Absorption of fluorides by enamel, dentin, bone, and hydroxyapatite was first reported in 1940, followed by introduction of the Na¹⁸F radiotracer as a bone imaging agent in 1962 and approval by the U.S. Food and Drug Administration (FDA) in 1972 [8, 9]. Because high-energy 511-keV annihilation photons of Na¹⁸F precluded the use of Anger gamma cameras, the initial Na¹⁸F bone scans instead used high-energy rectilinear scanners [10]. Logistical challenges presented by the 110-minute half-life of Na¹⁸F, the introduction of cheaper ^99mTc-labeled radiopharmaceuticals, and the development of Anger gamma cameras optimized for the 140-keV photons of ^99mTc subsequently resulted in the withdrawal of FDA approval for Na¹⁸F in 1975 [9, 11].

In 1992, Dahlbom et al. [12] used Na¹⁸F PET in the development of a whole-body PET technique, which allowed higher geometric spatial resolution, with 100 times greater photon capture efficiency through coincident detection than was previously attainable through ^99mTc-MDP bone scintigraphy [12, 13]. In 1993, whole-body Na¹⁸F PET skeletal imaging was introduced, with early studies showing limited, but encouraging, results for the evaluation of both malignant and metabolic bone disease [12, 14]. Given these encouraging preliminary data, FDA approval was issued in 2000 for the use of Na¹⁸F radiotracer for PET bone scintigraphy [10]. The development of combination PET/CT scanners in subsequent years and shortages of ⁹⁹Mo and ^99mTc generators fostered a surge of interest in the utility of Na¹⁸F PET. Subsequently, beginning in April 2009, the Centers for Medicare and Medicaid Services initiated a series of reimbursement approvals for Na¹⁸F PET, which culminated in February 2011 with the approval of Na¹⁸F PET for the detection of bony metastasis at sites participating in the National Oncology PET Registry [15]. The National Oncologic PET Registry was developed in response to a proposal by the Centers for Medicare and Medicaid Services to expand coverage for PET with FDG to include cancers and indications not presently eligible for Medicare reimbursement.

Na¹⁸F, a positron emitter with annihilation energies of 511 keV ± 40 eV, is well-suited for PET/CT, because it allows higher spatial resolution, greater sensitivity, and higher image quality than is attainable by planar scintigraphy with SPECT [16–18]. For comparative characteristics of Na¹⁸F PET, FDG PET, and ^99mTc-MDP bone scintigraphy, see Table 1. As a skeletal imaging agent, Na¹⁸F binding is similar to conventional ^99mTc compounds with the substitution of ¹⁸F ion for hydroxyl groups and covalent binding to hydroxyapatite to form fluoroapatite compounds. However, Na¹⁸F shows more desirable skeletal kinetics than does ^99mTc, including faster blood clearance and twofold higher osseous uptake [15, 19]. Na¹⁸F distribution is dependent on regional blood flow and osteogenic activity. Higher capillary permeability and increased bone turnover seen in many osseous metastases result in high utility of Na¹⁸F radiotracer for detection of these lesions [9, 19]. In addition, although Na¹⁸F and ^99mTc-MDP uptake are both contingent on osteogenic activity, the improved spatial resolution of PET and increased target-to-background signal ratio of Na¹⁸F radiotracer likely explain the ability of Na¹⁸F PET to detect some lytic and early marrow-based metastases that are not identified by ^99mTc-MDP bone scintigraphy [9, 15].

Fluorine-18 ions show rapid plasma clearance with animal models, suggesting first-pass extraction in bone of nearly 100% [20, 21]. Low plasma protein binding and rapid urinary excretion of ¹⁸F ions result in decreased radiation exposure to the bone versus ^99mTc-MDP bone scintigraphy. There is associated rapid equilibration with high target-to-blood pool signal ratios that allow shorter injection-to-scan times, as well as shorter total imaging times for Na¹⁸F PET, compared with FDG PET and ^99mTc-MDP bone scintigraphy [9, 10, 19, 20]. Primarily because of the rapid rate of renal excretion of ¹⁸F ions, the urinary bladder receives the highest radiation dose with Na¹⁸F PET and FDG PET, compared with ^99mTc-MDP bone scintigraphy, for which the bone surface receives the highest radiation dose [22]. Current Society of Nuclear Medicine (SNM) guidelines result in Na¹⁸F PET radiopharmaceutical radiation dose of 4.4–8.9 mSv with an additional 2.0–4.0 mSv incurred if CT for attenuation correction and anatomic localization is applied [15, 19, 23].

The literature search yielded 357 original publications with 261 articles excluded on the basis of abstract reviews for topic relevancy. Full-text copies of the remaining 96 articles were reviewed, and 41 articles were excluded for poor topical relevance, outdated data, or redundant information, yielding 55 articles for our final sources. A review of references from the 96 retrieved articles produced 19 additional potential sources, with 12 included as final sources in this literature review. Two additional sources were obtained via an independent PubMed search of recent United States' data for costs and mortality associated with pulmonary neoplasm resection. The final review encompassed 69 publications, including original research and review articles.

Many studies have found superior sensitivity and specificity of Na¹⁸F PET in the detection of osseous metastatic disease in a wide range of malignancies, including breast, lung, and prostate cancer, as compared with planar ^99mTc-MDP bone scintigraphy [2, 7, 24–28] or ^99mTc-MDP bone scintigraphy with SPECT [24–27, 29–34]. Figure 1 shows sclerotic foci in a patient at our institution with prostate cancer within the left iliac bone. These lesions showed no increased uptake on planar ^99mTc-MDP bone scintigraphy, but did show abnormal increased activity on Na¹⁸F PET obtained for further characterization. Figure 2 confirms osseous metastases by disease progression on 2-year follow-up imaging. Schirrmeister et al. [7] found improved accuracy of Na¹⁸F PET over planar ^99mTc-MDP bone scintigraphy for the detection of skeletal metastasis in 44 patients with primary prostate, lung, or thyroid cancer. Na¹⁸F PET correctly detected 96 metastatic lesions in 15 patients, whereas planar ^99mTc-MDP bone scintigraphy identified only 46 metastases in 13 patients, with improved AUC values of 0.99 and 0.64, respectively, on a per-lesion basis, and greatest improvement in identification of lesions within the spine and pelvis [7]. Figure 3 shows a similar example at our institution in which Na¹⁸F PET/CT identified osseous metastases seen on planar ^99mTc-MDP bone scintigraphy, as well as multiple additional osseous metastases that were not apparent on the initial planar scintigraphy study. Concordant findings were also reported by Withofs et al. [31] comparing Na¹⁸F PET/CT and ^99mTc-MDP bone scintigraphy with SPECT. In 34 patients with breast or prostate cancer, the accuracy of Na¹⁸F PET/CT was significantly superior to that of ^99mTc-MDP bone scintigraphy for detecting pelvic and lumbar lesions. Na¹⁸F PET/CT enabled a correct diagnosis in 32 of 33 patients, compared with 28 of 33 for ^99mTc-MDP bone scintigraphy with SPECT [31].

In addition to improved sensitivity and specificity, Na¹⁸F PET provides multiple technical advantages over ^99mTc-MDP bone scintigraphy with or without SPECT. First, Na¹⁸F shows high-affinity uptake with improved sensitivity for the detection of both sclerotic and lytic metastases [29, 31, 32, 35, 36]. Second, Na¹⁸F PET produces enhanced image quality with increased efficiency for photon capture and improved spatial resolution versus traditional scintigraphy [13]. Third, Na¹⁸F shows superior pharmacokinetics over ^99mTc-MDP [18] with high first-pass uptake [21], higher lesion-to-background signal ratio, and rapid blood clearance [37], allowing shorter injection-to-scan intervals that improve patient tolerance and increase imaging center throughput.

Given consensus data supporting the improved diagnostic utility of Na¹⁸F PET/CT versus ^99mTc-MDP bone scintigraphy with SPECT, evaluation of the impediments to adoption of Na¹⁸F PET/CT for standard of care is warranted. Aside from limited availability, two drawbacks of Na¹⁸F PET/CT have been cited in the literature: increased patient radiation dose, with a significant portion obtained through CT for attenuation correction acquisitions [19, 20, 38, 39], and increased study cost [10, 15, 20, 38–42]. Although current guidelines provide similar radiopharmaceutical dosimetry of 4.4–8.9 mSv and 4.2–6.3 mSv for Na¹⁸F PET and ^99mTc-MDP bone scintigraphy, respectively [19, 43], high target-to-background signal ratio of Na¹⁸F and time-of-flight PET/CT cameras may allow significant reductions of injected Na¹⁸F dose. Recently, Ohnona et al. [44] performed standard 60 s/bed position PET acquisitions with 30 s/bed position reconstructions to simulate the administration of one half the SNM-recommended 5.0–10.0 mCi (185.0–370.0 MBq) dose of Na¹⁸F with no loss of information on a semiquantitative level or decrease in lesion detection sensitivity, suggesting the viability of 2.5–5.0 mCi (92.5–185.0 MBq) dosing [44]. Although this would provide a patient dose of only 2.2–4.4 mSv, it is important to note that even this dose reduction remains well above the original FDA-approved dose for Na¹⁸F radiotracer of 0.5–2.0 mCi (18.5–74.0 MBq) [33].

Although CT for attenuation correction image acquisition for PET/CT improves specificity on a per-lesion basis [11, 19, 20] and sensitivity on a per-patient basis [45], current low-dose whole-body acquisition protocols result in 2.0–4.0 mSv increased patient dose [15, 22]. Higher quality “low-dose” protocols are used at some institutions, although the application of iterative reconstruction algorithms and recent data from ultra-low-dose CT investigations are likely to further decrease the CT component of PET/CT dosimetry [46, 47]. In addition, the relative increase in patient radiation dose with PET/CT versus ^99mTc-MDP bone scintigraphy has been progressively mitigated through increased utilization of SPECT/CT, with whole-body SPECT/CT attenuation correction images providing patient dosimetry similar to levels observed in PET/CT studies [48].

Although a detailed cost-effectiveness analysis for Na¹⁸F PET/CT versus ^99mTc-MDP bone scintigraphy with SPECT has not been performed in the United States, a German study issued in December 2003 [24] evaluated the cost effectiveness of Na¹⁸F PET for lung cancer staging. In this study of 103 patients with lung cancer evaluated by planar ^99mTc-MDP bone scintigraphy, ^99mTc-MDP bone scintigraphy with SPECT, and Na¹⁸F PET, 13 of 33 patients with bone metastases had false-negative results on planar ^99mTc-MDP bone scintigraphy, four had false-negative results on ^99mTc-MDP bone scintigraphy with SPECT, and two had false-negative results on Na¹⁸F PET. Despite improved sensitivity with detection of osseous metastases in 6.5% more patients by Na¹⁸F PET than ^99mTc-MDP bone scintigraphy with SPECT, the proposed threshold for improved cost effectiveness of Na¹⁸F PET was only $424.35 [24]. The value of $424.35 was calculated from the reported cost of €345 by Hetzel et al. [24] with an exchange rate of $1.24 to €1 at the time of publication in December 2003. Although compelling, this cost-effectiveness analysis did not incorporate the cost incurred from 2.5 times higher utilization of follow-up MRI scans for indeterminate findings after bone scintigraphy with SPECT versus Na¹⁸F PET or consider 40–80-minute longer acquisition times and lower patient compliance observed with ^99mTc-MDP bone scintigraphy with SPECT. With average hospitalization costs for lobectomy of $78,000–$89,000 in the United States [49], perioperative mortality for pneumonectomy ranging from 5% to 11% [50], and the potential for significant postoperative morbidity, more comprehensive cost-effectiveness analyses of cancer-specific cohorts are warranted to evaluate improved treatment planning and decreased incidence of noncurative surgical intervention that may be obtained from the increased diagnostic sensitivity of Na¹⁸F PET.

Despite the high economic premium on the improved diagnostic accuracy of Na¹⁸F PET, it is possible that increasing the availability of Na¹⁸F could partially alleviate the increased cost of utilization [40]. Modification to billing structures provides an additional opportunity to improve cost-effectiveness analyses in favor of Na¹⁸F PET. As mentioned by Bridges et al. [10], by including whole-body tomographic skeletal scintigraphy without acquiring information for soft-tissue metabolic activity, Na¹⁸F PET interpretation is more comprehensive than that of ^99mTc-MDP bone scintigraphy with ROI SPECT interpretation, while remaining less technically demanding than interpretation for FDG PET. Decreased interpretation complexity, with reduced image acquisition time [40] as compared with FDG PET, may enable improved patient throughput and justify reimbursement of Na¹⁸F PET at a level between ^99mTc-MDP bone scintigraphy with SPECT and FDG PET, while also preserving imaging center productivity.

Given the relative advantages of FDG PET for lytic metastases and ^99mTc-MDP bone scintigraphy for sclerotic metastases [3, 51–60], in the context of the improved sensitivity and specificity of Na¹⁸F PET versus ^99mTc-MDP bone scintigraphy, it is not surprising to find further improvement in the detection of sclerotic osseous metastases with Na¹⁸F PET/CT over FDG PET/CT [32], as shown in Figure 4. However, despite the improved sensitivity of Na¹⁸F PET for osteolytic metastases compared with ^99mTc-MDP bone scintigraphy, FDG PET retains a slight advantage in sensitivity over Na¹⁸F PET for some lytic and early marrow-based lesions [29, 31, 61, 62]. Although recent data suggest that Na¹⁸F PET/CT is the most comprehensive study for evaluating osseous metastatic disease in breast, lung, and prostate cancer [2, 31, 32, 63], at least one study of patients with lung cancer has reported improved sensitivity on a per-lesion basis for FDG PET/CT compared with Na¹⁸F PET, although the sensitivities of the two modalities on a per-patient basis was 78% and 92%, respectively [29].

Multiple researchers have anticipated the replacement of ^99mTc-MDP bone scintigraphy with Na¹⁸F PET/CT for evaluating osseous metastatic disease [10, 11, 25, 61]. Given the propensity of FDG PET for early lytic osseous lesions and its sensitivity for primary and metastatic soft-tissue lesions, complementary roles of these modalities appear likely [2, 32, 39, 61, 64]. Recent data by Iagaru et al. [2, 33, 64] have renewed inquiry for the technique proposed by Hoegerle et al. [65] for combined Na¹⁸F and FDG PET [64–67]. In patients with various malignancies evaluated by FDG PET/CT and combined Na¹⁸F and FDG PET/CT, more lesions were detected by the combined scan in 16 of the 47 patients for whom malignancy was identified. For five patients, combined Na¹⁸F and FDG PET/CT also identified osseous metastases that were negative for metastasis by FDG PET/CT [67]. An international multicenter trial subsequently evaluated 115 patients with various cancers by serial imaging with FDG PET/CT, Na¹⁸F PET/CT, and combined Na¹⁸F and FDG PET/CT. In this series, combined Na¹⁸F and FDG PET/CT showed more extensive osseous metastases than did FDG PET/CT in 19 patients and positive findings in an additional 29 patients who were negative for bone metastases by FDG PET/CT. Although two skull lesions seen on Na¹⁸F PET/CT and three subcentimeter lung nodules seen on FDG PET/CT were missed in a total of four patients on the combined scan, disease staging was not affected [66].