Klaus Engelke

Clinical use of quantitative computed tomography and peripheral quantitative computed tomography in the management of osteoporosis in adults: the 2007 ISCD Official Positions.

The International Society for Clinical Densitometry (ISCD) has developed Official Positions for the clinical use of dual-energy X-ray absorptiometry (DXA) and non-DXA technologies. While only DXA can be used for diagnostic classification according to criteria established by the World Health Organization, DXA and some other technologies may predict fracture risk and be used to monitor skeletal changes over time. ISCD task forces reviewed the evidence for clinical applications of non-DXA techniques and presented reports with recommendations at the 2007 ISCD Position Development Conference. Here we present the ISCD Official Positions for quantitative computed tomography (QCT) and peripheral QCT (pQCT), with supporting medical evidence, rationale, controversy, and suggestions for further study. QCT is available for bone mineral density measurements at the spine, hip, forearm, and tibia. The ISCD Official Positions presented here focus on QCT of the spine and pQCT of the forearm. Measurements at the hip may have clinical relevance, as this is an important fracture site; however, due to limited medical evidence, definitive advice on its use in clinical practice cannot be provided until more data emerge.

A new accurate and precise 3-D segmentation method for skeletal structures in volumetric CT data

We developed a highly automated three-dimensionally based method for the segmentation of bone in volumetric computed tomography (CT) datasets. The multistep approach starts with three-dimensional (3-D) region-growing using local adaptive thresholds followed by procedures to correct for remaining boundary discontinuities and a subsequent anatomically oriented boundary adjustment using local values of cortical bone density. We describe the details of our approach and show applications in the proximal femur, the knee, and the skull. The accuracy of the determination of geometrical parameters was analyzed using CT scans of the semi-anthropomorphic European spine phantom. Depending on the settings of the segmentation parameters cortical thickness could be determined with an accuracy corresponding to the side length of 1 to 2.5 voxels. The impact of noise on the segmentation was investigated by artificially adding noise to the CT data. An increase in noise by factors of two and five changed cortical thickness corresponding to the side length of one voxel. Intraoperator and interoperator precision was analyzed by repeated analysis of nine pelvic CT scans. Precision errors were smaller than 1% for trabecular and total volumes and smaller than 2% for cortical thickness. Intraoperator and interoperator precision errors were not significantly different. Our segmentation approach shows: 1) high accuracy and precision and is 2) robust to noise, 3) insensitive to user-defined thresholds, 4) highly automated and fast, and 5) easy to initialize.

Accuracy limits for the determination of cortical width and density: the influence of object size and CT imaging parameters

In this study we analysed the accuracy of computed tomography (CT) measurements in assessing cortical bone. We determined the dependency of thickness and density measurements on the true width and density of the cortex and on the spatial resolution in the CT images using two optimized segmentation methods. As a secondary goal, we assessed the ability of CT to reflect small changes in cortical thickness. Two different bone-mimicking phantoms with varying cortical thickness were scanned with single-slice CT on a Somatom Plus 4 scanner. Images were reconstructed with both a standard and a high-resolution convolution kernel. Two special operator-independent segmentation methods were used to automatically detect the edges of the cortical shell. We measured cortical thickness and density and compared the phantom measurements with theoretical computations by simulating a cross-sectional shape of the cortical shell. Based on the simulations, we calculated CTs power to detect small changes in cortical thickness. Simulations and phantom measurements were in very good agreement. Cortical thickness could be measured with an error of less than 10% if the true thickness was larger than 0.9 (0.7) mm for the standard (high-resolution) kernel which is close to the full width at half maximum (FWHM) of the point spread functions for these kernels and our scanner. Density measurements yielded errors of less than 10% for true cortical thickness values above two to three times the FWHM corresponding to 2.5 (2) mm in our case. The simulations showed that a 10% change in cortical width would not be detected with satisfying probability in bones with a cortical shell thinner than 1.2 mm. An accurate determination of the cortical thickness is limited to bones with a thickness higher than the FWHM of the scanners point spread function. Therefore, the use of a high-resolution reconstruction kernel is crucial. Cortical bone mineral density can only be measured accurately in bones two to three times thicker than this number. In thinner bones, the measured density becomes dependent on the thickness. Changes in cortical thickness can only be assessed if the change is rather large or if the measured bone has sufficient thickness. Therefore, assessing density or thickness of the vertebral shell by CT should be treated with caution.

Advanced CT bone imaging in osteoporosis

Non-invasive and/or non-destructive techniques can provide structural information about bone, beyond simple bone densitometry. While the latter provides important information about osteoporotic fracture risk, many studies indicate that BMD only partly explains bone strength. Quantitative assessment of macro- and microstructural features may improve our ability to estimate bone strength. Methods for quantitatively assessing macrostructure include (besides conventional radiographs) DXA and CT, particularly volumetric quantitative CT (vQCT). Methods for assessing microstructure of trabecular bone non-invasively and/or non-destructively include high-resolution CT (hrCT), microCT (μCT), high-resolution magnetic resonance (hrMR) and microMR (μMR). vQCT, hrCT and hrMR are generally applicable in vivo; μCT and μMR are principally applicable in vitro. Despite recent progress made with these advanced imaging techniques, certain issues remain. The important balances between spatial resolution and sampling size, or between signal-to-noise and radiation dose or acquisition time, need further consideration, as do the complexity and expense of the methods vs their availability and accessibility. Clinically, the challenges for bone imaging include balancing the advantages of simple bone densitometry vs the more complex architectural features of bone or the deeper research requirements vs the broader clinical needs. The biological differences between the peripheral appendicular skeleton and the central axial skeleton must be further addressed. Finally, the relative merits of these sophisticated imaging techniques must be weighed with respect to their applications as diagnostic procedures, requiring high accuracy or reliability, compared with their monitoring applications, requiring high precision or reproducibility.

Bone loss before the clinical onset of rheumatoid arthritis in subjects with anticitrullinated protein antibodies

Objective Anticitrullinated protein antibodies (ACPA) are a major risk factor for bone loss in rheumatoid arthritis (RA). We have recently shown that ACPA directly induce bone loss by stimulating osteoclast differentiation. As ACPA precede the clinical onset of RA by years, we hypothesised that ACPA positive healthy individuals may already show skeletal changes. Methods We performed a comparative micro-CT analysis of the bone microstructure in the metacarpophalangeal joints of ACPA positive and ACPA negative healthy individuals without clinical signs of arthritis. Results ACPA positive (n=15) and negative (n=15) healthy individuals were not different in age (48.2±4.1 vs 51.4±3.8 years, p=0.57) or gender (eight women and two men in both groups). Bone mineral density was significantly reduced in ACPA positive individuals (mean±SEM 280±11 mg/cm3) compared with controls (327±6). Bone loss was based on cortical bone changes, with significant (p=0.044) reduction in cortical thickness in the ACPA positive group (mean±SEM 0.22±0.03 mm) compared with controls (0.32±0.03 mm). Areas of cortical porosity were significantly (p=0.0005) more widespread in ACPA positive (mean±SEM 7.4±1.4%) than in ACPA negative individuals (1.0±0.3%). Discussion Structural bone damage starts before the clinical onset of arthritis in subjects with ACPA. These findings revise the concept that bone damage is an exclusive consequence of synovitis in patients with RA.

A hierarchical 3D segmentation method and the definition of vertebral body coordinate systems for QCT of the lumbar spine

We have developed a new hierarchical 3D technique to segment the vertebral bodies in order to measure bone mineral density (BMD) with high trueness and precision in volumetric CT datasets. The hierarchical approach starts with a coarse separation of the individual vertebrae, applies a variety of techniques to segment the vertebral bodies with increasing detail and ends with the definition of an anatomic coordinate system for each vertebral body, relative to which up to 41 trabecular and cortical volumes of interest are positioned. In a pre-segmentation step constraints consisting of Boolean combinations of simple geometric shapes are determined that enclose each individual vertebral body. Bound by these constraints viscous deformable models are used to segment the main shape of the vertebral bodies. Volume growing and morphological operations then capture the fine details of the bone-soft tissue interface. In the volumes of interest bone mineral density and content are determined. In addition, in the segmented vertebral bodies geometric parameters such as volume or the length of the main axes of inertia can be measured. Intra- and inter-operator precision errors of the segmentation procedure were analyzed using existing clinical patient datasets. Results for segmented volume, BMD, and coordinate system position were below 2.0%, 0.6%, and 0.7%, respectively. Trueness was analyzed using phantom scans. The bias of the segmented volume was below 4%; for BMD it was below 1.5%. The long-term goal of this work is improved fracture prediction and patient monitoring in the field of osteoporosis. A true 3D segmentation also enables an accurate measurement of geometrical parameters that may augment the clinical value of a pure BMD analysis.

Regulatory T Cells Protect from Local and Systemic Bone Destruction in Arthritis

We previously demonstrated the suppressive effects of regulatory T cells (Treg cells) on osteoclast differentiation in vitro. In this article, we show that blood markers of bone resorption inversely correlate with the amount of circulating Treg cells in healthy controls and rheumatoid arthritis patients, further suggesting that Treg cells may control bone destruction in vivo. Indeed, bone marrow from Foxp3-transgenic (Foxp3tg) mice fully protected human TNF transgenic (hTNFtg) mice from TNF-α–induced bone destruction, whereas Foxp3-deficient bone marrow enhanced local and systemic bone loss. The same protective effect was also obtained by treating hTNFtg mice with the CD28 superagonist mAb (CD28 SA), which increased Treg cell numbers. In both models, bone protection by Treg cells was associated with reduced osteoclast numbers, resulting in less bone-resorbing activity. Reduced osteoclast numbers were not caused by an intrinsic defect in osteoclast differentiation because osteoclast precursors from hTNFtg/Foxp3tg chimeras responded normally to M-CSF and receptor activator of NF-κB ligand. Although a decrease in the clinical signs of arthritis was observed in Foxp3tg bone marrow-transferred and CD28 SA-treated hTNFtg mice, the bone-protective effect of Treg cells was independent of the suppression of inflammation, as demonstrated by the increased systemic bone density observed in wild-type mice treated with CD28 SA. This work demonstrated that increasing Treg cell numbers improved clinical signs of arthritis and suppressed local and systemic bone destruction. Thus, enhancing the activity of Treg cells would be beneficial for the treatment of inflammation-induced bone loss observed in rheumatoid arthritis.

Periarticular Bone Structure in Rheumatoid Arthritis Patients and Healthy Individuals Assessed by High-Resolution Computed Tomography

OBJECTIVE To define the nature of structural bone changes in patients with rheumatoid arthritis (RA) compared with those in healthy individuals by using the novel technique of high-resolution microfocal computed tomography (micro-CT). METHODS Fifty-eight RA patients and 30 healthy individuals underwent a micro-CT scan of the proximal wrist and metacarpophalangeal joints. Bone lesions such as cortical breaks, osteophytes, and surface changes were quantified on 2-dimensional (2-D) slices as well as by using 3-D reconstruction images, and exact localization of lesions was recorded. RESULTS Micro-CT scans could detect bone lesions <0.5 mm in width or depth. Small erosions could be observed in healthy individuals and RA patients, whereas lesions >1.9 mm in diameter were highly specific for RA. Cortical breaks were mostly found along the radial sites of the metacarpal heads. No significant difference in the presence of osteophytes between healthy individuals and RA patients was found. Cortical surface changes, presumably cortical thinning and fenestration, became evident from 3-D reconstructions and were more pronounced in RA patients. CONCLUSION Micro-CT allows exact detection of morphologic changes of juxtaarticular bone in healthy individuals and RA patients. Even healthy individuals occasionally show bone changes, but the severity of these lesions, with the exception of osteophytes, is greater in RA patients. Thus, micro-CT allows accurate differentiation among physiologic bone changes in joints and among types of pathologic bone damage resulting from RA.

Interactive 3D editing tools for image segmentation

Segmentation is an important part of image processing, which often has a large impact on quantitative image analysis results. Fully automated operator independent segmentation procedures that successfully work in a population with a larger biological variation are extremely difficult to design and usually some kind of operator intervention is required, at least in pathological cases. We developed a variety of 3D editing tools that can be used to correct or improve results of initial automatic segmentation procedures. Specifically we will discuss and show examples for three types of editing tools that we termed: hole-filling (tool 1), point-bridging (tool 2), and surface-dragging (tool 3). Each tool comes in a number of flavors, all of which are implemented in a truly 3D manner. We describe the principles, evaluate efficiency and flexibility, and discuss advantages and disadvantages of each tool. We further demonstrate the superiority of the 3D approach over the time-consuming slice-by-slice editing of 3D datasets, which is still widely used in medical image processing today. We conclude that performance criteria for automatic segmentation algorithms may be eased significantly by including 3D editing tools early in the design process.

Bone Density, Turnover, and Estimated Strength in Postmenopausal Women Treated With Odanacatib: A Randomized Trial

CONTEXT Odanacatib, a cathepsin K inhibitor, increases spine and hip areal bone mineral density (BMD) in postmenopausal women with low BMD and cortical thickness in ovariectomized monkeys. OBJECTIVE The objective of the study was to examine the impact of odanacatib on the trabecular and cortical bone compartments and estimated strength at the hip and spine. DESIGN This was a randomized, double-blind, 2-year trial. SETTING The study was conducted at a private or institutional practice. PARTICIPANTS PARTICIPANTS included 214 postmenopausal women with low areal BMD. INTERVENTION The intervention included odanacatib 50 mg or placebo weekly. MAIN OUTCOME MEASURES Changes in areal BMD by dual-energy x-ray absorptiometry (primary end point, 1 year areal BMD change at lumbar spine), bone turnover markers, volumetric BMD by quantitative computed tomography (QCT), and bone strength estimated by finite element analysis were measured. RESULTS Year 1 lumbar spine areal BMD percent change from baseline was 3.5% greater with odanacatib than placebo (P < .001). Bone-resorption marker C-telopeptide of type 1 collagen was significantly lower with odanacatib vs placebo at 6 months and 2 years (P < .001). Bone-formation marker procollagen I N-terminal peptide initially decreased with odanacatib but by 2 years did not differ from placebo. After 6 months, odanacatib-treated women had greater increases in trabecular volumetric BMD and estimated compressive strength at the spine and integral and trabecular volumetric BMD and estimated strength at the hip (P < .001). At the cortical envelope of the femoral neck, bone mineral content, thickness, volume, and cross-sectional area also increased from baseline with odanacatib vs placebo (P < .001 at 24 months). Adverse experiences were similar between groups. CONCLUSIONS Over 2 years, odanacatib decreased bone resorption, maintained bone formation, increased areal and volumetric BMD, and increased estimated bone strength at both the hip and spine.