Effects of high-intensity training on fatty infiltration in paraspinal muscles in elderly males with osteosarcopenia - the randomized controlled FrOST study.

BACKGROUND: Osteosarcopenia is a common geriatric syndrome with an increasing prevalence with age, leading to secondary diseases and complex consequences such as falls and fractures, as well as higher mortality and frailty rates. There is a great need for prevention and treatment strategies. METHODS: In this analysis, we used magnetic resonance imaging (MRI) data from the randomised controlled FrOST trial, which enrolled community-dwelling osteosarcopenic men aged > 72 years randomly allocated to 16 months of twice-weekly high-intensity resistance training (HIRT) or a non-training control group. MR Dixon imaging was used to quantify the effects of HIRT on muscle fat infiltration in the paraspinal muscles, determined as changes in muscle tissue, fat faction and intermuscular adipose tissue (IMAT) in the erector spinae and psoas major muscles. Intention-to-treat analysis with multiple imputation was used to analyse the data set. RESULTS: After 16 months of intervention, 15 men from the HIRT and 16 men from the CG were included in the MRI analysis. In summary, no positive effects on the fat infiltration of the erector spinae and psoas major muscles were observed. CONCLUSIONS: The previously reported positive effects on lumbar spine bone mineral density (BMD) suggest that mechanotransduction induces tropic effects on bone, but that fat infiltration of the erector spinae and psoas major muscles are either irreversible or, for some unknown reason, resistant to exercise. Because of the beneficial effects on spinal BMD, HIRT is still recommended in osteosarcopenic older men, but further research is needed to confirm appropriate age-specific training exercises for the paraspinal muscles. The potential of different MRI sequences to quantify degenerative and metabolic changes in various muscle groups must be better characterized. TRIAL REGISTRATIONS: FrOST was approved by the University Ethics Committee of the Friedrich-Alexander University of Erlangen-Nürnberg (number 67_15b and 4464b) and the Federal Office for Radiation Projection (BfS, number Z 5-2,246,212 - 2017-002). Furthermore, it fully complies with the Declaration of Helsinki and is registered at ClinicalTrials.gov: NCT03453463 (05/03/2018). JAMA 310:2191-2194, 2013.

Assessing muscle-specific potassium concentrations in human lower leg using potassium magnetic resonance imaging.

Noninvasively assessing tissue potassium concentrations (TPCs) using potassium magnetic resonance imaging (39 K MRI) could give valuable information on physiological processes connected to various pathologies. However, because of inherently low 39 K MR image resolution and strong signal blurring, a reliable measurement of the TPC is challenging. The aim of this work was to investigate the feasibility of a muscle-specific TPC determination with a focus on the influence of a varying residual quadrupolar interaction in human lower leg muscles. The quantification accuracy of a muscle-specific TPC determination was first assessed using simulated 39 K MRI data. In vivo 39 K and corresponding sodium (23 Na) MRI data of healthy lower leg muscles (n = 14, seven females) were acquired on a 7-T MR system using a double-resonant 23 Na/39 K birdcage Tx/Rx RF coil. Additional 1 H MR images were acquired on a 3-T MR system and used for tissue segmentation. Quantification of TPC was performed after a region-based partial volume correction (PVC) using five external reference phantoms. Simulations not only underlined the importance of PVC for correctly assessing muscle-specific TPC values, but also revealed the strong impact of a varying residual quadrupolar interaction between different muscle regions on the measured TPC. Using 39 K T2 * decay curves, we found significantly higher residual quadrupolar interaction in tibialis anterior muscle (TA; ωq = 194 ± 28 Hz) compared with gastrocnemius muscle (medial/lateral head, GM/GL; ωq = 151 ± 25 Hz) and soleus muscle (SOL; ωq = 102 ± 32 Hz). If considered in the PVC, TPC in individual muscles was similar (TPC = 98 ± 11/96 ± 14/99 ± 8/100 ± 12 mM in GM/GL/SOL/TA). Comparison with tissue sodium concentrations suggested that residual quadrupolar interactions might also influence the 23 Na MRI signal of lower leg muscles. A TPC determination of individual lower leg muscles is feasible and can therefore be applied in future studies. Considering a varying residual quadrupolar interaction for PVC of 39 K MRI data is essential to reliably assess potassium concentrations in individual muscles.

Opportunistic Screening Techniques for Analysis of CT Scans.

PURPOSE OF REVIEW: Opportunistic screening is a combination of techniques to identify subjects of high risk for osteoporotic fracture using routine clinical CT scans prescribed for diagnoses unrelated to osteoporosis. The two main components are automated detection of vertebral fractures and measurement of bone mineral density (BMD) in CT scans, in which a phantom for calibration of CT to BMD values is not used. This review describes the particular challenges of opportunistic screening and provides an overview and comparison of current techniques used for opportunistic screening. The review further outlines the performance of opportunistic screening. RECENT FINDINGS: A wide range of technologies for the automatic detection of vertebral fractures have been developed and successfully validated. Most of them are based on artificial intelligence algorithms. The automated differentiation of osteoporotic from traumatic fractures and vertebral deformities unrelated to osteoporosis, the grading of vertebral fracture severity, and the detection of mild vertebral fractures is still problematic. The accuracy of automated fracture detection compared to classical radiological semi-quantitative Genant scoring is about 80%. Accuracy errors of alternative BMD calibration methods compared to simultaneous phantom-based calibration used in standard quantitative CT (QCT) range from below 5% to about 10%. The impact of contrast agents, frequently administered in clinical CT on the determination of BMD and on fracture risk determination is still controversial. Opportunistic screening, the identification of vertebral fracture and the measurement of BMD using clinical routine CT scans, is feasible but corresponding techniques still need to be integrated into the clinical workflow and further validated with respect to the prediction of fracture risk.

The effect of ageing on fat infiltration of thigh and paraspinal muscles in men.

BACKGROUND: Myosteatosis, skeletal muscle fat infiltration, is associated with inflammation and fibrosis. The age-related increase of myosteatosis is an important characteristic of sarcopenia and contributes to fragility. AIMS: To investigate the impact of healthy aging on intermuscular adipose tissue (IMAT) and muscle fat fraction (FF) in the thigh and the paraspinal muscles in males. METHODS: In 54 healthy males (age 20-70), all active hobby golfers, magnetic resonance imaging was performed to determine volume of IMAT, volume of muscle tissue (MT) and of percentage of FF. RESULTS: Between ages 20-70, at the thigh, IMAT/MT volume and MT FF increased annually by 2.9% and 1.3%, respectively. At the psoas IMAT/Psoas volume did not change with age. MT FF increased by 1.5% annually. At the erector spinae IMAT/Erector volume decreased by 0.3% and MT FF increased by 2.8% annually. DISCUSSION: With increasing age, in males, thigh muscle atrophied, muscle tissue was partly replaced by adipose tissue and remaining muscle tissue also contained more fat. Similar effects were observed in the erector spinae. The psoas muscle did not atrophy, although MT FF also increased with age. Overall correlations with age were weak to moderate with higher correlations observed in the paraspinal muscles. CONCLUSIONS: Age-related increases of muscle fat infiltration were observed in the thigh and in the spine. Muscle atrophy did not occur in the psoas. In cross-sectional studies, an adjustment of volumetric parameters by muscle volume is advisable when comparing age-dependent results.

Segmentation of the fascia lata and reproducible quantification of intermuscular adipose tissue (IMAT) of the thigh.

OBJECTIVE: To develop a precise semi-automated segmentation of the fascia lata (FL) of the thigh to quantify IMAT volume in T1w MR images and fat fraction (FF) in Dixon MR images. MATERIALS AND METHODS: A multi-step segmentation approach was developed to identify fibrous structures of the FL and combining them into a closed 3D surface. 23 healthy young men with low and 50 elderly sarcopenic men with moderate levels of IMAT were measured by T1w and 6pt Dixon MRI at 3T. 20 datasets were used to determine reanalysis precision errors. IMAT volume was compared using the new FL segmentation versus an easier to segment but less accurate, tightly fitting envelope of the thigh muscle ensemble. RESULTS: The segmentation was successfully applied to all 73 datasets and took about 7 min per 28 slices. In particular, in elderly subjects, it includes a large amount of adipose tissue below the FL typically not accounted for in other segmentation approaches. Inter- and intra-operator RMS-CVs were 0.33% and 0.14%, respectively, for IMAT volume and 0.04% and 0.02%, respectively, for FFMT. DISCUSSION: The FL segmentation is an important step to quantify IMAT with high precision and may be useful to investigate effects of aging and treatment on changes of IMAT and FF. ClinicalTrials.gov identifier NCT2857660, August 5, 2016. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT2857660, August 5, 2016.

Quantification of hand muscle volume and composition in patients with rheumatoid arthritis, psoriatic arthritis and psoriasis.

BACKGROUND: Psoriasis (Pso), psoriatic arthritis (PsA) and rheumatoid arthritis (RA) are inflammatory diseases. PsA and RA are characterized by bone and muscle loss. In RA, bone loss has been extensively characterized, but muscle loss has, to the best of our knowledge, not been quantified to date. METHODS: A random forest based segmentation method was used to analyze hand muscle volume in T1 weighted MRI images of 330 patients suffering from Pso, PsA or RA. In addition, fat volume was quantified using MRI Dixon sequences in a small subset (n = 32). RESULTS: Males had a higher relative muscle volume than females (14% for Pso, 11% for PsA, n.s. for RA). Between 40 and 80 years male Pso patients lost 13%, male PsA patients 16%, male RA patients 23% and female PsA patients 30% of their relative muscle volume. After adjustment for age, relative muscle volume in males RA patients was 16% and in female RA patients 9% lower than in Pso patients. In male RA patients relative muscle volume was 13% lower in than in male PsA patients. There was no difference in females. A significant negative correlation (R2 = 0.18) between relative intramuscular fat content relative hand muscle volume was observed. CONCLUSION: These preliminary data showed that relative hand muscle volume significantly decreased with age in male and female patients with Pso, PsA and RA patients. Independent of age, relative hand muscle volume was significantly smaller in patients with RA compared to the patients with Pso and the difference was twice as large in males compared to females. Also in male but not in female RA patients relative hand muscle volume was significantly smaller than in PsA patients.

Three-dimensional Distribution of Muscle and Adipose Tissue of the Thigh at CT: Association with Acute Hip Fracture.

Purpose To evaluate determinants of hip fracture by assessing soft-tissue composition of the upper thigh at CT. Materials and Methods In this retrospective analysis of prospectively collected data, CT studies in 55 female control participants (mean age, 73.1 years ± 9.3 [standard deviation]) were compared with those in 40 female patients (mean age, 80.2 years ± 11.0) with acute hip fractures. Eighty-seven descriptors of the soft-tissue composition were determined. A multivariable best subsets analysis was used to extract parameters best associated with hip fracture. Results were adjusted for age, height, and weight. Results of soft-tissue parameters were compared with bone mineral density (BMD) and cortical bone thickness. Areas under the receiver operating characteristic curve (AUCs) adjusted for multiple comparisons were determined to discriminate fracture. Results The hip fracture group was characterized by lower BMD, lower cortical thickness, lower relative adipose tissue volume of the upper thigh, and higher extramyocellular lipid (EML) surface density. The relative volume of adipose tissue combined with EML surface density (model S1) was associated with hip fracture (AUC, 0.85; 95% confidence interval [CI]: 0.78, 0.93), as well as trochanteric trabecular BMD combined with neck cortical thickness (model B2) (AUC, 0.84; 95% CI: 0.75, 0.92). The model including all four parameters provided significantly better (P < .01) discrimination (AUC, 0.92; 95% CI: 0.86, 0.97) than model S1 or B2. Conclusion In addition to bone mineral density and geometry of the proximal femur, the amount of adipose tissue of the upper thigh and the distribution of the adipocytes in the muscles are significantly associated with acute hip fracture at CT. © RSNA, 2018 Online supplemental material is available for this article.

Romosozumab (sclerostin monoclonal antibody) versus teriparatide in postmenopausal women with osteoporosis transitioning from oral bisphosphonate therapy: a randomised, open-label, phase 3 trial.

BACKGROUND: Previous bisphosphonate treatment attenuates the bone-forming effect of teriparatide. We compared the effects of 12 months of romosozumab (AMG 785), a sclerostin monoclonal antibody, versus teriparatide on bone mineral density (BMD) in women with postmenopausal osteoporosis transitioning from bisphosphonate therapy. METHODS: This randomised, phase 3, open-label, active-controlled study was done at 46 sites in North America, Latin America, and Europe. We enrolled women (aged ≥55 to ≤90 years) with postmenopausal osteoporosis who had taken an oral bisphosphonate for at least 3 years before screening and alendronate the year before screening; an areal BMD T score of -2·5 or lower at the total hip, femoral neck, or lumbar spine; and a history of fracture. Patients were randomly assigned (1:1) via an interactive voice response system to receive subcutaneous romosozumab (210 mg once monthly) or subcutaneous teriparatide (20 µg once daily). The primary endpoint was percentage change from baseline in areal BMD by dual-energy x-ray absorptiometry at the total hip through month 12 (mean of months 6 and 12), which used a linear mixed effects model for repeated measures and represented the mean treatment effect at months 6 and 12. All randomised patients with a baseline measurement and at least one post-baseline measurement were included in the efficacy analysis. This trial is registered with ClinicalTrials.gov, number NCT01796301. FINDINGS: Between Jan 31, 2013, and April 29, 2014, 436 patients were randomly assigned to romosozumab (n=218) or teriparatide (n=218). 206 patients in the romosozumab group and 209 in the teriparatide group were included in the primary efficacy analysis. Through 12 months, the mean percentage change from baseline in total hip areal BMD was 2·6% (95% CI 2·2 to 3·0) in the romosozumab group and -0·6% (-1·0 to -0·2) in the teriparatide group; difference 3·2% (95% CI 2·7 to 3·8; p<0·0001). The frequency of adverse events was generally balanced between treatment groups. The most frequently reported adverse events were nasopharyngitis (28 [13%] of 218 in the romosozumab group vs 22 [10%] of 214 in the teriparatide group), hypercalcaemia (two [<1%] vs 22 [10%]), and arthralgia (22 [10%] vs 13 [6%]). Serious adverse events were reported in 17 (8%) patients on romosozumab and in 23 (11%) on teriparatide; none were judged treatment related. There were six (3%) patients in the romosozumab group compared with 12 (6%) in the teriparatide group with adverse events leading to investigational product withdrawal. INTERPRETATION: Transition to a bone-forming agent is common practice in patients treated with bisphosphonates, such as those who fracture while on therapy. In such patients, romosozumab led to gains in hip BMD that were not observed with teriparatide. These data could inform clinical decisions for patients at high risk of fracture. FUNDING: Amgen, Astellas, and UCB Pharma.

Biomechanical properties of bone are impaired in patients with ACPA-positive rheumatoid arthritis and associated with the occurrence of fractures.

OBJECTIVES: Bone loss is a well-established consequence of rheumatoid arthritis (RA). To date, bone disease in RA is exclusively characterised by bone density measurements, while the functional properties of bone in RA are undefined. This study aimed to define the impact of RA on the functional properties of bone, such as failure load and stiffness. METHODS: Micro-finite element analysis (µFEA) was carried out to measure failure load and stiffness of bone based on high-resolution peripheral quantitative CT data from the distal radius of anti-citrullinated protein antibody (ACPA)-positive RA (RA+), ACPA-negative RA (RA-) and healthy controls (HC). In addition, total, trabecular and cortical bone densities as well as microstructural parameters of bone were recorded. Correlations and multivariate models were used to determine the role of demographic, disease-specific and structural data of bone strength as well as its relation to prevalent fractures. RESULTS: 276 individuals were analysed. Failure load and stiffness (both P<0.001) of bone were decreased in RA+, but not RA-, compared with HC. Lower bone strength affected both female and male patients with RA+, was related to longer disease duration and significantly (stiffness P=0.020; failure load P=0.012) associated with the occurrence of osteoporotic fractures. Impaired bone strength was correlated with altered bone density and microstructural parameters, which were all decreased in RA+. Multivariate models showed that ACPA status (P=0.007) and sex (P<0.001) were independently associated with reduced biomechanical properties of bone in RA. CONCLUSION: In summary, µFEA showed that bone strength is significantly decreased in RA+ and associated with fractures.

Accuracy of bone mineral density quantification using dual-layer spectral detector CT: a phantom study.

OBJECTIVES: To investigate the accuracy of bone mineral density (BMD) quantification using dual-layer spectral detector CT (SDCT) at various scan protocols. METHODS: Two validated anthropomorphic phantoms containing inserts of 50-200 mg/cm3 calcium hydroxyapatite (HA) were scanned using a 64-slice SDCT scanner at various acquisition protocols (120 and 140 kVp, and 50, 100 and 200 mAs). Regions of interest (ROIs) were placed in each insert and mean attenuation profiles at monochromatic energy levels (90-200 keV) were constructed. These profiles were fitted to attenuation profiles of pure HA and water to calculate HA concentrations. For comparison, one phantom was scanned using dual energy X-ray absorptiometry (DXA). RESULTS: At both 120 and 140 kVp, excellent correlations (R = 0.97, P < 0.001) were found between true and measured HA concentrations. Mean error for all measurements at 120 kVp was -5.6 ± 5.7 mg/cm3 (-3.6 ± 3.2%) and at 140 kVp -2.4 ± 3.7 mg/cm3 (-0.8 ± 2.8%). Mean measurement errors were smaller than 6% for all acquisition protocols. Strong linear correlations (R2 ≥ 0.970, P < 0.001) with DXA were found. CONCLUSIONS: SDCT allows for accurate BMD quantification and potentially opens up the possibility for osteoporosis evaluation and opportunistic screening in patients undergoing SDCT for other clinical indications. However, patient studies are needed to extend and translate our findings. KEY POINTS: • Dual-layer spectral detector CT allows for accurate bone mineral density quantification. • BMD measurements on SDCT are strongly linearly correlated to DXA. • SDCT, acquired for several indications, may allow for evaluation of osteoporosis. • This potentially opens up the possibility for opportunistic osteoporosis screening.

Quantitative Computed Tomography-Current Status and New Developments.

This review focuses on new developments and current controversies in the field of quantitative computed tomography. Recent positions of the International Society for Clinical Densitometry acknowledged the clinical value of quantitative computed tomography of the spine and the hip using clinical whole-body computed tomography (CT) scanners. Opportunistic screening summarizes a number of new approaches describing the dual use of clinical CT scans. For example, CT scans may have been taken for tumor diagnosis but may also be used for the prediction of high or low fracture risks as an additional benefit for the patient. The assessment of the cortical parameters is another topic of current research. In CT images of the spine and the hip, a number of techniques have been developed to determine the thickness, mass, and bone density of the cortex. In higher-spatial resolution peripheral CT images of the radius and tibia obtained from special purpose scanners, 1 focus is the measurement of cortical porosity. Two different approaches, one based on the direct segmentation of the pores and one based on cortical density, will be reviewed.

Prediction of Hip Failure Load: In Vitro Study of 80 Femurs Using Three Imaging Methods and Finite Element Models-The European Fracture Study (EFFECT).

Purpose To evaluate the performance of three imaging methods (radiography, dual-energy x-ray absorptiometry [DXA], and quantitative computed tomography [CT]) and that of a numerical analysis with finite element modeling (FEM) in the prediction of failure load of the proximal femur and to identify the best densitometric or geometric predictors of hip failure load. Materials and Methods Institutional review board approval was obtained. A total of 40 pairs of excised cadaver femurs (mean patient age at time of death, 82 years ± 12 [standard deviation]) were examined with (a) radiography to measure geometric parameters (lengths, angles, and cortical thicknesses), (b) DXA (reference standard) to determine areal bone mineral densities (BMDs), and (c) quantitative CT with dedicated three-dimensional analysis software to determine volumetric BMDs and geometric parameters (neck axis length, cortical thicknesses, volumes, and moments of inertia), and (d) quantitative CT-based FEM to calculate a numerical value of failure load. The 80 femurs were fractured via mechanical testing, with random assignment of one femur from each pair to the single-limb stance configuration (hereafter, stance configuration) and assignment of the paired femur to the sideways fall configuration (hereafter, side configuration). Descriptive statistics, univariate correlations, and stepwise regression models were obtained for each imaging method and for FEM to enable us to predict failure load in both configurations. Results Statistics reported are for stance and side configurations, respectively. For radiography, the strongest correlation with mechanical failure load was obtained by using a geometric parameter combined with a cortical thickness (r(2) = 0.66, P < .001; r(2) = 0.65, P < .001). For DXA, the strongest correlation with mechanical failure load was obtained by using total BMD (r(2) = 0.73, P < .001) and trochanteric BMD (r(2) = 0.80, P < .001). For quantitative CT, in both configurations, the best model combined volumetric BMD and a moment of inertia (r(2) = 0.78, P < .001; r(2) = 0.85, P < .001). FEM explained 87% (P < .001) and 83% (P < .001) of bone strength, respectively. By combining (a) radiography and DXA and (b) quantitative CT and DXA, correlations with mechanical failure load increased to 0.82 (P < .001) and 0.84 (P < .001), respectively, for radiography and DXA and to 0.80 (P < .001) and 0.86 (P < .001) , respectively, for quantitative CT and DXA. Conclusion Quantitative CT-based FEM was the best method with which to predict the experimental failure load; however, combining quantitative CT and DXA yielded a performance as good as that attained with FEM. The quantitative CT DXA combination may be easier to use in fracture prediction, provided standardized software is developed. These findings also highlight the major influence on femoral failure load, particularly in the trochanteric region, of a densitometric parameter combined with a geometric parameter. (©) RSNA, 2016 Online supplemental material is available for this article.

Inactivation of autophagy ameliorates glucocorticoid-induced and ovariectomy-induced bone loss.

OBJECTIVES: Autophagy has recently been shown to regulate osteoclast activity and osteoclast differentiation. Here, we aim to investigate the impact of autophagy inhibition as a potential therapeutic approach for the treatment of osteoporosis in preclinical models. METHODS: Systemic bone loss was induced in mice by glucocorticoids and by ovariectomy (OVX). Autophagy was targeted by conditional inactivation of autophagy-related gene 7 (Atg7) and by treatment with chloroquine (CQ). Bone density was evaluated by microCT. The role of autophagy on osteoclastogenesis was analysed by osteoclastogenesis and bone resorption assays. The quantification of receptor activator of nuclear factor κ B ligand and osteoprotegerin proteins in cocultures was performed using ELISA whereas that of osteoclast and osteoblast differentiation markers was by qPCR. RESULTS: Selective deletion of Atg7 in monocytes from Atg7(fl/fl)_x_LysM-Cre mice mitigated glucocorticoid-induced and OVX-induced osteoclast differentiation and bone loss compared with Atg7(fl/fl) littermates. Pharmacological inhibition of autophagy by treatment with CQ suppressed glucocorticoid-induced osteoclastogenesis and protected mice from bone loss. Similarly, inactivation of autophagy shielded mice from OVX-induced bone loss. Inhibition of autophagy led to decreased osteoclast differentiation with lower expression of osteoclast markers such as NFATc1, tartrate-resistant acid phosphatase, OSCAR and cathepsin K and attenuated bone resorption in vitro. In contrast, osteoblast differentiation was not affected by inhibition of autophagy. CONCLUSIONS: Pharmacological or genetic inactivation of autophagy ameliorated glucocorticoid-induced and OVX-induced bone loss by inhibiting osteoclastogenesis. These findings may have direct translational implications for the treatment of osteoporosis, since inhibitors of autophagy such as CQ are already in clinical use.

Additive effect of anti-citrullinated protein antibodies and rheumatoid factor on bone erosions in patients with RA.

OBJECTIVE: To determine whether there is an additive effect of anticitrullinated protein antibodies (ACPA) and rheumatoid factor (RF) on the number and size of bone erosions in patients with rheumatoid arthritis (RA) METHODS: 242 patients with RA received high-resolution peripheral quantitative CT (HR-pQCT) scans of the metacarpophalangeal joints. Demographic and disease-specific parameters including ACPA and RF levels were recorded from all patients. Erosion numbers and their size were assessed in 238 patients at 714 individual joints (MCP 2, 3 and 4) and 5712 sites (each 4 quadrants in metacarpal heads and phalangeal bases). The volume of erosions was calculated by a semiellipsoid formula. RESULTS: Of the 238 patients, 112 patients showed RF and ACPAs (ACPAs+RF+), 28 only RF (RF+), 29 only ACPAs (ACPA+) and 69 were antibody negative (NEG). Erosion number and size were highest in RF+ACPAs+ patient group with significant differences compared with NEG patients with respect to erosion number (p=0.001) and to ACPA-negative patients with respect to erosion size (p<0.001). Results maintained significance in a linear mixed model showing ACPAs+RF+ status and disease duration being associated with higher number (p=0.017 and p=0.005, respectively), and larger size (p=0.014 and p=0.013, respectively) of bone erosions. Furthermore, erosion size was influenced by the presence and titre of RF only in ACPA-positive patients with RA but not in ACPA-negative patients. CONCLUSIONS: ACPAs and RF show an additive effect on erosion number and erosion size. Concomitant presence of ACPAs and RF is associated with higher erosive disease burden in patients with RA. Furthermore, RF influences erosion size only in ACPA-positive but not in ACPA-negative patients.

Automated three-dimensional registration of high-resolution peripheral quantitative computed tomography data to quantify size and shape changes of arthritic bone erosions.

OBJECTIVE: To monitor size and shape changes of bone erosions and changes in BMD in the vicinity of the erosion and in the periarticular trabecular compartment of patients with RA using high-resolution peripheral quantitative CT (HR-pQCT) imaging and to compare an automated three-dimensional (3D) image processing technique with manual measurements of erosion width and depth. METHODS: The shape of 40 bone erosions and composition of bone around the erosions were analysed in the MCP joints of 22 RA patients both manually and by semi-automated 3D image processing at two different time points. Periosteal segmentation was performed using volume growing and morphological operations. Image registration was applied for transfer of baseline segmentations to follow-up datasets. RESULTS: Eight erosions decreased in size, 6 increased and 28 remained stable. Increasing erosions were more spherical and smaller at baseline compared with decreasing or stable erosions. BMD in the vicinity of shrinking erosions increased, while it decreased next to expanding erosions. There was moderate agreement in the determination of erosion volume between semi-automated and manual measurements, but agreement was poor when assessing changes in volume over time. CONCLUSION: Longitudinal changes in erosion size and shape and of BMD in the vicinity of an erosion can be measured. BMD changes are associated with progression and regression of erosions. However, the semi-automated and manual approaches did not classify longitudinal changes of erosion volume in the same way. Further research is necessary to define the nature of these differences.

Executive Summary of the 2015 ISCD Position Development Conference on Advanced Measures From DXA and QCT: Fracture Prediction Beyond BMD.

There have been many scientific advances in fracture risk prediction beyond bone density. The International Society for Clinical Densitometry (ISCD) convened a Position Development Conference (PDC) on the use of dual-energy X-ray absorptiometry beyond measurement of bone mineral density for fracture risk assessment, including trabecular bone score and hip geometry measures. Previously, no guidelines for nonbone mineral density DXA measures existed. Furthermore, there have been advances in the analysis of quantitative computed tomography (QCT) including finite element analysis, QCT of the hip, DXA-equivalent hip measurements, and opportunistic screening that were not included in the previous ISCD positions. The topics and questions for consideration were developed by the ISCD Board of Directors and the Scientific Advisory Committee and were designed to address the needs of clinical practitioners. Three task forces were created and asked to conduct comprehensive literature reviews to address specific questions. The task forces included participants from many countries and a variety of interests including academic institutions and private health care delivery organizations. Representatives from industry participated as consultants to the task forces. Task force reports with proposed position statements were then presented to an international panel of experts with backgrounds in bone densitometry. The PDC was held in Chicago, Illinois, USA, contemporaneously with the Annual Meeting of the ISCD, February 26 through February 28, 2015. This Executive Summary describes the methodology of the 2015 PDC on advanced measures from DXA and QCT and summarizes the approved official positions. Six separate articles in this issue will detail the rationale, discussion, and additional research topics for each question the task forces addressed.

Clinical Use of Quantitative Computed Tomography (QCT) of the Hip in the Management of Osteoporosis in Adults: the 2015 ISCD Official Positions-Part I.

The International Society for Clinical Densitometry (ISCD) has developed new official positions for the clinical use of quantitative computed tomography of the hip. The ISCD task force for quantitative computed tomography reviewed the evidence for clinical applications and presented a report with recommendations at the 2015 ISCD Position Development Conference. Here, we discuss the agreed on ISCD official positions with supporting medical evidence, rationale, controversy, and suggestions for further study. Parts II and III address the advanced techniques of finite element analysis applied to computed tomography scans and the clinical feasibility of existing techniques for opportunistic screening of osteoporosis using computed tomography scans obtained for other diagnosis such as colonography was addressed.

Clinical Use of Quantitative Computed Tomography-Based Finite Element Analysis of the Hip and Spine in the Management of Osteoporosis in Adults: the 2015 ISCD Official Positions-Part II.

The International Society for Clinical Densitometry (ISCD) has developed new official positions for the clinical use of quantitative computed tomography (QCT)-based finite element analysis of the spine and hip. The ISCD task force for QCT reviewed the evidence for clinical applications and presented a report with recommendations at the 2015 ISCD Position Development Conference. Here we discuss the agreed upon ISCD official positions with supporting medical evidence, rationale, controversy, and suggestions for further study. Parts I and III address the clinical use of QCT of the hip, and the clinical feasibility of existing techniques for opportunistic screening of osteoporosis using CT scans obtained for other diagnosis such as colonography was addressed.

Clinical Use of Quantitative Computed Tomography-Based Advanced Techniques in the Management of Osteoporosis in Adults: the 2015 ISCD Official Positions-Part III.

The International Society for Clinical Densitometry (ISCD) has developed new official positions for the clinical use of computed tomography (CT) scans acquired without a calibration phantom, for example, CT scans obtained for other diagnosis such as colonography. This also addresses techniques suggested for opportunistic screening of osteoporosis. The ISCD task force for quantitative CT reviewed the evidence for clinical applications of these new techniques and presented a report with recommendations at the 2015 ISCD Position Development Conference. Here we discuss the agreed upon ISCD official positions with supporting medical evidence, rationale, controversy, and suggestions for further study. Advanced techniques summarized as statistical parameter mapping methods were also reviewed. Their future use is promising but the clinical application is premature. The clinical use of QCT of the hip is addressed in part I and of finite element analysis of the hip and spine in part II.

RSK2 protects mice against TNF-induced bone loss.

Tumor necrosis factor (TNF)-α is a key cytokine regulator of bone and mediates inflammatory bone loss. The molecular signaling that regulates bone loss downstream of TNF-α is poorly defined. Here, we demonstrate that inactivating the pro-osteoblastogenic ERK-activated ribosomal S6 kinase RSK2 leads to a drastically accelerated and amplified systemic bone loss in mice ectopically expressing TNF-α [human TNF transgenic (hTNFtg) mice]. The phenotype is associated with a decrease in bone formation because of fewer osteoblasts as well as a drastically increased bone destruction by osteoclasts. The molecular basis of this phenotype is a cell autonomous increased sensitivity of osteoblasts and osteocytes to TNF-induced apoptosis combined with an enhancement of their osteoclast supportive activity. Thus, RSK2 exerts a strong negative regulatory loop on TNF-induced bone loss.