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Studies of skeletal metabolism using measurements of bone metabolic flux (K i ) obtained with [ 18 F] sodium fluoride ([ 18 F]NaF) positron emission tomography (PET) scans have been used in clinical research for the last 30 years. The technique has proven useful as an imaging biomarker in trials of novel drug treatments for osteoporosis and investigating other metabolic bone diseases, including chronic kidney disease mineral and bone disorder. It has also been shown to be valuable in metastatic bone disease in breast cancer patients and may have potential in other cancer types, such as prostate cancer, to assess early bone fracture risk. However, these studies have usually required a 60-min dynamic PET scan and measurement of the arterial input function (AIF), making them difficult to translate into the clinic for diagnostic purposes. We have previously proposed a simplified method that estimates the K i value at an imaging site from a short (4-min) static scan and venous blood samples. A key advantage of this method is that, by acquiring a series of static scans, values of K i can be quickly measured at multiple sites using a single injection of the tracer. To date, the widespread use of [ 18 F]NaF PET has been limited by the need to measure the AIF required for the mathematical modeling of tracer kinetics to derive K i and other kinetic parameters. In this report, we review different methods of measuring the AIF, including direct arterial sampling, the use of a semi-population input function (SP-AIF), and image-derived input function, the latter two requiring only two or three venous blood samples obtained between 30 and 60 min after injection. We provide an SP-AIF model and a spreadsheet for calculating K i values using the static scan method that others can use to study bone metabolism in metabolic and metastatic bone diseases without requiring invasive arterial blood sampling. The method shortens scan times, simplifies procedures, and reduces the cost of multicenter trials without losing accuracy or precision., (© 2022 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

This report describes the significance of the kinetic parameters (k-values) obtained from the analysis of dynamic positron emission tomography (PET) scans using the Hawkins model describing the pharmacokinetics of sodium fluoride ([ 18 F]NaF) to understand bone physiology. Dynamic [ 18 F]NaF PET scans may be useful as an imaging biomarker in early phase clinical trials of novel drugs in development by permitting early detection of treatment-response signals that may help avoid late-stage attrition.

[18F]NaF PET imaging is a useful tool for measuring regional bone metabolism. However, due to tracer in urine, [18F]NaF PET images of the hip reconstructed using filtered back projection (FBP) frequently show streaking artifacts in slices through the bladder leading to noisy time-activity curves unsuitable for quantification. This study compares differences between quantitative outcomes at the hip derived from images reconstructed using the FBP and ordered-subset expectation maximization (OSEM) methods. Dynamic [18F]NaF PET data at the hip for four postmenopausal women were reconstructed using FBP and nine variations of the OSEM algorithm (all combinations of 1, 5, 15 iterations and 10, 15, 21 subsets). Seven volumes of interest were placed in the hip. Bone metabolism was measured using standardized uptake values, Patlak analysis (Ki-PAT) and Hawkins model Ki-4k. Percentage differences between the standardized uptake values and Ki values from FBP and OSEM images were assessed. OSEM images appeared visually smoother and without the streaking artifacts seen with FBP. However, due to loss of counts, they failed to recover the quantitative values in VOIs close to the bladder, including the femoral head and femoral neck. This was consistent for all quantification methods. Volumes of interest farther from the bladder or larger and receiving greater counts showed good convergence with 5 iterations and 21 subsets. For VOIs close to the bladder, including the femoral neck and femoral head, 15 iterations and 10, 15 or 21 subsets were not enough to obtain OSEM images suitable for measuring bone metabolism and showed no improvement compared to FBP., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Our purpose was to establish whether noninvasive measurement of changes in 18 F-fluoride metabolic flux to bone mineral (K i ) by PET/CT can provide incremental value in response assessment of bone metastases in breast cancer compared with SUV max and SUV mean Methods: Twelve breast cancer patients starting endocrine treatment for de novo or progressive bone metastases were included. Static 18 F-fluoride PET/CT scans were acquired 60 min after injection, before and 8 wk after commencing treatment. Venous blood samples were taken at 55 and 85 min after injection to measure plasma 18 F-fluoride activity concentrations, and K i in individual bone metastases was calculated using a previously validated method. Percentage changes in K i , SUV max , and SUV mean were calculated from the same index lesions (≤5 lesions) from each patient. Clinical response up to 24 wk, assessed in consensus by 2 experienced oncologists masked to PET imaging findings, was used as a reference standard. Results: Of the 4 patients with clinically progressive disease (PD), mean K i significantly increased (>25%) in all, SUV max in 3, and SUV mean in 2. Of the 8 non-PD patients, K i decreased or remained stable in 7, SUV max in 5, and SUV mean in 6. A significant mean percentage increase from baseline for K i , compared with SUV max and SUV mean , occurred in the 4 patients with PD (89.7% vs. 41.8% and 43.5%, respectively; P < 0.001). Conclusion: After 8 wk of endocrine treatment for bone-predominant metastatic breast cancer, K i more reliably differentiated PD from non-PD than did SUV max and SUV mean , probably because measurement of SUV underestimates fluoride clearance by not considering changes in input function., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

Objective: The aim of the study was to examine whether (18)F-fluoride PET ((18)F-PET) static scan measurements of bone plasma clearance (Ki) can be corrected for tracer efflux from bone from the time of injection., Materials and Methods: The efflux of tracer from bone mineral to plasma was described by a first-order rate constant kloss. A modified Patlak analysis was applied to 60-min dynamic (18)F-PET scans of the spine and hip acquired during trials on the bone anabolic agent teriparatide to find the best-fit values of kloss at the lumbar spine, total hip and femoral shaft. The resulting values of kloss were used to extrapolate the modified Patlak plots to 120 min after injection and derive a sequence of static scan estimates of Ki at 4-min intervals that were compared with the Patlak Ki values from the 60-min dynamic scans. A comparison was made with the results of the standard static scan analysis, which assumes kloss=0., Results: The best-fit values of kloss for the spine and hip regions of interest averaged 0.006/min and did not change when patients were treated with teriparatide. Static scan values of Ki calculated using the modified analysis with kloss=0.006/min were independent of time between 10 and 120 min after injection and were in close agreement with findings from the dynamic scans. In contrast, by 2 h after injection the static scan Ki values calculated using the standard analysis underestimated the dynamic scan results by 20%., Conclusion: Using a modified analysis that corrects for F efflux from bone, estimates of Ki from static PET scans can be corrected for time up to 2 h after injection. This simplified approach may obviate the need to perform dynamic scans and hence shorten the scanning procedure for the patient and reduce the cost of studies. It also enables reliable estimates of Ki to be obtained from multiple skeletal sites with a single injection of tracer.

Unlabelled: The assessment of regional skeletal metabolism using (18)F-fluoride PET ((18)F-PET) requires segmentation of the tissue region of interest (ROI). The aim of this study was to validate a novel approach to define multiple ROIs at the proximal femur similar to those used in dual x-ray absorptiometry. Regions were first drawn on low-dose CT images acquired as a routine part of the PET/CT study and transferred to the (18)F-PET images for the quantitative analysis of bone turnover., Methods: Four healthy postmenopausal women with a mean age of 65.1 y (range, 61.8-70.0 y), and with no history of metabolic bone disorder and not currently being administered treatment affecting skeletal metabolism, underwent dynamic (18)F-PET/CT at the hip with an injected activity of 180 MBq. The ROIs at the proximal femur included femoral shaft, femoral neck, and total hip and were segmented using both a semiautomatic method and manually by 8 experts at manual ROI delineation. The mean of the 8 manually drawn ROIs was considered the gold standard against which the performances of the semiautomatic and manual methods were compared in terms of percentage overlap and percentage difference. The time to draw the ROIs was also compared., Results: The percentage overlaps between the gold standard and the semiautomatic ROIs for total hip, femoral neck, and femoral shaft were 86.1%, 37.8%, and 96.1%, respectively, and the percentage differences were 14.5%, 89.7%, and 4.7%, respectively. In the same order, the percentage overlap between the gold standard and the manual ROIs were 85.2%, 39.1%, and 95.2%, respectively, and the percentage differences were 19.9%, 91.6%, and 12.2%, respectively. The semiautomatic method was approximately 9.5, 2.5, and 67 times faster than the manual method for segmenting total-hip, femoral-neck, and femoral-shaft ROIs, respectively., Conclusion: We have developed and validated a semiautomatic procedure whereby ROIs at the hip are defined using the CT component of an (18)F-PET/CT scan. The percentage overlap and percentage difference results between the semiautomatic method and the manual method for ROI delineation were similar. Two advantages of the semiautomatic method are that it is significantly quicker and eliminates some of the variability associated with operator or reader input. The tube current used for the CT scan was associated with an effective dose 8 times lower than that associated with a typical diagnostic CT scan. These results suggest that it is possible to segment bone ROIs from low-dose CT for later transfer to PET in a single PET/CT procedure without the need for an additional high-resolution CT scan.

Purpose: We describe a semipopulation input function for evaluating bone plasma clearance from static and dynamic (18)F-fluoride PET scans., Methods: The semipopulation input function was derived by fitting an exponential curve to venous plasma measurements obtained 30-60 min after injection and adding a population residual curve representing the bolus peak scaled for injected activity and adjusted for time of peak counts. The residual curve was found from nine postmenopausal women who had continuous arterial blood samples and venous samples taken every 10 min. The precision errors of plasma clearance measurements derived from the semipopulation input function using Patlak analysis and the Hawkins compartmental model were compared with the precision errors for four image-derived input functions using data from 20 women who had undergone repeated dynamic PET scans., Results: Venous and arterial concentrations were equal by 30 min after injection. The exponential fitted to the 30-60-min venous data accounted for 76% of the total 0-60 min area under the curve, and the SD of the area under the residual curve was 2.6% of the total 0-60 min area under the curve. For Patlak analysis, the precision error (% coefficient of variation) was 13.0% using the semipopulation input function compared with 14.9-21.7% using the four image-derived input functions. For the Hawkins model the equivalent figures were 14.5 and 20.1-30.9%, respectively., Conclusion: Accurate and precise measurements of bone plasma clearance were obtained when (18)F-fluoride PET scans were analysed using an input function obtained by adding a population residual curve to the exponential obtained from venous blood samples taken 30-60 min after injection.

Unlabelled: The planning of research studies requires an understanding of the minimum number of subjects required. The aim of this study was to evaluate different methods of analyzing (18)F-fluoride PET ((18)F(-) PET) dynamic spine scans to find the approach that requires the smallest sample size to detect a statistically significant response to treatment., Methods: Eight different approaches to (18)F(-) PET analysis (3 variants of the Hawkins 3-tissue compartmental model, 3 variants of spectral analysis, deconvolution, and Patlak analysis) were used to evaluate the fluoride plasma clearance to bone mineral (K(i)). Standardized uptake values (SUVs) were also studied. Data for 20 women who had (18)F(-) PET spine scans at 0, 6, and 12 mo after stopping long-term bisphosphonate treatment were used to compare precision errors. Data for 18 women who had scans at baseline and 6 mo after starting teriparatide treatment were used to compare response to treatment., Results: The 4 approaches that fitted the rate constant k(4) describing the reverse flow of (18)F from bone as a free variable showed close agreement in K(i) values, with correlation coefficients greater than 0.97. Their %CVs were 14.4%-14.8%, and treatment response to teriparatide was 23.2%-23.8%. The 3 methods that assumed k(4) = 0 gave K(i) values 20%-25% lower than the other methods, with correlation coefficients of 0.83-0.94, percentage coefficients of variation (%CVs) of 12.9%-13.3%, and treatment response of 25.2%-28.3%. A Hawkins model with k(4) = 0.01 min(-1) did not perform any better (%CV, 14.2%; treatment response, 26.1%). Correlation coefficients between SUV and the different K(i) methods varied between 0.60 and 0.65. Although SUV gave the best precision (%CV, 10.1%), the treatment response (3.1%) was not statistically significant., Conclusion: Methods that calculated K(i) assuming k(4) = 0 required fewer subjects to demonstrate a statistically significant response to treatment than methods that fitted k(4) as a free variable. Although SUV gave the smallest precision error, the absence of any significant changes make it unsuitable for examining response to treatment in this study.

Introduction: The use of image-derived arterial input functions (IDAIF) for the dynamic quantification of bone metabolism using 18F-fluoride positron emission tomography 18F-PET is an attractive alternative to direct arterial blood sampling., Purposes: (a) To validate a method for obtaining the IDAIF by imaging the femoral artery against a method for deriving the IDAIF at the aorta that was previously validated against direct arterial sampling. (b) To compare the accuracy of bone plasma clearance measurements (Ki) at the total hip site obtained using the femoral artery IDAIF against Ki values at the same site obtained using the aorta IDAIF., Methods: Twelve healthy postmenopausal women with a mean age of 62.6 years (range, 52.3-70.6 years) had 60-min dynamic 18F-PET scans of the lumbar spine and proximal femur 2 weeks apart. The femoral artery IDAIF was obtained from the proximal femur scan using four different algorithms: (a) fixed partial volume correction (PVC) method; (b) variable PVC method; (c) Chen method; and (d) Cook-Lodge method. The aorta IDAIF was obtained from the lumbar spine scan using a previously validated method and the respective Ki values in the hip were used to assess the performance of each of the femoral artery algorithms., Results: When the femoral artery IDAIF methods were compared with the aorta IDAIF in terms of the area under the curve AUC values calculated in 4-min time intervals over 0-60 min, the absolute root mean square errors were: (a) fixed PVC, 0.52; (b) variable PVC, 0.54; (c) Chen, 0.72; and (d) Cook-Lodge, 0.49 in MBq s/ml. There were small, but statistically significant differences, in the Ki values found by all four femoral artery IDAIF methods when compared with the figures obtained using the aorta IDAIF. Bland-Altman plots of Ki values showed the best agreement for the fixed PVC method with a standard deviation of 0.0020 ml/min/ml, followed by variable PVC, Cook-Lodge and Chen method with standard deviations of 0.0022, 0.0024 and 0.0042 ml/min/ml, respectively., Conclusion: We have demonstrated that it is possible to measure regional bone turnover at the hip without the need to perform direct arterial sampling to acquire the arterial input function (AIF). The differences in the Ki values obtained at the hip by using aorta IDAIF and any of the four image-based AIF methods at the femoral artery were small and clinically insignificant. The performance of fixed PVC, variable PVC and Cook-Lodge method was similar although the latter was less robust than the other two methods.

Objectives: (i) To validate two new image-based methods for finding the plasma arterial input function (AIF) and evaluate the performance of these and two similar techniques against arterial sampling. (ii) To evaluate the performance of all four image-derived AIF (IDAIF) methods against arterial sampling for measuring the F plasma clearance (Ki) to the lumbar spine., Methods: Eight healthy postmenopausal women had a F-fluoride positron emission tomography scan of the lumbar spine. Venous blood samples were used to estimate the IDAIFs from: (i) a fixed population-based partial volume correction (PVC) factor method, (ii) a variable PVC factor method, (iii) the Chen method, and (iv) the Cook-Lodge method. Continuous arterial sampling and the respective Ki values were used as the gold standard against which the performance of the IDAIF methods was compared., Results: The IDAIFs were compared with direct arterial sampling in terms of the area under the curve values. The percentage root mean square error in area under the curves compared with arterial sampling were: (i) fixed PVC: 12.7%, (ii) variable PVC: 12.0%, (iii) Chen: 39.0%, and (iv) Cook-Lodge: 17.3%. There were small but significant differences in the Ki values found by all four methods compared with arterial sampling. Bland-Altman plots of Ki values showed the best agreement for the variable and fixed PVC methods with a standard deviation of 0.0026 and 0.0030 ml/min/ml, respectively., Conclusion: The differences in the Ki values obtained at the lumbar spine using direct arterial sampling and any of the IDAIF methods at the aorta were clinically nonsignificant. The variable PVC and fixed PVC methods performed better than the Cook-Lodge and Chen methods.

Unlabelled: (18)F-Fluoride PET allows noninvasive evaluation of regional bone metabolism and has the potential to become a useful tool for assessing patients with metabolic bone disease and evaluating novel drugs being developed for these diseases. The main PET parameter of interest, termed K(i), reflects regional bone metabolism. The aim of this study was to compare the long-term precision of (18)F-fluoride PET with that of biochemical markers of bone turnover assessed over 6 mo., Methods: Sixteen postmenopausal women with osteoporosis or significant osteopenia and a mean age of 64 y underwent (18)F-fluoride PET of the lumbar spine and measurements of biochemical markers of bone formation (bone-specific alkaline phosphatase and osteocalcin) and bone resorption (urinary deoxypyridinoline) at baseline and 6 mo later. Four different methods for analyzing the (18)F-fluoride PET data were compared: a 4k 3-compartmental model using nonlinear regression analysis (K(i-4k)), a 3k 3-compartmental model using nonlinear regression analysis (K(i-3k)), Patlak analysis (K(i-PAT)), and standardized uptake values., Results: With the exception of a small but significant decrease in K(i-3k) at 6 mo, there were no significant differences between the baseline and 6-mo values for the PET parameters or biochemical markers. The long-term precision, expressed as the coefficient of variation (with 95% confidence interval in parentheses), was 12.2% (9%-19%), 13.8% (10%-22%), 14.4% (11%-22%), and 26.6% (19%-40%) for K(i-3k), K(i-PAT), mean standardized uptake value, and K(i-4k), respectively. For comparison, the precision of the biochemical markers was 10% (7%-15%), 18% (13%-27%), and 14% (10%-21%) for bone-specific alkaline phosphatase, osteocalcin, and urinary deoxypyridinoline, respectively. Intraclass correlation between the baseline and 6-mo values ranged from 0.44 for K(i-4k) to 0.85 for K(i-3k). No significant correlation was found between the repeated mean standardized uptake value measurements., Conclusion: The precision and intraclass correlation observed for K(i-3k) and K(i-PAT) was equivalent to that observed for biochemical markers. This study provided initial data on the long-term precision of (18)F-fluoride PET measured at the lumbar spine, which will aid in the accurate interpretation of changes in regional bone metabolism in response to treatment.

The purpose of this study was to quantify indices of regional bone metabolism in Paget's disease and to compare these indices with normal bone using dynamic 18F-fluoride positron emission tomography (PET). Seven patients with vertebral Paget's disease had 1 h dynamic 18F-fluoride PET scans performed. The scans included a diseased vertebra and an adjacent normal vertebra. Arterial plasma input functions were also measured. A three-compartment, four-parameter model was used with nonlinear regression analysis to estimate bone kinetic variables. Compared with normal bone, pagetic bone demonstrated higher values of plasma clearance to bone mineral (Ki; 1.03 x 10(-1) vs. 0.36 x 10(-1) ml/min per milliliter; p = 0.018) and clearance to total bone tissue (K1; 2.38 x 10(-1) vs. 1.25 x 10(-1) ml/min per milliliter; p = 0.018), reflecting increased mineralization and blood flow, respectively. Release of 18F-fluoride from bone mineral (k4) was lower in pagetic bone (p = 0.022), suggesting tighter binding of 18F-fluoride to bone mineral. The notional volume of the extravascular bone compartment (K1/k2) was greater in pagetic bone (p = 0.018). Although the unidirectional extraction efficiency from the extravascular space to bone mineral (Ki/K1) was greater in pagetic bone (p = 0.018), a lower pagetic value of k2 (p = 0.028), describing the rate of transfer from the bone extravascular compartment to plasma, suggests that the 18F-fluoride that enters the relatively fibrotic marrow space of pagetic bone may be less accessible for return to plasma. These findings confirm some of the known pathophysiology of Paget's disease, introduce some new observations, and show how dynamic 18F-fluoride PET may be of value in the measurement of regional metabolic parameters in focal bone disorders.

We report a study of the renal and whole-blood kinetics of (18)F-fluoride and (99m)Tc-methylene diphosphonate ((99m)Tc-MDP) and their effect on the evaluation of the skeletal kinetics of the two bone tracers. Data were obtained during an investigation of postmenopausal women taking hormone replacement therapy who were compared with untreated, age-matched controls. After intravenous injection of 18F-fluoride (1 MBq), (99m)Tc-MDP (1 MBq), (51)Cr-ethylenediaminetetraacetic acid (51Cr-EDTA) (3 MBq) and (125)I-human serum albumin ((125)I-HSA) (0.25 MBq), multiple blood samples and urine collections were taken between 0 and 4 h after injection. (51)Cr-EDTA data were used to evaluate the glomerular filtration rate (GFR) and the completeness of each timed urine collection. (125)I-HSA data were used to evaluate the plasma volume and the red cell uptake of the other three tracers. At 4 h, the cumulative urine excretions (and standard deviations, SDs) were: (99m)Tc-MDP, 58.2% (4.8%); (18)F-fluoride, 36.1% (5.7%); (51)Cr-EDTA, 81.5% (4.5%). Plots of the renal clearance of (18)F-fluoride against urine volume showed that urine flow rates greater than 5 ml.min-1 were necessary to ensure a constant renal clearance of (18)F and hence stable conditions for the evaluation of bone tracer kinetics. In contrast, a low urine flow rate had no effect on the renal kinetics of (99m)Tc-MDP. For MDP, the evaluation of skeletal kinetics requires data on protein binding so that calculations can be performed for free MDP. In the present study, protein binding of MDP was evaluated from the ratio of total (99m)Tc-MDP renal clearance to GFR based on the principle that free (99m)Tc-MDP is a GFR tracer. Between 0 and 4 h after injection, the fractional protein binding of MDP increased linearly with time, changing from 21+/-5% immediately after injection to 58+/-5% at 4 h. Although red cell uptake of (99m)Tc-MDP was negligible, for (18)F-fluoride around 30% of circulating tracer was transported in red cells. In view of the data showing the rapid transport of (18)F-fluoride across the red cell membrane, bone kinetic data for (18)F are more accurately reported as whole-blood clearance rather than plasma clearance.

This article discusses methods for quantifying bone turnover based on tracer kinetic studies of the short-lived radiopharmaceuticals 99mTc-MDP and 18F-fluoride. Measurements of skeletal clearance obtained by using these tracers reflect the combined effects of skeletal blood flow and osteoblastic activity. The pharmacokinetics of each tracer is described, together with some of the quantitative tests of skeletal function that have been described in the literature. The physiologic interpretation of quantitative measurements of bone obtained with the use of short half-life radionuclides is discussed, and the advantages and limitations of 99mTc-MDP and 18F-fluoride are compared and contrasted. Currently, 18F-fluoride dynamic positron emission tomography (PET) is the technique of choice for physiologically precise quantitative studies of bone. However, comparable data could probably be obtained by using 99mTc-MDP if methods for single photon emission computed tomography (SPECT) quantitation were improved.