Amelia Moore

Assessment of regional changes in skeletal metabolism following 3 and 18 months of teriparatide treatment

Teriparatide (TPTD) increases skeletal mass, bone turnover markers, and bone strength, but in vivo effects at individual skeletal sites have not been characterized. Quantitative radionuclide imaging studies reflect bone blood flow and osteoblast activity to assess regional changes in bone metabolism. Changes in bone plasma clearance using technetium‐99m methylene diphosphonate (99mTc‐MDP) were quantified and correlated with changes in bone turnover markers in 10 postmenopausal women with osteoporosis. Subjects underwent bone scintigraphy at baseline and 3 and 18 months after initiating TPTD 20 µg/day subcutaneously. Subjects were injected with 600 MBq 99mTc‐MDP, and whole‐body bone scan images were acquired at 10 minutes and 1, 2, 3, and 4 hours. Multiple blood samples were taken between 5 minutes and 4 hours after treatment, and free 99mTc‐MDP was measured using ultrafiltration. The Patlak plot method was used to evaluate whole‐skeleton 99mTc‐MDP plasma clearance (Kbone) and derive regional bone clearance for the calvarium, mandible, spine, pelvis, and upper and lower extremities using gamma camera counts. Bone turnover markers were measured at baseline and 3, 12, and 18 months. Median increases from baseline in whole‐skeleton Kbone were 22.3% (p = .004) and 33.7% (p = .002) at 3 and 18 months, respectively. Regional Kbone values were increased significantly in all six subregions at 3 months and in all subregions except the pelvis at 18 months. Bone markers were increased significantly from baseline at 3 and 18 months and correlated significantly with whole‐skeleton Kbone. This is the first study showing a direct metabolic effect of TPTD at different skeletal sites in vivo, as measured by tracer kinetics.

The Precision and Sensitivity of 18F-Fluoride PET for Measuring Regional Bone Metabolism: A Comparison of Quantification Methods

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 18F-fluoride PET (18F− 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 18F− 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 (Ki). Standardized uptake values (SUVs) were also studied. Data for 20 women who had 18F− 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 k4 describing the reverse flow of 18F from bone as a free variable showed close agreement in Ki 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 k4 = 0 gave Ki 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 k4 = 0.01 min−1 did not perform any better (%CV, 14.2%; treatment response, 26.1%). Correlation coefficients between SUV and the different Ki 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 Ki assuming k4 = 0 required fewer subjects to demonstrate a statistically significant response to treatment than methods that fitted k4 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.

Radionuclide studies of bone metabolism: do bone uptake and bone plasma clearance provide equivalent measurements of bone turnover?

Quantitative radionuclide imaging using (18)F-fluoride positron emission tomography (18F-PET) or (99m)Tc-methylene diphosphonate ((99m)Tc-MDP) bone scans provides a novel tool for studying regional and whole skeleton bone turnover that complements the information provided by biochemical markers. Radionuclide bone scans can be quantified by measuring either tracer uptake or, if blood sampling is performed, bone plasma clearance. This study examines whether these two methods provide equivalent information about bone turnover. We examined data from two clinical trials of the bone anabolic agent teriparatide. In Study 1 twenty osteoporotic women had 18F-PET scans of the lumbar spine at baseline and after 6 months treatment with teriparatide. Bone uptake in the lumbar spine was expressed as standardised uptake values (SUV) and blood samples taken to evaluate plasma clearance. In Study 2 ten women had (99m)Tc-MDP scans at baseline, 3 and 18 months after starting teriparatide. Blood samples were taken and whole skeleton plasma clearance and bone uptake calculated. In Study 1 spine plasma clearance increased by 23.8% after 6-months treatment (P=0.0003), whilst SUV increased by only 3.0% (P=0.84). In Study 2 whole skeleton plasma clearance increased by 37.1% after 18-months treatment (P=0.0002), whilst the 4-hour whole skeleton uptake increased by only 25.5% (P=0.0001). During treatment the 18F- plasma concentration decrease by 20% and (99m)Tc-MDP concentration by 13%, and these latter changes were sufficient to explain the differences between the uptake and plasma clearance results. Measurements of response to treatment using bone uptake and plasma clearance gave different results because the effects of teriparatide on bone resulted in a sufficiently increased demand for radionuclide tracer from the skeleton that the concentration in the circulation decreased. Similar effects may occur with other therapies that have a large enough effect on bone metabolism. In these circumstances changes in bone plasma clearance give a truer impression of response to treatment than those in SUV or uptake.

18F‐fluoride PET as a noninvasive imaging biomarker for determining treatment efficacy of bone active agents at the hip: A prospective, randomized, controlled clinical study

The functional imaging technique of 18F‐fluoride positron emission tomography (18F‐PET) allows the noninvasive quantitative assessment of regional bone formation at any skeletal site, including the spine and hip. The aim of this study was to determine if 18F‐PET can be used as an early biomarker of treatment efficacy at the hip. Twenty‐seven treatment‐naive postmenopausal women with osteopenia were randomized to receive teriparatide and calcium and vitamin D (TPT group, n = 13) or calcium and vitamin D only (control group, n = 14). Subjects in the TPT group were treated with 20 µg/day teriparatide for 12 weeks. 18F‐PET scans of the proximal femur, pelvis, and lumbar spine were performed at baseline and 12 weeks. The plasma clearance of 18F‐fluoride to bone, Ki, a validated measurement of bone formation, was measured at four regions of the hip, lumbar spine, and pelvis. A significant increase in Ki was observed at all regions of interest (ROIs), including the total hip (+27%, p = 0.002), femoral neck (+25%, p = 0.040), hip trabecular ROI (+21%, p = 0.017), and hip cortical ROI (+51%, p = 0.001) in the TPT group. Significant increases in Ki in response to TPT were also observed at the lumbar spine (+18%, p = 0.001) and pelvis (+42%, p = 0.001). No significant changes in Ki were observed for the control group. Changes in BMD and bone turnover markers were consistent with previous trials of teriparatide. In conclusion, this is the first study to our knowledge to demonstrate that 18F‐PET can be used as an imaging biomarker for determining treatment efficacy at the hip as early as 12 weeks after initiation of therapy.

¹⁸F-fluoride PET as a non-invasive imaging biomarker for determining treatment efficacy of bone active agents at the hip

The functional imaging technique of 18F‐fluoride positron emission tomography (18F‐PET) allows the noninvasive quantitative assessment of regional bone formation at any skeletal site, including the spine and hip. The aim of this study was to determine if 18F‐PET can be used as an early biomarker of treatment efficacy at the hip. Twenty‐seven treatment‐naive postmenopausal women with osteopenia were randomized to receive teriparatide and calcium and vitamin D (TPT group, n = 13) or calcium and vitamin D only (control group, n = 14). Subjects in the TPT group were treated with 20 µg/day teriparatide for 12 weeks. 18F‐PET scans of the proximal femur, pelvis, and lumbar spine were performed at baseline and 12 weeks. The plasma clearance of 18F‐fluoride to bone, Ki, a validated measurement of bone formation, was measured at four regions of the hip, lumbar spine, and pelvis. A significant increase in Ki was observed at all regions of interest (ROIs), including the total hip (+27%, p = 0.002), femoral neck (+25%, p = 0.040), hip trabecular ROI (+21%, p = 0.017), and hip cortical ROI (+51%, p = 0.001) in the TPT group. Significant increases in Ki in response to TPT were also observed at the lumbar spine (+18%, p = 0.001) and pelvis (+42%, p = 0.001). No significant changes in Ki were observed for the control group. Changes in BMD and bone turnover markers were consistent with previous trials of teriparatide. In conclusion, this is the first study to our knowledge to demonstrate that 18F‐PET can be used as an imaging biomarker for determining treatment efficacy at the hip as early as 12 weeks after initiation of therapy.

Radionuclide and Hybrid Bone Imaging

Quantitative bone scan imaging has a useful role in studies of the pathophysiology of metabolic bone disease and the response of patients to treatment. The advantage of nuclear medicine imaging as a way of studying bone remodelling is that it offers a unique way of measuring bone turnover both for the whole skeleton and in selected localised regions of interest (ROI). This chapter reviews methods of quantifying 99mTc-MDP and 18F-fluoride skeletal tracer kinetics by combining imaging data with blood sampling to measure bone plasma clearance. For studies using 99mTc-MDP, we describe three methods of measuring whole-skeleton plasma clearance (K bone): (1) The area-under-the-curve (AUC) method based on taking six blood samples between 5 min and 4 h and measuring the plasma concentration of free 99mTc-MDP by ultrafiltration. The AUC method requires a simultaneous measurement of glomerular filtration rate (GFR) using 51Cr-EDTA as a co-tracer. (2) The modified Brenner method, which measures K bone by drawing a soft tissue ROI over the adductor muscles and plotting the soft tissue counts at 1, 2, 3 and 4 h against the AUC values at the corresponding time points. (3) The Patlak method based on combining gamma camera measurements of whole-body retention with plasma data and finding K bone from the slope of the Patlak plot fitted to the 2, 3 and 4 h data points. Unlike the first two methods, the Patlak plot can also be used to measure regional values of K bone for any chosen ROI. Studies of 18F-fluoride skeletal tracer kinetics are performed using a 60-min dynamic positron emission tomography (PET) scan with measurement of the input function by either direct arterial sampling or using an image-derived input function from the heart, aorta or femoral artery and can be used to measure the net plasma clearance to the bone mineral compartment (K i ) at either the spine, hip or humerus. Further studies are required comparing radionuclide measurements with the gold standard of bone biopsy. Nuclear medicine measurements of bone turnover have an established role as a research technique, and there is a need for further studies to examine their role in assessing the pathophysiology of metabolic bone diseases, such as osteoporosis, Paget’s disease and renal osteodystrophy, and better understanding the effects of new pharmaceutical treatments at various sites throughout the skeleton.

Validation of image-derived arterial input functions at the femoral artery using 18F-fluoride positron emission tomography

IntroductionThe 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. MethodsTwelve 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. ResultsWhen 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. ConclusionWe 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.

Quantitative Studies of Bone Using 99mTc-Methylene Diphosphonate Skeletal Plasma Clearance

Quantitative bone scan imaging has a useful role in research for examining the pathophysiology of metabolic bone diseases and the response of patients to treatment. The advantage of nuclear medicine imaging as a way of measuring the rate of bone remodeling is that either the whole skeleton or discrete regions of interest (ROIs) may be studied depending on whether there is diffuse or localized disease. This article reviews methods of quantifying (99m)Tc-methylene diphosphonate ((99m)Tc-MDP) kinetics based on a standard bone scan examination by measuring the plasma clearance of tracer to the whole skeleton and/or selected ROIs drawn on the bone scan image. Although the measurement of bone plasma clearance requires blood sampling to find the input curve for free (eg, nonprotein bound) (99m)Tc-MDP, we argue that plasma clearance studies give a more physiological approach in a better accord with the underlying changes in bone turnover than conventional measurements of whole-body retention or bone uptake. We describe 3 methods of measuring whole-skeleton (99m)Tc-MDP plasma clearance (K(bone)): (1) the area under the curve (AUC) method based on taking 6 blood samples at 5, 15, 60, 120, 180, and 240 minutes and measuring the plasma concentration of free (99m)Tc-MDP by ultrafiltration using a 30-kDa filter. The AUC method requires a simultaneous measurement of glomerular filtration rate using (51)Cr-EDTA as a cotracer; (2) the modified Brenner method, which measures K(bone) by drawing a soft-tissue ROI over the adductor muscles and plotting the soft tissue counts at 1, 2, 3, and 4 hours against the AUC values at the corresponding time points; (3) the Patlak method based on combining gamma camera measurements of whole-body retention with plasma data and measuring K(bone) from the slope of the Patlak plot fitted to the 2, 3, and 4 hours data points. Unlike the first 2 methods, the Patlak plot can also be used to measure regional values of K(bone) for any chosen ROI. Initial studies have shown good agreement between the 3 methods of measuring K(bone), and highly significant correlations between the change in K(bone) values during treatment and the corresponding changes in serum and urinary measurements of biochemical markers of bone formation and bone resorption.

Imaging of Site Specific Bone Turnover in Osteoporosis Using Positron Emission Tomography

The functional imaging technique of dynamic fluorine-18 labeled sodium fluoride positron emission tomography (18F-NaF PET) allows the quantitative assessment of regional bone formation by measuring the plasma clearance of fluoride to bone at any site in the skeleton. 18F-NaF PET provides a novel and noninvasive method of studying site-specific bone formation at the hip and spine, as well as areas of pure cortical or trabecular bone. The technique complements conventional measurements of bone turnover using biochemical markers and bone biopsy as a tool to investigate new treatments for osteoporosis, and holds promise of a future role as an early biomarker of treatment efficacy in clinical trials. This article reviews methods of acquiring and analyzing 18F-NaF PET scan data, and outlines a simplified approach that uses 5-minute static PET scan images combined with venous blood samples to estimate 18F-NaF plasma clearance at multiple sites in the skeleton with a single injection of tracer.

A semipopulation input function for quantifying static and dynamic 18F-fluoride PET scans.

PurposeWe describe a semipopulation input function for evaluating bone plasma clearance from static and dynamic 18F-fluoride PET scans. MethodsThe 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. ResultsVenous 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. ConclusionAccurate and precise measurements of bone plasma clearance were obtained when 18F-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.