Positron emission tomography for bone imaging, as an in vivo tracer technique, allows the measurement of the regional concentration of radioactivity proportional to the image pixel values averaged over a region of interest (ROI) in bones. Positron emission tomography is a functional imaging technique that uses [18F]NaF radiotracer to visualise and quantify regional bone metabolism and blood flow. [18F]NaF has been used for imaging bones for the last 60 years. This article focuses on the pharmacokinetics of [18F]NaF in bones, and various semi-quantitative and quantitative methods for quantifying regional bone metabolism using [18F]NaF PET images.
Use of [18F]NaF PET The measurement of regional bone metabolism is critical to understand the pathophysiology of metabolic bone diseases.
Bone biopsy is considered the gold standard to quantify bone turnover; however, it is invasive, complex and costly to perform and subject to significant measurement errors. Measurements of serum or urine biomarkers of bone turnover are simple, cheap, quick, and non-invasive in measuring changes in bone metabolism, but only provide information on the global skeleton. The functional imaging technique of dynamic [18F]NaF PET scans can quantify regional bone turnover at specific sites of clinical importance such as the lumbar spine and hip and has been validated by comparison with the gold standard of bone biopsy.
Pharmacokinetics of [18F]NaF
The chemically stable anion of Fluorine-18-Fluoride is a bone-seeking radiotracer in skeletal imaging. [18F]NaF has an affinity to deposit at areas where the bone is newly mineralizing. Many studies have [18F]NaF PET to measure bone metabolism at the hip, lumbar spine, and humerus. [18F]NaF is taken-up in an exponential manner representing the equilibration of tracer with the extracellular and cellular fluid spaces with a half-life of 0.4 hours, and with kidneys with a half-life of 2.4 hours. The single passage extraction of [18F]NaF in bone is 100%. After an hour, only 10% of the injected activity remains in the blood.
18F- ions are considered to occupy extracellular fluid spaces because, firstly, they equilibrate with transcellular fluid spaces and secondly, they are not entirely extracellular ions. Fluoride undergoes equilibrium with hydrogen fluoride, which has a high permeability allowing fluoride to cross the plasma blood membrane. The fluoride circulation in red blood cells accounts for 30%. However, it is freely available to the bone surface for uptake because the equilibrium between erythrocytes and plasma is much faster than the capillary transit time. This is supported by studies reporting 100% single-passage extraction of whole-blood 18F- ion by bone and the rapid release of 18F- ions from erythrocytes with a rate constant of 0.3 per second.
[18F]NaF is also taken-up by immature erythrocytes in the bone marrow, which plays a role in fluoride kinetics. The plasma protein binding of [18F]NaF is negligible. [18F]NaF renal clearance is affected by diet and pH level, due to its re-absorption in the nephron, which is mediated by hydrogen fluoride. However, large differences in urine flow rate are avoided for controlled experiments by keeping patents well hydrated.
The exchangeable pool and the size of the metabolically active surfaces in bones determines the amount of tracer accumulated or exchanged with bone extracellular fluid, chemisorption onto hydroxyapatite crystals to form fluorapatite, as shown in the following equation:
Fluoride ions from the crystalline matrix of bone are released when the bone is remodelled, thus providing a measure of the rate of bone metabolism.
Use of [18F]NaF in PET imaging and radiation dosimetry In [18F]NaF PET bone imaging, a typical injected activity of 250 MBq delivers an estimated radiation dose of about 4.3 mSv, consistent with international safety standards. Actual dose varies with organ uptake, clearance, and patient anatomy, and additional exposure may result from an accompanying CT scan, depending on scan settings. Lower doses, such as 90 MBq, can provide sufficient image quality in regions like the lumbar spine, and research continues on dose reduction.
Imaging procedure and patient preparation
Before [18F]NaF PET, patients are advised to stay relaxed and hydrated and to empty their bladder to reduce variability. During imaging, they lie supine with the target region in the scanner field. A CT scan is performed first, followed by intravenous tracer injection and saline flush. Imaging data are collected continuously, and blood samples are taken to measure tracer concentrations in plasma and whole blood. Samples are processed and weighed to calculate volumes, and concentrations over time are used to estimate the arterial input function for kinetic modelling.
Dose correction and data accuracy To ensure consistent analysis, all tracer concentration values, whether from imaging or blood samples, are corrected to a single reference time point, typically the time of injection. The residual tracer left in the syringe after injection is also measured and adjusted for radioactive decay to calculate the actual amount of tracer delivered to the patient. [18F]NaF does not undergo metabolism or significant protein binding, so the tracer concentration in plasma reflects the parent compound directly. This simplifies the calculation of tracer kinetics.
Image reconstruction and quantification The PET data are processed using various frame duration to accurately capture both the early rapid changes and the later slower changes in tracer distribution. Corrections for physical factors such as scatter, random coincidences, dead time, and attenuation are applied during reconstruction. Quantitative analysis can be performed using either two-dimensional (2D) or three-dimensional (3D) image reconstruction methods. Each has strengths and limitations. 3D reconstruction generally provides better visualisation due to higher sensitivity but may introduce variability in measured activity across the field of view. In contrast, 2D reconstruction offers more uniform sensitivity, which may make it more reliable for quantitative analysis. Thus, the choice of reconstruction method can impact the accuracy of tracer uptake measurements.
Measuring SUV using static PET images
Definition The standardized uptake value (SUV) is defined as tissue concentration (KBq/ml) divided by activity injected normalized for body weight.
Appropriateness The SUV measured from the large ROI smooths out the noise and, therefore, more appropriate in [18F]NaF bone studies as the radiotracer is fairly uniformly taken up throughout the bone. The measurement of SUV is easy, cheap, and quicker to perform, making it more attractive for clinical use. It has been used in diagnosing and assessing the efficacy of therapy. SUV can be measured at a single site, or the whole skeleton using a series of static scans and restricted by the small field-of-view of the PET scanner.
Known Issues The SUV has emerged as a clinically useful, albeit controversial, semi-quantitative tool in PET analysis. Standardizing imaging protocols and measuring the SUV at the same time post-injection of the radiotracer, is necessary to obtain a correct SUV because imaging before the uptake plateau introduces unpredictable errors of up to 50% with SUVs. Noise, image resolution, and reconstruction do affect the accuracy of SUVs, but correction with phantom can minimize these differences when comparing SUVs for multi-centre clinical trials. SUV may lack sensitivity in measuring response to treatment as it is a simple measure of tracer uptake in bone, which is affected by the tracer uptake in other competing tissues and organs in addition to the target ROI.
Measuring Ki using serial/dynamic PET images The quantification of dynamic PET studies to measure Ki requires the measurement of the skeletal time-activity curves (TAC) from the region of interest (ROI) and the arterial input function (AIF), which can be measured in various different ways. However, the most common is to correct the image-based blood time-activity curves using several venous blood samples taken at discrete time points while the patient is scanned. The calculation of rate constants or Ki requires three steps:
Measurement of the arterial input function (AIF), which acts as the first input to the mathematical model of tracer distribution. Measurement of the time-activity curve (TAC) within the skeletal region of interest, which acts as the second input to the mathematical model of tracer distribution. Kinetic modelling of AIF and TAC using mathematical modelling to obtain net plasma clearance (Ki) to the bone mineral.
Spectral method The method was first described by Cunningham & Jones in 1993 for the analysis of dynamic PET data obtained in the brain. It assumes that the tissue impulse response function (IRF) can be described as a combination of many exponentials. Since A tissue TAC can be expressed as a convolution of measured arterial input function with IRF, Cbone(t) can be expressed as:
where, is a convolution operator, Cbone(t) is the bone tissue activity concentration of tracer (in units: MBq/ml) over a period of time t, Cplasma(t) is the plasma concentration of tracer (in units: MBq/ml) over a period of time t, IRF(t) is equal to the sum of exponentials, β values are fixed between 0.0001 sec−1 and 0.1 sec−1 in intervals of 0.0001, n is the number of α components that resulted from the analysis and β1, β2,..., βn corresponds to the respective α1, α2,..., αn components from the resulted spectrum. The values of α are then estimated from the analysis by fitting multi-exponential to the IRF. The intercept of the linear fit to the slow component of this exponential curve is considered the plasma clearance (Ki) to the bone mineral.
Deconvolution method The method was first described by Williams et al. in the clinical context. The method was used by numerous other studies. This is perhaps the simplest of all the mathematical methods for the calculation of Ki but the one most sensitive to noise present in the data. A tissue TAC is modelled as a convolution of measured arterial input function with IRF, the estimates for IRF are obtained iteratively to minimise the differences between the left- and right-hand side of the following Equation:
where, is a convolution operator, Cbone(t) is the bone tissue activity concentration of tracer (in units: MBq/ml) over a period of time t, Cplasma(t) is the plasma concentration of tracer (in units: MBq/ml) over a period of time t, and IRF(t) is the impulse response of the system (i.e., a tissue in this case). The Ki is obtained from the IRF in a similar fashion to that obtained for the spectral analysis, as shown in the figure.
Hawkins model The measurement of Ki from dynamic PET scans require tracer kinetic modelling to obtain the model parameters describing the biological processes in bone, as described by Hawkins et al. Since this model has two tissue compartments, it is sometimes called a two-tissue compartmental model. Various different versions of this model exist; however, the most fundamental approach is considered here with two tissue compartments and four tracer-exchange parameters. The whole kinetic modelling process using Hawkins model can be summed up in a single image as seen on the right-hand-side. The following differential equations are solved to obtain the rate constants:
The rate constant K1 (in units: ml/min/ml) describes the unidirectional clearance of fluoride from plasma to the whole of the bone tissue, k2 (in units: min−1) describes the reverse transport of fluoride from the ECF compartment to plasma, k3 and k4 (in units min−1) describe the forward and backward transportation of fluoride from the bone mineral compartment.