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Background: With the availability of disease-modifying therapies for Alzheimer's disease (AD), it is important for clinicians to have tests to aid in AD diagnosis, especially when the presence of amyloid pathology is a criterion for receiving treatment., Methods: High-throughput, mass spectrometry-based assays were used to measure %p-tau217 and amyloid beta (Aβ)42/40 ratio in blood samples from 583 individuals with suspected AD (53% positron emission tomography [PET] positive by Centiloid > 25). An algorithm (PrecivityAD2 test) was developed using these plasma biomarkers to identify brain amyloidosis by PET., Results: The area under the receiver operating characteristic curve (AUC-ROC) for %p-tau217 (0.94) was statistically significantly higher than that for p-tau217 concentration (0.91). The AUC-ROC for the PrecivityAD2 test output, the Amyloid Probability Score 2, was 0.94, yielding 88% agreement with amyloid PET. Diagnostic performance of the APS2 was similar by ethnicity, sex, age, and apoE4 status., Discussion: The PrecivityAD2 blood test showed strong clinical validity, with excellent agreement with brain amyloidosis by PET., (© 2024 C2N Diagnostics LLC. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Objective: The objective of this study was to examine clinicians' patient selection and result interpretation of a clinically validated mass spectrometry test measuring amyloid beta and ApoE blood biomarkers combined with patient age (PrecivityAD® blood test) in symptomatic patients evaluated for Alzheimer's disease (AD) or other causes of cognitive decline., Methods: The Quality Improvement and Clinical Utility PrecivityAD Clinician Survey (QUIP I, ClinicalTrials.gov Identifier: NCT05477056) was a prospective, single-arm cohort study among 366 patients evaluated by neurologists and other cognitive specialists. Participants underwent blood biomarker testing and received an amyloid probability score (APS), indicating the likelihood of a positive result on an amyloid positron emission tomography (PET) scan. The primary study outcomes were appropriateness of patient selection as well as result interpretation associated with PrecivityAD blood testing., Results: A 95% (347/366) concordance rate was noted between clinicians' patient selection and the test's intended use criteria. In the final analysis including these 347 patients (median age 75 years, 56% women), prespecified test result categories incorporated 133 (38%) low APS, 162 (47%) high APS, and 52 (15%) intermediate APS patients. Clinicians' pretest and posttest AD diagnosis probability changed from 58% to 23% in low APS patients and 71% to 89% in high APS patients (p < 0.0001). Anti-AD drug therapy decreased by 46% in low APS patients (p < 0.0001) and increased by 57% in high APS patients (p < 0.0001)., Interpretation: These findings demonstrate the clinical utility of the PrecivityAD blood test in clinical care and may have added relevance as new AD therapies are introduced., (© 2023 C2N Diagnostics and The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: The amyloid probability score (APS) is the model read-out of the analytically validated mass spectrometry-based PrecivityAD ® blood test that incorporates the plasma Aβ42/40 ratio, ApoE proteotype, and age to identify the likelihood of brain amyloid plaques among cognitively impaired individuals being evaluated for Alzheimer's disease., Purpose: This study aimed to provide additional independent evidence that the pre-established APS algorithm, along with its cutoff values, discriminates between amyloid positive and negative individuals., Methods: The diagnostic performance of the PrecivityAD test was analyzed in a cohort of 200 nonrandomly selected Australian Imaging, Biomarker & Lifestyle Flagship Study of Aging (AIBL) study participants, who were either cognitively impaired or healthy controls, and for whom a blood sample and amyloid PET imaging were available., Results: In a subset of the dataset aligned with the Intended Use population (patients aged 60 and older with CDR ≥0.5), the pre-established APS algorithm predicted amyloid PET with a sensitivity of 84.9% (CI: 72.9-92.1%) and specificity of 96% (CI: 80.5-99.3%), exclusive of 13 individuals for whom the test was inconclusive., Interpretation: The study shows individuals with a high APS are more likely than those with a low APS to have abnormal amounts of amyloid plaques and be on an amyloid accumulation trajectory, a dynamic and evolving process characteristic of progressive AD pathology. Exploratory data suggest APS retains its diagnostic performance in healthy individuals, supporting further screening studies in the cognitively unimpaired., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Importance: The diagnostic evaluation for Alzheimer disease may be improved by a blood-based diagnostic test identifying presence of brain amyloid plaque pathology., Objective: To determine the clinical performance associated with a diagnostic algorithm incorporating plasma amyloid-β (Aβ) 42:40 ratio, patient age, and apoE proteotype to identify brain amyloid status., Design, Setting, and Participants: This cohort study includes analysis from 2 independent cross-sectional cohort studies: the discovery cohort of the Plasma Test for Amyloidosis Risk Screening (PARIS) study, a prospective add-on to the Imaging Dementia-Evidence for Amyloid Scanning study, including 249 patients from 2018 to 2019, and MissionAD, a dataset of 437 biobanked patient samples obtained at screenings during 2016 to 2019. Data were analyzed from May to November 2020., Exposures: Amyloid detected in blood and by positron emission tomography (PET) imaging., Main Outcomes and Measures: The main outcome was the diagnostic performance of plasma Aβ42:40 ratio, together with apoE proteotype and age, for identifying amyloid PET status, assessed by accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC)., Results: All 686 participants (mean [SD] age 73.2 [6.3] years; 368 [53.6%] men; 378 participants [55.1%] with amyloid PET findings) had symptoms of mild cognitive impairment or mild dementia. The AUC of plasma Aβ42:40 ratio for PARIS was 0.79 (95% CI, 0.73-0.85) and 0.86 (95% CI, 0.82-0.89) for MissionAD. Ratio cutoffs for Aβ42:40 based on the Youden index were similar between cohorts (PARIS: 0.089; MissionAD: 0.092). A logistic regression model (LRM) incorporating Aβ42:40 ratio, apoE proteotype, and age improved diagnostic performance within each cohort (PARIS: AUC, 0.86 [95% CI, 0.81-0.91]; MissionAD: AUC, 0.89 [95% CI, 0.86-0.92]), and overall accuracy was 78% (95% CI, 72%-83%) for PARIS and 83% (95% CI, 79%-86%) for MissionAD. The model developed on the prospectively collected samples from PARIS performed well on the MissionAD samples (AUC, 0.88 [95% CI, 0.84-0.91]; accuracy, 78% [95% CI, 74%-82%]). Training the LRM on combined cohorts yielded an AUC of 0.88 (95% CI, 0.85-0.91) and accuracy of 81% (95% CI, 78%-84%). The output of this LRM is the Amyloid Probability Score (APS). For clinical use, 2 APS cutoff values were established yielding 3 categories, with low, intermediate, and high likelihood of brain amyloid plaque pathology., Conclusions and Relevance: These findings suggest that this blood biomarker test could allow for distinguishing individuals with brain amyloid-positive PET findings from individuals with amyloid-negative PET findings and serve as an aid for Alzheimer disease diagnosis.

Background: There is an unmet need for an accessible, less invasive, cost-effective method to facilitate clinical trial enrollment and aid in clinical Alzheimer's disease (AD) diagnosis. APOE genotype affects the clearance and deposition of amyloid-beta (Aβ) with APOE4 carriers having increased risk while APOE2 alleles appear to be protective. Lower plasma Aβ42/40 correlates with brain amyloidosis. In response, C 2 N has developed the PrecivityAD™ test; plasma LC-MS/MS assays for Aβ isoform quantitation and qualitative APOE isoform-specific proteotyping., Methods: In accord with CLIA standards, we developed and validated assay performance: precision, accuracy, linearity, limit of detection (LoD), interferences., Results: Within-day precision varied from 1.5-3.0% (Aβ40) and 2.5-8.4% (Aβ42). Total (within-lab) variability was 2.7-7.7% (Aβ40) and 3.1-9.5% (Aβ42). Aβ40 quantitation was linear from 10 to 1780 pg/mL; Aβ42 was linear from 2 to 254 pg/mL. LoD was 11 and 2 pg/mL for Aβ40 and Aβ42, respectively. APOE proteotypes were 100% concordant with genotype, while LoD (fM) was much lower than APOE concentrations observed in plasma (mM)., Conclusions: The PrecivityAD™ assays are precise, accurate, sensitive, and linear over a wide analytical range, free from significant interferences, and suitable for use in the clinical laboratory., (Copyright © 2021 C2N Diagnostics. Published by Elsevier B.V. All rights reserved.)

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

Background: The development of blood-based biomarker tests that are accurate and robust for Alzheimer's disease (AD) pathology have the potential to aid clinical diagnosis and facilitate enrollment in AD drug trials. We developed a high-resolution mass spectrometry (MS)-based test that quantifies plasma Aβ42 and Aβ40 concentrations and identifies the ApoE proteotype. We evaluated robustness, clinical performance, and commercial viability of this MS biomarker assay for distinguishing brain amyloid status., Methods: We used the novel MS assay to analyze 414 plasma samples that were collected, processed, and stored using site-specific protocols, from six independent US cohorts. We used receiver operating characteristic curve (ROC) analyses to assess assay performance and accuracy for predicting amyloid status (positive, negative, and standard uptake value ratio; SUVR). After plasma analysis, sites shared brain amyloid status, defined using diverse, site-specific methods and cutoff values; amyloid PET imaging using various tracers or CSF Aβ42/40 ratio., Results: Plasma Aβ42/40 ratio was significantly (p < 0.001) lower in the amyloid positive vs. negative participants in each cohort. The area under the ROC curve (AUC-ROC) was 0.81 (95% CI = 0.77-0.85) and the percent agreement between plasma Aβ42/40 and amyloid positivity was 75% at the optimal (Youden index) cutoff value. The AUC-ROC (0.86; 95% CI = 0.82-0.90) and accuracy (81%) for the plasma Aβ42/40 ratio improved after controlling for cohort heterogeneity. The AUC-ROC (0.90; 95% CI = 0.87-0.93) and accuracy (86%) improved further when Aβ42/40, ApoE4 copy number and participant age were included in the model., Conclusions: This mass spectrometry-based plasma biomarker test: has strong diagnostic performance; can accurately distinguish brain amyloid positive from amyloid negative individuals; may aid in the diagnostic evaluation process for Alzheimer's disease; and may enhance the efficiency of enrolling participants into Alzheimer's disease drug trials.

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 18 F-sodium fluoride ( 18 F-NaF) in the aortic wall reflects metabolically active areas of calcification. The aim of this study was to determine if 18 F-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 18 F-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 cm 3 ( 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, 18 F-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 original version of this article unfortunately contained an error. The name and affiliation of "Frédéric Paycha" needs to be corrected. Given in this article is the correct author name and affiliation.

Dynamic positron emission tomography (PET) imaging with fluorine-18 labelled sodium fluoride ([ 18 F]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 [ 18 F]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 [ 18 F]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 [ 18 F]NaF plasma clearance at multiple sites in the skeleton with just a single injection of tracer., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Tauopathies are a group of disorders in which the cytosolic protein tau aggregates and accumulates in cells within the brain, resulting in neurodegeneration. A promising treatment being explored for tauopathies is passive immunization with anti-tau antibodies. We previously found that administration of an anti-tau antibody to human tau transgenic mice increased the concentration of plasma tau. We further explored the effects of administering an anti-tau antibody on plasma tau. After peripheral administration of an anti-tau antibody to human patients with tauopathy and to mice expressing human tau in the central nervous system, there was a dose-dependent increase in plasma tau. In mouse plasma, we found that tau had a short half-life of 8 min that increased to more than 3 hours after administration of anti-tau antibody. As tau transgenic mice accumulated insoluble tau in the brain, brain soluble and interstitial fluid tau decreased. Administration of anti-tau antibody to tau transgenic mice that had decreased brain soluble tau and interstitial fluid tau resulted in an increase in plasma tau, but this increase was less than that observed in tau transgenic mice without these brain changes. Tau transgenic mice subjected to acute neuronal injury using 3-nitropropionic acid showed increased interstitial fluid tau and plasma tau. These data suggest that peripheral administration of an anti-tau antibody results in increased plasma tau, which correlates with the concentration of extracellular and soluble tau in the brain., (Copyright © 2017, American Association for the Advancement of Science.)

Tau neurofibrillary tangles are found in the brains of patients suffering from Alzheimer's disease and other tauopathies. The progressive spreading of tau pathology from one brain region to the next is believed to be caused by extracellular transsynaptic transmission of misfolded tau between neurons. Preclinical studies have shown that antibodies against tau can prevent this transfer of misfolded tau between cells. Thus, antibodies against tau have the potential to stop or slow the progression of tau pathology observed in human tauopathies. To test this hypothesis, a humanized anti-tau antibody (ABBV-8E12) was developed and a phase 1 clinical trial of this antibody has been completed. The double-blind, placebo-controlled phase 1 study tested single doses of ABBV-8E12 ranging from 2.5 to 50 mg/kg in 30 patients with progressive supranuclear palsy (PSP). ABBV-8E12 was found to have an acceptable safety profile with no clinically concerning trends in the number or severity of adverse events between the placebo and dosed groups. Pharmacokinetic modelling showed that the antibody has a plasma half-life and cerebrospinal fluid:plasma ratio consistent with other humanized antibodies, and there were no signs of immunogenicity against ABBV-8E12. Based on the acceptable safety and tolerability profile of single doses of ABBV-8E12, AbbVie is currently enrolling patients into two phase 2 clinical trials to assess efficacy and safety of multiple doses of ABBV-8E12 in patients with early Alzheimer's disease or PSP., Competing Interests: TW, IHH, PBV, and IF are full time employees and/or advisors of C2N Diagnostics, receiving stock and/or stock options. RJB is a co-founder of C2N Diagnostics. RJB and Washington University in St. Louis have equity ownership interest in C2N Diagnostics and may receive royalty income based on technology licensed by Washington University to C2N Diagnostics. RJB receives lab research funding from the Tau SILK Consortium (AbbVie, Biogen, and Eli Lilly and Co.), Eli Lilly and Co, Hoffman La-Roche, Janssen, Avid Radiopharmaceuticals, and the DIAN Pharma Consortium (Abbvie, Amgen, AstraZeneca, Biogen, Eisai, Eli Lilly and Co, Hoffman La-Roche, Janssen, Pfizer, and Sanofi). RJB has received honoraria from Janssen and Pfizer as a speaker and from Merck and Pfizer as an Advisory Board member. In addition, RJB receives income from C2N Diagnostics for serving on the Scientific Advisory Board. JBB is a co-founder and employee of C2N Diagnostics, receiving stock and/or stock options. KB, HF, and NM are employees of AbbVie, receiving stock and/or stock options. DMH co-founded and is on the scientific advisory board of C2N Diagnostics. DMH is an inventor on a submitted patent “Antibodies to Tau”, PCT/US2013/049333, that is licensed by Washington University to C2N Diagnostics. This patent was subsequently licensed to AbbVie. DMH receives research grants from the C2N Diagnostics, AbbVie, Eli Lilly, and Denali. DMH consults for Genentech, AbbVie, Eli Lilly, Proclara Biosciences, Glaxosmithkline, and Denali.

Objective: The superiority of sodium F-fluoride PET (F-PET)/computed tomography (CT) over planar and single field-of-view single-photon emission computed tomography (SPECT) bone scintigraphy with Tc-methylene diphosphonate in bone metastases detection has been established. The present study prospectively compares whole-body Tc-methylene diphosphonate SPECT (WB-SPECT) and F-PET performance indices for the detection of bone metastases in breast cancer., Methods: A total of 41 pairs of studies in female breast cancer patients (average age 58 years, range 30-75) were included. Half-time WB-SPECT and F-PET/CT were performed at a 4-day average interval (range 0-36 days), with subsequent fusion of CT to WB-SPECT. Two readers independently interpreted the studies, with differences resolved by consensus. Composite gold standard included the CT component of the F-PET/CT study with follow-up CT, MRI, F-fluoro-deoxyglucose-PET/CT, and bone scans., Results: On patient-based analysis, metastases were diagnosed in 21 patients, with 19 patients detected by WB-SPECT and 21 with F-PET, the latter being the only modality to detect a single metastasis in two patients. The sensitivity of WB-SPECT and F-PET was 90 and 100% (P=NS), and the specificity were 95 and 85%, respectively (P=NS). On lesion-based analysis, 284 total sites of increased uptake were found. WB-SPECT detected 171/284 (60%) and F-PET 268/284 (94%) lesions, with good interobserver agreement for WB-SPECT (κ=0.679) and excellent agreement for F-PET (κ=0.798). The final analysis classified 204 lesions as benign and 80 as metastases. WB-SPECT identified 121 benign and 50 malignant sites compared with 192 and 76, respectively, for F-PET. WB-SPECT and F-PET had a sensitivity of 63 vs. 95%, P-value of less than 0.001, and a specificity of 97 vs. 96% (P=NS), respectively, on lesion-based analysis., Conclusion: F-PET had higher sensitivity for the diagnosis of bone metastases from breast cancer compared with WB-SPECT, showing a statistically significant 32% increase on lesion-based analysis.

Context: Women with premature ovarian failure (POF) face many years of estrogen deficiency. One of the major consequences is bone loss. The optimal form of estrogen replacement is unknown and management is not evidence based. The 2 broad options are combined hormone replacement therapy (HRT) or the combined oral contraceptive pill (COCP)., Objectives: To compare the effects of HRT and COCP on bone density and turnover in women with spontaneous POF and to observe the effects of no treatment., Design: Two-year open randomized trial comparing HRT and COCP and nonrandomized observation of women declining treatment using the same protocol., Setting: London teaching hospital., Participants: A total of 59 women with spontaneous POF aged 18-44, 30 women elected to take treatment and were randomized, and 29 declined treatment., Intervention: Randomization was to HRT (Nuvelle) or COCP (Microgynon 30)., Main Outcome Measures: The primary outcome was change in lumbar spine bone mineral density. Changes in total hip and femoral neck bone density and bone turnover markers were also assessed., Results: A total of 36 women (61%) completed the trial (no treatment 52%; HRT 60%; COCP 80%). In comparison with COCP, treatment with HRT increased bone density at the lumbar spine at 2 years (+0.050 g/cm(2); 95% confidence interval 0.007-0.092; P = .025). Bone turnover markers showed similar reductions in the 2 treatment groups. In the no treatment group, bone density dropped at all sites and bone turnover markers remained relatively unchanged., Conclusions: The results suggest that HRT is superior to COCP in increasing bone density at the lumbar spine in women with spontaneous POF. The limitations of a small sample size and high drop-out rate mean that further research is required to confirm the findings. However, either treatment is clearly superior to no treatment.

Objectives: Treatment discontinuation after long-term bisphosphonate (BP), termed a 'drug holiday', has been proposed to reduce the risk of BP-associated complications. The duration of treatment cessation remains unclear. Changes in bone mineral density (BMD), bone turnover markers (BTMs) and their relationship with FRAX were assessed to help determine the optimum length of a 'drug holiday'., Methods: A retrospective analysis of 134 patients (13M, 121F) aged [mean (SD)] 68·4 (8·2) years who discontinued BPs after treatment for 5·9 (3·0) years for osteoporosis was undertaken. BMD at the lumbar spine (LS), total hip (TH), and femoral neck (FN) and biochemical parameters including serum 25 (OH) vitamin D, bone turnover markers (plasma CTX, P1NP) and FRAX scores were determined at discontinuation, 12-18 months and 24-30 months off treatment., Results: BMD decreased significantly at the LS [% change mean (SD): -0·94 (3·6), P = 0·008], TH [-1·4 (2·4), P < 0·001] and FN [-1·8 (4·4), P < 0·001] after treatment discontinuation for 12-18 months. In the subgroup who remained off treatment for 24-30 months, a progressive decline in BMD was seen at the TH and FN with total % decrease of -2·52 (3·5) and -2·7 (4·76), P < 0·001, respectively. CTX and P1NP increased significantly at 12-18 months after discontinuation [% change CTX: 95 (88), P < 0·001, P1NP: 88 (73), P < 0·001]. FRAX scores were significant predictors of % change in BMD at the FN (P < 0·05), independently of bone turnover and vitamin D status. In summary, our data show that following a 'drug holiday', the use of DEXA scans, BTMs and FRAX may help guide when to resume treatment., (© 2015 John Wiley & Sons Ltd.)

The effects of vitamin E on cardiovascular and bone health are conflicting with beneficial and detrimental findings reported. To investigate this further, we carried out a cross-sectional study to determine the relationship between circulating concentrations of the 2 vitamin E isomers, α- and γ-tocopherol (TP) with bone turnover and arterial stiffness. Two hundred and seventy eight post-menopausal women with mean age [SD] 60.9 [6.0] years were studied. Fasting serum α-TP and γ-TP, bone turnover markers; procollagen type 1 amino-terminal propeptide (P1NP) and C-terminal telopeptide of type 1 collagen (CTX), parathyroid hormone (PTH), total cholesterol (TC) and triglycerides (TG) were measured. Pulse wave velocity (PWV) and central augmentation index (AI) as markers of arterial stiffness were also determined. A positive correlation was observed between α-TP and γ-TP (r=0.14, p=0.022). A significant negative association between α-TP and P1NP only was seen in multiple linear regression analysis following adjustment for serum TC and TG (p=0.016). In a full multi-linear regression model, following correction for age, years since menopause, smoking habits, alcohol intake, use of calcium supplements, BMI, PTH, serum calcium, and estimated glomerular filtration rate (eGFR), the association between α-TP and P1NP remained significant (p=0.011). We did not observe any significant association between γ-TP or α-TP/γ-TP ratio with P1NP or CTX. P1NP was significantly lower in subjects with α-TP concentrations of >30 μmol/L (α-TP >30 μmol/L; P1NP: 57.5 [20.7], α-TP<30 μmol/L; P1NP: 65.7 [24.9] μg/L, p=0.005). PWV was significantly associated with α-TP/γ-TP ratio (p=0.04) but not with serum α-TP or γ-TP in a full multi-linear regression model adjusting for serum lipids, age, and blood pressure. The data suggest that high serum concentrations of α-TP may have a negative effect on bone formation. The balance of α-TP and γ-TP may be important in maintaining arterial compliance. Longitudinal studies are needed to investigate the impact of the vitamin E isomers on bone and cardiovascular health., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Classic radiological and nuclear medicine signs have been reported extensively because of a myriad of pathophysiological processes. When encountered, they aid in diagnosis of conditions and add confidence for the reader, at times even hinting at a specific diagnosis. The naming of signs is commonly associated with objects from everyday life to establish familiarity with visual findings. Association of signs and disease comes with regular practice and improves understanding of the image and its underlying cause. In this article, we have collated nuclear medicine signs reported in the literature since 1970., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The aim of this guideline is to provide minimum standards for the performance and interpretation of (18)F-NaF PET/CT scans. Standard acquisition and interpretation of nuclear imaging modalities will help to provide consistent data acquisition and numeric values between different platforms and institutes and to promote the use of PET/CT modality as an established diagnostic modality in routine clinical practice. This will also improve the value of scientific work and its contribution to evidence-based medicine.

The radionuclide (99m)Tc-MDP bone scan is one of the most commonly performed nuclear medicine studies and helps in the diagnosis of different pathologies relating to the musculoskeletal system. With its increasing utility in clinical practice, it becomes more important to be aware of various limitations of this imaging modality to avoid false interpretation. It is necessary to be able to recognize various technical, radiopharmaceutical, and patient-related artifacts that can occur while carrying out a bone scan. Furthermore, several normal variations of tracer uptake may mimic pathology and should be interpreted cautiously. There is an important limitation of a bone scan in metastatic disease evaluation as the inherent mechanism of tracer uptake is not specific for tumor but primarily relies on an osteoblastic response. Thus, it is crucial to keep in mind uptake in benign lesions, which can resemble malignant pathologies. The utility of a planar bone scan in benign orthopedic diseases, especially at sites with complex anatomy, is limited owing to lack of precise anatomical information. SPECT/CT has been significantly helpful in these cases. With wider use of PET/CT and reintroduction of the (18)F-fluoride bone scan, increasing knowledge of potential pitfalls on an (18)F-fluoride bone scan and (18)F-FDG-PET/CT will help in improving the accuracy of clinical reports., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Several different techniques, radiopharmaceuticals, and imaging modalities are commonly used in nuclear medicine for studies of endocrine organs. Nuclear medicine is used in the management of benign and malignant thyroid, parathyroid, and neuroendocrine disorders. Thus, it is essential to acknowledge pitfalls and the limitations of nuclear medicine imaging for accurate diagnosis and patient management., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Total body (TB) dual-energy X-ray absorptiometry (DXA) is increasingly being used to measure body composition in research and clinical settings. This study investigated the effect of body mass index (BMI) and body fat on precision errors for total and regional TB DXA measurements of bone mineral density, fat tissue, and lean tissue using the GE Lunar Prodigy (GE Healthcare, Bedford, UK). One hundred forty-four women with BMI's ranging from 18.5 to 45.9 kg/m(2) were recruited. Participants had duplicate DXA scans of the TB with repositioning between examinations. Participants were divided into 3 groups based on their BMI, and the root mean square standard deviation and the percentage coefficient of variation were calculated for each group. The root mean square standard deviation (percentage coefficient of variation) for the normal (<25 kg/m²; n = 76), overweight (25-30 kg/m²; n = 36), and obese (>30 kg/m²; n = 32) BMI groups, respectively, were total BMD (g/cm(2)): 0.009 (0.77%), 0.009 (0.69%), 0.011 (0.91%); total fat (g): 545 (2.98%), 486 (1.72%), 677 (1.55%); total lean (g): 551 (1.42%), 540 (1.34%), and 781 (1.68%). These results suggest that serial measurements in obese subjects should be treated with caution because the least significant change may be larger than anticipated., (Copyright © 2015 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

Bisphosphonates (BPs) have been shown to influence angiogenesis. This may contribute to BP-associated side-effects such as osteonecrosis of the jaw (ONJ) or atypical femoral fractures (AFF). The effect of BPs on the production of angiogenic factors by osteoblasts is unclear. The aims were to investigate the effect of (1) alendronate on circulating angiogenic factors; vascular endothelial growth factor (VEGF) and angiopoietin-1 (ANG-1) in vivo and (2) zoledronate and alendronate on the production of VEGF and ANG-1 by osteoblasts in vitro. We studied 18 post-menopausal women with T score⩽-2 randomized to calcium/vitamin D only (control arm, n=8) or calcium/vitamin D and alendronate 70mg weekly (treatment arm, n=10). Circulating concentrations of VEGF and ANG-1 were measured at baseline, 3, 6 and 12months. Two human osteoblastic cell lines (MG-63 and HCC1) and a murine osteocytic cell line (MLO-Y4) were treated with zoledronate or alendronate at concentrations of 10(-12)-10(-6)M. VEGF and ANG-1 were measured in the cell culture supernatant. We observed a trend towards a decline in VEGF and ANG-1 at 6 and 12months following treatment with alendronate (p=0.08). Production of VEGF and ANG-1 by the MG-63 and HCC1 cells decreased significantly by 34-39% (p<0.01) following treatment with zoledronate (10(-9)-10(-6)M). Treatment of the MG-63 cells with alendronate (10(-7) and 10(-6)) led to a smaller decrease (25-28%) in VEGF (p<0.05). Zoledronate (10(-10)-10(-)(6)M) suppressed the production of ANG-1 by MG-63 cells with a decrease of 43-49% (p<0.01). Co-treatment with calcitriol (10(-8)M) partially reversed this zoledronate-induced inhibition. BPs suppress osteoblastic production of angiogenic factors. This may explain, in part, the pathogenesis of the BP-associated side-effects., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Osteoporosis is a highly prevalent condition, characterized by compromised bone strength and fragility fractures and with an important associated socio-economic burden. Bisphosphonates are well established as the first line treatment for osteoporosis. However, while randomized control trials have in general demonstrated reasonable anti-fracture efficacy at the spine, they have shown moderate reduction in fracture incidence for non-vertebral sites. Furthermore, oral bisphosphonates are commonly associated with adverse gastrointestinal effects and both oral and parenteral bisphosphonates have been linked with osteonecrosis of the jaw and atypical femoral fracture, two rare but debilitating side effects. In addition, bisphosphonates are not recommended in patients with GFR <35 ml/min/1.73 m(2). Hence, there is a clear requirement for newer agents, which are able to reduce fracture risk further, whilst overcoming the limitations of bisphosphonates. Over the past 20 years, knowledge and a deeper understanding of the various signalling pathways involved in bone remodelling has increased, enabling identification of additional targets for therapy. This review focuses on these newer therapies and includes anti-resorptive agents such as raloxifene and other selective oestrogen receptor modulators, the monoclonal antibody denosumab (which inhibits the RANKL pathway), odanacatib, a cathepsin K inhibitor and the anabolic agents, PTH analogue; PTH (1-34) and anti-sclerostin antibodies (activator of the Wnt pathway). Strontium ranelate will not be reviewed as recent reports highlight concerns surrounding its cardiovascular safety and together with an apparent increased risk of thrombosis, its future use remains uncertain. Some of these agents such as raloxifene, denosumab and teriparatide are already in clinical use whilst others are at varying stages of development. This review will provide an overview of the mechanisms of action of these therapeutic agents on the skeleton and assess their efficacy in osteoporosis and fracture prevention.

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.

Studies suggest that optimal vitamin D status is required for the maximal effect of antiresorptive agents. We investigated the relationship between vitamin D status, serum parathyroid hormone (PTH) concentrations, and change in bone mineral density (BMD) following iv zoledronate and denosumab. We carried out a retrospective analysis of 111 patients, mean age 70 (SD 13) years, 89 women and 22 men, prescribed zoledronate and 43 postmenopausal women treated with denosumab for osteoporosis. We measured BMD at the lumbar spine (LS) and total hip (TH), serum 25 (OH) vitamin D, PTH, and bone turnover markers (plasma CTX, P1NP) at 1 year. In patients on zoledronate, BMD increased at the LS and TH (mean LS change [SEM] = 2.6 % [0.5 %], mean TH change = 1.05 % [0.5 %], p < 0.05). A significant increase in BMD was seen at the LS only in the denosumab group (p = 0.001). Significant decreases in CTX and P1NP were observed at 12 months in both treatment groups. At baseline and at 12 months, 34 % and 23 % of the patients on zoledronate had a serum vitamin D of <50 nmol/L, respectively. The mean PTH concentration in patients with 25 (OH) vitamin D <50 nmol/L was 44 ng/L (SEM 16.6). Patients with PTH concentration <44 ng/L had significantly higher increases in TH BMD compared to those with PTH >44 ng/L (zoledronate 1.9 [0.83] vs. -0.43 [0.81], p = 0.04; denosumab 4.1 [0.054] vs. -1.7 [0.04], p = 0.004). Optimal vitamin D status and PTH concentrations improve the skeletal response to zoledronate and denosumab.

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 ((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.

Inflammatory/pro-resorptive cytokines and chemokines form part of a complex inter-dependent network and may be influenced by vitamin D. We investigated their inter-relationship and the effect of a loading dose of vitamin D. We measured plasma concentrations of an array of cytokines including tumour necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), IL-6, IL-17, IL-8, granulocyte macrophage colony stimulating factor (GM-CSF), and the chemokine monocyte chemoattractant protein-1 (MCP-1). Cytokines, 25 (OH) vitamin D, 1,25 (OH)2 vitamin D, the Wnt inhibitor, DKK1 concentrations and bone turnover markers were measured at baseline and 3 months following a bolus dose (300,000 IU) of vitamin D2 in 39 subjects with vitamin D insufficiency. We observed strong correlations between TNF-α with GM-CSF (r=0.628, p<0.001), IL-17 (r=0.7, p<0.001) and MCP-1 (r=0.5, p=0.001), between IL-1β with IL-17 (r=0.45, p=0.004) and between the 2 chemokines, IL-8 and MCP-1 (r=0.45, p=0.004). A positive correlation was seen between DKK1 and IL-1β (r=0.35, p=-0.029). Following vitamin D loading at 3 months, the relationships between some of the cytokines changed (TNF-α and MCP-1: r=0.38, p=0.017, IL-1β and IL-17: r=0.3, p=0.06). 1,25 (OH)2 vitamin D increased markedly following supplementation. Significant correlations were seen between 25 (OH) vitamin D (r=0.4 p=0.016) and 1,25 (OH)2 vitamin D (r=0.39 p=0.02) with plasma CTX (marker of bone resorption) at 3 months. TNF-α and IL-1β increased significantly at 3 months (p<0.05). The close association between several cytokines is influenced by vitamin D status. Acute increases in 1,25 (OH)2 vitamin D, achieved with loading doses of vitamin D, lead to increases in pro-resorptive cytokines., (© 2013 Elsevier B.V. All rights reserved.)

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., (Copyright © 2013. Published by Elsevier Inc.)

The T-score discordance among skeletal sites is an important aspect of dual-energy X-ray absorptiometry (DXA) measurements. In the spine, large T-score differences between vertebrae are frequently seen in elderly patients owing to degenerative disease. However, it is unclear how often such differences occur in younger adults with healthy spines. The T-scores for individual lumbar vertebrae were compared for 2391 female singletons (18-79 yr) recruited to the Twins UK Adult Twin Register. Women were divided into 6 age bands and 5 bands by body weight, respectively, and the T-score differences between the pairs of vertebrae were examined using correlation coefficients and the standard error of the estimate (SEE) from linear regression analysis. Correlations between the T-scores for adjacent lumbar vertebrae were r = 0.92 decreasing to r = 0.79 between L1 and L4. When plotted as a function of age, r-values were constant for the 5 younger age bands, but decreased in the oldest group. In contrast, the T-score SEE values increased progressively with age from 0.4 to 0.5 for the younger groups to 0.7 for the oldest. Similar trends were seen when women were divided according to body weight. Both increasing age and higher body weight were statistically significantly associated with a higher T-score SEE. The incidence of large T-score differences between vertebrae varies with age and body weight, but is common even among younger women. Clinically significant T-score differences can occur in the absence of osteoarthritis, and visual assessment of spine DXA scans for evidence of degenerative disease is advised before vertebrae are omitted from scan analyses., (Copyright © 2013 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

Purpose: To establish the sensitivity and specificity of cross-sectional scintigraphy [single photon emission computed tomography (SPECT)] combined with computed X-ray tomography (CT) in the detection of sacroiliac joint (SIJ) mechanical dysfunction and evaluate reproducibility of reporting., Methods: Patients with pelvic girdle pain either on the basis of peri-partum SIJ dysfunction or trauma were included. These patients were imaged with bone scintigraphy with hybrid imaging with SPECT/CT., Results: The study group comprised 100 patients (72 females, 28 males). Trauma accounted for 52% and the remainder were patients with peri-partum pain. Average age was 43 years and average length of history was >2 years. The major finding was increased uptake in the upper SIJ and posterior soft-tissues/ligaments. Hybrid imaging had a sensitivity of 95% and specificity of 99%. Positive predictive value was 99% and negative predictive value 94%. Power of the test was 1.0. Reproducibility of the test was good with kappa values of 0.85., Conclusion: Hybrid imaging with SPECT/CT reproducibly demonstrates metabolic alterations around the SIJ in patients with SIJ dysfunction, which we have termed SIJ incompetence. The condition is more common than previously recognised and frequently occurs after trauma, which has not been reported previously.

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., (Copyright © 2013 American Society for Bone and Mineral Research.)

Bone scintigraphy (BS) has a good sensitivity but limited specificity. Moreover, planar imaging limits localization of lesion especially of overlapping structures in close proximity. SPECT allows tomographic imaging, resulting in better localization and characterization of the lesion. Addition of CT to SPECT in hybrid SPECT/CT further improves the precision of localization and accuracy of characterization of the lesion. Combining functional and anatomical imaging is complementary with improved sensitivity, specificity, and diagnostic confidence. These advantages of SPECT/CT are illustrated by 3 cases where diagnostic confidence was higher with SPECT/CT compared to BS or CT alone, highlighting the incremental value of SPECT/CT in assessing knee pain.

Context: Several trials have reported an increased risk of fractures and falls after intermittent high-dose vitamin D. Treatment with loading doses of vitamin D may increase 1,25(OH)(2) vitamin D catabolism through changes in calcium/phosphate homeostasis and fibroblast growth factor-23 (FGF-23)., Objective: The aim was to determine the effects of high-dose vitamin D on circulating concentrations of 1,25(OH)(2) vitamin D and FGF-23 in patients with osteoporosis and vitamin D insufficiency., Design, Setting, Patients, and Intervention: We carried out a prospective study of 45 subjects with vitamin D deficiency/insufficiency treated with a bolus dose of 300 000 IU of vitamin D(2) im. Blood samples were obtained at baseline and 1, 2, and 3 months after treatment., Outcome Measures: Changes in 1,25(OH)(2)-vitamin D and FGF-23 were measured., Results: Loading dose of vitamin D(2) increased 1,25(OH)(2)-vitamin D(2) at 3 months, with a mean [SD] of 41 [56] pmol/L at baseline and 162.3 [137.8] pmol/L at 3 months (P < .001). FGF-23 increased significantly at all time points with a peak at 3 months, with percent change from baseline (mean [SEM]) of 50% [48%] at 3 months (P < .01). There was a positive correlation between FGF-23 and serum phosphate (r = 0.36, P = .024) and calcium (r = 0.532, P < .001) and a negative correlation between total 1,25(OH)(2)-vitamin D and FGF-23 (r = -0.32, P = .036) at 3 months., Conclusions: High-dose vitamin D increases 1,25(OH)(2)-vitamin D and FGF-23 concentration. Further studies are required to determine whether adjusting vitamin D dose and frequency to minimize increases in FGF-23 may prevent the adverse outcomes associated with high-dose intermittent vitamin D supplementation.

Introduction: Impingement syndrome and soft-tissue pathology have been recognized as significant causes of chronic ankle pain. Conventional bone scintigraphy was traditionally used for osseous pathology, but with the advent of single photon emission computed tomography/computed tomography (SPECT/CT) the role of bone scintigraphy in these patients is being reconsidered., Aim: The aim of this study was to assess the potential role of multislice SPECT/CT in diagnosing impingement syndrome and soft-tissue pathology of the ankle and foot., Materials and Methods: A total of 209 patients (age range: 19-80 years) underwent a two-phase Tc-99m methylene diphosphonate bone scan followed by SPECT/CT between 2006 and 2009 for various ankle and foot pathologies. These scans were reviewed for impingement syndrome and soft-tissue pathology. The diagnosis made on SPECT/CT was compared with the clinical diagnosis, and two-phase bone scan findings and additional findings obtained from SPECT/CT were noted., Results: Out of the 209 patients, 43 (21%) were diagnosed with impingement syndrome or soft-tissue pathology. Clinical diagnosis versus bone SPECT/CT: in 24/43 (56%) patients, SPECT/CT provided information not suspected on clinical diagnosis. In 19/43 (44%) patients, SPECT/CT confirmed the clinical diagnosis. Two-phase bone scan versus SPECT/CT: in 31/43 (72%) patients, SPECT/CT provided additional information, which was not diagnosed on the conventional two-phase bone scan. The findings of the two-phase bone scan and SPECT/CT were concordant in 12/43 (28%) patients., Conclusion: Tc-99m methylene diphosphonate bone SPECT/CT is useful in localizing and characterizing impingement syndrome and soft-tissue pathology in patients with ankle/foot pain. SPECT/CT may complement MRI and ultrasonography in the investigation of impingement syndrome and soft-tissue pathology.

Summary: This study showed that regional bone blood flow and (18)F-fluoride bone plasma clearance measured by positron emission tomography are three times lower at the hip than the lumbar spine., Introduction: Measurements of effective bone plasma flow (K (1)), bone plasma clearance (K ( i )) and standardised uptake values (SUV) using (18)F-fluoride positron emission tomography ((18)F-PET) provide a useful means of studying regional bone metabolism at different sites in the skeleton. This study compares the regional (18)F-fluoride kinetics and SUV at the hip and lumbar spine (LS)., Methods: Twelve healthy postmenopausal women with no history of metabolic bone disease apart from two with untreated osteoporosis were recruited. Each subject underwent 60-min dynamic (18)F-PET scans at the LS and proximal femur two weeks apart. K (1), K ( i ) and SUV were measured at the LS (mean of L(1)-L(4)), femoral neck (FN), total hip (TH) and femoral shaft (FS). Differences between sites were assessed using the nonparametric Kruskal-Wallis test with a Bonferroni correction for multiple comparisons., Results: Values of K (1), K ( i ) and SUV at the FN, TH and FS were three times lower than at the LS (p = 0.003). Amongst the proximal femur sites, K ( i ) and SUV were lower at the FS compared with the FN and TH, and SUV was lower at the TH compared with the FN (all p < 0.05). The volume of distribution was lower at the TH and FS compared with the LS (p < 0.05)., Conclusion: The lower values of K (1), K ( i ) and SUV at the hip suggest that lower bone blood flow in the proximal femur is an important factor explaining the principal reason for the differences in bone fluoride kinetics between the LS and hip sites.

Unlabelled: We assessed the precision of lumbar spine (18)F-PET measurements based on 58 scans performed on 20 postmenopausal women. The percentage coefficient of variation (%CV) (95% confidence interval) was 9.2% (7.5-11.8) for standardised uptake values, 11.7% (9.5-14.9) for plasma clearance measurements using the Patlak method and 14.5% (11.7-18.5) for plasma clearance measurements using the Hawkins three-compartment model., Introduction: (18)F-Fluoride positron emission tomography ((18)F-PET) is a non-invasive technique that allows the assessment of regional bone turnover in patients with metabolic bone disease. Knowledge of the precision errors of (18)F-PET measurements is important for planning the number of subjects required for research studies., Methods: Twenty osteoporotic postmenopausal women had (18)F-PET scans of the lumbar spine at 0, 6 and 12 months after stopping long-term bisphosphonate treatment. No significant changes in the PET measurements were seen over the 12-month period, and the data were deemed suitable for a precision study. Precision errors were evaluated for standardised uptake values (SUVs) and for the fluoride plasma clearance to bone mineral (K (i)) determined using the Patlak and Hawkins methods. Precision errors were expressed as the %CV and were calculated for the mean L1-L4 region and for individual vertebrae., Results: %CV (95% confidence interval) for the L1-L4 region was 9.2% (7.5-11.8) for SUV, 11.7% (9.5-14.9) for K (i) measured using the Patlak method and 14.5% (11.7-18.5) for K (i) measured using the Hawkins method. There was no significant difference between precision errors obtained for the L1-L4 region and those obtained for a single vertebra., Conclusions: SUV measurements showed the smallest precision error followed by the Patlak method, while the Hawkins method gave the largest error. Measuring a smaller region of interest did not increase the precision error, suggesting that the factor determining the errors may be scanner calibration.

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.

Unlabelled: The aim of this study was to examine the effects of bisphosphonate discontinuation on bone metabolism at the spine and hip measured using (18) F-fluoride PET. Bone metabolism at the spine remained stable following discontinuation of alendronate and risedronate at 1 year but increased in the hip in the alendronate group only., Introduction: Bisphosphonates such as alendronate (ALN) or risedronate (RIS) have persistent effects on spine BMD following discontinuation., Methods: Positron emission tomography (PET) was used to examine regional bone metabolism in 20 postmenopausal women treated with ALN (n = 11) or RIS (n = 9) for a minimum of 3 years at screening (range 3-9 years, mean 5 years for both groups). Subjects underwent a dynamic scan of the lumbar spine and a static scan of both hips at baseline and 6 and 12 months following treatment discontinuation. (18) F-fluoride plasma clearance (K(i)) at the spine was calculated using a three-compartment model. Standardised uptake values (SUV) were calculated for the spine, total hip, femoral neck and femoral shaft. Measurements of BMD and biochemical markers of bone turnover were also performed., Results: With the exception of a significant decrease in spine BMD in the ALN group, BMD remained stable. Bone turnover markers increased significantly from baseline by 12 months for both study groups. Measurements of K(i) and SUV at the spine and femoral neck did not change significantly in either group. SUV at the femoral shaft and total hip increased significantly but in the ALN group only, increasing by 33.8% (p = 0.028) and 24.0% (p = 0.013), respectively., Conclusions: Bone metabolism at the spine remained suppressed following treatment discontinuation. A significant increase in SUV at the femoral shaft and total hip after 12 months was observed but for the ALN group only. This study was small, and further clinical studies are required to fully evaluate the persistence of BP treatment.

The evaluation of the osseous ankle and foot pathology often poses a clinical and diagnostic challenge because of the complex anatomy and structural biomechanics of the region. Further investigation involves a multimodality imaging approach. Although both structural and functional imaging techniques have their strengths, namely, the high specificity of the former and superior sensitivity of the latter, they also have a number of limitations when used in isolation. These include the inability to determine the functional significance of pathological anatomical abnormalities or to further characterize or localize abnormal metabolic activity. The development of integrated single-photon emission computed tomography/computed tomography systems has aimed to overcome the limitations of separate anatomical and functional imaging techniques. This may be of particular value in ankle and foot assessments, in which multiple joints may be affected by different pathologies. This review article aims to highlight the role of both structural and functional imaging techniques, with particular emphasis on the incremental value of single-photon emission computed tomography/computed tomography in evaluation of this complex anatomical region.

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.