.J.
      • et al.
      Utility of 18F-fluorodeoxy glucose and 18F-sodium fluoride positron emission tomography/computed tomography in the diagnosis of medication-related osteonecrosis of the jaw: a preclinical study in a rat model.
      • Kubota S.
      • Inaba Y.
      • Kobayashi N.
      • et al.
      Prediction of femoral head collapse in osteonecrosis using 18F-fluoride positron emission tomography.
      • Guggenberger R.
      • Fischer D.R.
      • Metzler P.
      • et al.
      Bisphosphonate-induced osteonecrosis of the jaw: comparison of disease extent on contrast-enhanced MR imaging, [18F] fluoride PET/CT, and conebeam CT imaging.
      • Gayana S.
      • Bhattacharya A.
      • Kashyap R.
      • et al.
      (18)F-fluoride PET/CT in avascular necrosis of the femoral head.
      • Aratake M.
      • Yoshifumi T.
      • Takahashi A.
      • et al.
      Evaluation of lesion in a spontaneous osteonecrosis of the knee using 18F-fluoride positron emission tomography.
      in addition to assessment of fibrous dysplasia.
      • van der Bruggen W.
      • Hagelstein-Rotman M.
      • de Geus-Oei L.F.
      • et al.
      Quantifying skeletal burden in fibrous dysplasia using sodium fluoride PET/CT.
      ,
      • Lee H.
      • Lee K.S.
      • Lee W.W.
      18F-NaF PET/CT findings in fibrous dysplasia.
      Increased NaF uptake in the otic capsule in patients with otosclerosis compared with healthy controls suggests a potential role in diagnosis.
      • Waterval J.J.
      • Vallinga M.
      • Brans B.
      • et al.
      18F-fluoride PET/CT scan for quantification of bone metabolism in the inner ear in patients with otosclerosis--a pilot study.
      With regard to benign primary bone tumors, both osteoid osteoma and osteoblastoma are known to show NaF avidity.
      • Ovadia D.
      • Metser U.
      • Lievshitz G.
      • et al.
      Back pain in adolescents: assessment with integrated 18F-fluoride positron-emission tomography-computed tomography.
      ,
      • Bhure U.
      • Roos J.E.
      • Strobel K.
      Osteoid osteoma: multimodality imaging with focus on hybrid imaging.
      • Seniaray N.
      • Jain A.
      Osteoid osteoma mimicking inflammatory synovitis.
      • Batouli A.
      • Gholamrezanezhad A.
      • Petrov D.
      • et al.
      Management of primary osseous spinal tumors with PET.
      Similarly, malignancies such as osteosarcoma and Ewing sarcoma can be identified with this modality.
      • Broadhead M.L.
      • Lokmic Z.
      • Tan M.L.
      • et al.
      Applying advanced imaging techniques to a murine model of orthotopic osteosarcoma.
      • Campanile C.
      • Arlt M.J.
      • Kramer S.D.
      • et al.
      Characterization of different osteosarcoma phenotypes by PET imaging in preclinical animal models.
      • Franzius C.
      • Hotfilder M.
      • Poremba C.
      • et al.
      Successful high-resolution animal positron emission tomography of human Ewing tumours and their metastases in a murine xenograft model.
      • Brenner W.
      • Bohuslavizki K.H.
      • Eary J.F.
      PET imaging of osteosarcoma.
      Case reports show the successful identification of osteosarcoma metastases by NaF-PET in the lungs, in the right ventricle of the heart, and in the abdominal and paraspinal muscles.
      • Usmani S.
      • Marafi F.
      • Rasheed R.
      • et al.
      Unsuspected metastases to muscles in osteosarcoma detected on 18F-Sodium Fluoride PET-CT.
      • Chou Y.H.
      • Ko K.Y.
      • Cheng M.F.
      • et al.
      18F-NaF PET/CT images of cardiac metastasis from osteosarcoma.
      • Tse N.
      • Hoh C.
      • Hawkins R.
      • et al.
      Positron emission tomography diagnosis of pulmonary metastases in osteogenic sarcoma.
      Further, by detecting greater osteosarcoma disease extent than was apparent on structural imaging, NaF-PET contributed to the decision in 1 case of changing from curative intent to palliative intent.
      • Brunkhorst T.
      • Boerner A.R.
      • Bergh S.
      • et al.
      Pretherapeutic assessment of tumour metabolism using a dual tracer PET technique.
      Regarding disorders arising from nonosseous structures, NaF activity has been observed in Langerhans cell histiocytosis, in which focal uptake was observed throughout the skeleton.
      • Caoduro C.
      • Ungureanu C.M.
      • Rudenko B.
      • et al.
      18F-fluoride PET/CT aspect of an unusual case of Erdheim-Chester disease with histologic features of Langerhans cell histiocytosis.
      Significant uptake has also been shown in a case of vertebral body hemangioma.
      • Bastawrous S.
      • Bhargava P.
      • Behnia F.
      • et al.
      Newer PET application with an old tracer: role of 18F-NaF skeletal PET/CT in oncologic practice.
      Other neoplasms reported to show NaF activity include neurofibroma,
      • Liu H.
      • Chen Y.
      • Yang L.
      • et al.
      18F-NaF uptake in retroperitoneal neurofibroma and uterine leiomyoma calcifications.
      meningioma,
      • Woodhead G.J.
      • Avery R.J.
      • Kuo P.H.
      Atlas of extraosseous findings detected by 18F-NaF PET/CT bone scan.
      uterine leiomyoma,
      • Kothekar E.
      • Raynor W.Y.
      • Werner T.J.
      • et al.
      18F-NaF uptake in calcified uterine leiomyoma.
      ,
      • Al-Zaghal A.
      • Werner T.J.
      • Hoilund-Carlsen P.F.
      • et al.
      The detection of uterine leiomyoma (fibroid) calcifications on 18F-NaF PET/CT.
      ovarian cancer,
      • Zhu Y.
      • Chen Y.
      • Huang Z.
      • et al.
      Unsuspected metastatic ovarian cancer revealed by 18F-NaF PET/CT performed to evaluate lower-back pain.
      bladder cancer,
      • Shao F.
      • Zou Y.
      • Cai L.
      • et al.
      Unexpected detection of urinary bladder cancer on dual phase 18F-NaF PET/CT in a patient with back pain.
      glioblastoma,
      • Ishimura M.
      • Yamamoto Y.
      • Mitamura K.
      • et al.
      A case of glioblastoma with calcified region imaged with 18F-NaF PET/CT.
      and medullary thyroid carcinoma.
      • Duarte P.S.
      • Marin J.F.G.
      • De Carvalho J.W.A.
      • et al.
      Brain metastasis of medullary thyroid carcinoma without macroscopic calcification detected first on 68Ga-dotatate and then on 18F-fluoride PET/CT.
      Certain normal tissues, such as breast tissue, have moderate NaF activity at baseline,
      • Sarikaya I.
      • Sharma P.
      • Sarikaya A.
      F-18 fluoride uptake in primary breast cancer.
      which can even be appreciated in drug-induced gynecomastia in men.
      • Kothekar E.
      • Raynor W.Y.
      • Al-Zaghal A.
      • et al.
      Incidental 18F-NaF uptake in drug-induced gynecomastia.
      NaF-PET can also show physiologic calcification of intracranial structures,
      • Usmani S.
      • Marafi F.
      • Al Kandari F.
      • et al.
      Normal Variant 18F-sodium fluoride uptake in the falx cerebri ossification.
      ,
      • Al-Zaghal A.
      • Mehdizadeh Seraj S.
      • Werner T.J.
      • et al.
      Assessment of physiological intracranial calcification in healthy adults using (18)F-NaF PET/CT.
      as well as heterotopic ossification after surgery.
      • Seraj S.M.
      • Al-Zaghal A.
      • Ostergaard B.
      • et al.
      Identification of heterotopic ossification using 18F-NaF PET/CT.
      In addition, NaF uptake has been reported in the gastrointestinal wall caused by hypercalcemia
      • Shao F.
      • Zhang S.
      • Qi C.
      • et al.
      Diffuse increased sodium fluoride gastric activity in a patient with hypercalcemia.
      and as a sequela of Japanese schistosomiasis.
      • Zhang W.
      • Chen L.
      • Wan Q.
      • et al.
      18F-NaF PET/CT finding in a patient with abdominal discomfort after schistosomiasis.
      Although the significance of these findings is still unclear, an important extraosseous indication for NaF-PET is in the evaluation of vascular microcalcification, with the possibility of NaF surpassing FDG as the PET tracer of choice in assessing atherosclerotic activity.
      • Raynor W.Y.
      • Borja A.J.
      • Rojulpote C.
      • et al.
      (18)F-sodium fluoride: an emerging tracer to assess active vascular microcalcification.
      ,
      • Hoilund-Carlsen P.F.
      • Sturek M.
      • Alavi A.
      • et al.
      Atherosclerosis imaging with (18)F-sodium fluoride PET: state-of-the-art review.

      Summary

      The rise of NaF-PET and its combination with CT and MR present new opportunities to assess benign musculoskeletal disorders with a greater sensitivity compared with conventional approaches. In particular, conditions affecting the skeleton and joints stand to benefit greatly from PET findings that would otherwise be missed on conventional radiographs, BS, CT, or MR. As a result, previously undetermined causes of bone pain may be elucidated, and sites of occult traumatic injury could be discovered, findings that have important implications for patient care. In addition to its diagnostic role, NaF-PET can be used to evaluate pharmacologic and surgical interventions designed to treat osseous structures. Orthopedic surgeons in particular are faced with managing complications that can be better characterized by NaF-PET than with other modalities. Moreover, drugs such as teriparatide and bisphosphonates cause direct changes in NaF activity before the effects are evident by any other means. As clinicians continue to gain a better understanding of this modality, its future role in other bone and soft tissue disorders is still undetermined, and large-scale prospective studies are warranted to investigate its utility.

      Clinics care points

      • Although NaF-PET/CT can be used to detect bone metastases, PET tracers that portray tumor activity such as FDG or radiolabeled PSMA ligands are more appropriate in this setting.
      • Many benign musculoskeletal conditions can be detected by NaF-PET, which can play a role in diagnosis and monitoring.
      • NaF-PET and its hybrid modalities can assist in orthopedic planning as well as in evaluation for postsurgical complications such as infection.
      • PET quantification allows precise evaluation of metabolic bone diseases. NaF uptake reflects bone turnover, pathologic changes in which are present years before changes in bone mineral density.

      Disclosure

      The authors have nothing to disclose.

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