Utility of a simplified [18F] sodium fluoride PET imaging method to quantify bone metabolic flux for a wide range of clinical applications.

We review the rationale, methodology, and clinical utility of quantitative [18F] sodium fluoride ([18F]NaF) positron emission tomography-computed tomography (PET-CT) imaging to measure bone metabolic flux (Ki, also known as bone plasma clearance), a measurement indicative of the local rate of bone formation at the chosen region of interest. We review the bone remodelling cycle and explain what aspects of bone remodelling are addressed by [18F]NaF PET-CT. We explain how the technique works, what measurements are involved, and what makes [18F]NaF PET-CT a useful tool for the study of bone remodelling. We discuss how these measurements can be simplified without loss of accuracy to make the technique more accessible. Finally, we briefly review some key clinical applications and discuss the potential for future developments. We hope that the simplified method described here will assist in promoting the wider use of the technique.

Evaluating the suitability of close-kin mark-recapture as a demographic modelling tool for a critically endangered elasmobranch population.

Estimating the demographic parameters of contemporary populations is essential to the success of elasmobranch conservation programmes, and to understanding their recent evolutionary history. For benthic elasmobranchs such as skates, traditional fisheries-independent approaches are often unsuitable as the data may be subject to various sources of bias, whilst low recapture rates can render mark-recapture programmes ineffectual. Close-kin mark-recapture (CKMR), a novel demographic modelling approach based on the genetic identification of close relatives within a sample, represents a promising alternative approach as it does not require physical recaptures. We evaluated the suitability of CKMR as a demographic modelling tool for the critically endangered blue skate (Dipturus batis) in the Celtic Sea using samples collected during fisheries-dependent trammel-net surveys that ran from 2011 to 2017. We identified three full-sibling and 16 half-sibling pairs among 662 skates, which were genotyped across 6291 genome-wide single nucleotide polymorphisms, 15 of which were cross-cohort half-sibling pairs that were included in a CKMR model. Despite limitations owing to a lack of validated life-history trait parameters for the species, we produced the first estimates of adult breeding abundance, population growth rate, and annual adult survival rate for D. batis in the Celtic Sea. The results were compared to estimates of genetic diversity, effective population size (N e ), and to catch per unit effort estimates from the trammel-net survey. Although each method was characterized by wide uncertainty bounds, together they suggested a stable population size across the time-series. Recommendations for the implementation of CKMR as a conservation tool for data-limited elasmobranchs are discussed. In addition, the spatio-temporal distribution of the 19 sibling pairs revealed a pattern of site fidelity in D. batis, and supported field observations suggesting an area of critical habitat that could qualify for protection might occur near the Isles of Scilly.

Input function and modeling for determining bone metabolic flux using [18 F] sodium fluoride PET imaging: A step-by-step guide.

Studies of skeletal metabolism using measurements of bone metabolic flux (Ki ) 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 Ki 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 Ki 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 Ki 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 Ki 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.

Population and seascape genomics of a critically endangered benthic elasmobranch, the blue skate Dipturus batis.

The blue skate (Dipturus batis) has a patchy distribution across the North-East Atlantic Ocean, largely restricted to occidental seas around the British Isles following fisheries-induced population declines and extirpations. The viability of remnant populations remains uncertain and could be impacted by continued fishing and by-catch pressure, and the projected impacts of climate change. We genotyped 503 samples of D. batis, obtained opportunistically from the widest available geographic range, across 6 350 single nucleotide polymorphisms (SNPs) using a reduced-representation sequencing approach. Genotypes were used to assess the species' contemporary population structure, estimate effective population sizes and identify putative signals of selection in relation to environmental variables using a seascape genomics approach. We identified genetic discontinuities between inshore (British Isles) and offshore (Rockall and Faroe Island) populations, with differentiation most pronounced across the deep waters of the Rockall Trough. Effective population sizes were largest in the Celtic Sea and Rockall, but low enough to be of potential conservation concern among Scottish and Faroese sites. Among the 21 candidate SNPs under positive selection was one significantly correlated with environmental variables predicted to be affected by climate change, including bottom temperature, salinity and pH. The paucity of well-annotated elasmobranch genomes precluded us from identifying a putative function for this SNP. Nevertheless, our findings suggest that climate change could inflict a strong selective force upon remnant populations of D. batis, further constraining its already-restricted habitat. Furthermore, the results provide fundamental insights on the distribution, behaviour and evolutionary biology of D. batis in the North-East Atlantic that will be useful for the establishment of conservation actions for this and other critically endangered elasmobranchs.

[18F] Sodium Fluoride PET Kinetic Parameters in Bone Imaging.

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 ([18F]NaF) to understand bone physiology. Dynamic [18F]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.

A Short Dynamic Scan Method of Measuring Bone Metabolic Flux Using [18F]NaF PET.

[18F]NaF PET measurements of bone metabolic flux (Ki) are conventionally obtained with 60-min dynamic scans analysed using the Hawkins model. However, long scan times make this method expensive and uncomfortable for subjects. Therefore, we evaluated and compared measurements of Ki with shorter scan times analysed with fixed values of the Hawkins model rate constants. The scans were acquired in a trial in 30 postmenopausal women, half treated with teriparatide (TPT) and half untreated. Sixty-minute PET-CT scans of both hips were acquired at baseline and week 12 after injection with 180 MBq [18F]NaF. Scans were analysed using the Hawkins model by fitting bone time-activity curves at seven volumes of interest (VOIs) with a semi-population arterial input function. The model was re-run with fixed rate-constants for dynamic scan times from 0-12 min increasing in 4-min steps up to 0-60 min. Using the Hawkins model with fixed rate-constants, Ki measurements with statistical power equivalent or superior to conventionally analysed 60-min dynamic scans were obtained with scan times as short as 12 min.

Comparison of ordered-subset expectation maximization and filtered back projection reconstruction based on quantitative outcome from dynamic [18F]NaF PET images.

[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.

Evaluation of aortic 18F-NaF tracer uptake using PET/CT as a predictor of aortic calcification in postmenopausal women: A longitudinal study.

INTRODUCTION: Aortic calcification as detected by computed tomography is associated with arterial stiffening and is an important predictor of cardiovascular morbidity and mortality. Uptake of 18F-sodium fluoride (18F-NaF) in the aortic wall reflects metabolically active areas of calcification. The aim of this study was to determine if 18F-NaF uptake in the aorta is associated with calcification and progression of calcification as detected by computed tomography. METHODS: Twenty-one postmenopausal women (mean age 62 ± 6 years) underwent assessment of aortic 18F-NaF uptake using positron emission tomography/computer tomography at baseline and a repeat computed tomography scan after a mean follow-up of 3.8 ± 1.3 years. Tracer uptake was quantified by calculating the target-to-background (TBR) ratios at baseline and follow-up. Calcification was assessed at baseline and follow-up using computed tomography. RESULTS: Over the follow-up period, aortic calcium volume increased from 0.46 ± 0.62 to 0.71 ± 0.93 cm3 (P < 0.05). However, the change in calcium volume did not correlate with baseline TBR either unadjusted (r = 0.00, P = 1.00) or adjusted for age and baseline calcium volume (beta coefficient = -0.18, P = 0.42). TBR at baseline did not differ between participants with (n = 16) compared to those without (n = 5) progression in calcium volume (2.43 ± 0.46 vs. 2.31 ± 0.38, P = 0.58). In aortic segments identified to have the highest tracer uptake at baseline, calcium volume did not significantly change over the follow-up period (P = 0.41). CONCLUSION: In a cohort of postmenopausal women, 18F-NaF uptake as measured by TBR in the lumbar aorta did not predict progression of aortic calcification as detected by computed tomography over a four-year follow-up.

The influence of CT and dual-energy X-ray absorptiometry (DXA) bone density on quantitative [18F] sodium fluoride PET.

BACKGROUND: [18F] sodium fluoride PET/CT provides quantitative measures of bone metabolic activity expressed by the parameters standardised uptake value (SUV) and bone plasma clearance (K i) that correlate with measurements of bone formation rate obtained by bone biopsy with double tetracycline labelling. Both SUV and K i relate to the tracer uptake in each millilitre of tissue. In general, the bone region of interest (ROI) includes both mineralised bone {generally with a high concentration of [18F]NaF} and bone marrow (with a much lower concentration), suggesting that correcting SUV and K i for volumetric bone mineral density (vBMD) and measuring them with respect to the tracer uptake in each gram of bone mineral might improve the correlation with the findings of bone biopsy. As a first test of this hypothesis, we looked for positive correlations between SUV and K i values with CT and DXA bone mineral density (BMD) parameters measured in the same ROI. METHODS: A retrospective reanalysis was performed of 63 lumbar spine [18F]NaF PET/CT scans acquired in four earlier studies. The quantitative PET parameters SUV and K i were measured in L1-L4 and Hounsfield units (HU) measured on the CT scans in the same ROI. Spine BMD data was also obtained from DXA scans in the form of areal BMD and used to derive the bone mineral apparent density (BMAD, an estimate of vBMD). Scatter plots were drawn of SUV and K i against HU, BMAD and areal BMD and the Spearman rank correlation coefficients derived for each plot. RESULTS: All correlations were positive and statistically significant. Correlations were highest for HU (SUV: RS =0.513, P<0.0001; K i: RS =0.429, P=0.0005) and lowest for areal BMD (SUV: RS =0.353, P=0.005; K i: RS =0.274, P=0.03). CONCLUSIONS: The results demonstrate significant positive correlations between SUV and K i and vBMD measurements in the form of HU from CT or BMAD and areal BMD from DXA. These findings justify further exploration of the relationship between SUV and K i [18F]NaF PET/CT measurements and CT or DXA measurements of vBMD to examine whether normalization for bone density might improve their correlation with bone metabolic activity as measured by bone biopsy.

Site specific measurements of bone formation using [18F] sodium fluoride PET/CT.

Dynamic positron emission tomography (PET) imaging with fluorine-18 labelled sodium fluoride ([18F]NaF) allows the quantitative assessment of regional bone formation by measuring the plasma clearance of fluoride to bone at any site in the skeleton. Today, hybrid PET and computed tomography (CT) dual-modality systems (PET/CT) are widely available, and [18F]NaF PET/CT offers a convenient non-invasive method of studying bone formation at the important osteoporotic fracture sites at the hip and spine, as well as sites of pure cortical or trabecular bone. The technique complements conventional measurements of bone turnover using biochemical markers or bone biopsy as a tool to investigate new therapies for osteoporosis, and has a potential role as an early biomarker of treatment efficacy in clinical trials. This article reviews methods of acquiring and analyzing dynamic [18F]NaF PET/CT scan data, and outlines a simplified approach combining venous blood sampling with a series of short (3- to 5-minute) static PET/CT scans acquired at different bed positions to estimate [18F]NaF plasma clearance at multiple sites in the skeleton with just a single injection of tracer.

A rectal cancer feasibility study with an embedded phase III trial design assessing magnetic resonance tumour regression grade (mrTRG) as a novel biomarker to stratify management by good and poor response to chemoradiotherapy (TRIGGER): study protocol for a randomised controlled trial.

BACKGROUND: Pre-operative chemoradiotherapy (CRT) for MRI-defined, locally advanced rectal cancer is primarily intended to reduce local recurrence rates by downstaging tumours, enabling an improved likelihood of curative resection. However, in a subset of patients complete tumour regression occurs implying that no viable tumour is present within the surgical specimen. This raises the possibility that surgery may have been avoided. It is also recognised that response to CRT is a key determinant of prognosis. Recent radiological advances enable this response to be assessed pre-operatively using the MRI tumour regression grade (mrTRG). Potentially, this allows modification of the baseline MRI-derived treatment strategy. Hence, in a 'good' mrTRG responder, with little or no evidence of tumour, surgery may be deferred. Conversely, a 'poor response' identifies an adverse prognostic group which may benefit from additional pre-operative therapy. METHODS/DESIGN: TRIGGER is a multicentre, open, interventional, randomised control feasibility study with an embedded phase III design. Patients with MRI-defined, locally advanced rectal adenocarcinoma deemed to require CRT will be eligible for recruitment. During CRT, patients will be randomised (1:2) between conventional management, according to baseline MRI, versus mrTRG-directed management. The primary endpoint of the feasibility phase is to assess the rate of patient recruitment and randomisation. Secondary endpoints include the rate of unit recruitment, acute drug toxicity, reproducibility of mrTRG reporting, surgical morbidity, pathological circumferential resection margin involvement, pathology regression grade, residual tumour cell density and surgical/specimen quality rates. The phase III trial will focus on long-term safety, regrowth rates, oncological survival analysis, quality of life and health economics analysis. DISCUSSION: The TRIGGER trial aims to determine whether patients with locally advanced rectal cancer can be recruited and subsequently randomised into a control trial that offers MRI-directed patient management according to radiological response to CRT (mrTRG). The feasibility study will inform a phase III trial design investigating stratified treatment of good and poor responders according to 3-year disease-free survival, colostomy-free survival as well as an increase in cases managed without a major resection. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02704520 . Registered on 5 February 2016.

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 ((18)F-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. (18)F-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 (18)F-NaF PET scan data, and outlines a simplified approach that uses 5-minute static PET scan images combined with venous blood samples to estimate (18)F-NaF plasma clearance at multiple sites in the skeleton with a single injection of tracer.

Correcting (18)F-fluoride PET static scan measurements of skeletal plasma clearance for tracer efflux from bone.

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.

(18)F-fluoride positron emission tomography measurements of regional bone formation in hemodialysis patients with suspected adynamic bone disease.

(18)F-fluoride positron emission tomography ((18)F-PET) allows the assessment of regional bone formation and could have a role in the diagnosis of adynamic bone disease (ABD) in patients with chronic kidney disease (CKD). The purpose of this study was to examine bone formation at multiple sites of the skeleton in hemodialysis patients (CKD5D) and assess the correlation with bone biopsy. Seven CKD5D patients with suspected ABD and 12 osteoporotic postmenopausal women underwent an (18)F-PET scan, and bone plasma clearance, K i, was measured at ten skeletal regions of interest (ROI). Fifteen subjects had a transiliac bone biopsy following double tetracycline labeling. Two CKD5D patients had ABD confirmed by biopsy. There was significant heterogeneity in K i between skeletal sites, ranging from 0.008 at the forearm to 0.028 mL/min/mL at the spine in the CKD5D group. There were no significant differences in K i between the two study groups or between the two subjects with ABD and the other CKD5D subjects at any skeletal ROI. Five biopsies from the CKD5D patients had single tetracycline labels only, including the two with ABD. Using an imputed value of 0.3 µm/day for mineral apposition rate (MAR) for biopsies with single labels, no significant correlations were observed between lumbar spine K i corrected for BMAD (K i/BMAD) and bone formation rate (BFR/BS), or MAR. When biopsies with single labels were excluded, a significant correlation was observed between K i/BMAD and MAR (r = 0.81, p = 0.008) but not BFR/BS. Further studies are required to establish the sensitivity of (18)F-PET as a diagnostic tool for identifying CKD patients with ABD.

The relationship between inhibitors of the Wnt signalling pathway (Dickkopf-1(DKK1) and sclerostin), bone mineral density, vascular calcification and arterial stiffness in post-menopausal women.

Epidemiological studies have shown an association between bone loss/osteoporosis and vascular calcification (VC). Recent studies have implicated the Wnt signalling pathway in the pathogenesis of VC. We investigated the association between circulating concentrations of Wnt inhibitors; DKK1 and sclerostin with bone mineral density (BMD), abdominal aortic calcification (AAC) and arterial stiffness in post-menopausal women. One hundred and forty six post-menopausal women aged (mean [SD]) 61.5[6.5] years were studied. Sclerostin and DKK1 were measured in serum. BMD was measured at the lumbar spine (LS), femoral neck (FN), total hip (TH). AAC was detected by Vertebral Fracture Assessment (VFA) imaging and quantified using an 8- and 24- point scoring methods. Arterial stiffness was determined by aortic pulse wave velocity (PWV). A significant positive correlation was observed between sclerostin and BMD at the FN (r = 0.166, p = 0.043) and TH (r = 0.165, p = 0.044). The association remained significant at the FN (p = 0.045) and TH (p = 0.026) following adjustment for confounders. No significant correlation was observed between DKK1 and BMD. In contrast, there was a significant negative correlation between log DKK1 and AAC (24-point score: r = -0.25, p = 0.008 and 8-point score: r = -0.21, p = 0.024). Subjects with AAC score of 1 or less had significantly higher DKK1 (p = 0.01). The association between DKK1 and AAC remained significant following correction for age, blood pressure, cholesterol (24-point score: p = 0.017, 8-point score: p = 0.044). In adjusted linear regression analysis, sclerostin was positively associated with AAC (24-point score: p = 0.048, 8-point score: p = 0.031). Subjects with a PWV>9 m/s had significantly higher sclerostin than those with PWV <9 m/s: 23.8[12.3], vs 29.7 [14] pmol/l, p = 0.03). No association was observed between DKK1 and PWV. The opposite association between AAC and the 2 Wnt signaling inhibitors is of interest and merits further investigations. Future longitudinal studies are needed to establish the precise role of sclerostin and DKK1 in the pathogenesis of VC.

Abdominal aortic calcification detection using dual-energy X-ray absorptiometry: validation study in healthy women compared to computed tomography.

Abdominal aortic calcification (AAC) is an independent determinant of cardiovascular events. Computed tomography (CT) is currently the gold standard measure of AAC but is limited by high radiation exposure. Lateral dual-energy X-ray absorptiometry (DXA) has the potential to detect AAC at a fraction of the radiation dose. Our objective was to determine the accuracy of lateral-DXA in detecting AAC compared to CT in healthy women. Women from the TwinsUK registry aged 52-80 years (n = 105) underwent noncontrast CT and lateral-DXA imaging of the abdominal aorta at lumbar vertebrae L1-L4. Presence of calcium on CT was scored using the volume method. Lateral-DXA images were scored using the previously validated semiquantitative 24-point score and simplified 8-point score. Calcification was present in 81 % of women as determined by CT and 49 % with lateral-DXA. The mean volume score and the 24- and 8-point scores of AAC were 0.20 ± 0.41 cm(2), 2.39 ± 3.91 arbitrary units, and 1.47 ± 2.13 arbitrary units, respectively. There was moderate agreement between CT and 24-point lateral-DXA (Spearman's rank correlation coefficient r = 0.58, P < 0.0001). The sensitivity of lateral-DXA for detecting AAC was 56 % and specificity was 80 %. Sensitivity and specificity of lateral-DXA improved to 64 and 84 % when analysis was limited to calcium volumes ≥0.008 cm(3) as detected by CT. Lateral-DXA imaging may provide a useful alternative to CT in detecting AAC with minimal radiation exposure, which may be used with concurrent bone mineral density assessment.

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, K(i), a validated measurement of bone formation, was measured at four regions of the hip, lumbar spine, and pelvis. A significant increase in K(i) 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 K(i) 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 K(i) 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.

Semiautomatic region-of-interest validation at the femur in (18)F-fluoride PET/CT.

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.

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

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.

Comparison of six quantitative methods for the measurement of bone turnover at the hip and lumbar spine using 18F-fluoride PET-CT.

AIM: The aim of this study was to evaluate the relationship between different quantification methods used for the measurement of bone plasma clearance (K(i)) using F-PET at the hip and lumbar spine. METHODS: Twelve healthy postmenopausal women aged 52-71 years were recruited. Each participant underwent 60-min dynamic F-PET scans at the lumbar spine and hip on two separate occasions with an injected activity of 90 and 180 MBq, respectively. Image-derived input functions were obtained at the aorta from the lumbar spine scans. K(i) was evaluated using a three-compartment four-parameter model (K(i-4k)), three-compartment three-parameter model (K(i-3k)), Patlak analysis (K(i-Pat)), spectral analysis (K(i-Spec)) and deconvolution (K(i-Decon)). Standardized uptake values (SUVs) were also measured. RESULTS: The Pearson correlation between K(i-4k) and K(i-3k), K(i-Pat), K(i-Spec), K(i-Decon) and SUV were 0.91, 0.97, 0.94, 0.95 and 0.93, respectively, with a significance of P less than 0.0001. The differences between the correlations measured using Fisher's Z-test were not significant (P>0.05). Bland-Altman analysis showed that the limits of agreement for K(i) measured as the SD of the differences were 0.0082 (25.9%), 0.0062 (11.7%), 0.0098 (20.1%) and 0.0056 (25.5%) ml/min/ml, respectively, and the biases were -0.0081 (-23.8%), -0.0075 (-23.7%), -0.0107 (-29.5%) and -0.0015 (0.8%) ml/min/ml, respectively. CONCLUSION: All five methods of quantification (K(i-3k), K(i-Pat), K(i-Spec), K(i-Decon) and SUV) strongly correlated with K(i-4k). Although systematic differences of up to 29% were found between K(i-4k) and the other methods (K(i-3k), K(i-Pat), K(i-Spec) and K(i-Decon)), these should not affect the conclusions of clinical studies, provided the methods are applied consistently. However, care should be taken when comparing reports that use different methods of quantification.