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Li Xu,1,* Yanping Gong,2,* Qian Zhao,3 Glen M Blake,4 Kai Li,1 Yong Zhang,1 Qianqian Liu,2 Chunlin Li,2 Xiaoguang Cheng1 1Department of Radiology, Beijing Jishuitan Hospital, Beijing, People’s Republic of China; 2Department of Endocrinology, the Second Medical Center, the Chinese People’s Liberation Army General Hospital, National Clinical Research Center for Geriatric Disease, Beijing, 100853, People’s Republic of China; 3International Medical Center, Sichuan University West China Hospital, Chengdu, People’s Republic of China; 4Biomedical Engineering Department, King’s College London, London, UK*These authors contributed equally to this workCorrespondence: Xiaoguang Cheng, Department of Radiology, Beijing Jishuitan Hospital, Beijing, 100035, People’s Republic of China, Email xiao65@263.net Chunlin Li, Department of Endocrinology, the Second Medical Center, the Chinese People’s Liberation Army General Hospital, National Clinical Research Center for Geriatric Disease, Beijing, 100853, People’s Republic of China, Email lichunlin301@163.comPurpose: To investigated the factors that influence BMAC.Patients and Methods: Quantitative computed tomography (QCT) and magnetic resonance imaging (MRI) were applied to measure abdominal fat areas, liver fat content, erector muscle fat content, and BMAC of the L2-4 vertebrae. Sex hormone, adipokine, and inflammatory factor levels were measured on the same day.Results: Although age, erector muscle fat content, estradiol, testosterone, and adiponectin/leptin levels showed correlations with BMAC in the correlation analysis, the equations obtained from the whole population by multivariate analysis were unclear. Patients were stratified according to BMAC quartiles, and differences were found in vBMD, age, estradiol, testosterone, and erector muscle fat content among the four quartiles. Logistic analyses confirmed that age, estradiol/testosterone ratio, and TNF-α had independent effects on BMAC in all quartiles. In addition, height was related to higher BMAC quartiles, and glucose was related to lower BMAC quartiles.Conclusion: Compared to other body fats, BMAC is a unique fat depot. Age, estradiol/testosterone ratio, and TNF-α are all key influencing factors related to BMAC in postmenopausal women. Furthermore, height and glucose levels were related to BMAC in the higher and lower BMAC quartiles, respectively.Keywords: bone marrow adiposity, postmenopausal women, age, adipokines, sex hormones

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. [ABSTRACT FROM AUTHOR]

Diabetes mellitus and metabolic syndrome are closely linked with visceral body composition, but clinical assessment is limited to external measurements and laboratory values including hemoglobin A1c (HbA1c). Modern deep learning and AI algorithms allow automated extraction of biomarkers for organ size, density, and body composition from routine computed tomography (CT) exams. Comparing visceral CT biomarkers across groups with differing glycemic control revealed significant, progressive CT biomarker changes with increasing HbA1c. For example, in the unenhanced female cohort, mean changes between normal and poorly-controlled diabetes showed: 53% increase in visceral adipose tissue area, 22% increase in kidney volume, 24% increase in liver volume, 6% decrease in liver density (hepatic steatosis), 16% increase in skeletal muscle area, and 21% decrease in skeletal muscle density (myosteatosis) (all p < 0.001). The multisystem changes of metabolic syndrome can be objectively and retrospectively measured using automated CT biomarkers, with implications for diabetes, metabolic syndrome, and GLP-1 agonists., (© 2024. The Author(s).)

Background: Uptake to anastrozole for breast cancer prevention is low, partly due to women's concerns about side effects including gains in weight and specifically gains in body fat. Previous evidence does not link anastrozole with gains in weight, but there is a lack of data on any effects on body composition i.e. changes in fat and fat free mass. Here we assess association of anastrozole with body composition changes in a prospective sub-study from the second international breast intervention trial (IBIS-II)., Methods: Participants had DXA scans at baseline and for five years of anastrozole/placebo and beyond (between March 2004 and September 2017. Primary outcomes were changes in body weight, body fat and fat free mass at 9-18 months. A linear model was used to estimate the size of a differential effect in these outcomes by randomised treatment allocation adjusted for baseline value and time since last scan, age, 10-year breast cancer risk, smoking and HRT status., Results: 203 postmenopausal women were recruited (n = 95 anastrozole, n = 108 placebo), mean age 58 years (SD = 5.4), BMI 28.0 kg/m 2 (SD = 5.5). There was no evidence of a strong association between anastrozole or placebo and endpoints at 9-18 months; effect size (95 %CI) for anastrozole minus placebo for body weight (per/kg) -0.11 (-1.29-1.08); body fat 0.11 (-0.75-0.96) and fat free mass -0.30 (-0.79-0.19)., Conclusions: There is unlikely to be a clinically significant change to body composition with anastrozole for breast cancer prevention., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Inc.)

Purpose: Predictors of 'imminent' risk of second hip fracture are unknown. The aims of the study were to explore strength of hip areal bone mineral density (aBMD), and muscle area and density for predicting second hip fracture at different time intervals., Methods: Data of the Chinese Second Hip Fracture Evaluation were analyzed, a longitudinal study to evaluate the risk of second hip fracture (of the contralateral hip) by using CT images obtained immediately after first hip fracture. Muscle cross-sectional area and density were measured of the gluteus maximus (G.MaxM) and gluteus medius and minimus (G.Med/MinM) and aBMD of the proximal femur at the contralateral unfractured side. Patients were followed up for a median time of 4.5 years. Separate Cox models were used to predict second hip fracture risk at different time intervals after first event adjusted for age, sex, BMI and diabetes., Results: The mean age of subjects with imminent (within 1st or 2nd year) second hip fracture was 79.80 ± 5.16 and 81.56 ± 3.64 years. In the 1st year after the first hip fracture, femoral neck (FN) aBMD predicted second hip fracture (HR 5.88; 95 % CI, 1.32-26.09). In the remaining years of follow-up after 2nd year, muscle density predicted second hip fracture (G.MaxM HR 2.13; 95 % CI, 1.25-3.65,G.Med/MinM HR 2.10; 95 % CI, 1.32-3.34)., Conclusions: Our results show that femoral neck aBMD is an important predictor for second hip fracture within the first year and therefore suggest supports the importance concept of early and rapid-acting bone-active drugs to increase hip BMD. In addition, the importance of muscle density predicting second hip fracture after the second year suggest post hip fracture rehabilitation and exercise programs could also be important to reduce muscle fatty infiltration., Competing Interests: KE is a part time employee of Clario, Inc.. Other authors declare no conflict of interest., (© 2023 Published by Elsevier Inc.)

Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-23-1090/coif). YXJW serves as the Editor-in-Chief of Quantitative Imaging in Medicine and Surgery. The other authors have no conflicts of interest to declare.

Older women with a first hip fracture exhibit heightened susceptibility and incidence of second fracture and potentially severe consequences. This prospective study was to compare the predictive power of qualitative and quantitative muscle parameters for a second hip fracture in older women with a first hip fracture. A total of 206 subjects were recruited from the longitudinal Chinese Second Hip Fracture Evaluation study. Hip computed tomography (CT) scans were obtained immediately after the first fracture. Muscle fat infiltration was assessed according to the Goutallier classification qualitatively. Quantitative parameters included cross-sectional area and density of gluteus maximus (G.MaxM) and gluteus medius and minimus (G.Med/MinM) muscles. CT X-ray absorptiometry was used to measure the areal bone mineral density (aBMD) of the contralateral femur. Cox proportional hazards models were used to compute hazard ratios (HR) of second hip fracture risk. The mean age of subjects was 74.9 (±9.5) years at baseline. After 4.5 years, 35 had a second hip fracture, 153 without a second hip fracture, and 18 died. Except for the combined G.MinM Goutallier grade 3 and 4 groups before adjustment for covariates (HR = 5.83; 95% confidence interval [CI] 1.49-22.83), there were no significant HRs for qualitative classification to predict a second hip fracture. Among quantitative metrics, after adjustment for covariates, G.Med/MinM density was significant in the original (HR = 1.44; CI 1.02-2.04) and competing risk analyses (HR = 1.46; CI 1.02-2.07). After additional adjustment for femoral neck (FN) aBMD, G.Med/MinM density remained borderline significant for predicting a second hip fracture in competing risk analysis (HR = 1.43; CI 0.99-2.06; p  = 0.057). Our study revealed that Goutallier classification was less effective than quantitative muscle metrics for predicting hip second fracture in this elderly female cohort. After adjustment for FN aBMD, G.Med/MinM density is a borderline independent predictor of second hip fracture risk. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research., (© 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.)

We review the rationale, methodology, and clinical utility of quantitative [ 18 F] sodium fluoride ([ 18 F]NaF) positron emission tomography-computed tomography (PET-CT) imaging to measure bone metabolic flux (K i , also known as bone plasma clearance), a measurement indicative of the local rate of bone formation at the chosen region of interest. We review the bone remodelling cycle and explain what aspects of bone remodelling are addressed by [ 18 F]NaF PET-CT. We explain how the technique works, what measurements are involved, and what makes [ 18 F]NaF PET-CT a useful tool for the study of bone remodelling. We discuss how these measurements can be simplified without loss of accuracy to make the technique more accessible. Finally, we briefly review some key clinical applications and discuss the potential for future developments. We hope that the simplified method described here will assist in promoting the wider use of the technique., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Puri, Frost, Moore, Choudhury, Vinjamuri, Mahajan, Fynbo, Vrist, Theil, Kairemo, Wong, Zaidi, Revheim, Werner, Alavi, Cook and Blake.)

Background: Mortality following hip fracture is high and incompletely understood. We hypothesize that hip musculature size and quality are related to mortality following hip fracture. This study aims to investigate the associations of hip muscle area and density from hip CT with death following hip fracture as well as assess the dependence of this association on time after hip fracture., Methods: In this secondary analysis of the prospectively collected CT images and data from the Chinese Second Hip Fracture Evaluation, 459 patients were enrolled between May 2015 and June 2016 and followed up for a median of 4.5 years. Muscle cross-sectional area and density were measured of the gluteus maximus (G.MaxM) and gluteus medius and minimus (G.Med/MinM) and aBMD of the proximal femur. The Goutallier classification (GC) was used for qualitatively assessing muscle fat infiltration. Separate Cox models were used to predict mortality risk adjusted for covariates., Results: At the end of the follow-up, 85 patients were lost, 81 patients (64% women) had died, and 293 (71% women) survived. The mean age of non-surviving patients at death (82.0 ± 8.1 years) was higher than that of the surviving patients (74.4 ± 9.9 years). The Parker Mobility Score and the American Society of Anesthesiologists scores of the patients that died were respectively lower and higher compared to the surviving patients. Hip fracture patients received different surgical procedures, and no significant difference in the percentage of hip arthroplasty was observed between the dead and the surviving patients (P = 0.11). The cumulative survival was significantly lower for patients with low G.MaxM area and density and low G.Med/MinM density, independent of age and clinical risk scores. The GC grades were not associated with the mortality after hip fracture. Muscle density of both G.MaxM (adj. HR 1.83; 95% CI, 1.06-3.17) and G.Med/MinM (adj. HR 1.98; 95% CI, 1.14-3.46) was associated with mortality in the 1st year after hip fracture. G.MaxM area (adj. HR 2.11; 95% CI, 1.08-4.14) was associated with mortality in the 2nd and later years after hip fracture., Conclusion: Our results for the first time show that hip muscle size and density are associated with mortality in older hip fracture patients, independent of age and clinical risk scores. This is an important finding to better understand the factors contributing to the high mortality in older hip fracture patients and to develop better future risk prediction scores that include muscle parameters., (© 2023 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Purpose: This study aimed to investigate the increase in bone marrow adipose tissue (BMAT) in overweight and obese women with polycystic ovary syndrome (PCOS) and its relationship with hyperandrogenism, obesity, and metabolic disorders., Methods: The study included 87 overweight or obese women with PCOS (mean age 29 ± 4 years), as well as 87 age-matched controls recruited from a separate population study. All PCOS patients were measured for anthropometric features, abdominal adipose tissue areas, BMAT, biochemistry, and sex hormones. BMAT was compared between the PCOS patients and controls. In PCOS patients, subgroup comparisons of BMAT and its associations with body adiposity indices, biochemistry, and sex hormones were analyzed. The odds ratios (ORs) of elevated BMAT (defined as BMAT ≥ 38%) were calculated., Results: On average BMAT was increased by 5.6% ( ± 11.3%) in PCOS patients compared to controls. BMAT were significantly higher in the upper tertiles of total cholesterol (TC) and low density lipoprotein-cholesterol (LDL-C). BMAT was not correlated with abdominal adiposity indices or biochemistry except for LDL-C (r = 0.253-0.263, p = 0.014-0.018). LDL-C was not significantly different between the normal and abnormal androgen PCOS subgroups ( p = 0.10-0.887). LDL-C, follicle stimulating hormone (FSH), and total testosterone (TT) were risk factors for elevated BMAT, with ORs of 1.899 ( p = 0.038-0.040), 1.369 ( p = 0.030-0.042), and 1.002 ( p = 0.040-0.044) for each unit increase, respectively., Conclusion: BMAT was increased in overweight and obese PCOS patients, but the increase in BMAT was not associated with the hyperandrogenism related obesity or metabolic disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Xu, Min, Li, Blake, Zhao, Ruan and Cheng.)

Purpose: This study evaluated the prevalence of vertebral fractures (VF) in middle-aged and elderly Chinese men and women and explored the differences in lumbar spine volumetric bone mineral density (vBMD) derived from quantitative CT (QCT) between those with a grade 1 vertebral fracture and non-fractured individuals., Materials and Methods: 3,457 participants were enrolled in the China Action on Spine and Hip Status (CASH) study and had upper abdominal CT examinations. Vertebral fractures were identified by Genant's semi-quantitative method from lateral CT scout views or CT sagittal views. L1-3 vBMD was measured by Mindways QCT Pro v5.0 software. The characteristics of different fracture severity groups were compared using one-way ANOVA, independent-samples t-tests, and Kruskal-Wallis H-tests., Results: 1267 males (aged 62.77 ± 9.20 years) and 2170 females (aged 61.41 ± 9.01 years) were included in the analysis. In men, the prevalence of VF increased from 14.7% at age&lt;50 years to 23.2% at age ≥70 years, and in women from 5.1% at age&lt;50 years to 33.0% at age ≥70 years. Differences in mean age and vBMD were found between the different fracture grade groups. After age stratification, vBMD differences in men aged &lt; 50 years old disappeared (p = 0.162) but remained in the older age bands. There was no significant difference in mean vBMD between those with multiple mild fractures and those with a single mild fracture., Conclusion: In women, the prevalence of VF increased rapidly after age 50, while it grew more slowly in men. In general, with the exception of men &lt;50 years old, participants with a grade 1 VF had lower vBMD than non-fractured individuals. The majority of women younger than 50 with a grade 1 VF had normal bone mass. We recommend that a vertebral height reduction ratio of &lt;25% be diagnosed as a deformity rather than a fracture in people under the age of 50. The presence of multiple mild fractured vertebrae does not imply lower BMD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Liu, Yu, Li, Wang, Huang, Geng, Zhang, Duanmu, Blake and Cheng.)

Background: Radiographic absorptiometry (RA) is one of the earliest methods of bone densitometry and has been used to measure the phalanges and metacarpals where soft tissue attenuation is minimal. The aim of this study was to determine whether the technique can be adapted to correct for soft tissue attenuation and measure areal bone mineral density (aBMD) in the forearm., Methods: A total of 51 patients referred for a clinical spine and hip dual-energy X-ray absorptiometry (DXA) examination and 8 young and middle-aged volunteers were recruited to this study. The first 29 participants (20 women, 9 men, aged 61±14 years) served as the training cohort, and the remaining 30 (20 women, 10 men, aged 55±16 years) comprised the validation cohort. All participants underwent a DXA scan of their non-dominant forearm, and a digital X-ray image of the same arm was acquired with a step phantom. Identical regions of interest (ROIs) in the radius and ulna at the one-third radius site were measured on the X-ray and DXA images, and a soft tissue ROI was measured on X-ray images between the radius and ulna. The X-ray measurements in the training cohort were expressed as equivalent step phantom thickness (Eq. SPT) and used to estimate forearm aBMD using a linear equation calibrated against the DXA scans. Estimates of forearm aBMD made from the digital X-ray images acquired in the validation cohort were compared with the results of the DXA scans., Results: Digital X-ray estimates of radius and ulna aBMD at the one-third radius site in the validation cohort showed a good correlation with GE-Lunar iDXA scanner measurements (r=0.795; P<0.001). The Bland-Altman plot had a mean bias of -0.002 g/cm 2 and 95% limits of agreement of -0.185 to +0.181 g/cm 2 ., Conclusions: Digital X-ray estimates of proximal forearm aBMD corrected for soft tissue attenuation correlated with DXA measurements with correlation coefficients comparable to those seen for other peripheral bone densitometry technologies., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-21-842/coif). Klaus Engelke is a part-time employee of BioClinica, Inc. The other authors have no conflicts of interest to declare., (2022 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

Background: Patients with a first hip fracture are at high risk of fracturing their other hip. Despite this, preventive therapy is often not given. Because little is known about specific risk factors of a second hip fracture, we investigated the association with areal bone mineral density (aBMD), muscle size, and density. We also investigated whether muscle parameters predict the risk of a contralateral fracture independently of aBMD., Methods: Three groups were included, one without hip fracture (a subcohort of the China Action on Spine and Hip Status study), one with a first, and one with a second hip fracture. Subjects with fractures were recruited from the longitudinal Chinese Second Hip Fracture Evaluation (CSHFE). Computed tomography scans of CSHFE patients, which were obtained immediately following their first fracture, were used to measure cross-sectional area and density of the gluteus maximus (G.MaxM) and gluteus medius and minimus (G.Med/MinM) muscles. Computed tomography X-ray absorptiometry was used to measure aBMD of the contralateral femur. Median follow-up time to second fracture was 4.5 years. Cox proportional hazards models were used to compute hazard ratios (HR) of second hip fracture risk in subjects with a first hip fracture. Multivariate logistic regressions were used to compare odds ratios (OR) for the risk of a first and second hip fracture., Results: Three hundred and one participants (68.4 ± 6.1 years, 64% female) without and 302 participants (74.6 ± 9.9 years, 71% female) with a first hip fracture were included in the analysis. Among the latter, 45 (79.2 ± 7.1 years) sustained a second hip fracture. ORs for first hip fracture were significant for aBMD and muscle size and density. ORs for a second fracture were smaller by a factor of 3 to 4 and no longer significant for femoral neck (FN) aBMD. HRs for predicting second hip fracture confirmed the results. G.Med/MinM density (HR, 1.68; CI, 1.20-2.35) and intertrochanter aBMD (HR, 1.62; CI, 1.13-2.31) were the most significant. FN aBMD was not significant. G.Med/MinM density remained significant for predicting second hip fracture after adjustment for FN (HR, 1.66; Cl, 1.18-2.30) or total hip aBMD (HR, 1.50; 95% Cl, 1.04-2.15)., Conclusions: Density of the G.Med/MinM muscle is an aBMD independent predictor of the risk of second hip fracture. Intertrochanteric aBMD is a better predictor of second hip fracture than FN and total hip aBMD. These results may trigger a paradigm shift in the assessment of second hip fracture risk and prevention strategies., (© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Background and Purpose: Although it is widely recognized that hip BMD is reduced in patients with hip fracture, the differences in geometrical parameters such as cortical volume and thickness between subjects with and without hip fracture are less well known., Materials and Methods: Five hundred and sixty two community-dwelling elderly women with hip CT scans were included in this cross-sectional study, of whom 236 had an acute hip fracture. 326 age matched women without hip fracture served as controls. MIAF-Femur software was used for the measurement of the intact contralateral femur in patients with hip fracture and the left femur of the controls. Integral and cortical volumes (Vols) of the total hip (TH), femoral head (FH), femoral neck (FN), trochanter (TR) and intertrochanter (IT) were analyzed. In the FH and FN the volumes were further subdivided into superior anterior (SA) and posterior (SP) as well as inferior anterior (IA) and posterior (IP) quadrants. Cortical thickness (CortThick) was determined for all sub volumes of interest (VOIs) listed above., Results: The average age of the control and fracture groups was 71.7 and 72.0 years, respectively. The fracture patients had significantly lower CortThick and Vol of all VOIs except for TRVol. In the fracture patients, cortical thickness and volume at the FN were significantly lower in all quadrants except for cortical volume of quadrant SA (p= 0.635). Hip fracture patients had smaller integral FN volume and cross-sectional area (CSA) before and after adjustment of age, height and weight. With respect to hip fracture discrimination, cortical volume performed poorer than cortical thickness across the whole proximal femur. The ratio of Cort/TrabMass (RCTM), a measure of the internal distribution of bone, performed better than cortical thickness in discriminating hip fracture risk. The highest area under curve (AUC) value of 0.805 was obtained for the model that included THCortThick, FHVol, THRCTM and FNCSA., Conclusion: There were substantial differences in total and cortical volume as well as cortical thickness between fractured and unfractured women across the proximal femur. A combination of geometric variables resulted in similar discrimination power for hip fracture risk as aBMD., Competing Interests: KE is a part-time employee of BioClinica, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Yang, Liu, Ge, Zhu, Su, Cheng, Wu, Blake and Engelke.)

Background and Purpose: Type 2 diabetes mellitus patients have an increased fracture risk despite having higher areal bone mineral density (aBMD) measured by DXA. This apparent paradox might be explained by the overestimation of BMD by DXA due to the higher fat mass in type 2 diabetes mellitus patients. Volumetric BMD (vBMD) as assessed by quantitative CT (QCT) is not influenced by fat mass. We assessed the association of vBMD and fasting plasma glucose in a large cohort of Chinese subjects and compared the vBMD in healthy and diabetic subjects. In addition, we compared the relation between aBMD, vBMD, glucose and fat mass in a subset of this cohort., Materials and Methods: 10309 participants from the China Biobank project underwent QCT based on chest low dose CT to compute vBMD of L1 and L2 vertebrae and FPG measurements between 2018 and 2019. Among them, 1037 subjects also had spine DXA scans. Data was analyzed using linear regression models., Results: In the total cohort (5889 men and 4420 women, mean age 53 years, range 30-96), there was no significant association between vBMD and FPG after adjustment for age (women: p=0.774; men: p=0.149). 291 women and 606 men fitted the diagnostic criteria of diabetes. Both women and men with diabetes had lower vBMD compared to non-diabetic subjects, but this became non-significant after adjusting for age in the total cohort (women: p=0.817; men: p=0.288) and after propensity score matching based on age (women: p=0.678; men: p=0.135). In the DXA subcohort, aBMD was significantly higher in men with diabetes after adjusting for age and this difference disappeared after further adjusting for total fat area (p=0.064)., Conclusion: We did not find any effect of fasting plasma glucose or diabetes on the volumetric BMD measured with QCT after adjustment for age. Therefore, vBMD measured with QCT might be a more reliable measurement to diagnose osteoporosis and assess fracture risk than aBMD measured with DXA in diabetic patients., Competing Interests: KE is a part-time employee of BioClinica, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Zhao, Zha, Ran, Su, Yang, Shuang, Liu, Xu, Blake, Cheng, Engelke and Vlug.)

This report describes the significance of the kinetic parameters (k-values) obtained from the analysis of dynamic positron emission tomography (PET) scans using the Hawkins model describing the pharmacokinetics of sodium fluoride ([ 18 F]NaF) to understand bone physiology. Dynamic [ 18 F]NaF PET scans may be useful as an imaging biomarker in early phase clinical trials of novel drugs in development by permitting early detection of treatment-response signals that may help avoid late-stage attrition.

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

Little is known about the effect of lumbar intervertebral disc herniation (LDH) on lumbar bone mineral density (BMD), and few previous studies have used quantitative computed tomography (QCT) to assess whether the staging of LDH correlates with lumbar vertebral trabecular volumetric bone mineral density (Trab.vBMD). To explore the relationship between lumbar Trab.vBMD and LDH, seven hundred and fifty-four healthy participants aged 20-60 years were enrolled in the study from an ongoing study on the degeneration of the spine and knee between June 2014 and 2017. QCT was used to measure L2-4 Trab.vBMD and lumbar spine magnetic resonance images (MRI) were performed to assess the incidence of disc herniation. After 9 exclusions, a total of 322 men and 423 women remained. The men and women were divided into younger (age 20-39 years) and older (age 40-60 years) groups and further into those without LDH, with a single LDH segment, and with ≥2 segments. Covariance analysis was used to adjust for the effects of age, BMI, waistline, and hipline on the relationship between Trab.vBMD and LDH. Forty-one younger men (25.0%) and 59 older men (37.3%) had at least one LDH segment. Amongst the women, the numbers were 46 (22.5%) and 80 (36.4%), respectively. Although there were differences in the characteristics data between men and women, the difference in Trab.vBMD between those without LDH and those with single and ≥2 segments was not statistically significant ( p > 0.05). These results remained not statistically significant after further adjusting for covariates ( p > 0.05). No associations between lumbar disc herniation and vertebral trabecular volumetric bone mineral density were observed in either men or women.

Opportunistic screening for osteoporosis can be performed using low-dose computed tomography (LDCT) imaging obtained for other clinical indications. In this study we explored the CT-derived bone mineral density (BMD) and prevalence of osteoporosis from thoracic LDCT in a large population cohort of Chinese men and women. A total of 69,095 adults (40,733 men and 28,362 women) received a thoracic LDCT scan for the purpose of lung cancer screening between 2018 and 2019, and data were obtained for analysis from the China Biobank Project, a prospective nationwide multicenter population study. Lumbar spine (L 1 -L 2 ) trabecular volumetric bone mineral density (vBMD) was derived from these scans using quantitative computed tomography (QCT) software and the American College of Radiology QCT diagnostic criteria for osteoporosis were applied. Geographic regional differences in the prevalence of osteoporosis were assessed and the age-standardized, population prevalence of osteoporosis in Chinese men and women was estimated from the 2010 China census. The prevalence of osteoporosis by QCT for the Chinese population aged >50 years was 29.0% for women and 13.5% for men, equating to 49.0 million and 22.8 million, respectively. In women, this rate is comparable to estimates from dual-energy X-ray absorptiometry (DXA), but in men, the prevalence is double. Prevalence varied geographically across China, with higher rates in the southwest and lower rates in the northeast. Trabecular vBMD decreased with age in both men and women. Women had higher peak trabecular vBMD (185.4 mg/cm 3 ) than men (176.6 mg/cm 3 ) at age 30 to 34 years, but older women had lower trabecular vBMD (62.4 mg/cm 3 ) than men (92.1 mg/cm 3 ) at age 80 years. We show that LDCT-based opportunistic screening could identify large numbers of patients with low lumbar vBMD, and that future cohort studies are now required to evaluate the clinical utility of such screening in terms of fracture prevention and supporting national health economic analyses. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).., (© 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)

Background: Muscle weakness is a key factor in the increase risk of falls and might also play a significant role in the increase of risk of hip fracture. Computed tomography-measured muscle size and muscle density are well-established imaging biomarkers used in studies of physical function, frailty or cancer, but limited to hip fracture. In particular, it is warranted to have a better understanding of the performance of muscle size and density in the discrimination of acute hip fractures. We also aim to determine age-related differences of muscle size and density in healthy controls and hip fracture patients., Methods: Four hundred thirty-eight low-energy acute hip fracture cases and 316 healthy controls from the China Action on Spine and Hip Status study were included in the study. Muscle cross-sectional area and density were measured for the gluteus maximus and gluteus medius and minimus. Areal bone mineral density (aBMD) of the femoral neck and total hip was measured. Using propensity score matching, we generated three samples with cases and controls matched for age, body mass index, and gender: femoral neck fracture (FNF), intertrochanteric fracture (ITF), and any hip fracture vs. controls, respectively., Results: Handgrip strength, gluteus muscle area and density, and bone parameters of the matched hip fracture groups were lower than those of the correspondence control groups, respectively (P < 0.05). The univariate analysis showed that associations of aBMD with FNF and with ITF were significantly weaker than associations between fracture and muscle parameters. Gluteus medius and minimus muscle density showed the highest areas under the curve (AUC) with FNF (0.88, 95% confidence interval, 0.85-0.92) and trochanteric fracture (0.95, 95% confidence interval, 0.92-0.97). The model including all muscle and bone parameters provided the highest AUC (FNF: AUC 0.912; ITF: AUC 0.958), and AUC results of another selected model without muscle density showed that association with fracture significantly dropped (FNF: AUC 0.755; ITF: AUC 0.858). Separate results for the two age groups younger and older than 70 years showed no age-related significant differences in discriminate models., Conclusions: Muscle density performs better than aBMD from hip computed tomography X-ray absorptiometry and muscle size in discrimination of hip fracture. Combination of aBMD and muscle density provided the best discrimination. The integration of muscle assessments may trigger a paradigm shift in hip fracture prediction. Gluteus muscle density should also be evaluated as treatment outcome., (© 2020 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Background and Purpose: Muscle weakness and bone fragility are both associated with hip fracture. In general, muscle contractions create forces to the bone, and bone strength adapts to mechanical loading through changes in bone architecture and mass. However, the relationship between impairment of muscle and bone function remain unclear. In particular, the associations of muscle with properties of proximal femur cortical and trabecular bone are still not well understood. The aim of this study was to explore the associations of hip/thigh muscle density (CT attenuation value in Hounsfield units) and size with cortical and trabecular bone mineral density (BMD) of the proximal femur. Materials and Methods: Three-dimensional quantitative computed tomography (QCT) imaging of the lumber, hip and mid-thigh was performed in a total of 301 participants (mean age 68.4 ± 6.1 years, 194 women and 107 men) to derive areal BMD (aBMD) and volumetric BMD (vBMD). Handgrip strength (HGS) and the Timed Up and Go (TUG) test were also performed. From the CT images, cross-sectional area (CSA), and density were determined for the gluteus maximus muscle (G.MaxM), trunk muscle at the vertebrae L2 level, and mid-thigh muscle. Multivariate generalized linear models were applied to assess associations. Results: Total hip (TH) aBMD was associated significantly with G.MaxM CSA (men: P = 0.042; women: P < 0.001) and density (men: P = 0.012; women: P = 0.043). In women, 0.035 cm 2 of mid-thigh CSA (95% CI, 0.014-0.057; P = 0.002) increased per SD increase in TH aBMD, but this significance was not observed in men ( P = 0.095). Trunk muscle density and CSA were not associated with proximal femur BMD. The associations of hip/thigh muscle parameters with femoral neck BMD were weaker than those with trochanter and intertrochanter BMD. Furthermore, compared to muscle density, muscle CSA showed better associations with vBMD. G.MaxM CSA was associated with trochanter (TR) Cort. vBMD in men (β, 19.898; 95% CI, 0.924-38.871; P = 0.040) and in women (β, 15.426; 95% CI, 0.893-29.958; P = 0.038). Handgrip strength was only associated with TR aBMD (β, 0.038; 95% CI, 0.006-0.070; P = 0.019) and intertrochanter aBMD (β, 0.049; 95% CI, 0.009-0.090; P = 0.016) in men. Conclusions: We observed positive associations of the gluteus and thigh muscle size with proximal femur volumetric BMD. Specifically, the gluteus maximus muscle CSA was associated with trochanter cortical vBMD in both men and women., (Copyright © 2020 Yin, Xu, Wang, Li, Zhao, Su, Sun, Liu, Yang, Yu, Blake, Wu, Veldhuis-Vlug, Cheng, Hind and Engelke.)

Background Although chemical shift-encoded (CSE) MRI proton density fat fraction (PDFF) is the current noninvasive reference standard for liver fat quantification, the liver is more frequently imaged with CT. Purpose To validate quantitative CT measurements of liver fat against the MRI PDFF reference standard. Materials and Methods In this prospective study, 400 healthy participants were recruited between August 2015 and July 2016. Each participant underwent same-day abdominal unenhanced quantitative CT with a calibration phantom and CSE 3.0-T MRI. CSE MRI liver fat measurements were used to calibrate an equation to adjust CT fat measurements and put them on the PDFF measurement scale. CT and PDFF liver fat measurements were plotted as histograms, medians, and interquartile ranges compared; scatterplots and Bland-Altman plots obtained; and Pearson correlation coefficients calculated. Receiver operating characteristic curves including areas under the curve were evaluated for mild (PDFF, 5%) and moderate (PDFF, 14%) steatosis thresholds for both raw and adjusted CT measurements. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated. Results Four hundred volunteers (mean age, 52.6 years ± 15.2; 227 women) were evaluated. MRI PDFF measurements of liver fat ranged between 0% and 28%, with 41.5% (166 of 400) of participants with PDFF greater than 5%. Both raw and adjusted quantitative CT values correlated well with MRI PDFF ( r 2 = 0.79; P < .001). Bland-Altman analysis of adjusted CT values showed no slope or bias. Both raw and adjusted CT had areas under the receiver operating characteristic curve of 0.87 and 0.99, respectively, to identify participants with mild (PDFF, >5%) and moderate (PDFF, >14%) steatosis, respectively. The sensitivity, specificity, positive predictive value, and negative predictive value for unadjusted CT was 75.9% (126 of 166), 85.0% (199 of 234), 78.3% (126 of 161), and 83.3% (199 of 239), respectively, for PDFF greater than 5%; and 84.8% (28 of 33), 98.4% (361 of 367), 82.4% (28 of 34), and 98.6% (361 of 366), respectively, for PDFF greater than 14%. Results for adjusted CT were mostly identical. Conclusion Quantitative CT liver fat exhibited good correlation and accuracy with proton density fat fraction measured with chemical shift-encoded MRI. © RSNA, 2019 Online supplemental material is available for this article.

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.

Our purpose was to establish whether noninvasive measurement of changes in 18 F-fluoride metabolic flux to bone mineral (K i ) by PET/CT can provide incremental value in response assessment of bone metastases in breast cancer compared with SUV max and SUV mean Methods: Twelve breast cancer patients starting endocrine treatment for de novo or progressive bone metastases were included. Static 18 F-fluoride PET/CT scans were acquired 60 min after injection, before and 8 wk after commencing treatment. Venous blood samples were taken at 55 and 85 min after injection to measure plasma 18 F-fluoride activity concentrations, and K i in individual bone metastases was calculated using a previously validated method. Percentage changes in K i , SUV max , and SUV mean were calculated from the same index lesions (≤5 lesions) from each patient. Clinical response up to 24 wk, assessed in consensus by 2 experienced oncologists masked to PET imaging findings, was used as a reference standard. Results: Of the 4 patients with clinically progressive disease (PD), mean K i significantly increased (>25%) in all, SUV max in 3, and SUV mean in 2. Of the 8 non-PD patients, K i decreased or remained stable in 7, SUV max in 5, and SUV mean in 6. A significant mean percentage increase from baseline for K i , compared with SUV max and SUV mean , occurred in the 4 patients with PD (89.7% vs. 41.8% and 43.5%, respectively; P < 0.001). Conclusion: After 8 wk of endocrine treatment for bone-predominant metastatic breast cancer, K i more reliably differentiated PD from non-PD than did SUV max and SUV mean , probably because measurement of SUV underestimates fluoride clearance by not considering changes in input function., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: [ 18 F] sodium fluoride PET/CT provides quantitative measures of bone metabolic activity expressed by the parameters standardised uptake value (SUV) and bone plasma clearance ( K i ) that correlate with measurements of bone formation rate obtained by bone biopsy with double tetracycline labelling. Both SUV and K i relate to the tracer uptake in each millilitre of tissue. In general, the bone region of interest (ROI) includes both mineralised bone {generally with a high concentration of [ 18 F]NaF} and bone marrow (with a much lower concentration), suggesting that correcting SUV and K i for volumetric bone mineral density (vBMD) and measuring them with respect to the tracer uptake in each gram of bone mineral might improve the correlation with the findings of bone biopsy. As a first test of this hypothesis, we looked for positive correlations between SUV and K i values with CT and DXA bone mineral density (BMD) parameters measured in the same ROI., Methods: A retrospective reanalysis was performed of 63 lumbar spine [ 18 F]NaF PET/CT scans acquired in four earlier studies. The quantitative PET parameters SUV and K i were measured in L1-L4 and Hounsfield units (HU) measured on the CT scans in the same ROI. Spine BMD data was also obtained from DXA scans in the form of areal BMD and used to derive the bone mineral apparent density (BMAD, an estimate of vBMD). Scatter plots were drawn of SUV and K i against HU, BMAD and areal BMD and the Spearman rank correlation coefficients derived for each plot., Results: All correlations were positive and statistically significant. Correlations were highest for HU (SUV: R S =0.513, P<0.0001; K i : R S =0.429, P=0.0005) and lowest for areal BMD (SUV: R S =0.353, P=0.005; K i : R S =0.274, P=0.03)., Conclusions: The results demonstrate significant positive correlations between SUV and K i and vBMD measurements in the form of HU from CT or BMAD and areal BMD from DXA. These findings justify further exploration of the relationship between SUV and K i [ 18 F]NaF PET/CT measurements and CT or DXA measurements of vBMD to examine whether normalization for bone density might improve their correlation with bone metabolic activity as measured by bone biopsy., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

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.

Background: Studies of soft tissue composition using computed tomography (CT) scans are often semi-quantitative and based on Hounsfield units (HU) measurements that have not been calibrated with a quantitative CT (QCT) phantom. We describe a study to establish the water (H 2 O) and dipotassium hydrogen phosphate (K 2 HPO 4 ) basis set equivalent densities of fat and fat-free liver tissue. With this information liver fat can be accurately measured from any abdominal CT scan calibrated with a suitable phantom., Methods: Liver fat content was measured by comparing single-energy QCT (SEQCT) HU measurements of the liver with predicted HU values for fat and fat-free liver tissue calculated from their H 2 O and K 2 HPO 4 equivalent densities and calibration data from a QCT phantom. The equivalent densities of fat were derived from a listing of its constituent fatty acids, and those of fat-free liver tissue from a dual-energy QCT (DEQCT) study performed in 14 healthy Chinese subjects. This information was used to calculate liver fat from abdominal SEQCT scans performed in a further 541 healthy Chinese subjects (mean age 62 years; range, 31-95 years) enrolled in the Prospective Urban Rural Epidemiology (PURE) Study., Results: The equivalent densities of fat were 941.75 mg/cm 3 H 2 O and -43.72 mg/cm 3 K 2 HPO 4 , and for fat-free liver tissue 1,040.13 mg/cm 3 H 2 O and 21.34 mg/cm 3 K 2 HPO 4 . Liver fat in the 14 subjects in the DEQCT study varied from 0-17.9% [median: 4.5%; interquartile range (IQR): 3.0-7.9%]. Liver fat in the 541 PURE study subjects varied from -0.3-29.9% (median: 4.9%; IQR: 3.4-6.9%)., Conclusions: We have established H 2 O and K 2 HPO 4 equivalent densities for fat and fat-free liver tissue that allow a measurement of liver fat to be obtained from any abdominal CT scan acquired with a QCT phantom. Although radiation dose considerations preclude the routine use of QCT to measure liver fat, the method described here facilitates its measurement in patients having CT scans performed for other purposes. Further studies comparing the results with magnetic resonance (MR) measurements of liver fat are required to validate the method as a useful clinical tool., Competing Interests: Conflicts of Interest: JK Brown is a stockholder and employee of Mindways Software, Inc. The other authors have no conflicts of interest to declare.

Objective: To determine comparative fracture risk in HIV patients compared with uninfected controls., Design: A randomised cross-sectional study assessing bone mineral density (BMD), fracture history and risk factors in the 2 groups., Setting: Hospital Outpatients., Subbbjects: 222 HIV infected patients and an equal number of age-matched controls., Assessments: Fracture risk factors were assessed and biochemical, endocrine and bone markers measured. BMD was assessed at hip and spine. 10-year fracture probability (FRAX) and remaining lifetime fracture probability (RFLP) were calculated., Main Outcome Measures: BMD, and history of fractures., Results: Reported fractures occurred more frequently in HIV than controls, (45 vs. 16; 20.3 vs. 7%; OR=3.27; p=0.0001), and unsurprisingly in this age range, non-fragility fractures in men substantially contributed to this increase. Osteoporosis was more prevalent in patients with HIV (17.6% vs. 3.6%, p<0.0001). BMD was most reduced, and predicted fracture rates most increased, at the spine. Low BMD was associated with antiretroviral therapy (ART), low body mass index and PTH. 10-year FRAX risk was <5% for all groups. RLFP was greater in patients with HIV (OR=1.22; p=0.003) and increased with ART (2.4 vs. 1.50; OR= 1.50; p=0.03)., Conclusions: The increased fracture rate in HIV patients in our relatively youthful population is partly driven by fractures, including non-fragility fractures, in men. Nonetheless, these findings may herald a rise in osteoporotic fractures in HIV patients. An appropriate screening and management response is required to assess these risks and identify associated lifestyle factors that are also associated with other conditions such as cardiovascular disease and diabetes.

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.)

Unlabelled: The planning of research studies requires an understanding of the minimum number of subjects required. The aim of this study was to evaluate different methods of analyzing (18)F-fluoride PET ((18)F(-) PET) dynamic spine scans to find the approach that requires the smallest sample size to detect a statistically significant response to treatment., Methods: Eight different approaches to (18)F(-) PET analysis (3 variants of the Hawkins 3-tissue compartmental model, 3 variants of spectral analysis, deconvolution, and Patlak analysis) were used to evaluate the fluoride plasma clearance to bone mineral (K(i)). Standardized uptake values (SUVs) were also studied. Data for 20 women who had (18)F(-) PET spine scans at 0, 6, and 12 mo after stopping long-term bisphosphonate treatment were used to compare precision errors. Data for 18 women who had scans at baseline and 6 mo after starting teriparatide treatment were used to compare response to treatment., Results: The 4 approaches that fitted the rate constant k(4) describing the reverse flow of (18)F from bone as a free variable showed close agreement in K(i) values, with correlation coefficients greater than 0.97. Their %CVs were 14.4%-14.8%, and treatment response to teriparatide was 23.2%-23.8%. The 3 methods that assumed k(4) = 0 gave K(i) values 20%-25% lower than the other methods, with correlation coefficients of 0.83-0.94, percentage coefficients of variation (%CVs) of 12.9%-13.3%, and treatment response of 25.2%-28.3%. A Hawkins model with k(4) = 0.01 min(-1) did not perform any better (%CV, 14.2%; treatment response, 26.1%). Correlation coefficients between SUV and the different K(i) methods varied between 0.60 and 0.65. Although SUV gave the best precision (%CV, 10.1%), the treatment response (3.1%) was not statistically significant., Conclusion: Methods that calculated K(i) assuming k(4) = 0 required fewer subjects to demonstrate a statistically significant response to treatment than methods that fitted k(4) as a free variable. Although SUV gave the smallest precision error, the absence of any significant changes make it unsuitable for examining response to treatment in this study.

Teriparatide increases skeletal mass, bone turnover markers, and bone strength, but local effects on bone tissue may vary between skeletal sites. We used positron emission tomography (PET) to study (18)F-fluoride plasma clearance (K(i)) at the spine and standardized uptake values (SUVs) at the spine, pelvis, total hip, and femoral shaft in 18 postmenopausal women with osteoporosis. Subjects underwent a 1-hour dynamic scan of the lumbar spine and a 10-minute static scan of the pelvis and femurs at baseline and after 6 months of treatment with 20 µg/day teriparatide. Blood samples were taken to derive the arterial input function and lumbar spine K(i) values evaluated using a three-compartment model. SUVs were calculated for the spine, pelvis, total hip, and femoral shaft. After 6 months treatment with teriparatide, spine K(i) values increased by 24% (p = .0003), while other model parameters were unchanged except for the fraction of tracer going to bone mineral (k(3)/[k(2) + k(3)]), which increased by 23% (p = .0006). In contrast to K(i) , spine SUVs increased by only 3% (p = .84). The discrepancy between changes in K(i) and SUVs was explained by a 20% decrease in (18)F(-) plasma concentration. SUVs increased by 37% at the femoral shaft (p = .0019), 20% at the total hip (p = .032), and 11% at the pelvis (p = .070). Changes in bone turnover markers and BMD were consistent with previous trials. We conclude that the changes in bone formation rate during teriparatide treatment as measured by (18)F(-) PET differ at different skeletal sites, with larger increases in cortical bone than at trabecular sites., (Copyright © 2011 American Society for Bone and Mineral Research.)

Teriparatide (TPTD) increases skeletal mass, bone turnover markers, and bone strength, but in vivo effects at individual skeletal sites have not been characterized. Quantitative radionuclide imaging studies reflect bone blood flow and osteoblast activity to assess regional changes in bone metabolism. Changes in bone plasma clearance using technetium-99m methylene diphosphonate ((99m)Tc-MDP) were quantified and correlated with changes in bone turnover markers in 10 postmenopausal women with osteoporosis. Subjects underwent bone scintigraphy at baseline and 3 and 18 months after initiating TPTD 20 microg/day subcutaneously. Subjects were injected with 600 MBq (99m)Tc-MDP, and whole-body bone scan images were acquired at 10 minutes and 1, 2, 3, and 4 hours. Multiple blood samples were taken between 5 minutes and 4 hours after treatment, and free (99m)Tc-MDP was measured using ultrafiltration. The Patlak plot method was used to evaluate whole-skeleton (99m)Tc-MDP plasma clearance (K(bone)) and derive regional bone clearance for the calvarium, mandible, spine, pelvis, and upper and lower extremities using gamma camera counts. Bone turnover markers were measured at baseline and 3, 12, and 18 months. Median increases from baseline in whole-skeleton K(bone) were 22.3% (p = .004) and 33.7% (p = .002) at 3 and 18 months, respectively. Regional K(bone) values were increased significantly in all six subregions at 3 months and in all subregions except the pelvis at 18 months. Bone markers were increased significantly from baseline at 3 and 18 months and correlated significantly with whole-skeleton K(bone). This is the first study showing a direct metabolic effect of TPTD at different skeletal sites in vivo, as measured by tracer kinetics., ((c) 2010 American Society for Bone and Mineral Research.)

Unlabelled: (18)F-Fluoride PET allows noninvasive evaluation of regional bone metabolism and has the potential to become a useful tool for assessing patients with metabolic bone disease and evaluating novel drugs being developed for these diseases. The main PET parameter of interest, termed K(i), reflects regional bone metabolism. The aim of this study was to compare the long-term precision of (18)F-fluoride PET with that of biochemical markers of bone turnover assessed over 6 mo., Methods: Sixteen postmenopausal women with osteoporosis or significant osteopenia and a mean age of 64 y underwent (18)F-fluoride PET of the lumbar spine and measurements of biochemical markers of bone formation (bone-specific alkaline phosphatase and osteocalcin) and bone resorption (urinary deoxypyridinoline) at baseline and 6 mo later. Four different methods for analyzing the (18)F-fluoride PET data were compared: a 4k 3-compartmental model using nonlinear regression analysis (K(i-4k)), a 3k 3-compartmental model using nonlinear regression analysis (K(i-3k)), Patlak analysis (K(i-PAT)), and standardized uptake values., Results: With the exception of a small but significant decrease in K(i-3k) at 6 mo, there were no significant differences between the baseline and 6-mo values for the PET parameters or biochemical markers. The long-term precision, expressed as the coefficient of variation (with 95% confidence interval in parentheses), was 12.2% (9%-19%), 13.8% (10%-22%), 14.4% (11%-22%), and 26.6% (19%-40%) for K(i-3k), K(i-PAT), mean standardized uptake value, and K(i-4k), respectively. For comparison, the precision of the biochemical markers was 10% (7%-15%), 18% (13%-27%), and 14% (10%-21%) for bone-specific alkaline phosphatase, osteocalcin, and urinary deoxypyridinoline, respectively. Intraclass correlation between the baseline and 6-mo values ranged from 0.44 for K(i-4k) to 0.85 for K(i-3k). No significant correlation was found between the repeated mean standardized uptake value measurements., Conclusion: The precision and intraclass correlation observed for K(i-3k) and K(i-PAT) was equivalent to that observed for biochemical markers. This study provided initial data on the long-term precision of (18)F-fluoride PET measured at the lumbar spine, which will aid in the accurate interpretation of changes in regional bone metabolism in response to treatment.

Human height is a highly heritable and complex trait but finding important genes has proven more difficult than expected. One reason might be the composite measure of height which may add heterogeneity and noise. The aim of this study was to conduct a genome-wide linkage scan to identify quantitative trait loci (QTL) for lengths of spine, femur, tibia, humerus and radius. These were investigated as alternative measures for height in a large, population-based twin sample with the potential to find genes underlying bone size and bone diseases. 3,782 normal Caucasian females, 18-80 years old, with whole body dual energy X-ray absorptiometry (DXA) images were used. A novel and reproducible method, linear pixel count (LPC) was used to measure skeletal sizes on DXA images. Intraclass correlations and heritability estimates were calculated for lengths of spine, femur, tibia, humerus and radius on monozygotic (MZ; n = 1,157) and dizygotic (DZ; n = 2,594) twins. A genome-wide linkage scan was performed on 2000 DZ twin subjects. All skeletal sites excluding spine were highly correlated. Intraclass correlations showed results for MZ twins to be significantly higher than DZ twins for all traits. Heritability results were as follows: spine, 66%; femur, 73%; tibia, 65%; humerus, 57%; radius, 68%. Results showed reliable evidence of highly suggestive linkage on chromosome 5 for spine (LOD score = 3.0) and suggestive linkage for femur (LOD score = 2.19) in the regions of 105cM and 155cM respectively. We have shown strong heritability of all skeletal sizes measured in this study and provide preliminary evidence that spine length is linked to the chromosomal region 5q15-5q23.1. Bone size phenotype appears to be more useful than traditional height measures to uncover novel genes. Replication and further fine mapping of this region is ongoing to determine potential genes influencing bone size and diseases affecting bone.

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

Background: Skeletal ratios and bone lengths are widely used in anthropology and forensic pathology and hip axis length is a useful predictor of fracture. The aim of this study was to show that skeletal ratios, such as length of femur to height, could be accurately measured from a DXA (dual energy X-ray absorptiometry) image., Methods: 90 normal Caucasian females, 18-80 years old, with whole body DXA data were used as subjects. Two methods, linear pixel count (LPC) and reticule and ruler (RET) were used to measure skeletal sizes on DXA images and compared with real clinical measures from 20 subjects and 20 x-rays of the femur and tibia taken in 2003., Results: Although both methods were highly correlated, the LPC inter- and intra-observer error was lower at 1.6% compared to that of RET at 2.3%. Both methods correlated positively with real clinical measures, with LPC having a marginally stronger correlation coefficient (r2 = 0.94; r2 = 0.84; average r2 = 0.89) than RET (r2 = 0.86; r2 = 0.84; average r2 = 0.85) with X-rays and real measures respectively. Also, the time taken to use LPC was half that of RET at 5 minutes per scan., Conclusion: Skeletal ratios can be accurately and precisely measured from DXA total body scan images. The LPC method is easy to use and relatively rapid. This new phenotype will be useful for osteoporosis research for individuals or large-scale epidemiological or genetic studies.

Dual energy x ray absorptiometry (DXA) scans to measure bone mineral density (BMD) at the spine and hip have an important role in the evaluation of individuals at risk of osteoporosis, and in helping clinicians advise patients about the appropriate use of antifracture treatment. Compared with alternative bone densitometry techniques, hip and spine DXA examinations have a number of advantages that include a consensus that BMD results can be interpreted using the World Health Organization T-score definition of osteoporosis, a proven ability to predict fracture risk, proven effectiveness at targeting antifracture therapies, and the ability to monitor response to treatment. This review discusses the evidence for these and other clinical aspects of DXA scanning, including its role in the new WHO algorithm for treating patients on the basis of their individual fracture risk.

Unlabelled: Strontium ranelate is a new treatment for osteoporosis that results in large increases in BMD, much of which is an artefact caused by high bone strontium content. We used clinical trial data and a model of long-term strontium kinetics to estimate the effect of past strontium treatment on future BMD measurements., Introduction: The oral administration of strontium ranelate causes a clinically significant overestimation of BMD because of the high attenuation of X-rays by strontium atoms in bone. As more patients are treated with strontium ranelate, questions will arise about the correct interpretation of their future BMD measurements. We performed a theoretical study to calculate the long-term effect of strontium treatment on BMD and establish the duration of past treatment for which the remaining bone strontium content (BSC) has a negligible effect on BMD., Materials and Methods: The BMD changes measured at the spine and hip during strontium ranelate treatment were interpolated from clinical trial data. The long-term retention of strontium in bone was estimated using the International Commission on Radiological Protection (ICRP) strontium retention function modified for use in postmenopausal women. Estimates of the strontium BMD artefact after treatment has stopped were performed on the assumption that the BSC effect accounts for 75% of the total measured BMD change at 3 years., Results: If 75% of the BMD changes are explained by BSC, in the average patient, 3-year treatment leads to a spine BMD artefact of 11.2%, decreasing to 3.8% 10 years after stopping treatment. The BMD artefacts at the total hip and femoral neck sites are smaller by factors of 0.65 and 0.53, respectively. If pre- and post-therapy BMD measurements are available, these predictions can be tailored to the individual patient. On average, 6-month treatment is required for the spine BMD artefact to exceed 3%, the figure adopted as the maximum BMD change caused by bone strontium that has a negligible effect on scan interpretation. Ten years after stopping treatment, 28 months of treatment are required for the residual BMD artefact to still exceed the 3% threshold., Conclusions: Strontium ranelate treatment lasting for >6 months can affect BMD measurements for many years afterward.

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

Strontium ranelate is a new orally administered agent for the treatment of women with postmenopausal osteoporosis that reduces the risk of vertebral and hip fractures. Evidence for the safety and efficacy of strontium ranelate comes from two large multinational trials, the SOTI (Spinal Osteoporosis Therapeutic Intervention) and TROPOS (Treatment Of Postmenopausal Osteoporosis) studies. The SOTI study evaluated vertebral fracture prevention in 1649 postmenopausal women with a mean age of 69 y. The subjects all had at least one previous vertebral fracture and a low spine bone mineral density (BMD) (equivalent to a Hologic spine T-score below -1.9). The strontium ranelate group had a 41% lower risk of a new vertebral fracture than the placebo group over the three-year study period (relative risk [RR] = 0.59; 95% confidence interval [CI]: 0.48-0.73; p < 0.001). The TROPOS study evaluated non-vertebral fracture prevention in 5091 postmenopausal women with a mean age of 77 y. The subjects were aged 74 y and over (or 70-74 y with one additional risk factor) and a low femoral neck BMD (equivalent to an NHANES III [Third National Health and Nutrition Examination Survey] T-score below -2.2). Over the three-year study period there was a 16% reduction in all non-vertebral fractures (RR = 0.84; 95% CI 0.702-0.995; p = 0.04) and a 19% reduction at the principal sites for non-vertebral fractures. The TROPOS study was not powered to investigate hip fracture risk. However, in a high risk group of women aged 74 y and over and with an NHANES III femoral neck T-score less than -2.4 there was a 36% reduction in hip fracture risk (RR = 0.64; 95% CI: 0.412-0.997; p = 0.046). The overall incidence of adverse events did not differ significantly from placebo and were generally mild and transient, the most common being nausea and diarrhea. Strontium ranelate is a useful addition to the range of anti-fracture treatments available for treating postmenopausal women with osteoporosis and is the only treatment proven to be effective at preventing both vertebral and hip fractures in women aged 80 y and over.

Unlabelled: Regional bone metabolism measured using 18F-fluoride PET was assessed in 72 postmenopausal women classified as normal, osteopenic, or osteoporotic. Lower values of regional bone formation activity at the lumbar spine were seen in osteoporotic women, whereas global markers of bone formation were significantly increased., Introduction: Evaluations of global bone remodeling have revealed that increased bone turnover is a feature of patients with osteoporosis. The noninvasive functional imaging technique of 18F-fluoride positron emission tomography (PET) allows the direct quantitative assessment of bone metabolism at specific sites in the skeleton, including the clinically important site of the lumbar spine., Materials and Methods: The aim of this study was to compare regional skeletal kinetics in 72 postmenopausal women (mean age, 61 years) classified as normal, osteopenic, or osteoporotic according to their BMD T score at the lumbar spine. Each woman had a dynamic PET scan of the lumbar spine after injection of 90 MBq 18F-fluoride ion and measurements of biochemical markers of bone formation and resorption. The arterial plasma input function was derived using aorta arterial activity from the PET image. Time-activity curves were obtained by placing regions of interest over the lumbar vertebrae. A three-compartmental model was used to calculate bone blood flow (K1) and the net plasma clearance of tracer to bone mineral (Ki), reflecting regional osteoblastic activity (ml/minutes/ml). Rate constants k2, k3, and k4, which describe transport between plasma, the extracellular fluid (ECF) compartment, and the bone mineral compartment, were also measured., Results: The net uptake of fluoride to the bone mineral compartment (Ki) was significantly lower in the osteoporotic group compared with both the osteopenic and normal groups, with a mean difference of 0.005 ml/minutes/ml (16.7%). The fraction of the tracer in the extravascular tissue space that underwent specific binding to bone mineral (k3/k2 + k3) was also significantly reduced in the women classified as osteoporotic. In contrast, levels of bone-specific alkaline phosphatase (BSALP) were significantly higher in the osteoporotic group compared with the normal and osteopenic groups by 35% and 27%, respectively. A significant negative correlation (r = -0.41) was observed between levels of BSALP and the fraction of the tracer that underwent specific binding to bone mineral., Conclusion: Lower values of Ki, a measurement of regional bone formation activity, were seen in women classified as osteoporotic, whereas levels of BSALP, a measure of global bone formation, were significantly increased. These findings are suggestive of increased global skeletal bone turnover in women with postmenopausal osteoporosis but with relatively reduced regional bone formation at the predominantly trabecular site of the lumbar spine.

Background: More elderly patients are being treated with chemotherapy. Reliable and accurate measures of renal function are needed to obtain predictable, safe and effective exposure to renally excreted drugs. The Jelliffe, Cockroft-Gault and Wright formulae have been used to evaluate renal function, although they have not been validated in elderly oncology patients. We performed a retrospective evaluation of these formulae using the [51Cr]-ethylenediamine tetraacetic acid ([51Cr]-EDTA) method of measuring glomerular filtration rate (GFR) as the 'gold standard'., Patients and Methods: Inclusion criteria were age > or = 70 years and serum creatinine <250 micromol/l, performed within 4 weeks of glomerular filtration rate (GFR) measurement. Creatinine clearance was calculated using the Cockroft-Gault, Jelliffe and Wright formulae. The precision and accuracy of the three formulae were compared with the gold standard., Results: Two hundred and twenty-five patients were evaluated: median age, 74 years (range 70-89); males, 108; females, 117; median creatinine, 84 micromol/l (range 44-186). Correlation coefficients of the Jelliffe, Cockroft-Gault and Wright formulae were similar. In the specific GFR ranges of 50-70, 70-90 and 90-120 ml/min, the bias [mean percentage error (MPE)] was +8%, -4% and -13%, respectively. The degree of bias was greater with the Cockroft-Gault and Jelliffe formulae across the same range of GFR with the MPE being -15%, -25%, -32% and -12%, -19% and -23%, respectively. All three formulae have reduced precision and greater bias at the extremes of GFR., Conclusions: The Wright formula is the most accurate, precise and least biased formula for the calculation of GFR in elderly patients with a GFR >50 ml/min. These results allow the physician to make a decision regarding the use of the formula based on an expected degree of bias.

Unlabelled: The effect of risedronate on bone metabolism at the lumbar spine was assessed in 18 women who had a 18F-fluoride PET scan at baseline and after 6 months of therapy. The net plasma clearance of fluoride to bone mineral reflecting osteoblastic activity decreased significantly after therapy., Introduction: Quantitative radionuclide studies of bone reflect bone blood flow and regional osteoblastic activity, and the latter should change after treatment with a bisphosphonate, although this has not been previously demonstrated. The aim of this study was to examine regional 18F-fluoride kinetics in the lumbar spine measured by 18F-fluoride positron emission tomography (PET) before and after treatment with risedronate., Materials and Methods: Eighteen women, with a mean age of 67.0 years and a T-score of less than -2 at the spine or hip, had a dynamic PET scan of the lumbar spine after the injection of 90 MBq 18F-fluoride ion at baseline and 6 months after commencing risedronate therapy. The arterial plasma input function was derived using aorta arterial activity from the PET image. Time-activity curves were measured by placing regions of interest over the lumbar vertebrae. A three-compartmental model was used to calculate bone blood flow (K(1)) and the net plasma clearance of tracer to bone mineral (K(i)). Rate constants k(2), k(3), and k(4), which describe transport between plasma, the extracellular fluid (ECF) compartment, and the bone mineral compartment, respectively, were also measured., Results: Mean vertebral K(i) decreased significantly by 18.4% from baseline (3.32 x 10(-2) ml/min/ml) to 6 months post-treatment (2.71 x 10(-2) ml/min/ml; p = 0.04). This decrease was similar in magnitude to the decrease observed for bone-specific alkaline phosphatase, a marker of bone formation. There was no significant difference in K(1) from baseline (1.49 x 10(-1) ml/min/ml) to 6 months after treatment (1.38 x 10(-1) ml/min/ml; p > 0.05). There was a significant increase in k(2), reflecting the reverse transport of fluoride from the extravascular tissue compartment to plasma, after 6 months of treatment (2.90 x 10(-1)/min versus 4.43 x 10(-1)/min; p = 0.01). No significant changes were seen for k(3) or k(4). There was a significant decrease from baseline in the fraction of tracer in the extravascular tissue space that underwent specific binding to the bone matrix (k(3)/[k(2) + k(3)]), decreasing by 18.1% (p = 0.02)., Conclusion: K(i), the net plasma clearance to bone mineral reflecting regional osteoblastic activity, displayed a significant decrease after 6 months of antiresorptive therapy. This is the first study to show a direct metabolic effect of antiresorptive therapy on skeletal kinetics at the clinically important site of the lumbar spine. The use of 18F-fluoride PET may provide a useful noninvasive tool to assess novel treatments currently being developed for osteoporosis.