Research ArticleClinical Investigation
Open Access

Prospective Head-to-Head Comparison of 18F-PSMA PET/CT and 18F-NaF PET/CT for Assessing Bone Metastases in 160 Patients with Newly Diagnosed High-Risk Prostate Cancer

Claus Madsen, Dan Fuglø, Maria Pedersen, Rikke Broholm, Peter B. Østergren, Rasmus Bisbjerg, Per Kongsted, Kayalvili Nielsen, Christian Haarmark and Helle Zacho
Journal of Nuclear Medicine January 2025, jnumed.124.268275; DOI: https://doi.org/10.2967/jnumed.124.268275

Abstract

Prostate-specific membrane antigen (PSMA) PET/CT is increasingly used for primary staging in prostate cancer (PC), mainly because of its improved accuracy in detecting lymph node metastases compared with conventional imaging. However, the diagnostic benefit of PSMA PET/CT for detecting bone metastases is less well established. This study compares the diagnostic accuracy of 18F-PSMA PET/CT and 18F-NaF PET/CT for detecting bone metastases in patients newly diagnosed with PC. Methods: This prospective study included patients with histologically confirmed high-risk PC. All participants were referred from the department of urology to 18F-NaF PET/CT and underwent 18F-PSMA PET/CT within 3 weeks. Images were reviewed by 2 nuclear medicine physicians unaware of the results of the other imaging modality. Presence or absence of bone metastases and number of metastatic lesions were recorded. A reference standard was established at the patient level based on agreement between the 2 imaging modalities. In cases of concordance, both modalities were deemed correct. In cases of discordance, additional follow-up scans were performed. Diagnostic performance metrics, including sensitivity, specificity, and accuracy, were calculated. Results: In total, 160 participants were included. Sensitivity, specificity, and accuracy for detecting bone metastases at the patient level were 0.98, 0.99, and 0.99, respectively, for 18F-PSMA PET/CT, and 0.91, 1.00, and 0.97, respectively, for 18F-NaF PET/CT. No significant differences were found. The concordance rate of bone metastases between 18F-NaF and 18F-PSMA PET/CT at the patient level was observed in 154 patients (96.3%). 18F-PSMA PET/CT tended to identify more bone metastases per patient than 18F-NaF PET/CT. Conclusion: Both 18F-NaF and 18F-PSMA PET/CT exhibit high diagnostic accuracy for detecting bone metastases in newly diagnosed high-risk PC patients. 18F-PSMA PET/CT may detect additional metastatic lesions compared with 18F-NaF PET/CT. Subsequent 18F-NaF PET/CT may be redundant if no bone metastases are found on 18F-PSMA PET/CT.

Prostate cancer (PC) is among the most frequently diagnosed malignancies globally (1). It predominantly spreads to lymph nodes and bones. Accurate initial staging is essential for selecting appropriate treatment. Imaging modalities typically include bone scintigraphy and CT (2,3). However, CT has limited sensitivity for detecting lymph node metastases (4).

Prostate-specific membrane antigen (PSMA) ligands are used in PET and recognized for their potential in imaging metastatic PC. The ligand binds to a membrane glycoprotein that is upregulated on the surface of PC cells (5), serving as a direct marker of disease distribution, including bone involvement.

In contrast, imaging with bone-seeking agents, such as diphosphonates used in bone scintigraphy and 18F-NaF used in 18F-NaF PET/CT, reflects osteoblastic bone reformation. This reformation is influenced by, among other factors, metastases from PC. 18F-NaF PET/CT offers several advantages over bone scintigraphy, including higher spatial resolution and rapidly acquired tomographic imaging of the entire area of interest.

Several studies have demonstrated improved diagnostic accuracy of PSMA PET/CT for detecting lymph node metastases compared with CT and MRI. (6–8). Consequently, the European Association of Urology now recommends PSMA PET/CT for initial staging in patients with high-risk PC (3). Although multiple studies suggest that PSMA PET/CT is superior to bone scintigraphy for detecting bone metastases (9), the efficacy of the PSMA radioligand compared with 18F-NaF for skeletal evaluation in initial staging remains uncertain. Indeed, no large prospective studies have compared PSMA PET/CT with 18F-NaF PET/CT in patients with newly diagnosed disease.

The aims of this study were to compare 18F-PSMA PET/CT and 18F-NaF PET/CT for the assessment of bone metastases in patients with newly diagnosed high-risk PC and to determine whether 18F-NaF PET/CT can be omitted when no bone metastases are found on 18F-PSMA PET/CT.

MATERIALS AND METHODS

Participants

This prospective, single-center study included consecutive patients with histologically proven PC, categorized as high-risk according to the D’Amico criteria (T stage ≥ cT2c, International Society of Urological Pathology grade group ≥ 4, or prostate-specific antigen > 20 ng/mL) (10). T stage was based on digital rectal examination. Patients with a high clinical suspicion of PC (high prostate-specific antigen or T2c-T4 tumor) were often referred for metastatic evaluation before definitive histology of the prostate biopsies and could thus be included in the study. Patients were excluded from the analysis if the final histopathologic results did not confirm PC.

All patients underwent 18F-NaF PET/CT as part of the standard diagnostic work-up at Copenhagen University Hospital Herlev and Gentofte. Participant enrollment took place from May 4, 2021, to February 20, 2024.

Patients were excluded if they were diagnosed with a nonprostate malignancy within the last 5 y or during the diagnostic work-up for PC (except for basal cell or squamous cell skin cancer), had commenced androgen deprivation therapy, had severe obesity, or could not cooperate.

Informed oral and written consent from the participants was obtained at the Department of Nuclear Medicine before the clinical 18F-NaF PET/CT scan. The 18F-PSMA PET/CT was performed as a study-specific procedure within 3 wk of the 18F-NaF PET/CT.

18F-NaF PET/CT

18F-NaF PET/CT was conducted as part of daily clinical practice. A mean dose of 199 MBq (SD, ±3 MBq; range, 172–207 MBq) was injected 30 min before image acquisition. PET/CT was performed using a Biograph mCT (Siemens Healthineers). Images were acquired from the top of the skull to above the knees, with an acquisition time of 1 min per bed position. The 18F-NaF PET was combined with either low-dose CT (tube current–time product of 40 mAs with dose modulation, 120 kV, pitch of 0.8, and 5-mm slice thickness) or diagnostic CT (tube current–time product of 180 mAs with dose modulation, 120 kV, pitch of 0.8, and 3-mm slice thickness) if soft-tissue evaluation was indicated. In diagnostic CT, iodinated contrast medium was infused if tolerated. The choice between low-dose and diagnostic CT was made at the discretion of the referring urologist.

18F-PSMA PET/CT

The 18F-labeled 18F-PSMA-1007 ligand was used for the study. A mean dose of 256 MBq (SD, ±14 MBq; range, 210–316 MBq) was injected 60 min before image acquisition on a Biograph mCT PET/CT scanner. Images were acquired from the top of the skull to above the knees, with an acquisition time of 3 min per bed position. The PET scan was combined with a diagnostic CT scan.

Image Analysis

The image analyses of 18F-NaF and 18F-PSMA PET/CT were performed independently by 2 board-certified nuclear medicine physicians, each with extensive experience in interpreting 18F-NaF PET/CT and 18F-PSMA PET/CT. The readers did not know the results of the other imaging modality or the clinical information, except for the diagnosis of high-risk PC.

At the patient level, whether the patient had bone metastases was recorded. The level of confidence was noted as either no doubt or with doubt; an inconclusive scan was not an available option. At the lesion level, the number of bone metastases was recorded as 1, 2, 3, 4, 5, or more than 5. Factors influencing the interpretation toward bone metastasis included 18F-PSMA uptake equal to or above the spleen (11), well-defined lesion borders, involvement of cancellous bone, an osteoblastic appearance on CT, and multiple lesions with metastatic characteristics.

The treating physicians did not know the results of the 18F-PSMA PET/CT, as it was not part of the standard diagnostic work-up at our institution. However, if requested by the treating physicians, a report of the 18F-PSMA PET/CT scan was provided.

Reference Standard

Histopathologic reference standards for the presence or absence of bone metastases were not available for ethical and practical reasons in most cases. If neither 18F-NaF PET/CT nor 18F-PSMA PET/CT revealed any bone metastases, the patient was categorized as having no bone metastases. If both modalities agreed on the location of at least 1 bone metastasis, the patient was categorized as having bone metastases. In cases of discordance between 18F-NaF and 18F-PSMA PET/CT, both scans were repeated once at least 6 mo after the initial 18F-PSMA PET/CT scan (Fig. 1). The subsequent 18F-NaF and 18F-PSMA PET/CT, along with all available clinical data including treatment and biochemical data, were included in a composite reference standard, determined by a multidisciplinary panel consisting of a urologist, an oncologist, and 2 nuclear medicine specialists.

FIGURE 1.
FIGURE 1.

Flowchart illustrating process of achieving final diagnosis of bone metastases on patient level.

Statistics

Statistical analyses were performed using RStudio, version 4.4.0 (Posit Software). Patients’ clinical characteristics are reported as descriptive statistics, including mean or median, SD, and range. For each imaging modality, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy, along with 95% confidence intervals, were calculated on a patient level using the epiR package. The McNemar test was performed to compare diagnostic accuracies using the DTComPair package. The threshold for rejecting no difference between the 2 imaging methods was 0.05.

All data were collected in the REDCap database (Vanderbilt University). The Sankey diagram was made with SankeyMATIC.

Ethics

This study complied with the Helsinki II Declaration. All patients provided written informed consent to participate. The study protocol was approved by the regional ethics committee (approval H-20060829) and the Danish Data Protection Agency.

RESULTS

Study Population

In total, 846 potentially eligible participants were screened, and 332 were not invited to participate because of other types of active cancer, initiation of androgen-deprivation therapy before the scan, or other reasons (Fig. 2). Thus, 514 patients were invited to participate, and 175 accepted the invitation. Fifteen patients were excluded from the data analysis: 12 had a benign final histopathologic result from the prostate biopsies, 2 were diagnosed with an additional malignancy during the diagnostic work-up for PC, and one did not undergo 18F-PSMA PET/CT because of 18F-PSMA production failure. The final study population comprised 160 patients with newly diagnosed high-risk PC (Table 1). All were diagnosed with acinar adenocarcinoma of the prostate. One patient had a component of small cell neuroendocrine carcinoma, which made up 25% of the tumor. On average, 10 d (range, 1–21 d) elapsed between the routine 18F-NaF PET/CT and the 18F-PSMA PET/CT.

FIGURE 2.
FIGURE 2.

Flowchart illustrating inclusion process of study participants.

View this table:
TABLE 1.

Demographic Data of Study Population

Patient-Based Diagnostic Accuracy Measurements

According to the reference standard, 44 patients (27.5%) had bone metastases. In 154 of 160 patients (96.3%), there was concordance between 18F-PSMA and 18F-NaF PET/CT regarding the presence or absence of bone metastases at the patient level. Both scans were thus deemed correct in these cases. 18F-PSMA PET/CT differed from 18F-NaF PET/CT in 6 patients (3.8%), who subsequently underwent additional 18F-PSMA and 18F-NaF PET/CT 6 mo later. Of all available imaging and patient records, 18F-NaF PET/CT correctly classified 2 patients, whereas 18F-PSMA PET/CT correctly classified the remaining 4 patients (Table 2; Fig. 3). Sensitivity, specificity, and accuracy for detecting bone metastases at the patient level were 0.98, 0.99, and 0.99, respectively, for 18F-PSMA PET/CT and 0.91, 1.00, and 0.97, respectively, for 18F-NaF PET/CT (Table 3). There was no significant difference in diagnostic performance between 18F-PSMA and 18F-NaF PET/CT (P = 0.18, 0.31, and 0.68, respectively) according to the McNemar test.

View this table:
TABLE 2.

Patients with Discordant Findings on 18F-NaF PET/CT and 18F-PSMA PET/CT and with Repeated Scans 6 Months Later

FIGURE 3.
FIGURE 3.

Patient with discordant findings on baseline 18F-NaF and 18F-PSMA PET/CT. (A) Maximum-intensity projection and axial projection of 18F-NaF PET/CT scan with no evidence of bone metastases. (B) 18F-PSMA PET/CT scan showing 2 lesions, one in left ilium and another in right costa 6, which were suspected of being bone metastases (red arrows). Third faint lesion in right ilium was not interpreted as bone metastasis (green arrows). Because of absence of metastatic lesions on 18F-NaF PET/CT (conventional scan), patient was observed, without treatment. (C and D) Follow-up scans conducted 6 months later revealed detectable uptake in lesion in right ilium on 18F-NaF PET/CT and increasing uptake on 18F-PSMA PET/CT (orange arrows). There are multiple 18F-PSMA-avid lymph nodes on follow-up scan.

View this table:
TABLE 3.

Diagnostic Performances at Patient Level

Number of Bone Metastases

In each scan, the number of metastases was assessed (1–5 or >5). Generally, 18F-PSMA PET/CT revealed more bone metastases than 18F-NaF PET/CT (Fig. 4). In 8 patients, 18F-NaF PET/CT identified a single metastatic lesion. Of these, anatomically correlated lesions were also detected on 7 18F-PSMA PET/CT scans; however, in 1 patient, 18F-PSMA PET/CT incorrectly interpreted the lesion (located in the ischial tuberosity) as benign. Conversely, 18F-PSMA PET/CT detected additional bone metastases in 3 patients compared with 18F-NaF PET/CT, revealing 2 additional bone metastases in 1 patient and polymetastatic disease (>5) in 2 patients.

FIGURE 4.
FIGURE 4.

Sankey diagram of number of bone metastases detected by 18F-NaF PET/CT and 18F-PSMA PET/CT in 44 patients with bone metastases according to reference standard. bm = bone metastases.

18F-PSMA PET/CT identified more patients with polymetastatic disease (n = 28) than did 18F-NaF PET/CT (n = 22). Among patients with oligometastatic (1–5) bone involvement according to 18F-NaF PET/CT (n = 18), the pelvis was involved in most cases (n = 14, 78%). The 4 patients (22%) with exclusively extrapelvic bone involvement each had only 1 metastatic lesion detected.

Level of Confidence

The reader of 18F-NaF PET/CT was confident about the presence or absence of bone metastases at the patient level in 139 (87%) of 160 scans (Table 4). The reader of 18F-PSMA PET/CT was confident in 143 (89%) scans. The level of confidence was highest for both modalities (100%) when 3 or more bone metastases were detected. Conversely, when only 1 suggestive lesion was detected, the reader of 18F-NaF PET/CT was confident in 1 of 8 scans (13%) whereas the reader of 18F-PSMA PET/CT was confident in 4 of 7 scans (57%).

View this table:
TABLE 4.

Proportion of Scans with Confident Conclusions, Stratified by Number of Bone Metastases

DISCUSSION

This study was, to the best of our knowledge, the first large prospective study comparing 18F-PSMA and 18F-NaF PET/CT for detecting bone metastases in a homogeneous cohort of patients at the primary staging of PC. The study revealed high concordance between the 2 modalities for detecting bone metastases, with crude agreement in 96% of the patients. There was a trend for 18F-PSMA PET/CT to detect more patients with bone metastases and to identify a higher number of lesions in metastatic patients. However, both imaging modalities demonstrated high diagnostic accuracy for detecting bone metastases.

Few studies have compared the diagnostic accuracy of PSMA radioligands and 18F-NaF PET/CT for detecting bone metastases. Dyrberg et al. examined 55 patients across various stages of PC. Both 18F-NaF and 68Ga-PSMA PET/CT demonstrated high diagnostic accuracy, ranging from 96% to 100% (12). Zacho et al. found comparably high sensitivity and specificity for both modalities in 68 patients with biochemically recurrent PC (13).Two smaller studies, including patients with metastatic PC (14) and those after curative treatment (15), showed promising results for both modalities.

Bone scintigraphy has been more extensively compared with PSMA PET/CT. A prospective study of 113 patients with newly diagnosed PC showed that 68Ga-PSMA PET/CT had significantly higher sensitivity and accuracy than bone scintigraphy (16). Other studies have confirmed the improved sensitivity and specificity of 68Ga-PSMA PET/CT in PC patients at different stages (17–20). The large prospective proPSMA study also found that 68Ga-PSMA PET/CT had significantly higher accuracy for detecting distant metastases, although bone metastases were not assessed separately (21). In conclusion, the sensitivity of PSMA PET/CT is superior to that of bone scintigraphy in patients with PC, both at primary staging and at later disease stages.

We found a high concordance between 18F-PSMA and 18F-NaF PET/CT at the patient level, but 18F-PSMA PET/CT detected bone metastases in 4 additional patients. Moreover, 18F-PSMA PET/CT tended to identify more bone metastases in the individual patients. This finding opposes a study by Fourquet et al., who compared 18F-DCFPyL and 18F-NaF PET/CT in 61 men with known metastatic disease (22). 18F-NaF PET detected significantly more bone metastases than 18F-DCFPyL. However, the cohort comprised patients at different disease stages, and the difference between the 2 ligands was particularly clear for patients receiving treatment. The PSMA radioligands serve as direct markers of metastatic bone disease, whereas 18F-NaF reflects increased bone turnover, often a consequence of bone metastases from PC. This suggests that PSMA PET/CT might detect early metastatic presence in the bone marrow, followed by osteoblastic activity visible on 18F-NaF PET, and later by sclerotic bone formation on CT.

The low discordance rate of 3.8% in our study aligns with findings from a retrospective study involving a subset of patients who underwent 68Ga-PSMA and 18F-NaF PET/CT for primary staging (23). Three of 80 patients (3.8%) had bone metastases detected exclusively by 68Ga-PSMA PET/CT. Similar to our study, there was a trend indicating that 68Ga-PSMA PET/CT identified more metastatic bone lesions than did 18F-NaF PET/CT.

In our study, only 1 18F-PSMA PET/CT scan was false-positive, showing a small lesion in the femoral neck. Unspecific bone uptake of 18F-PSMA-1007, used in this study, is well known (24), particularly in the ribs and pelvis (25). In patients with no detected bone metastases, the reviewers of 18F-PSMA and 18F-NaF PET/CT were uncertain in 11% and 10% of the scans, respectively, mostly because of unspecific bone uptake. The high proportion of unspecific bone uptake on 18F-PSMA PET/CT has been described as a major pitfall compared with 68Ga-PSMA-11 PET/CT (26). To minimize the risk of false positives, the present study involved the criterion that at least 1 bone metastasis should be anatomically correlated between 18F-PSMA and 18F-NaF PET/CT. We found a high specificity at the patient level. Thus, 18F-PSMA-1007 PET/CT is excellent for evaluating osseous involvement, but careful and experienced reading is crucial.

In both modalities, the lowest proportion of scans with a confident reading was observed when only 1 bone metastasis was detected. Treatment decisions depend on the diagnosis of bone metastases and whether oligo- or polymetastatic bone involvement is present (3). Indeed, diagnosing oligometastatic bone disease remains challenging. However, when 3 or more bone metastases were detected, the readers of both modalities felt confident in the diagnosis.

A limitation of the study was that only 19% of the potentially eligible participants were included. The 18F-PSMA PET/CT scans were anonymized and used solely for study purposes without remuneration. Consequently, selection bias may have occurred.

Another limitation was the single-center setup. Confirmation of the high diagnostic accuracies is warranted. Additionally, the cohort included patients with both curative and noncurative PC, and thus many of the patients had high prostate-specific antigen levels. The high concordance between 18F-PSMA and 18F-NaF PET/CT could be due to the high proportion of polymetastatic bone disease. Fewer bone metastases led to less reviewer confidence, increasing the risk of errors.

An additional limitation is the absence of a histopathologic reference standard. When no bone metastases were detected on either 18F-PSMA or 18F-NaF PET/CT, both modalities were deemed correct, which could mean that both might be false-negative because of micrometastatic bone involvement. Conversely, both imaging modalities could also have been false-positive, misinterpreting benign lesions as bone metastases. Indeed, tracer uptake may be increased in various benign conditions, such as fractures, Paget disease, and fibrous dysplasia in both 18F-PSMA PET (27) and 18F-NaF PET (28). Additionally, unspecific bone uptake of 18F-PSMA-1007 (24) could induce a risk of false-positive skeletal findings.

CONCLUSION

We have presented the first—to our knowledge—large prospective trial comparing 18F-PSMA PET/CT and 18F-NaF PET/CT in patients with newly diagnosed high-risk PC. Both imaging modalities demonstrated high diagnostic accuracy for detecting bone metastases, with no significant difference between them. 18F-NaF PET/CT offers no additional value in patients for whom 18F-PSMA PET/CT does not identify bone metastases.

DISCLOSURE

No potential conflict of interest relevant to this article was reported.

KEY POINTS

QUESTION: Is 18F-PSMA PET/CT sufficient for detecting bone metastases in patients with newly discovered PC?

PERTINENT FINDINGS: This prospective study comprised 160 patients and demonstrated high diagnostic accuracies for both 18F-PSMA PET/CT and 18F-NaF PET/CT, with no significant difference between the two modalities.

IMPLICATIONS FOR PATIENT CARE: If no bone metastases are detected on 18F-PSMA PET/CT, additional 18F-NaF PET/CT may be redundant.

ACKNOWLEDGMENTS

We thank all the patients who made this study possible. Our gratitude goes to Bent Kristensen for statistical advice and to the staff at the PET Center, Herlev Hospital.

Footnotes

  • Published online Jan. 8, 2025.

Immediate Open Access: Creative Commons Attribution 4.0 International License (CC BY) allows users to share and adapt with attribution, excluding materials credited to previous publications. License: https://creativecommons.org/licenses/by/4.0/. Details: https://jnm.snmjournals.org/page/permissions.

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    2. Macapinlac HA
    . 18F-fluoride: benign bone disease. In: Kairemo K, Macapinlac HA, eds. Sodium Fluoride PET/CT in Clinical Use. Springer International Publishing; 2020:47–53.
  • Received for publication August 21, 2024.
  • Accepted for publication November 19, 2024.
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