Numerous publications have addressed the role of ¹⁸F-FDG PET-CT in staging and follow up of cancer patients. ¹⁸F-FDG PET imaging was shown to be superior to BS omitting the need to perform a separate BS for assessment of skeletal disease. In addition to its ability to detect metastasis confined to the marrow component, ¹⁸F-FDG-PET is highly sensitive for detection of lytic type cortical metastases characterized by their high rate of glycolysis and hypoxia while BS is relatively insensitive for detection of this type of cortical lesions (Fig. 1a). Although ¹⁸F-FDG-PET has been reported appropriate for detecting all types of bone metastases, it is considered to be somewhat less sensitive for detection of blastic type metastases that are considered generally less aggressive. Detection of the latter can be achieved, however, by reviewing the CT data of PET-CT [1–3, 6–8].

In spite of its proven relevance in various oncologic diseases, ¹⁸F-FDG-PET/CT has no place in imaging patients with non-FDG avid tumors. Neuroendocrine tumors (NET) and prostate cancer are examples of basically non-FDG avid tumors for which we now have alternative suitable PET tracers. ⁶⁸Ga-Somatostatin PET-CT is of value for staging and follow-up of patients with the NET showing high-expression of Somatostatin receptors. ⁶⁸Ga is a short lived PET tracer with a half-life of 68 min available from an in house generator of ⁶⁸Ge with a half-life of 270.8d independent of an onsite cyclotron. Analogues, mostly DOTA-derivatized peptides such as DOTA-Tyr3-octreotide (DOTATOC), show high affinity to Somatostatin receptors with beneficial pharmacokinetic properties. Combined with the better resolution of PET technology, ⁶⁸Ga-Somatostatin PET was reported to show high performance in assessment of bone involvement (Fig. 2a). It was found to be superior to BS, to CT and to gamma camera imaging with ¹¹¹In-Somatostatin (SRS). In a study on 89 patients with NET, SPECT STS identified only 72.5% and CT identified only 50% of the skeletal lesions identified by ⁶⁸Ga-Somatostatin PET [9–11].

PET with PSMA-ligands has gained attention as a promising imaging method in patients with prostate cancer. PSMA is a transmembrane protein with significantly elevated expression in most prostate cancer cells compared to benign prostatic tissue [12]. Comparison of ⁶⁸Ga-PSMA PET and planar BS for detection of skeletal involvement was the scope of a recently published manuscript. In a cohort of 126 patients with prostate cancer, sensitivity and specificity of PET were 98.7–100% and 88.2–100%, compared to 86.7–89.3% and 60.8–96.1% (p < 0.001) for BS, with ranges representing results for ‘optimistic’ or ‘pessimistic’ classification of equivocal lesions [13]. It should be noted, however that approximately 8% of prostate cancers do not show PSMA overexpression [14].

Monitoring response of bone metastases to therapy is an on going challenge on follow up imaging. Repair and active tumor may appear similar on BS and on CT, particularly when therapy protocol includes anti-osteoclastic agents such as bisphosphonates which encourage the appearance of sclerotic changes in the healing bone. The latter may remain permanent even when the metastasis is no longer active. ¹⁸F-FDG, ⁶⁸Ga-Somatostatin and ⁶⁸Ga-PSMA accumulate only in active tumor tissue regardless of its morphologic appearance thus PET using these tracers can assist in separating repair of bone and active bone metastasis (Fig. 1b). Sequential ¹⁸F-FDG PET-CT studies performed in patients with breast cancer have shown that ¹⁸F-FDG uptake reflects the immediate tumor activity of bone metastases. Response is associated with decrease in intensity of uptake [15, 16]. Similarly, in NET, response of bone metastases after treatment can be evaluated efficiently by SRS or ⁶⁸Ga-Somatostatin PET (Fig. 2) [13, 14].

Same ligands of Somatostatin and of PSMA can be labeled with either ⁶⁸Ga for imaging purposes or with ¹⁷⁷Lu for therapy following the theranostics paradigm [17]. ¹⁷⁷Lu-Somatostatin has been the first of the two to be used starting in the early 1990s. Lessons learned from the studies on treatment of metastatic NETs were that bone marrow suppression, and even myelodysplastic syndrome may be a side effect in patients treated with high dosages of >100 GBq (>3 Gy bone marrow radiation dose), therefore radiation dosimetry after each therapy is essential for individual optimization of future doses [18, 19]. However it should be noted that bone marrow involvement by itself is effectively controlled by PRRT, with long progression-free survival and overall survival [20].

Clinical data on the role of ¹⁷⁷Lu-PSMA for treatment of patients with metastatic prostate cancer is being accumulated. It appears that this mode of therapy is effective and safe in patients that are appropriately selected [21]. Diffuse bone marrow involvement is a risk factor for significant myelosuppression but could be identified by ⁶⁸GA PSMA imaging in advance [22]. It has been shown that as high as 58% with bone metastases treated with ¹⁷⁷Lu-PSMA report reduction in bone pain [23].

The forth PET tracer that can be used for assessment of skeletal bone involvement is ¹⁸F-Fluoride. In contrast with the three earlier discussed tracers that accumulate directly in the tumor tissue, ¹⁸F-Fluoride is a PET bone-seeking agent with uptake mechanism similar to that of ^99m Tc-MDP. Fluoride ions exchange with hydroxyl groups in hydroxyapetite crystal bone to form fluoroapatite, and are deposited at the bone surface where bone turnover is greatest. Similarly to ^99mTc-MDP, accumulation of ¹⁸F-Fluoride uptake in bone metastases reflects increased regional blood flow and high bone turnover, secondary changes occurring in bone as reaction to the presence of tumor cells. ¹⁸F-Fluoride has better pharmacokinetic characteristics compared to those of ^99mTc-MDP. The bone uptake of the former is two-fold higher, in contrast with ^99mTc-MDP it does not bind to protein. The capillary permeability of ¹⁸F-Fluoride is higher and its blood clearance is faster resulting in a better target- to- background ratio. Regional plasma clearance of ¹⁸F-Fluoride was reported to be 3–10 times higher in bone metastases compared with that in normal bone [7, 24].

¹⁸F-Fluoride-PET is very sensitive for detection of not only osteoblastic metastases but also of lytic ones, as the latter even when considered “pure lytic”, do have minimal osteoblastic activity which is enough for detection by ¹⁸F-Fluoride-PET. It should be borne in mind that ¹⁸F-Fluoride is not tumor specific and therefore is a sensitive modality for detection of any bone abnormalities, not only malignant.