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.

Bone turnover change after randomized switch from tenofovir disoproxil to tenofovir alafenamide fumarate in men with HIV.

OBJECTIVE: Bone loss in people with HIV (PWH) is poorly understood. Switching tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) has yielded bone mineral density (BMD) increases. PETRAM (NCT#:03405012) investigated whether BMD and bone turnover changes correlate. DESIGN: Open-label, randomized controlled trial. SETTING: Single-site, outpatient, secondary care. PARTICIPANTS: Nonosteoporotic, virologically suppressed, cis-male PWH taking TDF/emtricitabine (FTC)/rilpivirine (RPV) for more than 24 weeks. INTERVENTION: Continuing TDF/FTC/RPV versus switching to TAF/FTC/RPV (1 : 1 randomization). MAIN OUTCOME MEASURES: :[ 18 F]NaF-PET/CT for bone turnover (standardized uptake values, SUV mean ) and dual-energy x-ray absorptiometry for lumbar spine and total hip BMD. RESULTS: Thirty-two men, median age 51 years, 76% white, median duration TDF/FTC/RPV 49 months, were randomized between 31 August 2018 and 09 March 2020. Sixteen TAF:11 TDF were analyzed. Baseline-final scan range was 23-103 (median 55) weeks. LS-SUV mean decreased for both groups (TAF -7.9% [95% confidence interval -14.4, -1.5], TDF -5.3% [-12.1,1.5], P  = 0.57). TH-SUV mean showed minimal changes (TAF +0.3% [-12.2,12.8], TDF +2.9% [-11.1,16.9], P  = 0.77). LS-BMD changes were slightly more favorable with TAF but failed to reach significance (TAF +1.7% [0.3,3.1], TDF -0.3 [-1.8,1.2], P  = 0.06). Bone turnover markers decreased more with TAF ([CTX -35.3% [-45.7, -24.9], P1NP -17.6% [-26.2, -8.5]) than TDF (-11.6% [-28.8, +5.6] and -6.9% [-19.2, +5.4] respectively); statistical significance was only observed for CTX ( P  = 0.02, P1NP, P  = 0.17). CONCLUSION: Contrary to our hypothesis, lumbar spine and total hip regional bone formation (SUV mean ) and BMD did not differ postswitch to TAF. However, improved LS-BMD and CTX echo other TAF-switch studies. The lack of difference in SUV mean may be due to inadequate power.

(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.

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.

The additive effect of vitamin K supplementation and bisphosphonate on fracture risk in post-menopausal osteoporosis: a randomised placebo controlled trial.

This study assessed whether vitamin K, given with oral bisphosphonate, calcium and/or vitamin D has an additive effect on fracture risk in post-menopausal women with osteoporosis. No difference in bone density or bone turnover was observed although vitamin K1 supplementation led to a modest effect on parameters of hip geometry. PURPOSE: Some clinical studies have suggested that vitamin K prevents bone loss and may improve fracture risk. The aim was to assess whether vitamin K supplementation has an additive effect on bone mineral density (BMD), hip geometry and bone turnover markers (BTMs) in post-menopausal women with osteoporosis (PMO) and sub-optimum vitamin K status receiving bisphosphonate, calcium and/or vitamin D treatment. METHODS: We conducted a trial in 105 women aged 68.7[12.3] years with PMO and serum vitamin K1 ≤ 0.4 µg/L. They were randomised to 3 treatment arms; vitamin K1 (1 mg/day) arm, vitamin K2 arm (MK-4; 45 mg/day) or placebo for 18 months. They were on oral bisphosphonate and calcium and/or vitamin D. We measured BMD by DXA, hip geometry parameters using hip structural analysis (HSA) software and BTMs. Vitamin K1 or MK-4 supplementation was each compared to placebo. Intention to treat (ITT) and per protocol (PP) analyses were performed. RESULTS: Changes in BMD at the total hip, femoral neck and lumbar spine and BTMs; CTX and P1NP did not differ significantly following either K1 or MK-4 supplementation compared to placebo. Following PP analysis and correction for covariates, there were significant differences in some of the HSA parameters at the intertrochanter (IT) and femoral shaft (FS): IT endocortical diameter (ED) (% change placebo:1.5 [4.1], K1 arm: -1.02 [5.07], p = 0.04), FS subperiosteal/outer diameter (OD) (placebo: 1.78 [5.3], K1 arm: 0.46 [2.23] p = 0.04), FS cross sectional area (CSA) (placebo:1.47 [4.09],K1 arm: -1.02[5.07], p = 0.03). CONCLUSION: The addition of vitamin K1 to oral bisphosphonate with calcium and/or vitamin D treatment in PMO has a modest effect on parameters of hip geometry. Further confirmatory studies are needed. TRIAL REGISTRATION: The study was registered at Clinicaltrial.gov:NCT01232647.

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.

Changes observed in radionuclide bone scans during and after teriparatide treatment for osteoporosis.

PURPOSE: Visual changes on radionuclide bone scans have been reported with teriparatide treatment. To assess this, serial studies were evaluated and quantified in ten postmenopausal women with osteoporosis treated with teriparatide (20 µg/day subcutaneous) who had (99m)Tc-methylene diphosphonate (MDP) bone scans (baseline, 3 and 18 months, then after 6 months off therapy). METHODS: Women were injected with 600 MBq (99m)Tc-MDP, and diagnostic bone scan images were assessed at 3.5 h. Additional whole-body scans (10 min, 1, 2, 3 and 4 h) were analysed for (99m)Tc-MDP skeletal plasma clearance (K(bone)). Regional K(bone) differences were obtained for the whole skeleton and six regions (calvarium, mandible, spine, pelvis, upper and lower extremities). Bone turnover markers (BTM) were also measured. RESULTS: Most subjects showed visual changes on 3- and 18-month bone scan images that disappeared after 6 months off therapy. Enhanced uptake was seen predominantly in the calvarium and lower extremities. Whole skeleton K(bone) displayed a median increase of 22% (3 months, p = 0.004) and 34% (18 months, p = 0.002) decreasing to 0.7% (6 months off therapy). Calvarium K(bone) changes were three times larger than other sites. After 6 months off therapy, all K(bone) and BTM values returned towards baseline. CONCLUSION: The increased (99m)Tc-MDP skeletal uptake with teriparatide indicated increased bone formation which was supported by BTM increases. After 6 months off therapy, metabolic activity diminished towards baseline. The modulation of (99m)Tc-MDP skeletal uptake during treatment was the result of teriparatide's metabolic activity. These findings may aid the radiological evaluation of similar teriparatide patients having radionuclide bone scans.

Estimation of regional bone metabolism from whole-body 18F-fluoride PET static images.

PURPOSE: We evaluate a new quantitative method of acquiring and analysing (18)F positron emission tomography (PET) studies that enables regional bone plasma clearance (K ( i )) to be estimated from static scans acquired at multiple sites in the skeleton following a single injection of tracer. METHODS: Dynamic lumbar spine (18)F PET data from two clinical trials were used to simulate a series of static scans acquired 30-60 min after injection. Venous blood samples were taken at 30, 40, 50 and 60 min and K ( i ) evaluated by Patlak analysis and the static scan method. The data were used to evaluate the precision errors of the Patlak and static scan methods expressed as the percentage coefficient of variation (%CV) and compare their response to 6 months of treatment with the bone anabolic agent teriparatide. RESULTS: Static scan K ( i ) measurements 30-60 min after injection were highly correlated with the Patlak results (r > 0.99). The %CV for the static scan method was 17.5% 30 min after injection, decreasing to 14.5% at 60 min, compared with 13.0% for Patlak analysis. Response to teriparatide treatment was +25.2% for the static scan method compared with +24.3% for Patlak analysis. The mean ratio (SD) of the static scan and Patlak K ( i ) results was 1.006 (0.015) at 30 min after injection decreasing to 0.965 (0.015) at 60 min. CONCLUSION: (18)F-Fluoride bone plasma clearance can be estimated from a static scan and venous blood samples acquired 30-60 min after injection. The method enables K ( i ) to be estimated at multiple skeletal sites with a single injection of tracer.

The assessment of regional skeletal metabolism: studies of osteoporosis treatments using quantitative radionuclide imaging.

Studies of bone remodeling using bone biopsy and biochemical markers of bone turnover play an important role in research studies to investigate the effect of new osteoporosis treatments on bone quality. Quantitative radionuclide imaging using either positron emission tomography with fluorine-18 sodium fluoride or gamma camera studies with technetium-99m methylene diphosphonate provides a novel tool for studying bone metabolism that complements conventional methods, such as bone turnover markers (BTMs). Unlike BTMs, which measure the integrated response to treatment across the whole skeleton, radionuclide imaging can distinguish the changes occurring at sites of particular clinical interest, such as the spine or proximal femur. Radionuclide imaging can be used to measure either bone uptake or (if done in conjunction with blood sampling) bone plasma clearance. Although the latter is more complicated to perform, unlike bone uptake, it provides a measurement that is specific to the bone metabolic activity at the measurement site. Treatment with risedronate was found to cause a decrease in bone plasma clearance, whereas treatment with the bone anabolic agent teriparatide caused an increase. Studies of teriparatide are of particular interest because the treatment has different effects at different sites in the skeleton, with a substantially greater response in the flat bone of the skull and cortical bone in the femur compared with the lumbar spine. Future studies should include investigations of osteonecrosis of the jaw and atypical fractures of the femur to examine the associated regional changes in bone metabolism and to throw light on the underlying pathologies.

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.

Serum vitamin K1 (phylloquinone) is associated with fracture risk and hip strength in post-menopausal osteoporosis: A cross-sectional study.

PURPOSE: Vitamin K may play a potential role in bone metabolism, although further evidence is needed. The mechanisms behind its skeletal effects and optimum intake for maintaining bone health remain poorly defined. To elucidate these two issues, we investigated the association between circulating vitamin K1 (phylloquinone) concentrations with fracture risk, bone mineral density (BMD), hip geometry and plasma dephospho-uncarboxylated-Matrix Gla Protein (dp-ucMGP), an extra-hepatic vitamin K dependent protein (VKDP), in post-menopausal osteoporosis (PMO). METHODS: We studied 374 women aged (mean [SD]) 68.7[12.3] years with PMO. Information including demographics, lifestyle habits and previous fractures was captured through a questionnaire. Serum was analysed for vitamin K1. BMD at the lumbar spine (LS), total hip (TH) and femoral neck (FN) (n = 277) and hip structural analysis (HSA) parameters (n = 263) were derived from DXA scans. VKDPs including undercarboxylated prothrombin (PIVKA-II) and dp-ucMGP were measured in a sub-group (n = 130). RESULTS: Serum vitamin K1 was significantly lower in the group with fractures (prevalent fractures: 0.53 [0.41], no fractures; 0.65 [0.66] µg/L, p = 0.04) and independently associated with fracture risk. The adjusted odds ratio (95% CI) per µg/L increase in vitamin K1 was 0.550 (0.310-0.978, p = 0.042). Among the HSA parameters, serum vitamin K1 was positively associated with cross-sectional area (CSA) (p = 0.02), cross sectional moment of inertia (CSMI) (p = 0.028) and section modulus (Z) (p = 0.02) at the narrow neck (NN) of femur. Dp-ucMGP was detectable in 97 (75%) participants with serum vitamin K1 of 0.26 [0.15] µg/L, whilst PIVKA-II was above the clinical threshold in only 3.8%. CONCLUSIONS: Our data suggest that the positive effect of vitamin K on fracture risk may be related to its effects on bone strength. Higher concentrations of serum vitamin K1 may be required for vitamin K's skeletal effects compared to coagulation. Further prospective or interventional studies are needed for confirmation and should include measures of bone quality.

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.

Quantitative measurements of bone remodeling using 99mTc-methylene diphosphonate bone scans and blood sampling.

UNLABELLED: Quantitative studies of bone using (99m)Tc-methylene diphosphonate ((99m)Tc-MDP) have a potentially valuable role in investigating the treatment of patients with metabolic bone disease. In this study we compared 3 different methods of measuring whole-skeleton (99m)Tc-MDP plasma clearance (K(bone)) in 12 osteoporotic postmenopausal women (mean age, 67.3 y) before participation in a clinical trial of an osteoporosis therapy. The aim was to compare the consistency and accuracy of the 3 methods before their use in evaluating the subjects' response to treatment. METHODS: Subjects were injected with 600 MBq (99m)Tc-MDP and 3 MBq (51)Cr-ethylenediaminetetraacetic acid ((51)Cr-EDTA) and whole-body bone scan images were acquired at 10 min, 1, 2, 3, and 4 h. Two-minute static images of the thighs were acquired immediately after the 1- to 4-h whole-body scans. Six blood samples were taken between 5 min and 4 h, and free (99m)Tc-MDP was measured using ultrafiltration. The glomerular filtration rate (GFR) was estimated from the (51)Cr-EDTA plasma curve. The methods used to evaluate K(bone) were (a) the area-under-the-curve (AUC) method, in which the GFR measurement was subtracted from the total (bone plus renal) clearance (K(total)) measured from the free (99m)Tc-MDP plasma curve; (b) the modified Brenner method, in which (99m)Tc-MDP renal clearance estimated from the whole-body counts was subtracted from the total clearance measured from the rate of elimination of tracer from soft tissue; and (c) the Patlak plot method, which was also used to derive regional values of K(bone) for the skull, spine, pelvis, arms, and legs. RESULTS: There was good agreement between the 3 methods of measuring K(bone). (mean K(bone) +/- SD: AUC method, 30.3 +/- 6.4 mL x min(-1); Brenner method, 31.1 +/- 5.8 mL x min(-1); Patlak method, 35.7 +/- 5.8 mL x min(-1)). The correlation coefficients between the methods varied from r = 0.767 (P = 0.004) to r = 0.805 (P = 0.002). Regional measurements of (99m)Tc-MDP clearance gave the following percentages of the whole-skeleton clearance: skull, 13.3%; spine, 16.6%; pelvis, 17.2%; arms, 11.1%; legs, 23.7%. CONCLUSION: The 3 methods gave consistent and accurate measurements of K(bone). The Patlak method can be used to study regional as well as total-skeleton values of K(bone).

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 study to determine the dependence of 99mTc-MDP protein binding on plasma clearance and serum albumin concentration.

BACKGROUND: The measurement of protein binding is essential for accurate quantitative studies of skeletal kinetics using Tc-methylene diphosphonate (Tc-MDP). In this study, the dependence of Tc-MDP protein binding on total plasma clearance (Ktotal) and serum albumin concentration was investigated using data from two groups of patients. METHOD: The first group (study 1) consisted of 71 patients referred for a Tc-MDP bone scan examination. The second group (study 2) consisted of 100 subjects referred for a determination of glomerular filtration rate (GFR) and injected with 3 MBq Tc-MDP and 3 MBq Cr-EDTA. Free Tc-MDP was measured using ultrafiltration and the percentage of free Tc-MDP analysed for the effect of Ktotal and serum albumin concentration using multivariate regression analysis. RESULTS: When the percentage of free Tc-MDP was analysed for the effect of Ktotal and serum albumin, highly significant relationships were found at the 2, 3 and 4 h time points. Subjects with higher values of Ktotal or serum albumin concentration had a lower percentage of free Tc-MDP and the magnitude of the regression coefficients increased with time. CONCLUSION: Multivariate regression analysis confirmed that Ktotal and serum albumin were highly significant factors in determining the percentage of free Tc-MDP measured at the 2, 3 and 4 h time points.

Atypical Paget's disease with quantitative assessment of tracer kinetics.

INTRODUCTION: Paget's disease of bone is characterized by alterations in skeletal metabolism, affecting a single or multiple bones. Paget's is usually confined to an individual bone and typically does not spread or extend across joints. A patient with an unusual pattern of disease is presented together with quantitative assessment of the tracer kinetics pre- and posttreatment. MATERIAL AND METHODS: A 75-year-old lady patient presented to her general practitioner in May 2002 with a history of lethargy. Clinical examination was unremarkable and further investigations such as blood tests (alkaline phosphatase levels), Tc-99m MDP bone scan, biopsy, and CT scan were carried out. RESULTS: Alkaline phosphatase levels were greater than 2000 IU/L (Normal: 31-116 IU/L). The Tc-99m MDP bone scan showed strikingly increased uptake in the central skeleton involving the thoracic vertebrae and the adjoining ribs. The bone biopsy was inconclusive. CT scan revealed symmetrical expansion of the ribs with bridging osteophytes across the ribs and spine. The patient was treated with risedronate and quantitative analysis of the pre- and posttherapy bone scans showed reduced plasma clearance in the pagetic bones. CONCLUSIONS: This case illustrates an unusual distribution of bone lesions in Paget's disease, which we think could be due to the result of degenerative disease leading to bridging and allowing direct extension of disease from one bone to another.

Validation of a blood-sampling method for the measurement of 99mTc-methylene diphosphonate skeletal plasma clearance.

UNLABELLED: Quantitative studies of bone using (99m)Tc-methylene diphosphonate (MDP) reflect bone remodeling. The simplest method of evaluating (99m)Tc-MDP kinetics involves taking multiple blood samples and measuring total clearance (K(total)) from the area under the plasma curve (AUC) and deriving bone clearance (K(bone)) by subtracting glomerular filtration rate (GFR) from K(total). However, the accuracy of the AUC method is uncertain because of assumptions that the terminal exponential is reached by 2 h and that the rate constant k(4), representing the backflow of tracer from bone to plasma, is negligibly small. The aim of this study was to validate the accuracy of the AUC method by comparing K(bone) values obtained by that method with those obtained by gamma-camera imaging. METHODS: Seventy-one patients were injected with 600 MBq of (99m)Tc-MDP. For the first 22 patients, whole-body images were acquired at 15 min and at 1, 2, 3, and 4 h after injection, whereas the remaining 49 were imaged at 15 min and at 1 and 3 h. Two-minute static images of the thighs were acquired immediately before each whole-body scan. Multiple blood samples were taken between 5 min and 4 h, and free (99m)Tc-MDP was measured using ultrafiltration. Two gamma-camera methods were used to evaluate K(bone): the Patlak plot method and the Brenner method, which is based on measuring soft-tissue uptake in the thighs. The soft-tissue data were also used to measure k(4). RESULTS: The soft-tissue data gave a k(4) value of 0.0003 min(-1) (95% confidence interval, 0-0.0008 min(-1)). The mean (+/-SD) (99m)Tc-MDP K(bone) was 56.0 +/- 32.4 mL x min(-1) with the AUC method, 49.5 +/- 32.1 mL x min(-1) with the Patlak method, and 42.8 +/- 32.0 mL x min(-1) with the Brenner method. Correcting the AUC values of K(total) by factors of 0.95 and 0.90 gave K(bone) values in agreement with the Patlak and Brenner methods, respectively. CONCLUSION: Values of k(4) are too small to affect values of K(bone) measured using the AUC method. Correcting K(total) by factors in the range of 0.90-0.95 corrects for the error in the terminal exponential and brings K(bone) values measured using the AUC method into agreement with the gamma-camera results.

Validation of ultrafiltration as a method of measuring free 99mTc-MDP.

UNLABELLED: Quantitative studies of the kinetics of (99m)Tc-methylene diphosphonate ((99m)Tc-MDP) in metastatic and metabolic bone disease require the measurement of free tracer in plasma to derive the input function. Several methods of measuring free (99m)Tc-MDP have been described including ultrafiltration, precipitation using trichloroacetic acid, and a direct in vivo measurement based on the assumption that free MDP is cleared through the kidneys by glomerular filtration. The aim of this study was to validate ultrafiltration as a convenient and accurate method of measuring the free fraction of (99m)Tc-MDP by comparing it with the glomerular filtration rate (GFR) method. A second aim was to measure the percentage of free (99m)Tc-MDP in a cross-section of patients using ultrafiltration to determine the interpatient variability and, therefore, whether individual measurements are required for bone kinetic studies. METHODS: In study 1, 10 volunteers (7 women, 3 men; mean age, 37 y; range, 26-55 y) were injected with 3 MBq (99m)Tc-MDP and 3 MBq (51)Cr-ethylenediaminetetraacetic acid, and multiple blood and urine samples were taken between 0 and 4 h. Plasma samples were spun in 5-, 10-, and 30-kDa filters and counted in a gamma-counter. In study 2, 51 randomly selected patients (26 women, 25 men; mean age, 66 y; range, 31-87 y) attending our department for a routine bone scan were injected with 600 MBq (99m)Tc-MDP, and 4 blood samples were taken between 0 and 4 h and spun in 10-kDa filters. RESULTS: In study 1, the mean percentages (+/-SD) of free (99m)Tc-MDP at 5 min and 4 h after injection measured using the 10-kDa filters were 83.1% +/- 3.4% and 44.0% +/- 10.0%. The mean ratios (+/-SEM) of the free (99m)Tc-MDP in ultrafiltrate compared with the GFR method for the 5-, 10-, and 30-kDa filters were 0.894 +/- 0.010, 0.943 +/- 0.009, and 0.987 +/- 0.010. In study 2, the mean percentages (+/-SD) of free (99m)Tc-MDP at 15 min and 4 h were 75.3% +/- 8.0% and 48.8% +/- 9.5%, with a precision error of 2.3%. The percentages of free MDP at 150 min and 4 h were significantly correlated with GFR but not with serum albumin. CONCLUSION: Ultrafiltration provides an accurate method of evaluating free (99m)Tc-MDP in plasma for bone kinetic studies. The results from both the healthy volunteers in study 1 and the patients in study 2 show that protein binding varied with time and showed significant differences between individuals that were partly dependent on GFR. It is thus necessary to measure individual protein binding values for bone kinetic studies.

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.