PET scanning for evaluation of bone metabolism

Sir–With great interest we read the paper of Ullmark et al. on using positron emission tomography (PET) to assess bone metabolic activity (Ullmark et al. 2009). PET is an imaging tool that can provide functional rather than morphological information, and has thus attracted a lot of attention. The prerequisites for proper analysis and subsequent sufficient interpretation are very important, and most of these originate from the principles of PET. Unfortunately, Ullmark et al. do not address these important issues and, to avoid misinterpretations, we wish to highlight some of these important points. The principle of positron emission tomography PET scanning is based on a short-lived radioactive tracer, which decays by emitting a positron. The tracers can exist as single isotopes or be incorporated in larger molecules, depending on the application. This method suffers from low spatial resolution. Apart from single-positron emission tomography (SPECT), all PET systems utilize coincidence detection of the annihilation photons from positron decay. Since the paired gamma rays from the annihilation of the positron are anti-parallel, the detection of the gamma rays determines a line of response (LOR) along which the annihilation took place. Resolution is thus determined by the size/density of the detectors that are most often placed in a ring around the subject. However, the LOR is not completely linear and the gamma rays are released in a direction of 180° ± 0.5°. This physical phenomenon further limits the resolution. The spatial resolution of most clinical PET scanners is therefore only about 6–8 mm (Townsend 2004). Hence, the resulting images are known to be affected by partial-volume effects, which can cause small regions with high tracer uptake to be imaged as having an artificially low concentration and vice versa (Soret et al. 2007). When comparing regions of interest (ROIs), it is therefore important for the accuracy that the size is sufficiently high or that the tissue surrounding the ROIs has a comparable uptake of the tracer. For the reader to be able to interpret PET data, describing the size of the ROI is as important as the obvious adding of standard deviations to the results. The three basic analytical methods with or without blood sampling will not be addressed here. In orthopedic approaches, the use of the fluoride isotope [18F] is of particular interest because of its incorporation into the bone crystals. However, due to the rate of bone formation, [18F] is not incorporated into bone during a 1- to 2-hour scan. The fluoride ion exchanges with the hydroxyl groups in the hydroxyapatite crystal of bone (Ca10(PO4)6OH2) to form fluoroapatite (Ca10(PO4)6F2), and this can be interpreted as a 4-step event, which was originally described by Blau et al. as early as 1962—long before PET gained its clinical popularity and accessibility. The first 2 steps from the blood through extracellular space to the shell of bound water around exposed crystals are very rapid (minutes), step 2 being the irreversible step. Step 3 is the traveling of the tracer onto the crystal surface, and this is probably measured in hours. The final step of incorporation, step 4, may take days or weeks. Consequently, areas of high uptake result from processes that increase the exposed bone crystal surface and/or increase blood flow. Thus, areas of osteoclastic and osteoblatic activity are measured equally, and this is of crucial importance when interpreting these data sets (Blau et al. 1972). By directly translating SUV to “bone forming activity”, Ullmark et al. draw a dicey conclusion. This translation is apparently based on a study by Piert et al. correlating metabolic activity in the vertebral body from PET and histomorphometry in an iliac crest biopsy (Piert et al. 2001). However, that study investigated bone blood flow and metabolic rate in untreated bone, which most likely presents a steady state metabolic rate. This is obviously very different from new bone formation in an allograft-implanted area. The findings at 1 week postoperatively in Ullmark's study could very well be due to impaired blood flow in the impacted graft rather than being an assessment of metabolic rate per se (Berding et al. 1995, Piert et al. 1998). Furthermore, there is evidence that radiotracer uptake is not dependent on osteoblast number, but concentration of bone-forming minerals (Toegel et al. 2006). It is therefore important to notice that areas of osteoclastic and osteoblastic activity are labeled equally, and thus increased resorption would also result in increased tracer uptake without it necessarily resulting in a net increase in bone volume (Blau et al. 1972, Genant et al. 1974). Combined PET/CT and (most recently) PET/MRI scanners make it possible to correlate the functional data from PET with morphological images (Foldager et al. 2008). This has two advantages. First, it gives an exact morphological location of the metabolic event and secondly, ROIs can be made from CT or MRI images alone, which makes the placement of these more accurate and furthermore limits possible inter-observer errors. PET is indeed a fast-growing modality and both PET and cyclotron centers are opening and expanding in the western countries, thereby increasing accessibility for researchers in the field of orthopedics. We therefore find it very important that the limitations as well as the opportunities of this powerful tool are properly addressed and well understood to avoid misinterpretations and misunderstanding of this rather complex imaging modality.