Publications by authors named "Andrew J Burghardt"

69 Publications

Reliability and Change in Erosion Measurements by High-resolution Peripheral Quantitative Computed Tomography in a Longitudinal Dataset of Rheumatoid Arthritis Patients.

J Rheumatol 2020 Sep 15. Epub 2020 Sep 15.

RELEX-2 was hosted by the University of San Francisco, California, USA. The meeting was sponsored in part by Scanco Medical AG. PGC is supported in part by the UK National Institute for Health Research (NIHR) Leeds Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. S. Finzel, MD, Senior Attending Physician, Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Medical Faculty, University of Freiburg, Freiburg, Germany; S.L. Manske, PhD, Assistant Professor, Department of Radiology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; C.C. Barnabe, MD, MSc, Associate Professor, Departments of Medicine and Community Health Sciences, University of Calgary, and McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, Alberta, Canada; A.J. Burghardt, BS, Research Specialist, Department of Radiology and Biomedical Imaging, University of California San Francisco, California, USA; H. Marotte, MD, PhD, Professor, INSERM 1059, Université de Lyon, and Service de Rhumatologie, CHU de Saint-Etienne, Saint-Etienne, France; A. Scharmga, PhD, Maastricht University, Maastricht, the Netherlands; E.M. Hauge, MD, PhD, Professor, Department of Rheumatology, Aarhus University Hospital and Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; R. Chapurlat, MD, PhD, Professor, INSERM 1033, Hôpital Edouard Herriot, Lyon, France; K. Engelke, PhD, Professor, Department of Medicine 3, FAU University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany; X. Li, PhD, Professor, Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio, USA; B.C. van Teeffelen, Department of Biomedical Engineering, Melbourne School of Engineering, The University of Melbourne, Melbourne, Australia; P.G. Conaghan, MD, PhD, Professor, Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds and NIHR Leeds Biomedical Research Centre, Leeds, UK; K.S. Stok, PhD, Senior Lecturer, Institute for Biomechanics, ETH Zurich, Zurich, Switzerland, and Department of Biomedical Engineering, University of Melbourne, Melbourne, Australia. The authors state that they have no conflicts of interest. Address correspondence to Dr. S. Finzel, Head of Clinical Trials Unit Rheumatology, Department of Rheumatology and Clinical Immunology, University Medical Center, Medical Faculty, University of Freiburg, Hugstetter Strasse 55, 79110 Freiburg, Germany. Email: Accepted for publication September 5, 2020.

Objective: The aim of this multireader exercise was to assess the reliability and change over time of erosion measurements in patients with rheumatoid arthritis (RA) using high-resolution peripheral quantitative computed tomography (HR-pQCT).

Methods: HR-pQCT scans of 23 patients with RA were assessed at baseline and 12 months. Four experienced readers examined the dorsal, palmar, radial, and ulnar surfaces of the metacarpal head (MH) and phalangeal base (PB) of the second and third digits, blinded to time order. In total, 368 surfaces (23 patients´ 16 surfaces) were evaluated per timepoint to characterize cortical breaks as pathological (erosion) or physiological, and to quantify erosion width and depth. Reliability was evaluated by intraclass correlation coefficients (ICC), percentage agreement, and Light k; change over time was defined by means ± SD of erosion numbers and dimensions.

Results: ICC for the mean measurements of width and depth of the pathological breaks ranged between 0.819-0.883, and 0.771-0.907, respectively. Most physiological cortical breaks were found at the palmar PB, whereas most pathological cortical breaks were located at the radial MH. There was a significant increase in both the numbers and the dimensions of erosions between baseline and follow-up ( = 0.0001 for erosion numbers, width, and depth in axial plane; = 0.001 for depth in perpendicular plane).

Conclusion: This exercise confirmed good reliability of HR-pQCT erosion measurements and their ability to detect change over time.
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http://dx.doi.org/10.3899/jrheum.191391DOI Listing
September 2020

High-Resolution Peripheral Quantitative Computed Tomography for Bone Evaluation in Inflammatory Rheumatic Disease.

Front Med (Lausanne) 2020 15;7:337. Epub 2020 Jul 15.

Cumming School of Medicine, McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, AB, Canada.

High resolution peripheral quantitative computed tomography (HR-pQCT) is a 3-dimensional imaging modality with superior sensitivity for bone changes and abnormalities. Recent advances have led to increased use of HR-pQCT in inflammatory arthritis to report quantitative volumetric measures of bone density, microstructure, local anabolic (e.g., osteophytes, enthesiophytes) and catabolic (e.g., erosions) bone changes and joint space width. These features may be useful for monitoring disease progression, response to therapy, and are responsive to differentiating between those with inflammatory arthritis conditions and healthy controls. We reviewed 69 publications utilizing HR-pQCT imaging of the metacarpophalangeal (MCP) and/or wrist joints to investigate arthritis conditions. Erosions are a marker of early inflammatory arthritis progression, and recent work has focused on improvement and application of techniques to sensitively identify erosions, as well as quantifying erosion volume changes longitudinally using manual, semi-automated and automated methods. As a research tool, HR-pQCT may be used to detect treatment effects through changes in erosion volume in as little as 3 months. Studies with 1-year follow-up have demonstrated progression or repair of erosions depending on the treatment strategy applied. HR-pQCT presents several advantages. Combined with advances in image processing and image registration, individual changes can be monitored with high sensitivity and reliability. Thus, a major strength of HR-pQCT is its applicability in instances where subtle changes are anticipated, such as early erosive progression in the presence of subclinical inflammation. HR-pQCT imaging results could ultimately impact decision making to uptake aggressive treatment strategies and prevent progression of joint damage. There are several potential areas where HR-pQCT evaluation of inflammatory arthritis still requires development. As a highly sensitive imaging technique, one of the major challenges has been motion artifacts; motion compensation algorithms should be implemented for HR-pQCT. New research developments will improve the current disadvantages including, wider availability of scanners, the field of view, as well as the versatility for measuring tissues other than only bone. The challenge remains to disseminate these analysis approaches for broader clinical use and in research.
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http://dx.doi.org/10.3389/fmed.2020.00337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381125PMC
July 2020

Consensus approach for 3D joint space width of metacarpophalangeal joints of rheumatoid arthritis patients using high-resolution peripheral quantitative computed tomography.

Quant Imaging Med Surg 2020 Feb;10(2):314-325

McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, Canada.

Background: Joint space assessment for rheumatoid arthritis (RA) by ordinal conventional radiographic scales is susceptible to floor and ceiling effects. High-resolution peripheral quantitative computed tomography (HR-pQCT) provides superior resolution, and may detect earlier changes. The goal of this work was to compare existing 3D methods to calculate joint space width (JSW) metrics in human metacarpophalangeal (MCP) joints with HR-pQCT and reach consensus for future studies. Using the consensus method, we established reproducibility with repositioning as well as feasibility for use in second-generation HR-pQCT scanners.

Methods: Three published JSW methods were compared using datasets from individuals with RA from three research centers. A SPECTRA consensus method was developed to take advantage of strengths of the individual methods. Using the SPECTRA method, reproducibility after repositioning was tested and agreement between scanner generations was also established.

Results: When comparing existing JSW methods, excellent agreement was shown for JSW minimum and mean (ICC 0.987-0.996) but not maximum and volume (ICC 0.000-0.897). Differences were identified as variations in volume definitions and algorithmic differences that generated high sensitivity to boundary conditions. The SPECTRA consensus method reduced this sensitivity, demonstrating good scan-rescan reliability (ICC >0.911) except for minimum JSW (ICC 0.656). There was strong agreement between results from first- and second-generation HR-pQCT (ICC >0.833).

Conclusions: The SPECTRA consensus method combines unique strengths of three independently-developed algorithms and leverages underlying software updates to provide a mature analysis to measure 3D JSW. This method is robust with respect to repositioning and scanner generations, suggesting its suitability for detecting change.
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http://dx.doi.org/10.21037/qims.2019.12.11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063288PMC
February 2020

Objective measures of moderate to vigorous physical activity are associated with higher distal limb bone strength among elderly men.

Bone 2020 03 20;132:115198. Epub 2019 Dec 20.

Division of Epidemiology & Community Health, University of Minnesota, Minneapolis, MN, United States of America; Department of Medicine, University of Minnesota, Minneapolis, MN, United States of America; Center for Care Delivery & Outcomes Research, VA Health Care System, Minneapolis, MN, United States of America.

Our aim was to determine the association between objectively measured physical activity (PA) and bone strength of the distal limbs among older men. We studied 994 men from the MrOS cohort study (mean age 83.9) who had repeat (Year 7 and 14) 5-day activity assessment with at least 90% wear time (SenseWearPro3 Armband) and Year 14 measures using high resolution peripheral quantitative tomography (HR-pQCT) (Scanco). Total energy expenditure (TEE), total steps per day, peak cadence (mean of top 30 steps/min over 24 h) and time spent in a given level of activity: sedentary (reference, <1.5 metabolic equivalents of task [METs]), light (1.5 to <3 METs), or moderate to vigorous physical activity(MVPA: ≥3 METs) were calculated as mean over the two time points. Estimated failure load was determined from HR-pQCT data using finite element analysis. We used standardized variables and adjusted for potential confounders using linear regression. The means ±SDs for daily activity were: 2338 ± 356 kcal/d [TEE]; 5739 ± 2696 steps/day [step count], 60 ± 20 cpm [peak cadence], 67 ± 28 min/d [light activity], and 85 ± 52 min/d [MVPA]. Higher TEE, step count, and peak cadence were each associated with higher failure load of the distal radius (effect sizes respectively: 0.13 [95% CI: 0.05, 0.20], 0.11 [95% CI: 0.04, 0.18], and 0.08 [95% CI: 0.01, 0.15]) and higher failure load of the distal tibia (effect sizes respectively 0.21 [95% CI: 0.13, 0.28], 0.19 [95% CI: 0.13, 0.26], 0.19 [95% CI, 0.13, 0.25]). Time spent in MVPA vs. time sedentary was related to bone strength at both sites after adjustment, whereas time spent in light activity vs. time sedentary was not. TEE was associated with compartmental area and BMD parameters at distal tibia, but only area parameters at the distal radius. In summary, MVPA over a 7-year period of time may have a modest association with bone strength and geometry among older men.
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http://dx.doi.org/10.1016/j.bone.2019.115198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993955PMC
March 2020

HR-pQCT Measures of Bone Microarchitecture Predict Fracture: Systematic Review and Meta-Analysis.

J Bone Miner Res 2020 03 19;35(3):446-459. Epub 2019 Nov 19.

Research Center, Shriners Hospital for Children, Montreal, Canada.

High-resolution peripheral quantitative computed tomography (HR-pQCT) is a noninvasive imaging modality for assessing volumetric bone mineral density (vBMD) and microarchitecture of cancellous and cortical bone. The objective was to (1) assess fracture-associated differences in HR-pQCT bone parameters; and (2) to determine if HR-pQCT is sufficiently precise to reliably detect these differences in individuals. We systematically identified 40 studies that used HR-pQCT (39/40 used XtremeCT scanners) to assess 1291 to 3253 and 3389 to 10,687 individuals with and without fractures, respectively, ranging in age from 10.9 to 84.7 years with no comorbid conditions. Parameters describing radial and tibial bone density, microarchitecture, and strength were extracted and percentage differences between fracture and control subjects were estimated using a random effects meta-analysis. An additional meta-analysis of short-term in vivo reproducibility of bone parameters assessed by XtremeCT was conducted to determine whether fracture-associated differences exceeded the least significant change (LSC) required to discern measured differences from precision error. Radial and tibial HR-pQCT parameters, including failure load, were significantly altered in fracture subjects, with differences ranging from -2.6% (95% confidence interval [CI] -3.4 to -1.9) in radial cortical vBMD to -12.6% (95% CI -15.0 to -10.3) in radial trabecular vBMD. Fracture-associated differences reported by prospective studies were consistent with those from retrospective studies, indicating that HR-pQCT can predict incident fracture. Assessment of study quality, heterogeneity, and publication biases verified the validity of these findings. Finally, we demonstrated that fracture-associated deficits in total and trabecular vBMD and certain tibial cortical parameters can be reliably discerned from HR-pQCT-related precision error and can be used to detect fracture-associated differences in individual patients. Although differences in other HR-pQCT measures, including failure load, were significantly associated with fracture, improved reproducibility is needed to ensure reliable individual cross-sectional screening and longitudinal monitoring. In conclusion, our study supports the use of HR-pQCT in clinical fracture prediction. © 2019 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3901DOI Listing
March 2020

Hip Fracture Discrimination Based on Statistical Multi-parametric Modeling (SMPM).

Ann Biomed Eng 2019 Nov 31;47(11):2199-2212. Epub 2019 May 31.

Department of Radiology, Beijing Jishuitan Hospital, Beijing, China.

Studies using quantitative computed tomography (QCT) and data-driven image analysis techniques have shown that trabecular and cortical volumetric bone mineral density (vBMD) can improve the hip fracture prediction of dual-energy X-ray absorptiometry areal BMD (aBMD). Here, we hypothesize that (1) QCT imaging features of shape, density and structure derived from data-driven image analysis techniques can improve the hip fracture discrimination of classification models based on mean femoral neck aBMD (Neck.aBMD), and (2) that data-driven cortical bone thickness (Ct.Th) features can improve the hip fracture discrimination of vBMD models. We tested our hypotheses using statistical multi-parametric modeling (SMPM) in a QCT study of acute hip fracture of 50 controls and 93 fragility fracture cases. SMPM was used to extract features of shape, vBMD, Ct.Th, cortical vBMD, and vBMD in a layer adjacent to the endosteal surface to develop hip fracture classification models with machine learning logistic LASSO. The performance of these classification models was evaluated in two aspects: (1) their hip fracture classification capability without Neck.aBMD, and (2) their capability to improve the hip fracture classification of the Neck.aBMD model. Assessments were done with 10-fold cross-validation, areas under the receiver operating characteristic curve (AUCs), differences of AUCs, and the integrated discrimination improvement (IDI) index. All LASSO models including SMPM-vBMD features, and the majority of models including SMPM-Ct.Th features performed significantly better than the Neck.aBMD model; and all SMPM features significantly improved the hip fracture discrimination of the Neck.aBMD model (Hypothesis 1). An interesting finding was that SMPM-features of vBMD also captured Ct.Th patterns, potentially explaining the superior classification performance of models based on SMPM-vBMD features (Hypothesis 2). Age, height and weight had a small impact on model performances, and the model of shape, vBMD and Ct.Th consistently yielded better performances than the Neck.aBMD models. Results of this study clearly support the relevance of bone density and quality on the assessment of hip fracture, and demonstrate their potential on patient and healthcare cost benefits.
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http://dx.doi.org/10.1007/s10439-019-02298-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012369PMC
November 2019

Structural Changes over a Short Period Are Associated with Functional Assessments in Rheumatoid Arthritis.

J Rheumatol 2019 07 15;46(7):676-684. Epub 2019 Feb 15.

From the Department of Radiology and Biomedical Imaging, Musculoskeletal Quantitative Imaging Research, and the Department of Medicine, Division of Rheumatology, and the School of Pharmacy, at the University of California, San Francisco (UCSF), San Francisco, California; Department of Biomedical Engineering, Program of Advanced Musculoskeletal Imaging (PAMI), Cleveland Clinic, Cleveland, Ohio; Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.

Objective: To investigate the correlation between changes in radiological quantitative assessment with changes in clinical and functional assessment from baseline to 3 months in patients with rheumatoid arthritis (RA).

Methods: Twenty-eight patients with RA [methotrexate (MTX) and anti-tumor necrosis factor-α (TNF-α) group with high disease activity (n = 18); and MTX group with low disease activity (n = 10)] underwent assessments at baseline and 3 months: clinical [28-joint count Disease Activity Score (DAS28)], functional [Health Assessment Questionnaire (HAQ) and Michigan Hand Outcome Questionnaire (MHQ)], and imaging-based [3 Tesla magnetic resonance imaging (MRI) and high-resolution peripheral quantitative computed tomography (HR-pQCT)]. MR images were evaluated semiquantitatively [RA MRI scoring (RAMRIS)] and quantitatively for the volume of synovitis and bone marrow edema (BME) lesions. Erosion volumes were measured using HR-pQCT.

Results: After 3 months, the anti-TNF-α group demonstrated an improvement in disease activity through DAS28, HAQ, and MHQ. MRI showed significant decreases in synovitis and BME volume for the anti-TNF-α group, and significant increases in the MTX group. HR-pQCT showed significant decreases in bone erosion volume for the anti-TNF-α group, and significant increases in the MTX group. No significance was observed using RAMRIS. Changes in synovitis, BME, and erosion volumes, but not RAMRIS, were significantly correlated with changes in DAS28, HAQ, and MHQ.

Conclusion: Quantitative measures were more sensitive than semiquantitative grading when evaluating structural and inflammatory changes with treatment, and were associated with patient clinical and functional outcomes. Multimodality imaging with 3T MRI and HR-pQCT may provide promising biomarkers that help determine disease progression and therapy response.
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http://dx.doi.org/10.3899/jrheum.180496DOI Listing
July 2019

Accelerated Bone Loss in Older Men: Effects on Bone Microarchitecture and Strength.

J Bone Miner Res 2018 10 12;33(10):1859-1869. Epub 2018 Jun 12.

Oregon Health & Science University, Portland, OR, USA.

Accelerated bone loss (ABL) shown on routine dual-energy X-ray absorptiometry (DXA) may be accompanied by microarchitectural changes, increased cortical porosity, and lower bone strength. To test this hypothesis, we performed a cross-sectional study and used high-resolution peripheral quantitative computed tomography (HR-pQCT) scans (Scanco Medical AG, Brüttisellen, Switzerland) to measure estimated bone strength and microarchitecture in the distal radius and distal and diaphyseal tibia. We studied 1628 men who attended the year 14 exam of the Osteoporotic Fractures in Men (MrOS) study. We retrospectively characterized areal bone mineral density (aBMD) change from the year 7 to year 14 exam in three categories: "accelerated" loss, ≥10% loss at either the total hip or femoral neck (n = 299, 18.4%); "expected" loss, <10% (n = 1061, 65.2%), and "maintained" BMD, ≥0% (n = 268, 16.5%). The ABL cut-off was a safety alert established for MrOS. We used regression models to calculate adjusted mean HR-pQCT parameters in men with ABL, expected loss, or maintained BMD. Men who experienced ABL were older and had a lower body mass index and aBMD and experienced greater weight loss compared with other men. Total volumetric BMD and trabecular and cortical volumetric BMD were lower in men with ABL compared with the expected or maintained group. Men with ABL had significantly lower trabecular bone volume fraction (BV/TV), fewer trabeculae, and greater trabecular separation at both the distal radius and tibia than men with expected loss or who maintained aBMD, all p trend <0.001. Men with ABL had lower cortical thickness and lower estimated bone strength, but there was no difference in cortical porosity except at the tibia diaphyseal site. In summary, men with ABL have lower estimated bone strength, poorer trabecular microarchitecture, and thinner cortices than men without ABL but have similar cortical porosity. These impairments may lead to an increased risk of fracture. © 2018 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6330703PMC
October 2018

Volumetric Bone Mineral Density and Failure Load of Distal Limbs Predict Incident Clinical Fracture Independent HR-pQCT BMD and Failure Load Predicts Incident Clinical Fracture of FRAX and Clinical Risk Factors Among Older Men.

J Bone Miner Res 2018 07 22;33(7):1302-1311. Epub 2018 May 22.

Bone and Mineral Unit, Oregon Health Sciences University, Portland, OR, USA.

Our objective was to determine the associations of peripheral bone strength and microarchitecture with incident clinical and major osteoporotic fracture among older men after adjusting for major clinical risk factors. We used a prospective cohort study design with data from 1794 men (mean age 84.4 years) in the Osteoporotic Fractures in Men (MrOS) study. Eligible men attended the year 14 visit, had high-resolution peripheral quantitative computed tomography (HR-pQCT) scans of the distal radius and distal or diaphyseal tibia, DXA measured BMD, and were followed for mean 1.7 years for incident fracture. Failure load was estimated using finite element analysis. We used Cox proportional hazards models with standardized HR-pQCT parameters as exposure variables. Primary outcome was clinical fracture (n = 108). Covariates included either Fracture Risk Assessment Tool (FRAX) major osteoporotic fracture probability calculated with BMD (FRAX-BMD), or individual clinical risk factors (CRF) including age, total hip BMD, race, falls, and prevalent fracture after age 50 years. Lower failure load was associated with higher risk of incident clinical fracture and incident major osteoporotic fracture. For clinical fracture with FRAX-BMD adjustment, the associations ranged from hazard ratio (HR) 1.58 (95% CI, 1.25 to 2.01) to 2.06 (95% CI, 1.60 to 2.66) per SD lower failure load at the diaphyseal tibia and distal radius. These associations were attenuated after adjustment for individual CRFs, but remained significant at the distal sites. Associations of volumetric BMD with these outcomes were similar to those for failure load. At the distal radius, lower trabecular BMD, number, and thickness, and lower cortical BMD, thickness, and area were all associated with higher risk of clinical fracture, but cortical porosity was not. Among community-dwelling older men, HR-pQCT measures including failure load, volumetric BMD, and microstructure parameters at peripheral sites (particularly distal radius) are robust independent predictors of clinical and major osteoporotic fracture. © 2018 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6048962PMC
July 2018

Assessment of 3-month changes in bone microstructure under anti-TNFα therapy in patients with rheumatoid arthritis using high-resolution peripheral quantitative computed tomography (HR-pQCT).

Arthritis Res Ther 2017 Oct 4;19(1):222. Epub 2017 Oct 4.

Department of Radiology & Biomedical Imaging, Musculoskeletal Quantitative Imaging Research, University of California San Francisco, 185 Berry Street, Suite 350, San Francisco, CA, 94107, USA.

Background: Although one study showed minimal progression of erosions in patients with rheumatoid arthritis (RA) one year after TNFα inhibition therapy, no studies have investigated very early bone changes after initiation of anti-TNFα treatment. We investigated the effects of 3-month anti-TNFα treatment on bone erosion progression and bone microarchitecture in RA patients using high-resolution peripheral quantitative computed tomography (HR-pQCT).

Methods: Patients with RA (n = 27) (17 in the anti-TNFα and 10 in the MTX-only group) underwent assessment of disease activity score in 28 joints (DAS-28), radiographs, 3-T magnetic resonance imaging (MRI) and HR-pQCT of metacarpophalangeal and wrist joints at baseline and 3 months. HR-pQCT-derived erosion volume, joint volume/width and bone microarchitecture were computed and joint destruction was assessed using Sharp and RAMRIS scorings on radiographs and MRI, respectively.

Results: Overall, 73 erosions were identified by HR-pQCT at baseline. Over 3 months, the anti-TNFα group had decreased mean erosion volume; increased erosion volume was observed in one clinical non-responder. The MTX-only group in contrast, trended toward increasing erosion volume despite low disease activity. In the anti-TNFα group, joint-space width and volume of MCP joints decreased significantly and was positively correlated with erosion volume changes (R  = 0.311, p = 0.013; R  = 0.527, p = 0.003, respectively). In addition, erosion volume changes were significantly negatively correlated with changes in trabecular bone mineral density (R  = 0.353, p = 0.020) in this group. We observed significant correlation between percentage change in erosion volume and change in DAS-28 erythrocyte sedimentation rate and C-reactive protein CRP scores (R  = 0.558, p < 0.001; R  = 0.745, p < 0.001, respectively) in all patients.

Conclusions: Using HR-pQCT, our data suggest that anti-TNFα treatment prevents erosion progression and deterioration of bone microarchitecture within the first 3 months of treatment, one patient not responding to treatment, had significant progression of bone erosions within this short time period. Patients with low disease activity scores (<3.2) can have continuous HR-pQCT-detectable progression of erosive disease with MTX treatment only. HR-pQCT can be a sensitive, powerful tool to quantify bone changes and monitor RA treatment short term (such as 3 months).
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http://dx.doi.org/10.1186/s13075-017-1430-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5628475PMC
October 2017

The SPECTRA Collaboration OMERACT Special Interest Group: Current Research and Future Directions.

J Rheumatol 2017 Dec 1;44(12):1911-1915. Epub 2017 Aug 1.

From the Institute for Biomechanics, ETH Zurich, Zurich, Switzerland; Department of Biomedical Engineering, University of Melbourne, Melbourne, Victoria, Australia; Department of Rheumatology and Clinical Immunology, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Department of Radiology and Biomedical Imaging, University of California, San Francisco, California, USA; Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds and UK National Institute for Health Research (NIHR) Leeds Biomedical Research Centre, Leeds, UK; Departments of Medicine and Community Health Sciences, University of Calgary; McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, Alberta, Canada.

Objective: High-resolution peripheral quantitative computed tomography (HR-pQCT) has the potential to improve radiographic progression determination in clinical trials and longitudinal observational studies. The goal of this work was to describe the current state of research presented at Outcome Measures in Rheumatology (OMERACT) 2016 and ensuing future directions outlined during discussion among attendees.

Methods: At OMERACT 2016, SPECTRA (Study grouP for xtrEme-Computed Tomography in Rheumatoid Arthritis) introduced efforts to (1) validate the HR-pQCT according to OMERACT guidelines, focusing on rheumatoid arthritis (RA), and (2) find alternatives for automated joint space width (JSW) analysis. The Special Interest Group (SIG) was presented to patient research partners, physicians/researchers, and SIG leaders followed by a 40-min discussion on future directions.

Results: A consensus definition for RA erosion using HR-pQCT was demonstrated through a systematic literature review and a Delphi exercise. Histopathology and perfusion studies were presented that analyzed the true characteristics of cortical breaks in HR-pQCT images, and to provide criterion validity. Results indicate that readers were able to discriminate between erosion and small vascular channels. Moderate reliability (ICC 0.206-0.871) of direct erosion size measures was shown, which improved (> 0.9) only when experienced readers were considered. Quantification of erosion size was presented for scoring, direct measurement, and volumetric approaches, as well as a reliability exercise for direct measurement. Three methods for JSW measurement were compared, all indicating excellent reproducibility with differences at the extremes (i.e., near-zero and joint edge thickness).

Conclusion: Initial reports on HR-pQCT are promising; however, to consider its use in clinical trials and longitudinal observational studies, it is imperative to assess the responsiveness of erosion measurement quantification.
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http://dx.doi.org/10.3899/jrheum.161197DOI Listing
December 2017

Bone microstructure in men assessed by HR-pQCT: Associations with risk factors and differences between men with normal, low, and osteoporosis-range areal BMD.

Bone Rep 2016 Dec 2;5:312-319. Epub 2016 Nov 2.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, USA.

Purpose: The primary objective of this study was to analyze the relationships between bone microstructure and strength, and male osteoporosis risk factors including age, body mass index, serum 25-hydroxyvitamin D level, and testosterone level. A secondary objective was to compare microstructural and strength parameters between men with normal, low, and osteoporosis-range areal bone mineral density (aBMD).

Methods: Seventy-eight healthy male volunteers (mean age 62.4 ± 7.8 years, range 50-84 years) were recruited. The participants underwent dual-energy X-ray absorptiometry (DXA) and high-resolution peripheral quantitative computed tomography (HR-pQCT) of the ultra-distal radius and tibia. From the HR-pQCT images, volumetric bone mineral density (BMD) and cortical and trabecular bone microstructure were evaluated, and bone strength and cortical load fraction (Ct.LF) were estimated using micro-finite element analysis (μFEA).

Results: Age was more strongly correlated with bone microstructure than other risk factors. Age had significant positive correlations with cortical porosity at both ultra-distal radius and tibia ( = 0.36,  = 0.001, and  = 0.47,  < 0.001, respectively). At the tibia, age was negatively correlated with cortical BMD, whereas it was positively correlated with trabecular BMD. In μFEA, age was negatively correlated with Ct.LF, although not with bone strength. Compared with men with normal aBMD, men with low or osteoporosis-range aBMD had significantly poor trabecular bone microstructure and lower bone strength at the both sites, while there was no significant difference in cortical bone.

Conclusions: Cortical bone microstructure was negatively affected by aging, and there was a suggestion that the influence of aging may be particularly important at the weight-bearing sites.
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http://dx.doi.org/10.1016/j.bonr.2016.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5440848PMC
December 2016

Statistical Parametric Mapping of HR-pQCT Images: A Tool for Population-Based Local Comparisons of Micro-Scale Bone Features.

Ann Biomed Eng 2017 04 9;45(4):949-962. Epub 2016 Nov 9.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA.

HR-pQCT enables in vivo multi-parametric assessments of bone microstructure in the distal radius and distal tibia. Conventional HR-pQCT image analysis approaches summarize bone parameters into global scalars, discarding relevant spatial information. In this work, we demonstrate the feasibility and reliability of statistical parametric mapping (SPM) techniques for HR-pQCT studies, which enable population-based local comparisons of bone properties. We present voxel-based morphometry (VBM) to assess trabecular and cortical bone voxel-based features, and a surface-based framework to assess cortical bone features both in cross-sectional and longitudinal studies. In addition, we present tensor-based morphometry (TBM) to assess trabecular and cortical bone structural changes. The SPM techniques were evaluated based on scan-rescan HR-pQCT acquisitions with repositioning of the distal radius and distal tibia of 30 subjects. For VBM and surface-based SPM purposes, all scans were spatially normalized to common radial and tibial templates, while for TBM purposes, rescans (follow-up) were spatially normalized to their corresponding scans (baseline). VBM was evaluated based on maps of local bone volume fraction (BV/TV), homogenized volumetric bone mineral density (vBMD), and homogenized strain energy density (SED) derived from micro-finite element analysis; while the cortical bone framework was evaluated based on surface maps of cortical bone thickness, vBMD, and SED. Voxel-wise and vertex-wise comparisons of bone features were done between the groups of baseline and follow-up scans. TBM was evaluated based on mean square errors of determinants of Jacobians at baseline bone voxels. In both anatomical sites, voxel- and vertex-wise uni- and multi-parametric comparisons yielded non-significant differences, and TBM showed no artefactual bone loss or apposition. The presented SPM techniques demonstrated robust specificity thus warranting their application in future clinical HR-pQCT studies.
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http://dx.doi.org/10.1007/s10439-016-1754-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811200PMC
April 2017

Determining Metacarpophalangeal Flexion Angle Tolerance for Reliable Volumetric Joint Space Measurements by High-resolution Peripheral Quantitative Computed Tomography.

J Rheumatol 2016 10;43(10):1941-1944

From the Department of Medicine, Faculty of Medicine, University of Toronto, Toronto; Department of Mechanical Engineering, University of Waterloo, Waterloo, Ontario; McCaig Institute for Bone and Joint Health, University of Calgary; the departments of Radiology and Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Musculoskeletal Quantitative Imaging Research Group, Department of Radiology and Biomedical Imaging, University of California at San Francisco, San Francisco, California, USA; Institute for Biomechanics, ETH Zurich, Zurich, Switzerland; Schulich School of Engineering, University of Calgary; Faculty of Kinesiology, and Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada.S. Tom, MD, Rheumatology Resident, Department of Medicine, Faculty of Medicine, University of Toronto; M. Frayne, Bachelor of Applied Science Student, Mechanical Engineering, Department of Mechanical Engineering, University of Waterloo, and McCaig Institute for Bone and Joint Health, University of Calgary; S.L. Manske, PhD, Research Associate, McCaig Institute for Bone and Joint Health, University of Calgary, and Department of Radiology, Cumming School of Medicine, University of Calgary; A.J. Burghardt, BS, Research Specialist, Musculoskeletal Quantitative Imaging Research Group, Department of Radiology and Biomedical Imaging, University of California San Francisco; K.S. Stok, PhD, Senior Research Associate, Institute for Biomechanics, ETH Zurich; S.K. Boyd, PhD, Professor, Department of Radiology, McCaig Institute for Bone and Joint Health, and Department of Radiology, Cumming School of Medicine, and Schulich School of Engineering, and Faculty of Kinesiology, University of Calgary; C. Barnabe, MD, MSc, Assistant Professor, Department of Medicine and Department of Community Health Sciences, and McCaig Institute for Bone and Joint Health, University of Calgary.

Objective: The position-dependence of a method to measure the joint space of metacarpophalangeal (MCP) joints using high-resolution peripheral quantitative computed tomography (HR-pQCT) was studied.

Methods: Cadaveric MCP were imaged at 7 flexion angles between 0 and 30 degrees. The variability in reproducibility for mean, minimum, and maximum joint space widths and volume measurements was calculated for increasing degrees of flexion.

Results: Root mean square coefficient of variance values were < 5% under 20 degrees of flexion for mean, maximum, and volumetric joint spaces. Values for minimum joint space width were optimized under 10 degrees of flexion.

Conclusion: MCP joint space measurements should be acquired at < 10 degrees of flexion in longitudinal studies.
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http://dx.doi.org/10.3899/jrheum.160649DOI Listing
October 2016

Serum miRNA Signatures Are Indicative of Skeletal Fractures in Postmenopausal Women With and Without Type 2 Diabetes and Influence Osteogenic and Adipogenic Differentiation of Adipose Tissue-Derived Mesenchymal Stem Cells In Vitro.

J Bone Miner Res 2016 12 26;31(12):2173-2192. Epub 2016 Sep 26.

Musculoskeletal Quantitative Imaging Research Group, Department of Radiology & Biomedical Imaging, University of California San Francisco, San Francisco, CA, USA.

Standard DXA measurements, including Fracture Risk Assessment Tool (FRAX) scores, have shown limitations in assessing fracture risk in Type 2 Diabetes (T2D), underscoring the need for novel biomarkers and suggesting that other pathomechanisms may drive diabetic bone fragility. MicroRNAs (miRNAs) are secreted into the circulation from cells of various tissues proportional to local disease severity and were recently found to be crucial to bone homeostasis and T2D. Here, we studied, if and which circulating miRNAs or combinations of miRNAs can discriminate best fracture status in a well-characterized study of diabetic bone disease and postmenopausal osteoporosis (n = 80 postmenopausal women). We then tested the most discriminative and most frequent miRNAs in vitro. Using miRNA-qPCR-arrays, we showed that 48 miRNAs can differentiate fracture status in T2D women and that several combinations of four miRNAs can discriminate diabetes-related fractures with high specificity and sensitivity (area under the receiver-operating characteristic curve values [AUCs], 0.92 to 0.96; 95% CI, 0.88 to 0.98). For the osteoporotic study arm, 23 miRNAs were fracture-indicative and potential combinations of four miRNAs showed AUCs from 0.97 to 1.00 (95% CI, 0.93 to 1.00). Because a role in bone homeostasis for those miRNAs that were most discriminative and most present among all miRNA combinations had not been described, we performed in vitro functional studies in human adipose tissue-derived mesenchymal stem cells to investigate the effect of miR-550a-5p, miR-188-3p, and miR-382-3p on osteogenesis, adipogenesis, and cell proliferation. We found that miR-382-3p significantly enhanced osteogenic differentiation (p < 0.001), whereas miR-550a-5p inhibited this process (p < 0.001). Both miRNAs, miR-382-3p and miR-550a-5p, impaired adipogenic differentiation, whereas miR-188-3p did not exert an effect on adipogenesis. None of the miRNAs affected significantly cell proliferation. Our data suggest for the first time that miRNAs are linked to fragility fractures in T2D postmenopausal women and should be further investigated for their diagnostic potential and their detailed function in diabetic bone. © 2016 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.2897DOI Listing
December 2016

Kartogenin treatment prevented joint degeneration in a rodent model of osteoarthritis: A pilot study.

J Orthop Res 2016 10 1;34(10):1780-1789. Epub 2016 Mar 1.

Musculoskeletal Quantitative Imaging Research, Department of Radiology and Biomedical Imaging, University of California, San Francisco, California.

Osteoarthritis (OA) is a major degenerative joint disease characterized by progressive loss of articular cartilage, synovitis, subchondral bone changes, and osteophyte formation. Currently there is no treatment for OA except temporary pain relief and end-stage joint replacement surgery. We performed a pilot study to determine the effect of kartogenin (KGN, a small molecule) on both cartilage and subchondral bone in a rat model of OA using multimodal imaging techniques. OA was induced in rats (OA and KGN treatment group) by anterior cruciate ligament transection (ACLT) surgery in the right knee joint. Sham surgery was performed on the right knee joint of control group rats. KGN group rats received weekly intra-articular injection of 125 μM KGN 1 week after surgery until week 12. All rats underwent in vivo magnetic resonance imaging (MRI) at 3, 6, and 12 weeks after surgery. Quantitative MR relaxation measures (T and T ) were determined to evaluate changes in articular cartilage. Cartilage and bone turnover markers (COMP and CTX-I) were determined at baseline, 3, 6, and 12 weeks. Animals were sacrificed at week 12 and the knee joints were removed for micro-computed tomography (micro-CT) and histology. KGN treatment significantly lowered the T and T relaxation times indicating decreased cartilage degradation. KGN treatment significantly decreased COMP and CTX-I levels indicating decreased cartilage and bone turnover rate. KGN treatment also prevented subchondral bone changes in the ACLT rat model of OA. Thus, kartogenin is a potential drug to prevent joint deterioration in post-traumatic OA. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1780-1789, 2016.
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http://dx.doi.org/10.1002/jor.23197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348064PMC
October 2016

Microarchitecture and Peripheral BMD are Impaired in Postmenopausal White Women With Fracture Independently of Total Hip T-Score: An International Multicenter Study.

J Bone Miner Res 2016 06;31(6):1158-66

College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.

Because single-center studies have reported conflicting associations between microarchitecture and fracture prevalence, we included high-resolution peripheral quantitative computed tomography (HR-pQCT) data from five centers worldwide into a large multicenter analysis of postmenopausal women with and without fracture. Volumetric BMD (vBMD) and microarchitecture were assessed at the distal radius and tibia in 1379 white postmenopausal women (age 67 ± 8 years); 470 (34%) had at least one fracture including 349 with a major fragility fracture. Age, height, weight, and total hip T-score differed across centers and were employed as covariates in analyses. Women with fracture had higher BMI, were older, and had lower total hip T-score, but lumbar spine T-score was similar between groups. At the radius, total and trabecular vBMD and cortical thickness were significantly lower in fractured women in three out of five centers, and trabecular number in two centers. Similar results were found at the tibia. When data from five centers were combined, however, women with fracture had significantly lower total, trabecular, and cortical vBMD (2% to 7%), lower trabecular number (4% to 5%), and thinner cortices (5% to 6%) than women without fracture after adjustment for covariates. Results were similar at the radius and tibia. Similar results were observed with analysis restricted to major fragility fracture, vertebral and hip fractures, and peripheral fracture (at the radius). When focusing on osteopenic women, each SD decrease of total and trabecular vBMD was associated with a significantly increased risk of major fragility fracture (OR = 1.55 to 1.88, p < 0.01) after adjustment for covariates. Moreover, trabecular architecture modestly improved fracture discrimination beyond peripheral total vBMD. In conclusion, we observed differences by center in the magnitude of fracture/nonfracture differences at both the distal radius and tibia. However, when data were pooled across centers and the sample size increased, we observed significant and consistent deficits in vBMD and microarchitecture independent of total hip T-score in all postmenopausal white women with fracture and in the subgroup of osteopenic women, compared to women who never had a fracture. © 2016 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.2796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891284PMC
June 2016

Automatic multi-parametric quantification of the proximal femur with quantitative computed tomography.

Quant Imaging Med Surg 2015 Aug;5(4):552-68

1 Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA ; 2 Department of Endocrinology, Creighton University, Omaha, NE, USA ; 3 Department of Radiological Sciences, Department of Mechanical and Aerospace Engineering, Department of Biomedical Engineering, and Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, CA, USA ; 4 Intramural Research Program, National Institute on Aging, Bethesda, Maryland, USA ; 5 Division of Endocrinology, Diabetes, Metabolism and Nutrition, Department of Internal Medicine, College of Medicine, Mayo Clinic, Rochester, MN, USA.

Background: Quantitative computed tomography (QCT) imaging is the basis for multiple assessments of bone quality in the proximal femur, including volumetric bone mineral density (vBMD), tissue volume, estimation of bone strength using finite element modeling (FEM), cortical bone thickness, and computational-anatomy-based morphometry assessments.

Methods: Here, we present an automatic framework to perform a multi-parametric QCT quantification of the proximal femur. In this framework, the proximal femur is cropped from the bilateral hip scans, segmented using a multi-atlas based segmentation approach, and then assigned volumes of interest through the registration of a proximal femoral template. The proximal femur is then subjected to compartmental vBMD, compartmental tissue volume, FEM bone strength, compartmental surface-based cortical bone thickness, compartmental surface-based vBMD, local surface-based cortical bone thickness, and local surface-based cortical vBMD computations. Consequently, the template registrations together with vBMD and surface-based cortical bone parametric maps enable computational anatomy studies. The accuracy of the segmentation was validated against manual segmentations of 80 scans from two clinical facilities, while the multi-parametric reproducibility was evaluated using repeat scans with repositioning from 22 subjects obtained on CT imaging systems from two manufacturers.

Results: Accuracy results yielded a mean dice similarity coefficient of 0.976±0.006, and a modified Haussdorf distance of 0.219±0.071 mm. Reproducibility of QCT-derived parameters yielded root mean square coefficients of variation (CVRMS) between 0.89-1.66% for compartmental vBMD; 0.20-1.82% for compartmental tissue volume; 3.51-3.59% for FEM bone strength; 1.89-2.69% for compartmental surface-based cortical bone thickness; and 1.08-2.19% for compartmental surface-based cortical vBMD. For local surface-based assessments, mean CVRMS were between 3.45-3.91% and 2.74-3.15% for cortical bone thickness and vBMD, respectively.

Conclusions: The automatic framework presented here enables accurate and reproducible QCT multi-parametric analyses of the proximal femur. Our subjects were elderly, with scans obtained across multiple clinical sites and manufacturers, thus documenting its value for clinical trials and other multi-site studies.
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http://dx.doi.org/10.3978/j.issn.2223-4292.2015.08.02DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4559986PMC
August 2015

Quantitative characterization of metacarpal and radial bone in rheumatoid arthritis using high resolution- peripheral quantitative computed tomography.

Int J Rheum Dis 2017 Mar 10;20(3):353-362. Epub 2015 Apr 10.

Musculoskeletal Quantitative Imaging Research Group, Department of Radiology and Biomedical Imaging, University of California San Francisco (UCSF), San Francisco, CA, USA.

Aim: The objectives of this study were: (i) to develop a standardized method of quantifying bone mineral density (BMD) and microarchitecture in the hand and wrist bones of patients with rheumatoid arthritis (RA) using high resolution- peripheral quantitative computed tomography (HR-pQCT); (ii) to compare quantitative bone parameters between RA and post-menopausal osteopenic (PM-OP) subjects; and (iii) to correlate quantitative bone parameters at the distal radius with those at the metacarpal heads in RA subjects.

Methods: HR-pQCT imaging of the dominant hand and wrist was performed in 12 female RA patients. BMD and trabecular parameters for the 2-12% head region of the second and third metacarpals were calculated and compared between RA patients and healthy controls. Bone parameters were also calculated for 110 slices of the distal radius in RA patients and compared to data from controls and PM-OP women from a previous study.

Results: Compared to controls, RA patients had significantly decreased BMD, trabecular volume and number, and increased trabecular heterogeneity in the third metacarpal and distal radius. Significantly lower trabecular number and significantly higher ratio of outer annular trabecular BMD to inner trabecular BMD were observed in patients with RA, compared to patients with osteopenia (P < 0.05). Trabecular BMD in the third metacarpal and in the distal radius were significantly correlated (ρ = 0.918, P < 0.0001) in RA patients.

Conclusion: This study established a standardized method for quantifying bone density and trabecular properties in the hand and wrist bones of RA patients using HR-pQCT. Deterioration of bone structure in RA patients was found comparable to that in osteopenic women, and trabecular bone loss near affected joints was found to be correlated with bone loss away from joints.
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http://dx.doi.org/10.1111/1756-185X.12558DOI Listing
March 2017

Spatial distribution of intracortical porosity varies across age and sex.

Bone 2015 Jun 17;75:88-95. Epub 2015 Feb 17.

Musculoskeletal Quantitative Imaging Research Group, Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA. Electronic address:

Cortical bone porosity is a major determinant of strength, stiffness, and fracture toughness of cortical tissue. The goal of this work was to investigate changes in spatial distribution and microstructure of cortical porosity associated with aging in men and women. The specific aims were to: 1) develop an automated technique for spatial analysis of cortical microstructure based on HR-pQCT data, and; 2) apply this technique to explore sex- and age-specific spatial distribution and microstructure of porosity within the cortex. We evaluated HR-pQCT images of the distal tibia from a cross-sectional cohort of 145 individuals, characterizing detectable pores as being in the endosteal, midcortical, or periosteal layers of the cortex. Metrics describing porosity, pore number, and pore size were quantified within each layer and compared across sexes, age groups, and cortical layers. The elderly cohort (65-78 years, n=22) displayed higher values than the young cohort (20-29 years, n=29) for all parameters both globally and within each layer. While all three layers displayed significant age-related porosity increases, the greatest difference in porosity between the young and elderly cohort was in the midcortical layer (+344%, p<0.001). Similarly, the midcortical layer reflected the greatest differences between young and elderly cohorts in both pore number (+243%, p<0.001) and size (+28%, p<0.001). Females displayed greater age-related changes in porosity and pore number than males. Females and males displayed comparable small to non-significant changes with age in pore size. In summary, considerable variability exists in the spatial distribution of detectable cortical porosity at the distal tibia, and this variability is dependent on age and sex. Intracortical pore distribution analysis may ultimately provide insight into both mechanisms of pore network expansion and biomechanical consequences of pore distribution.
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http://dx.doi.org/10.1016/j.bone.2015.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4454740PMC
June 2015

Validation of bone marrow fat quantification in the presence of trabecular bone using MRI.

J Magn Reson Imaging 2015 Aug 25;42(2):539-44. Epub 2014 Nov 25.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California, USA.

Background: To validate six-echo, chemical-shift based MRI with T2 * correction for the quantification of bone marrow fat content in the presence of trabecular bone.

Methods: Ten bone phantoms were made using trabecular bone cores extracted from the distal femur and proximal tibia of 20 human cadaveric knees. Bone marrow was removed from the cores and the marrow spaces were filled with water-fat gelatin to mimic bone marrow of known fat fractions. A chemical-shift based water-fat separation method with T2 * correction was used to generate fat fraction maps. The proton density fat fractions (PDFF) between marrow regions with and without bone were compared with the reference standard of known fat fraction using the squared Pearson correlation coefficient and unpaired t-test.

Results: Strong correlations were found between the known fat fraction and measured PDFF in marrow without trabecular bone (R(2) = 0.99; slope = 0.99, intercept = 0.94) as well as in marrow with trabecular bone (R(2) = 0.97; slope = 1.0, intercept = -3.58). Measured PDFF between regions with and without bone were not significantly different (P = 0.5). However, PDFF was systematically underestimated by -3.2% fat fraction in regions containing trabecular bone.

Conclusion: Our implementation of a six-echo chemical-shift based MRI pulse sequence with T2 * correction provided an accurate means of determining fat content in bone marrow in the presence of trabecular bone.
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http://dx.doi.org/10.1002/jmri.24795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4442769PMC
August 2015

Correlation of structural abnormalities of the wrist and metacarpophalangeal joints evaluated by high-resolution peripheral quantitative computed tomography, 3 Tesla magnetic resonance imaging and conventional radiographs in rheumatoid arthritis.

Int J Rheum Dis 2015 Jul 8;18(6):628-39. Epub 2014 Oct 8.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California, USA.

Aim: In rheumatoid arthritis (RA) hands, we applied high-resolution peripheral quantitative computed tomography (HR-pQCT) and 3 Tesla (3 T) magnetic resonance imaging (MRI), which are new methods for erosion detection and bone marrow edema (BME) quantification. We compared the erosion measurements between these techniques with conventional radiographs (CR) in order to examine their significance for evaluating structural abnormalities.

Methods: In 16 RA patients, HR-pQCT of metacarpophalangeal and wrist joints, 3 T MRI of wrist joints, as well as CR in both hands and feet were performed. Ten patients had 1-year follow-up CR. CRs were graded according to the modified Sharp score (MSS). Bone erosions were evaluated in HR-pQCT and MRI. BME pattern was quantified from MRI for volume, signal change and total burden.

Results: The erosion detection sensitivity of MRI was 85.7% and CR was 60.9% when HR-pQCT was considered as a reference method. The smallest dimensions of erosion detected by HR-pQCT, MRI and CR were 0.09, 0.14 and 0.66 cm, respectively. Baseline total MSS was correlated with HR-pQCT erosion measures, MRI erosion measures and MRI BME volume (P < 0.05). The mean difference between baseline and 1-year follow-up MSS (delta MSS) was 1.2. A trend was observed toward a correlation between delta MSS and MRI BME volume and burden.

Conclusion: This study demonstrates that HR-pQCT detects more and smaller bone erosions compared to MRI and CR. In addition, 3 T MRI can provide quantitative measurement of BME. Combination of HR-pQCT and MRI modalities may provide powerful tools to evaluate joint inflammation and bone damage in RA.
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http://dx.doi.org/10.1111/1756-185X.12495DOI Listing
July 2015

Improved trabecular bone structure of 20-month-old male spontaneously hypertensive rats.

Calcif Tissue Int 2014 Sep 9;95(3):282-91. Epub 2014 Aug 9.

Physics Research Laboratory, Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA.

A few clinical studies have reported that elderly male participants with hypertensive disease frequently have higher bone mineral density (BMD) than the normotensive participants at several skeletal sites. The detailed mechanism is still unknown; therefore, a study of bone structure and density using the hypertensive animal models could be informative. We used micro-computed tomography to quantitatively evaluate the tibial and 3rd lumbar vertebral bones in the 20-month-old male spontaneous hypertensive rat (SHR). The BMD, volume fraction, and the microarchitecture changes of the SHR were compared to those of same-age normotensive controls (Wistar-Kyoto rat, WKY). We found that in the very old (20 month) male rats, the trabecular bone fraction and microstructure were higher than those in the same-age normotensive controls. The observation of the association of hypertension with BMD and bone strength in hypertensive rats warrants further investigations of bone mass and strength in elderly males with hypertension.
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http://dx.doi.org/10.1007/s00223-014-9893-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4153466PMC
September 2014

Bone structure and perfusion quantification of bone marrow edema pattern in the wrist of patients with rheumatoid arthritis: a multimodality study.

J Rheumatol 2014 Sep 1;41(9):1766-73. Epub 2014 Aug 1.

From the Musculoskeletal Quantitative Imaging Research Group, Department of Radiology and Biomedical Imaging, University of California, San Francisco; San Francisco, California, USA.J.R. Teruel, MSc, Research Fellow, Department of Radiology and Biomedical Imaging, University of California, San Francisco (UCSF); PhD Candidate, Department of Circulation and Medical Imaging, Norwegian University of Science and Technology (NTNU), Trondheim, Norway; A.J. Burghardt, Researcher, Department of Radiology and Biomedical Imaging, UCSF; J. Rivoire, PhD, Postdoctoral Research Fellow, Department of Radiology and Biomedical Imaging, UCSF; W. Srikhum, MD, Research Fellow, Department of Radiology and Biomedical Imaging, UCSF; Lecturer in Radiology, Department of Radiology, Thammasat University, Pathum Thani, Thailand; S.M. Noworolski, PhD, Associate Professor, Department of Radiology and Biomedical Imaging, UCSF; T.M. Link, MD, PhD, Professor of Radiology, Chief, Musculoskeletal Imaging and Clinical Director, Musculoskeletal and Quantitative Imaging Research Group, Department of Radiology and Biomedical Imaging, UCSF; J.B. Imboden, MD, Professor of Rheumatology, Department of Medicine, UCSF; X. Li, PhD, Associate Professor, Department of Radiology and Biomedical Imaging, UCSF.

Objective: To quantify bone structure and perfusion parameters in regions of bone marrow edema pattern (BMEP), non-edematous bone marrow (NBM), and pannus tissue areas in the wrists of patients with rheumatoid arthritis (RA) using 3-Tesla (3T) magnetic resonance imaging (MRI), and high resolution peripheral quantitative computed tomography (HR-pQCT).

Methods: Sixteen subjects fulfilling American College of Rheumatology classification were imaged using a HR-pQCT system and a 3T MRI scanner with an 8-channel wrist coil. Coronal T2-weighted and dynamic contrast-enhanced (DCE-MRI) images were acquired. BMEP and pannus tissue areas were segmented semiautomatically in T2-weighted images. NBM areas were placed at a similar distance from the joint space as BMEP regions. MR and HR-pQCT images were registered, and bone variables were calculated within the BMEP and NBM regions. Perfusion parameters in BMEP, pannus tissue, and NBM regions were calculated based on the signal-time curve obtained from DCE-MRI.

Results: Eighteen BMEP areas were segmented, 15 of them presented proximal to pannus-filled erosions. Significant increases in bone density and trabecular thickness and number were observed in all BMEP regions compared to NMB (p < 0.05). Significantly elevated perfusion measures were observed in both BMEP and pannus tissue regions compared to NBM (p < 0.05).

Conclusion: BMEP regions showed significantly increased bone density and structures as well as perfusion measures, suggesting bone remodeling and active inflammation. Combining MRI and HR-pQCT provides a powerful multimodality approach for understanding BMEP and erosions, and for potentially identifying novel imaging markers for disease progression in RA.
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http://dx.doi.org/10.3899/jrheum.131564DOI Listing
September 2014

Three-dimensional analysis of subchondral cysts in hip osteoarthritis: an ex vivo HR-pQCT study.

Bone 2014 Sep 10;66:140-5. Epub 2014 Jun 10.

Musculoskeletal Quantitative Imaging Research Group, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA.

Introduction: Subchondral cysts are deeply related to the pathogenesis of osteoarthritis (OA), but the factors contributing to cyst formation are not well known. A three-dimensional analysis of subchondral cysts at the micro-structural level was conducted using a high-resolution peripheral quantitative CT (HR-pQCT), and their relationships with cartilage attrition and subchondral bone microstructure were investigated.

Methods: Femoral heads extracted from ten female patients with hip OA were scanned using an HR-pQCT at a voxel size of 41μm. The volume fractions, numbers, and sizes of the cysts were measured in the subchondral bone region under the area of cartilage loss. Furthermore, the areas of cartilage loss, as well as the microstructure of the subchondral bones, were also measured, and their correlations with the cysts were analyzed.

Results: The volume fractions of cysts within subchondral bone regions varied from 2% to 33%, the numbers of cysts varied from 6 to 87, and the sizes varied from 1mm(3) to 657mm(3). There was a positive correlation between the number of cysts and bone volume (r>0.8, p<0.01).

Conclusion: The degree of cyst formation showed a wide distribution in number and volume, and there was a close relationship between multiple cyst formation and bone sclerosis, which might be caused by reactive bone formation that occurred around each cyst.
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http://dx.doi.org/10.1016/j.bone.2014.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4125434PMC
September 2014

The influence of disuse on bone microstructure and mechanics assessed by HR-pQCT.

Bone 2014 Jun 3;63:132-40. Epub 2014 Mar 3.

Department of Orthopaedic Surgery, University of California, San Francisco, San Francisco, CA, USA. Electronic address:

Numerous clinical cohorts are exposed to reduced skeletal loading and associated bone loss, including surgical patients, stroke and spinal cord injury victims, and women on bed rest during pregnancy. In this context, understanding disuse-related bone loss is critical to developing interventions to prevent fractures and the associated morbidity, mortality, and cost to the health care system. The aim of this pilot study was to use high-resolution peripheral QCT (HR-pQCT) to examine changes in trabecular and cortical microstructure and biomechanics during a period of non weight bearing (WB) and during recovery following return to normal WB. Surgical patients requiring a 6-week non WB period (n=12, 34.8±7.7 yrs) were scanned at the affected and contralateral tibia prior to surgery, after the 6-week non WB period, and 6 and 13 weeks after returning to full WB. At the affected ultradistal tibia, integral vBMD (including both trabecular and cortical compartments) decreased with respect to baseline (-1.2%), trabecular number increased (+5.6%), while trabecular thickness (-5.4%), separation (-4.6%), and heterogeneity (-7.2%) decreased (all p<0.05). Six weeks after return to full WB, trabecular structure measures reverted to baseline levels. In contrast, integral vBMD continued to decrease after 6 (-2.0%, p<0.05) and 13 weeks (-2.5%, p=0.07) of full WB. At the affected distal site, the disuse period resulted in increased porosity (+16.1%, p<0.005), which remained elevated after 6 weeks (+16.8%, p<0.01) and after 13 weeks (+16.2%, p<0.05). A novel topological analysis applied to the distal tibia cortex demonstrated increased number of canals with surface topology ("slabs" +21.7%, p<0.01) and curve topology ("tubes" +15.0%, p<0.05) as well as increased number of canal junctions (+21.4%, p<0.05) following the disuse period. Porosity increased uniformly through increases in both pore size and number. Finite element analysis at the ultradistal tibia showed decreased stiffness and failure load (-2.8% and -2.4%, p<0.01) following non WB. These biomechanical predictions remained depressed following 6 and 13 weeks of full WB. Finite element analysis at the distal site followed similar trends. Our results suggest that detectable microstructural and biomechanical degradation occurs--particularly within the cortical compartment--as a result of non WB and persists following return to normal loading. A better understanding of these microstructural changes and their short- and long-term influence on biomechanics may have clinical relevance in the context of disuse-related fracture prevention.
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http://dx.doi.org/10.1016/j.bone.2014.02.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4041600PMC
June 2014

Structural analysis of cortical porosity applied to HR-pQCT data.

Med Phys 2014 Jan;41(1):013701

Musculoskeletal Quantitative Imaging Research Group, Department of Radiology and Biomedical Imaging, University of California, San Francisco, California 94107.

Purpose: The investigation of cortical porosity is an important aspect of understanding biological, pathoetiological, and biomechanical processes occurring within the skeleton. With the emergence of HR-pQCT as a noninvasive tool suitable for clinical use, cortical porosity at appendicular sites can be directly visualized in vivo. The aim of this study was to introduce a novel topological analysis of the cortical pore network for HR-pQCT data and determine the influence of resolution on measures of cortical pore network microstructure and topology.

Methods: Cadaveric radii were scanned using HR-pQCT at two different voxel sizes (41 and 82 μm) and also using μCT at a voxel size of 18 μm. HR-pQCT and μCT image sets were spatially coregistered. Segmentation and quantification of cortical porosity (Ct.Po) and mean pore diameter (Ct.Po.Dm) were achieved using an established extended cortical analysis technique. Topological classification of individual pores was performed using topology-preserving skeletonization and multicolor dilation algorithms. Based on the pore skeleton topological classification, the following parameters were quantified: total number of planar surface-skeleton canals (N.Slabs), tubular curve-skeleton canals (N.Tubes), and junction elements (N.Junctions), mean slab volume (Slab.Vol), mean tube volume (Tube.Vol), mean slab orientation (Slab.θ), mean tube orientation (Tube.θ), N.Slabs/N.Tubes, and integral (total) slab volume/integral tube volume (iSlab.Vol/iTube.Vol). An in vivo reproducibility study was also conducted to assess short-term precision of the topology parameters. Precision error was characterized using root mean square coefficient of variation (RMSCV%).

Results: Correlations to μCT values for Ct.Po were significant for both the 41 and 82 μm HR-pQCT data (41: r(2) = 0.82, p < 0.001, 82: r(2) = 0.75, p < 0.001). For Ct.Po.Dm, only the 41 μm data were significantly predictive of μCT values (r(2) = 0.72, p < 0.01) Data at both HR-pQCT voxel sizes were strongly predictive of the μCT values for N.Slabs (41: r(2) = 0.93, p < 0.001; 82: r(2) = 0.84, p < 0.001), N.Tubes (41: r(2) = 0.94, p < 0.001; 82: r(2) = 0.84, p < 0.001), and N.Junctions (41: r(2) = 0.93, p < 0.001; 82: r(2) = 0.78, p < 0.001), though proportional bias was evident in these correlations. Weak correlations were seen for iSlab.Vol/iTube.Vol at both voxel sizes (41: r(2) = 0.52, p < 0.01; 82: r(2) = 0.39, p < 0.05). Slab.Vol was significantly correlated to μCT data at 41 μm (r(2) = 0.60, p < 0.01) but not at 82 μm, while Tube.Vol was significantly correlated at both voxel sizes (41: r(2) = 0.79, p < 0.001; 82: r(2) = 0.68, p < 0.01). In vivo precision error for these parameters ranged from 2.31 to 9.68 RMSCV%.

Conclusions: Strong correlations between μCT- and HR-pQCT-derived measurements were found, particularly in HR-pQCT images obtained at 41 μm. These data are in agreement with our previous study investigating the effect of voxel size on standard HR-pQCT metrics of trabecular and cortical microstructure, and extend our previous findings to include topological descriptors of the cortical pore network.
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http://dx.doi.org/10.1118/1.4851575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895089PMC
January 2014

Quantification of lower leg arterial calcifications by high-resolution peripheral quantitative computed tomography.

Bone 2014 Jan 14;58:42-7. Epub 2013 Aug 14.

Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria. Electronic address:

Vascular calcifications and bone health seem to be etiologically linked via common risk factors such as aging and subclinical chronic inflammation. Epidemiologic studies have shown significant associations between low bone mineral density (BMD), fragility fractures and calcifications of the coronary arteries and the abdominal aorta. In the last decade, high-resolution peripheral quantitative computed tomography (HR-pQCT) has emerged as in-vivo research tool for the assessment of peripheral bone geometry, density, and microarchitecture. Although vascular calcifications are frequently observed as incidental findings in HR-pQCT scans, they have not yet been incorporated into quantitative HR-pQCT analyses. We developed a semi-automated algorithm to quantify lower leg arterial calcifications (LLACs), captured by HR-pQCT. The objective of our study was to determine validity and reliability of the LLAC measure. HR-pQCT scans were downscaled to a voxel size of 250μm. After subtraction of bone volumes from the scans, LLACs were detected and contoured by a semi-automated, dual-threshold seed-point segmentation. LLAC mass (in mg hydroxyapatite; HA) was calculated as the product of voxel-based calcification volume (mm(3)) and mean calcification density (mgHA/cm(3))/1000. To determine validity, we compared LLACs to coronary artery calcifications (CACs), as quantified by multi-detector computed tomography (MDCT) and Agatston scoring in forty-six patients on chronic hemodialysis. Moreover, we investigated associations of LLACs with age, time on dialysis, type-2 diabetes mellitus, history of stroke, and myocardial infarction. In a second step, we determined intra- and inter-reader reliability of the LLAC measure. In the validity study, LLACs were present (>0mgHA) in 76% of patients, 78% of patients had CACs (>0mgHA). Median LLAC was 6.65 (0.08-24.40)mgHA and median CAC as expressed by Agatston score was 266.3 (15.88-1877.28). We found a significant positive correlation between LLAC and CAC (rho=0.6; p<0.01). Dialysis patients with type-2 diabetes mellitus (DM; 35%) and history of stroke (13%) had higher median LLAC than patients without those conditions (DM 20.0 fold greater, p=0.006; Stroke 5.1 fold greater, p=0.047). LLAC was positively correlated with time on dialysis (rho=0.337, p=0.029), there was a trend towards a positive association of LLAC and age (rho=0.289, p=0.053). The reliability study yielded excellent intra- and inter-reader agreement of the LLAC measure (intra-reader ICC=0.999, 95% CI=0.998-1.000; inter-reader ICC=0.998, 95% CI=0.994-0.999). Our study indicates that the LLAC measure has good validity and excellent reliability. The use of HR-pQCT for the simultaneous evaluation of arterial calcifications, peripheral bone geometry, bone density, and bone microarchitecture should facilitate future research on osteo-vascular interactions and potential associations with cardiovascular events.
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http://dx.doi.org/10.1016/j.bone.2013.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4042679PMC
January 2014

Quantitative in vivo HR-pQCT imaging of 3D wrist and metacarpophalangeal joint space width in rheumatoid arthritis.

Ann Biomed Eng 2013 Dec 26;41(12):2553-64. Epub 2013 Jul 26.

Musculoskeletal Quantitative Imaging Research Group, Department of Radiology and Biomedical Imaging, University of California, San Francisco, QB3 Building, Suite 203, 1700 4th St, San Francisco, CA, 94158, USA,

In this technique development study, high-resolution peripheral quantitative computed tomography (HR-pQCT) was applied to non-invasively image and quantify 3D joint space morphology of the wrist and metacarpophalangeal (MCP) joints of patients with rheumatoid arthritis (RA). HR-pQCT imaging (82 μm voxel-size) of the dominant hand was performed in patients with diagnosed rheumatoid arthritis (RA, N = 16, age: 52.6 ± 12.8) and healthy controls (CTRL, N = 7, age: 50.1 ± 15.0). An automated computer algorithm was developed to segment wrist and MCP joint spaces. The 3D distance transformation method was applied to spatially map joint space width, and summarized by the mean joint space width (JSW), minimal and maximal JSW (JSW.MIN, JSW.MAX), asymmetry (JSW.AS), and distribution (JSW.SD)-a measure of joint space heterogeneity. In vivo precision was determined for each measure by calculating the smallest detectable difference (SDD) and root mean square coefficient of variation (RMSCV%) of repeat scans. Qualitatively, HR-pQCT images and pseudo-color JSW maps showed global joint space narrowing, as well as regional and focal abnormalities in RA patients. In patients with radiographic JSN at an MCP, JSW.SD was two-fold greater vs. CTRL (p < 0.01), and JSW.MIN was more than two-fold lower (p < 0.001). Similarly, JSW.SD was significantly greater in the wrist of RA patients vs. CTRL (p < 0.05). In vivo precision was highest for JSW (SDD: 100 μm, RMSCV: 2.1%) while the SDD for JSW.MIN and JSW.SD were 370 and 110 μm, respectively. This study suggests that in vivo quantification of 3D joint space morphology from HR-pQCT, could improve early detection of joint damage in rheumatological diseases.
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http://dx.doi.org/10.1007/s10439-013-0871-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3823828PMC
December 2013

Heterogeneity of bone microstructure in the femoral head in patients with osteoporosis: an ex vivo HR-pQCT study.

Bone 2013 Sep 6;56(1):139-46. Epub 2013 Jun 6.

Musculoskeletal Quantitative Imaging Research Group, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA.

Introduction: Trabecular bone in the femoral head has a complicated and heterogeneous structure with few studies having analyzed heterogeneity in this structure quantitatively. We analyze trabecular bone microstructure in the femoral head with osteoporosis (OP) using high resolution peripheral quantitative CT (HR-pQCT) to investigate its regional characteristics.

Methods: Fifteen femoral heads extracted from female OP patients with femoral neck fracture (85 ± 7, 67-94 years) were scanned by HR-pQCT at 41 μm voxel size. The femoral head was segmented into 15 regions (3 longitudinal regions: superior, center, and inferior, and 5 axial subregions: center, medial, lateral, anterior, posterior). Of these 15 regions, five were excluded due to overlap with the fracture site, leaving a total of 10 regions of cancellous bone microstructures to be quantitatively assessed using the following parameters: bone volume fraction, trabecular thickness, number, separation, connectivity density, structure model index, and degree and orientation of anisotropy. These parameters were compared among each region.

Results: Trabecular bone at the center, superior, and supero-posterior regions of the femoral head had higher bone volume, trabecular number, thickness, narrower bone marrow spaces, higher connectivity and anisotropy, and more plate-like structure. This plate-like structure ran supero-inferiorly and antero-posteriorly at the superior and center regions. Bone volume at the anterior, posterior, and medial regions was almost half of the central and superior regions.

Conclusion: Significant heterogeneity of the trabecular bone microstructure in the OP femoral head was showed quantitatively in this study. These data offer new insight into bone microstructural anatomy and may prove to provide useful information on clinical medicine such as hip surgeries.
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http://dx.doi.org/10.1016/j.bone.2013.05.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3740186PMC
September 2013