Surgical radioguidance with beta-emitting radionuclides; challenges and possibilities: A position paper by the EANM.

Radioguidance that makes use of ß-emitting radionuclides is gaining in popularity and could have potential to strengthen the range of existing radioguidance techniques. While there is a strong tendency to develop new PET radiotracers, due to favorable imaging characteristics and the success of theranostics research, there are practical challenges that need to be overcome when considering use of ß-emitters for surgical radioguidance. In this position paper, the EANM identifies the possibilities and challenges that relate to the successful implementation of ß-emitters in surgical guidance, covering aspects related to instrumentation, radiation protection, and modes of implementation.

Dual [68Ga]DOTATATE and [18F]FDG PET/CT in patients with metastatic gastroenteropancreatic neuroendocrine neoplasms: a multicentre validation of the NETPET score.

BACKGROUND: Gastroenteropancreatic neuroendocrine neoplasms (GEPNENs) are heterogeneous in clinical course, biology, and outcomes. The NETPET score predicts survival by scoring uptake on dual [68Ga]DOTATATE and [18F]FDG PET/CT scans. We aimed to validate previous single-centre findings in a multicentre, international study. METHODS: Dual scans were assigned a NETPET score of P1 (DOTATATE positive/FDG negative), P2-4 (DOTATATE positive/FDG positive), or P5 (DOTATATE negative/FDG positive). NETPET score, histological grade, age at diagnosis, and presence/absence of extrahepatic disease were compared to overall survival/time to progression on univariate and multivariate analysis. RESULTS: 319 metastatic/unresectable GEPNEN patients were included. The NETPET score was significantly associated with overall survival and time to progression on univariate and multivariate analysis (all p < 0.01). Median overall survival/time to progression was 101.8/25.5 months for P1, 46.5/16.7 months for P2-4, and 11.5/6.6 months for P5. Histological grade correlated with overall survival and time to progression on univariate and multivariate analysis (all p < 0.01), while presence/absence of extrahepatic disease did not. Age at diagnosis correlated with overall survival on univariate and multivariate analysis (p < 0.01). The NETPET score also correlated with histological grade (p < 0.001). CONCLUSION: This study validates the NETPET score as a prognostic biomarker in metastatic GEPNENs, capturing the complexity of dual PET imaging.

Prospective study of Na[18F]F PET/CT for cancer staging in morbidly obese patients compared with [99mTc]Tc-MDP whole-body planar, SPECT and SPECT/CT.

PURPOSE: This prospective study aims to assess the diagnostic test characteristics of Na[18F]F PET/CT for the skeletal staging of cancer in morbidly obese patients compared with 99mTc-methylene diphosphonate (MDP), whole-body planar (WBS), SPECT, and SPECT/CT acquisitions. MATERIAL AND METHODS: One hundred seventeen obese patients (BMI 46.5 ± 6.1 kg/m2 and mean age, 59.0 years; range 32-89 years) with BMI > 40 kg/m2 were prospectively enrolled and underwent [99mTc]Tc-MDP WBS, SPECT, SPECT/CT, and Na[18F]F PET/CT within two weeks for the osseous staging of a malignancy. Images were assessed qualitatively using a 3-point scale. Patient and lesion-based diagnostic test characteristics were estimated using an optimistic and pessimistic dichotomization method. RESULTS: Bone metastases were confirmed in 44 patients. Patient-based optimistic diagnostic test characteristics were (sensitivity, specificity, overall accuracy): Na[18F]F PET/CT (95.5%, 95.9%, 95.7%), [99mTc]Tc-MDP WBS (52.3%, 71.2%, 64.1%), SPECT (61.4%, 80.8%, 73.5%) and SPECT/CT (65.9%, 91.8%, 82.1%). Lesion-based optimistic diagnostic test characteristics were: Na[18F]F PET/CT (97.7%, 97.9%, 97.7%), [99mTc]Tc-MDP WBS (39%, 67%, 48.9%), SPECT (52.9%, 93.6%, 67.3%) and SPECT/CT (65.9%, 91.8%, 82.1%). There was no significant difference in the specificity of Na[18F]F and SPECT/CT. All other pairwise comparisons were significant (p<.001). ROC curve analysis showed a high overall accuracy of Na[18F]F with significantly higher AUCs for Na[18F]F PET/CT compared to [99mTc]Tc-MDP WBS, SPECT, and SPECT/CT on both patient and lesion-based analysis (p<.001). Moreover, Na[18F]F PET/CT changed patient management in 38% of patients. CONCLUSIONS: Na[18F]F PET/CT may be the preferred imaging modality for skeletal staging in morbidly obese patients. The technique provides excellent diagnostic test characteristics superior to [99mTc]Tc-MDP bone scan (including SPECT/CT), impacts patient management, has an acceptable radiation exposure profile, and is well-tolerated. Further cost-effectiveness evaluations are warranted.

Update on imaging in chronic kidney disease-mineral and bone disorder: promising role of functional imaging.

Disorders of mineral metabolism and bone disease are common complications in chronic kidney disease (CKD) patients and are associated with increased morbidity and mortality. Bone biopsies, bone scintigraphy, biochemical markers, and plain films have been used to assess bone disorders and bone turnover. Of these, functional imaging is less invasive than bone/marrow sampling, more specific than serum markers and is therefore ideally placed to assess total skeletal metabolism. 18F-sodium fluoride (NaF) PET/CT is an excellent bone-seeking agent superior to conventional bone scan in CKD patients due to its high bone uptake, rapid single-pass extraction, and minimal binding to serum proteins. Due to these properties, 18F-NaF can better assess the skeletal metabolism on primary diagnosis and following treatment in CKD patients. With the increased accessibility of PET scanners, it is likely that PET scanning with bone-specific tracers such as 18F-NaF will be used more regularly for clinical assessment and quantitation of bone kinetics. This article describes the pattern of scintigraphic/functional appearances secondary to musculoskeletal alterations that might occur in patients with CKD.

COVID-19 in the act: incidental 18F-FDG PET/CT findings in asymptomatic patients and those with symptoms not primarily correlated with COVID-19 during the United Kingdom coronavirus lockdown.

PURPOSE: The emergence of the novel SARS-CoV-2 pathogen and lethal COVID-19 disease pandemic poses major diagnostic challenges. The study aims to describe the spectrum and prevalence of thoracic and extrathoracic incidental findings in patients who have undergone 18F-FDG PET/CT during the first 3 weeks of the COVID-19 UK lockdown. METHODS: This is a single-centre retrospective controlled observational study. 18F-FDG PET/CT scans (n = 160) acquired from 23/3/2020 to 9/4/2020 were retrospectively reviewed for incidental findings in the lungs and extrapulmonary sites (heart, nasal sinuses, parotid and salivary glands, colon, large vessels, renal cortex, brain, spleen and testes). A date-matched control group (n = 205) of patients from 2019 was used for comparison. RESULTS: The total prevalence of suspicious findings was 26/160 (16.25%). Fifteen patients presented with incidental findings in the lungs, while eleven patients had only non-pulmonary incidental findings. There was a significant increase in the appearance of incidental 18F-FDG PET/CT findings during the 2nd week (OR = 3.8) and 3rd week (OR = 7.6) in relation to the 1st week. There was a significant increase in the average maximum standardised uptake values (SUVmax) in the parotid/salivary glands of patients scanned during week 2 in relation to week 1 (p = 0.036). There was no significant difference in the prevalence of incidental findings compared to the control group, but the number of pulmonary vs. extrathoracic findings was different between the two populations. CONCLUSION: The study provides a novel base of evidence to identify asymptomatic patients and those without symptoms strongly associated with COVID-19 with incidental 18F-FDG PET/CT findings suspicious of SARS-CoV-2 infection during the initial stages of the pandemic.

177Lu-DOTATATE in older patients with metastatic neuroendocrine tumours: safety, efficacy and health-related quality of life.

PURPOSE: The safety and efficacy of 177Lu-DOTATATE in older patients with advanced neuroendocrine tumours (NET) are not well understood. METHODS: Patients ≥70 years of age and treated with 177Lu-DOTATATE were included. Toxicity, health-related quality of life (HRQoL), objective response, progression-free survival (PFS) and overall survival (OS) were assessed. The relationship between baseline characteristics and PFS and OS was analysed using the Kaplan-Meier method. Univariate analyses were performed using the Cox proportional hazards model. RESULTS: In total, 71 patients were included (76.1% midgut primary). The median age at diagnosis and age at 177Lu-DOTATATE treatment were 70 and 74 years, respectively. The majority (78.9%) of patients completed 4 cycles of 177Lu-DOTATATE. Clinically significant myelosuppression was rare (2.8%). There was no deterioration in HRQoL and 'disease-specific worries' significantly improved (P = 0.029). Radiological response assessment was available in 66 patients. Partial response, stable disease and progression of disease were found in 10 (15.2%), 52 (78.8%) and 4 patients (6.1%), respectively. Median PFS and OS were 36.0 and 47.0 months, respectively. Increased baseline alkaline phosphatase was associated with poorer PFS (P = 0.002) and OS (P = 0.006). CONCLUSION: Patients ≥70 years of age with advanced NET treated with 177Lu-DOTATATE have efficacy and toxicity profiles similar to the wider NET population, without deterioration of HRQoL.

Changes in the global impact of COVID-19 on nuclear medicine departments during 2020: an international follow-up survey.

AIM: As a follow-up to the international survey conducted by the International Atomic Energy Agency (IAEA) in April 2020, this survey aims to provide a situational snapshot of the COVID-19 impact on nuclear medicine services worldwide, 1 year later. The survey was designed to determine the impact of the pandemic at two specific time points: June and October 2020, and compare them to the previously collected data. MATERIALS AND METHODS: A web-based questionnaire, in the same format as the April 2020 survey was disseminated to nuclear medicine facilities worldwide. Survey data was collected using a secure software platform hosted by the IAEA; it was made available for 6 weeks, from November 23 to December 31, 2020. RESULTS: From 505 replies received from 96 countries, data was extracted from 355 questionnaires (of which 338 were fully completed). The responses came from centres across varying regions of the world and with heterogeneous income distributions. Regional differences and challenges across the world were identified and analysed. Globally, the volume of nuclear medicine procedures decreased by 73.3% in June 2020 and 56.9% in October 2020. Among the nuclear medicine procedures, oncological PET studies showed less of a decline in utilization compared to conventional nuclear medicine, particularly nuclear cardiology. The negative impact was also significantly less pronounced in high-income countries. A trend towards a gradual return to the pre-COVID-19 situation of the supply chains of radioisotopes, generators, and other essential materials was evident. CONCLUSION: The year 2020 has a significant decrease in nuclear medicine diagnostic and therapeutic procedures as a result of the pandemic-related challenges. In June, the global decline recorded in the survey was greater than in October when the situation began to show improvement. However, the total number of procedures remained below those recorded in April 2020 and fell to less than half of the volumes normally carried out pre-pandemic.

Antiproliferative Effect of Above-Label Doses of Somatostatin Analogs for the Management of Gastroenteropancreatic Neuroendocrine Tumors.

BACKGROUND: Above-label doses of somatostatin analogs (SSAs) are increasingly utilized in the management of inoperable/metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs), progressing on standard 4-weekly regimens. OBJECTIVE: To evaluate the antiproliferative effect of 3-weekly SSA administration in a retrospective GEP-NET cohort. METHODS: Patients with advanced GEP-NET, treated with long-acting release (LAR) octreotide 30 mg or lanreotide Autogel 120 mg at a 3-weekly interval, after disease progression on standard 4-weekly doses, were retrospectively identified. Clinicopathologic and treatment response data were collected. Progression-free survival (PFS; dose escalation to radiographic progression or death) was estimated with the Kaplan-Meier method. Factors associated with PFS were identified with the Cox proportional-hazards model. RESULTS: The inclusion criteria were fulfilled by 105 patients. Octreotide LAR was administered to 60 (57%) and lanreotide Autogel to 45 (43%). Indications for dose escalation were breakthrough carcinoid symptoms (58%), radiographic progression (35%) and/or increasing biomarkers (11%). Diarrheal and/or flushing symptomatic improvement was identified in 37/67 cases (55%) and 30/55 cases (55%) with available data, respectively. The disease control rate (radiographic partial response or stable disease) was achieved in 53 patients (50%). Median PFS was 25.0 months (95% CI 16.9-33.1). Patients with radiographic progression <12 months from 4-weekly SSA initiation had worse PFS after dose escalation (7.0 vs. 17.0 months, p = 0.002). In multivariate analysis, pancreatic NETs, a Ki-67 index ≥5% and multiple extrahepatic metastases were independently associated with inferior PFS. CONCLUSIONS: Above-label doses of SSAs may offer a considerable prolongation of PFS and could be utilized as a bridge to other more toxic treatments. Patients with small bowel/colorectal primaries, a Ki-67 index <5% and absence of/limited extrahepatic metastases are more likely to benefit from this approach.

Spectrum of false positive 18F-sodium fluoride (NaF) bone PET/CT findings in Oncology imaging; A narrative pictorial review of cases from a single institution.

Fluorine-18-sodium fluoride (18F-NaF) is a positron emission tomography (PET) bone imaging agent mainly used for oncology staging but may also be used in the evaluation of benign bone and joint pathology conditions. Fluorine-18-NaF is an excellent bone-seeking agent with high bone uptake owing to favorable biodistribution with rapid single-pass extraction, limited plasma protein binding and prompt renal clearance. Fluorine-18-NaF PET/computed tomography (CT) is highly sensitive in identifying both sclerotic and lytic bone metastatic lesions. Occasionally 18F-NaF uptake in benign bone lesions can mimic malignantpathology. In these cases, the pattern of 18F-NaF uptake may elicit a specific diagnosis and correlation with clinical information and morphological information from correlative CT is essential for a correct diagnosis. In the present article, we present a series of clinical cases demonstrating examples of 18F-NaF uptake in benign lesions which can simulate malignant pathology in patients undergoing cancer staging.

The role of bone SPECT/CT in patients with persistent or recurrent lumbar pain following lumbar spine stabilization surgery.

PURPOSE: Despite recent advances in lumbar spine stabilization surgery (LSSS), a high number of patients continue to complain of persistent/recurrent lumbar pain after LSSS. Conventional imaging (plain radiography, CT and MRI) is commonly performed to assess potential lumbar pain generators, but findings are equivocal in approximately 20% of patients. The purpose of this study was to assess the diagnostic performance of 99mTc-HDP bone SPECT/CT in identifying potential pain generators in patients with persistent/recurrent lumbar pain after LSSS but in whom conventional diagnostic imaging is inconclusive. METHODS: A total of 187 patients (median age 56 years, 70 men) with persistent/recurrent lumbar pain following LSSS with inconclusive conventional imaging (plain radiography, CT and/or MRI) underwent 99mTc-HDP bone SPECT/CT and were included in the study. Tracer uptake on SPECT/CT, as an indicator of ongoing or altered osteoblastic activity, was assessed in the lumbar spine stabilization segment(s) and in adjacent segments. Uptake intensity was graded as (1) high (the same as or more than iliac crest uptake), (2) mild (the same as or more than nondiseased vertebral uptake but less than iliac crest uptake), or (3) negative (normal scan). Mild and high uptake were regarded as positive. RESULTS: In 160 of the 187 patients (85.6%), SPECT/CT showed positive mild or high tracer uptake in the LSSS region. More than half of the patients had abnormal tracer uptake in the stabilized segments (56.7%) and/or in the adjacent segments (55.6%). Although positive stabilized segment findings were commonly seen at <2 years (70.3%) and the rate decreased with time after LSSS, they were seen at >6 years after surgery in 38.2% of patients. In 51.4% of patients, abnormal activity was seen in the adjacent segments <2 years after LSSS, suggesting early/accelerated degeneration after surgery. The proportion of patients with abnormal activity in the adjacent segments increased to 67.3% at >6 years after LSSS (p < 0.05). Positive SPECT/CT findings in the stabilized segments were more frequent in patients with three or more stabilized segments (p < 0.05), but were not more frequent in the adjacent segments. Overall, positive SPECT/CT guided therapy in 64% of patients, which included facet joint/nerve root injections or re-do surgery at active sites and/or adjacent sites. CONCLUSION: Bone SPECT/CT is a sensitive diagnostic tool for identifying altered osteoblastic activity, which might be a pain generator in patients with persistent/recurrent pain after lumbar surgery especially when conventional imaging is inconclusive.

Bloodpool SPECT as part of bone SPECT/CT in painful total knee arthroplasty (TKA): validation and potential biomarker of prosthesis biomechanics.

PURPOSE: To compare bloodpool SPECT with planar imaging in bone SPECT/CT of painful total knee arthroplasty (TKA) with respect to inter-rater agreement, confidence, prosthesis outcome, and biomechanical functioning. METHODS: Retrospective study of bloodpool SPECT and planar control images. Four raters used the validated Bruderholz scheme and a 5-point scale to grade uptake. Inter-rater agreement and overall confidence scores were calculated. Variable cluster analysis was performed to identify patterns of uptake, and associations between patterns and prosthesis outcome and biomechanical functioning were examined. RESULTS: In all, 55 knees in 43 patients were analyzed (median follow-up 17 months; revision rate 21.8%). SPECT significantly improved inter-rater agreement in 24% of regions (all P < 0.05) and overall confidence by 20% (P < 0.001). Regional uptake cluster analysis showed improved antero-posterior separation with SPECT, and distinct patterns associated with prosthesis survival in lateral femoral (P = 0.041) and medial tibial (P < 0.001) regions. The prognostic value of SPECT outperformed planar imaging for tibial (P < 0.001), patellar (P = 0.009), and synovial (P = 0.040) assessment. Internal femoral malrotation resulted in increased uptake in posteromedial (P = 0.042) and anterolateral (P = 0.016) femoral, and lateral patellar (P = 0.011) regions. Internal tibial malrotation increased uptake in posterolateral (P = 0.026) and posteromedial tibial (P = 0.005), and medial patellar regions (P = 0.004). Bloodpool SPECT improved the prognostic value of late-phase SPECT/CT for the assessment of the medial tibial region. CONCLUSIONS: Bloodpool SPECT outperforms planar assessment of painful TKAs and the identification of distinct uptake patterns make it a potentially clinically relevant biomarker of prosthesis survival and biomechanical functioning.

Molecular imaging of bone metastases using bone targeted tracers.

Molecular imaging using bone targeted tracers has been used in clinical practice for almost fifty years and still plays an essential role in the diagnosis and follow-up of bone metastases. It includes both [99mTc]bisphosphonates for bone scan and [18F]NaF for positron emission tomography/computed tomography (PET/CT) which are very sensitive to detect osteoblastic activity, but it is important to consider several aspects to increase the specificity of reported findings (such as specific tracer characteristics and mechanism of action, patient's clinical history, common metastatic patterns, changes after treatment, limitations of the technique, variations and pitfalls). This will enable useful information for clinical management being provided in the report. Furthermore, iatrogenic skeletal adverse events are common and they should also be identified, as they have impact on patient's quality of life. This review makes a brief summary of the mechanism of action of bone targeted tracers, followed by a discussion of classic patterns of bone metastasis, treatment response assessment and iatrogenic skeletal complications. The value of hybrid imaging techniques with bone targeted tracers, including single photon emission computed tomography and PET/CT is also explored. The final part summarizes new bone targeted tracers with superior imaging characteristics that are being developed, and which may further enhance the applications of radionuclide bone imaging.

Bone SPECT/CT in the postoperative spine: a focus on spinal fusion.

Low back pain is a global problem affecting one in 10 people. The management of low back pain varies from conservative to more invasive methods with a spectacular increase in the number of patients undergoing spinal fusion surgery during the last decade. Conventional radiological and radionuclide studies are often used in the assessment of persistent or recurring pain after spinal surgery with several advantages and limitations related to each technique. This article reviews the key contribution of integrated bone SPECT/CT in evaluating patients with persistent or recurring pain after spinal surgery, focusing on spinal fusion. Current literature supports the use of bone SPECT/CT as an adjunct imaging modality and problem-solving tool in evaluating patients with suspicion of pseudarthrosis, adjacent segment degeneration, and hardware failure. The role of bone SPECT/CT in post-operative orthopaedic scenarios is evolving, and this review highlights the need for further research on the role of bone SPECT/CT in these patients.

Real-time differential tracking of human neutrophil and eosinophil migration in vivo.

BACKGROUND: Hitherto, in vivo studies of human granulocyte migration have been based on indiscriminate labeling of total granulocyte populations. We hypothesized that the kinetics of isolated human neutrophil and eosinophil migration through major organs in vivo are fundamentally different, with the corollary that studying unseparated populations distorts measurement of both. METHODS: Blood neutrophils and eosinophils were isolated on 2 separate occasions from human volunteers by using Current Good Manufacturing Practice CD16 CliniMACS isolation, labeled with technetium 99m-hexamethylpropyleneamine oxime, and then reinfused intravenously. The kinetics of cellular efflux were imaged over 4 hours. RESULTS: Neutrophils and eosinophils were isolated to a mean purity of greater than 97% and greater than 95%, respectively. Activation of neutrophils measured as an increase in their CD11b mean fluorescence intensity in whole blood and after isolation and radiolabeling was 25.98 ± 7.59 and 51.82 ± 17.44, respectively, and was not significant (P = .052), but the mean fluorescence intensity of CD69 increased significantly on eosinophils. Analysis of the scintigraphic profile of lung efflux revealed exponential clearance of eosinophils, with a mean half-life of 4.16 ± 0.11 minutes. Neutrophil efflux was at a significantly slower half-life of 13.72 ± 4.14 minutes (P = .009). The migration of neutrophils and eosinophils was significantly different in the spleen at all time points (P = .014), in the liver at 15 minutes (P = .001), and in the bone marrow at 4 hours (P = .003). CONCLUSIONS: The kinetics of migration of neutrophils and eosinophils through the lung, spleen, and bone marrow of human volunteers are significantly different. Study of mixed populations might be misleading.

Molecular imaging agents for SPECT (and SPECT/CT).

The development of hybrid single photon emission computed tomography/computed tomography (SPECT/CT) cameras has increased the diagnostic value of many existing single photon radiopharmaceuticals. Precise anatomical localization of lesions greatly increases diagnostic confidence in bone imaging of the extremities, infection imaging, sentinel lymph node localization, and imaging in other areas. Accurate anatomical localization is particularly important prior to surgery, especially involving the parathyroid glands and sentinel lymph node procedures. SPECT/CT plays a role in characterization of lesions, particularly in bone scintigraphy and radioiodine imaging of metastatic thyroid cancer. In the development of novel tracers, SPECT/CT is particularly important in monitoring response to therapies that do not result in an early change in lesion size. Preclinical SPECT/CT devices, which actually have spatial resolution superior to PET/CT devices, have become essential in characterization of the biodistribution and tissue kinetics of novel tracers, allowing coregistration of serial studies within the same animals, which serves both to reduce biological variability and reduce the number of animals required. In conclusion, SPECT/CT increases the utility of existing radiopharmaceuticals and plays a pivotal role in the evaluation of novel tracers.

Assessment of regional and total skeletal metabolism using 18F-NaF PET/CT in patients with chronic kidney disease.

OBJECTIVE: The study aims to assess regional and total bone metabolic activity in patients with chronic kidney disease using Na[18F]F PET and correlation between semi-quantitative indices and blood parameters. METHODS: Seventy-two subjects (mean age 61.8 ± 13.8 years) were included. Of these 24/72 patients had end-stage renal disease (ESRD) (GFR < 15 mL/min/1.73 m2), 38/72 had chronic kidney disease (CKD) (GFR between 60 and 15 mL/min/1.73 m2), and 10/72 were controls with normal renal function. All subjects underwent Na[18F]F PET-CT with a dose activity of 0.06 mCi/Kg. Regional and total skeletal metabolism were assessed with mean SUVs in a skeletal volume of interest (VOI), bone to soft tissue index (B/S), global SUV mean (GSUV mean) of the whole bone, and uptake in the femoral neck. RESULTS: Statistically significant differences were observed in a number of 18F-NaF metrics like femoral neck metabolism in CKD and ERSD groups in comparison to control in right (P = 0.003) and left femur (P = 0.006), bone to soft tissue index in the femur (P = 0.016) and GSUV5 (P = 0.006). There is also a significant difference in SUV mean in lumbar vertebrae (L1-L4) among CKD, ESRD, and controls. There was a moderate correlation between 18F-NaF PET scan uptake and blood parameters such as ALP and PTH. Na[18F]F uptake parameters were significantly different in low versus high bone turnover state. CONCLUSIONS: The assessment of total skeleton and regional metabolism and bone turnover in CKD patients is feasible with Na[18F]F PET. Na[18F]F can help to detect early changes in bone metabolism and assess the progression of bone disease in this complex condition. Quantification with Na[18F]F PET might provide better assessment of the bone turnover. The difference in Na[18F]F uptake in CKD compared to controls is likely related to a change in bone turnover which, however, requires further validation.