Advanced PET Scan Reveals Bone Metastases Are Far Rarer in Intermediate-Risk Prostate Cancer Than Guidelines Assume

A sweeping analysis of more than 700 men with newly diagnosed prostate cancer has delivered a striking verdict on one of nuclear medicine’s most trusted imaging tools: while fluorine-18 sodium fluoride PET/CT is exceptionally good at spotting bone metastases, the scan may be almost pointless for a large subgroup of patients who are currently sent for it as a matter of routine. The study, published in the European Journal of Nuclear Medicine and Molecular Imaging, followed 734 consecutive patients staged at Copenhagen University Hospital Herlev and Gentofte between January 2019 and December 2020, and its findings challenge the evidence base on which international guidelines have quietly rested for years.

The numbers tell a story of two very different diseases hiding under one diagnostic umbrella. Among the 607 patients classified as high-risk under the European Association of Urology classification, fluorine-18 sodium fluoride PET/CT detected bone metastases in 224 individuals, or 37 percent of the group. Yet among the 127 patients with unfavourable intermediate-risk disease and a tumour grade of ISUP grade group 3, exactly one patient, or 0.8 percent, turned out to have metastatic bone involvement. Follow-up data suggested one additional intermediate-risk patient may have harboured a metastasis that the initial scan missed, but even taking that possibility into account, the yield in this subgroup was vanishingly small.

The imaging technique itself is worth understanding, because its physics explains both its power and its pitfalls. After intravenous injection, the fluoride ion travels through the bloodstream in proportion to regional blood flow and exchanges with hydroxyl ions in hydroxyapatite, the mineral scaffold of bone, to form fluoroapatite. This means the signal captured by the PET camera reflects two biological processes at once: bone perfusion and osteoblastic activity, the cellular machinery that lays down new bone. Bone metastases typically provoke exactly this kind of remodelling, which is why they light up brightly on the scan. The catch is that benign conditions, from arthritis to healing fractures, provoke the same response, so interpretation demands experienced readers who can distinguish malignant patterns from incidental noise.

In this study, ten nuclear medicine specialists who collectively analyse more than 3,000 scans per year interpreted the images. Only 24 of the 734 scans, roughly 3 percent, were classified as equivocal, and two experts blinded to the original reports reanalysed each of those cases to reach a consensus diagnosis, concluding that 20 of the 24 patients did not have bone metastases. That low equivocal rate stands in sharp contrast to the older technology that shaped current guidelines. Planar bone scintigraphy using technetium-99m labelled diphosphonates, the workhorse of previous decades, produces far more ambiguous results. In one retrospective study of 853 patients cited by the Danish team, 16 percent of scans were equivocal; in another of 703 patients, the figure reached 42 percent, forcing a cascade of additional imaging.

To establish how trustworthy the PET findings actually were, the researchers constructed a rigorous reference standard. A nuclear medicine specialist reviewed all available follow-up imaging alongside clinical records, and when the picture remained unclear, a urologic specialist weighed the full clinical data set. Evidence supporting metastatic disease ranged from histologic verification and confirmatory MRI or PSMA PET/CT findings down to patterns of increasing fluoride uptake or newly emerging lesions consistent with treatment failure. Evidence against included undetectable prostate-specific antigen after radical prostatectomy, negative complementary imaging, and consistently negative follow-up scans paired with stable or falling PSA in the absence of systemic therapy. For the 689 patients, 94 percent of the cohort, in whom this process yielded a conclusive verdict, fluorine-18 sodium fluoride PET/CT achieved a sensitivity of 0.90 and a specificity of 0.99, figures the authors describe as consistent with the best previous estimates.

Within the high-risk group, the analysis confirmed what clinicians have long suspected about the biology of prostate cancer’s spread to bone. Higher PSA levels, more advanced clinical tumour stage, and higher ISUP grade groups each carried independently increasing odds of metastasis in multivariate logistic regression, with the three variables adjusted for potential confounding. This dose-response relationship across the classic risk markers reinforces that bone imaging is genuinely informative precisely where the disease is most aggressive. The problem, the authors argue, is that guidelines extrapolated from planar bone scintigraphy-era evidence have never been systematically revalidated for modern scanners, and the diagnostic pathway itself has shifted underneath them, with MRI-targeted biopsies now upgrading many tumours into higher grade categories and shifting patients between risk groups.

The single intermediate-risk patient with a confirmed metastasis illustrates how subtle these cases can be. The scan revealed a single sclerotic lesion in the right pubic bone with avid fluoride uptake, subsequently confirmed by gallium-68 PSMA-11 PET/CT. The patient underwent radical prostatectomy as part of a clinical trial for oligometastatic disease, and histopathology of the removed prostate showed grade group 5 disease, a reminder that grade can be underestimated before the whole gland is examined. The second intermediate-risk patient, whose initial scan showed no lesions, received curative radiotherapy and 17 months of medical castration before treatment was stopped due to side effects; three and a half years later, a follow-up sodium fluoride PET/CT revealed a suspicious lesion in the left pubic bone, and the original scan was retrospectively classified as false-negative.

How do these results square with the newer contender in the field, PSMA PET/CT? A retrospective multicenter study of 396 intermediate-risk patients with grade group 3 disease, examined with four different PSMA radioligands, found bone metastases in 4 percent overall, but the rate varied dramatically by tracer: 21 percent with fluorine-18 PSMA-1007 against just 3 percent with gallium-68 labelled agents. That discrepancy matters because fluorine-18 PSMA-1007 is known to produce uptake in non-specific bone lesions, meaning some of those positives were likely false. A separate study of 1,253 consecutive men staged with gallium-68 PSMA-11 PET/CT detected bone metastases in only 3 percent of 638 intermediate-risk patients. Both figures align closely with the Danish sodium fluoride results, and they carry a practical warning: when the pretest probability of bone involvement is this low, isolated PSMA-avid bone lesions should be interpreted with considerable caution, since non-specific uptake may account for a substantial share of positive findings.

The authors are candid about the limitations that temper their conclusions. The retrospective, single-center design introduces potential selection bias and limits control over imaging indications and follow-up procedures. The reference standard relied on follow-up rather than histology in most cases, leaving room for misclassification, and systemic treatment started after the index scan may have masked metastases that would otherwise have declared themselves. The sensitivity estimate in the intermediate-risk subgroup rested on just two positive patients, making it statistically imprecise. Biopsy technique also varied across the cohort, with some men receiving systematic ultrasound-guided biopsies and others MRI-targeted sampling from March 2019 onward, a heterogeneity that may have influenced ISUP grading and therefore risk stratification itself.

Even with those caveats, the central message is hard to escape. Fluorine-18 sodium fluoride PET/CT performs superbly where it matters most, catching bone metastases in more than a third of high-risk patients with sensitivity and specificity approaching the ceiling of what imaging can achieve. But for men with unfavourable intermediate-risk disease and grade group 3 tumours, the scan found metastases in one patient out of 127, and the authors conclude that routine use in this subgroup appears to have limited clinical value. As hospitals worldwide weigh the cost, radiation exposure, and logistical burden of staging imaging against genuine benefit, this study offers a data-driven argument for narrowing the net, reserving advanced bone imaging for the patients in whom the disease is truly likely to have already reached the skeleton.

Subject of Research: Diagnostic accuracy of fluorine-18 sodium fluoride PET/CT for detecting bone metastases in newly diagnosed prostate cancer

Article Title: Risk of bone metastases on [18F]NaF PET/CT in 734 patients with newly diagnosed prostate cancer

Article References: Madsen, C., Zacho, H. D., Bisbjerg, R., Fuglø, D., & Østergren, P. B. (2026). Risk of bone metastases on [18F]NaF PET/CT in 734 patients with newly diagnosed prostate cancer. European Journal of Nuclear Medicine and Molecular Imaging. https://doi.org/10.1007/s00259-026-08148-y

Image Credits: AI Generated

DOI: 10.1007/s00259-026-08148-y

Keywords: prostate cancer, bone metastases, NaF PET/CT, PSMA PET/CT, bone scintigraphy, diagnostic accuracy, intermediate-risk, ISUP grade group, EAU guidelines, PSA, nuclear medicine, staging