Quantitative Computer Tomography in Children and Adolescents: The 2013 ISCD Pediatric Official Positions

Journal of Clinical Densitometry: Assessment & Management of Musculoskeletal Health, vol. 17, no. 2, 258e274, 2014 Ó Copyright 2014 by The International Society for Clinical Densitometry 1094-6950/17:258e274/$36.00 http://dx.doi.org/10.1016/j.jocd.2014.01.006

2013 Pediatric Position Development Conference

Quantitative Computer Tomography in Children and Adolescents: The 2013 ISCD Pediatric Official Positions Judith E. Adams,*,1,a Klaus Engelke,2,b Babette S. Zemel,3,b and Kate A. Ward4,b 1

Department of Clinical Radiology, The Royal Infirmary, Central Manchester University Hospitals NHS Foundation Trust, Oxford Road, Manchester, England, UK; 2Institute of Medical Physics, University of Erlangen, Erlangen, Germany and Synarc A/S, Germany; 3Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; and 4MRC Human Nutrition Research, Elsie Widdowson Laboratory, Cambridge, UK

Abstract In 2007, International Society of Clinical Densitometry Pediatric Positions Task Forces reviewed the evidence for the clinical application of peripheral quantitative computed tomography (pQCT) in children and adolescents. At that time, numerous limitations regarding the clinical application of pQCT were identified, although its use as a research modality for investigation of bone strength was highlighted. The present report provides an updated review of evidence for the clinical application of pQCT, as well as additional reviews of whole body QCT scans of the central and peripheral skeletons, and high-resolution pQCT in children. Although these techniques remain in the domain of research, this report summarizes the recent literature and evidence of the clinical applicability and offers general recommendations regarding the use of these modalities in pediatric bone health assessment. Key Words: Bone mineral density; children; fracture assessment; pQCT; QCT. independent of bone size. QCT has several other advantages: it measures cortical and trabecular bone compartments separately, can assess 3D geometric parameters that may contribute to bone strength, and has fast scan times if acquired on whole body general-purpose CT scanners. Because of concerns regarding radiation exposure, most QCT studies in children have investigated peripheral sites, primarily the radius and tibia. Often, dedicated peripheral CT scanners have been used, although these scans can also be performed on whole body clinical CT scanners. In children, QCT of the spine is a research application to obtain a measure of vBMD in the trabecular compartment of the vertebral bodies. Trabecular bone is approximately 8 times more metabolically active than cortical bone, and changes with time, disease, and treatment in trabecular bone may be large and greater than in cortical bone. QCT of the peripheral and central skeletons in children and adolescents is the topic of this report. The earlier International Society of Clinical Densitometry (ISCD) Official Positions on the clinical use of QCT and peripheral QCT (pQCT) in adults (6) and on pQCT in children (7) included a historical review and detailed technical descriptions that

Introduction Currently, dual-energy X-ray absorptiometry (DXA) is the most frequently applied quantitative technique for measuring areal bone mineral density (aBMD) and other skeletal parameters in children (1e3). However, the principal limitation of DXA is its 2-dimensional (2D) projectional nature, whereby the ‘‘depth’’ of the bone is not taken into account (4,5). aBMD (g/cm2) as measured by DXA is size dependent, a particular problem in growing children in whom the bones are changing in size, shape, and density. Quantitative computed tomography (QCT) (6), as a potential alternative skeletal measurement method, does not suffer from the projectional limitation of DXA. QCT is a 3-dimensional (3D) technique to quantify a true physical BMD in mg/cm3 (volumetric BMD [vBMD]), which is Received 01/14/14; Accepted 01/14/14. a

Task Force Chair

b

Task Force Member

*Address correspondence to: Judith Elizabeth Adams, MBBS, FRCR, FRCP, Department of Clinical Radiology, Central Manchester University Hospitals NHS Foundation Trust, Manchester M13 9WL, UK. E-mail: [email protected]

258

Quantitative CT in Children and Adolescents are largely up-to-date. The use of finite element modeling to predict bone strength has matured considerably in the last 5 yr (8), but to date, finite element modeling in pediatric studies has largely been used in maxillofacial applications and therefore will not be discussed further in this report. Here, we concentrate on the review and implications of clinical studies in children published since the last official ISCD position statements. As in the earlier report (7), to assess the utility of QCT in children and adolescents, the QCT task force addressed the following general areas: 1. What is the clinical application of QCT (including pQCT) in children and adolescents? 2. What are the important elements to be included in a QCT/ pQCT report? 3. How should quality be monitored? To address these areas of concern, we first provide a review of QCT technology with particular focus on issues related to children. The literature review on the clinical application of QCT in children resulted in the overall recommendation that there is no preferred QCT method for clinical application in children. Accordingly, we reviewed methodological issues related to the safe and effective use of QCT methodology in children as well as the use of QCT and pQCT in the research setting.

259 Calibration phantom (QRM GmbH, M€ohrendorf, Germany) allow for smaller field of views, providing optimized spatial resolution and are less prone to cause streak artifacts, which may be present with larger phantoms when used in children. The calibration of CT-to-BMD values assumes a 2component system (6), such as water and bone, being the only materials contributing to the X-ray absorption. In reality, fat is a third component, which has a similar mass absorption coefficient but lower density than water, thus the CT values of fat are negative. These factors result in an artificial reduction of BMD, primarily affecting the measurement of trabecular BMD because of the unknown fat-water composition of bone marrow. For adults, scanner-specific corrections have been suggested (9), which treat fat errors as a constant bias. For children, the situation is more complex because red (hematopoietic) marrow is gradually converted to yellow (fat) marrow during growth. Consequently, negative trabecular vBMD is sometimes measured in sites where only a few trabeculae may be present. Newer pQCT scanners (Stratec XCT 960, 2000, and 3000 models) add a constant of 60 mg/cm3 to the calibrated BMD values (10). Results from scanners calibrated with this fat offset correction cannot be compared with those from the scanners calibrated to water.

Peripheral QCT

The term QCT describes the analysis of the CT images using dedicated software to extract quantitative parameters. These include vBMD and BMC in trabecular or cortical volumes of interest (VOIs), geometrical measurements such as bone cross-sectional area (CSA) and cortical thickness in specific regions. The types of CT scanners used in bone densitometry are whole body clinical CT scanners and dedicated pQCT and high-resolution pQCT (HR-pQCT) scanners. pQCT is the application of QCT to appendicular skeletal sites (arms or legs), executed on dedicated peripheral or generalpurpose CT scanners. HR-pQCT is also a pQCT method but refers to a technique with which trabecular and cortical architecture can be quantified. The term central QCT refers to the technique applied to the spine and proximal femur.

Over the past 2 decades, pQCT studies in children were almost exclusively carried out on the XCT 2000 and 3000 scanners (Stratec Medizintechnik, Pforzheim, Germany). These scanners operate in a rotate/translate mode and measure a single 2D slice in approximately 1 min. The XCT 3000 models have a larger gantry, and the research series offers a slice thickness of 0.5 mm compared with the 2 mm of the standard XCT 2000/3000 models. A new high-resolution pQCT scanner (XtremeCT; Scanco, Br€uttisellen, Switzerland) has recently been introduced. The XtremeCT operates in cone beam geometry and in standard mode acquires a 9 mm thick volume of tissue (110 slices) in about 3 min. Three different spatial resolutions can be selected (11). In standard mode, the resulting 3D data set has an isotropic voxel size of 82 mm3 resulting in an isotropic spatial resolution of about 130 mm (12). Secure fixation of the limb and a quiet scanning environment are essential to minimize movement artifacts.

BMD Calibration

Central QCT

The gray values in a reconstructed CT image represent the CT value measured in Hounsfield units (HU). CT scanners are calibrated so that the CT value of water is 0 HU. Calibration of CT-to-BMD values uses a phantom with known densities of hydroxyapatite. On pQCT scanners, phantoms are measured separately from the patient. In central QCT, the phantom is measured simultaneously with the patient (Fig. 1). Some phantoms, such as the one used with QCTPro analysis software (Mindways, Inc., Austin, TX) (Fig. 1A), are rather large and not optimized for children. Smaller phantoms (Fig. 1B) such as the Siemens Osteo phantom (Siemens Healthcare, Erlangen, Germany) or the Bone Density

Only a few studies report spine QCT in children despite early publications from Gilsanz (13) and Kaste et al (14). Although general-purpose whole body CT scanners are widely available, they are typically located in radiology departments and used heavily for wide and varied clinical diagnoses. As a consequence, they are more difficult to access for measurement of QCT than dedicated pQCT scanners that are relatively small, do not require extensive radiation shielding, and are often located in centers specialized in research and clinical care of children with bone disorders. Also, few studies have used central QCT in children because of the perception that central CT is a technique involving high doses

Background: Review of QCT TechnologydPeripheral and Central

Journal of Clinical Densitometry: Assessment & Management of Musculoskeletal Health

Volume 17, 2014

260

Adams et al.

Fig. 1. Central quantitative computed tomography (QCT) lumbar spine with calibration phantoms: (A) Leftdwith the larger calibration phantom with fat, water 50, 100, and 200 mg of hydroxyapatite from Mindways, Inc. below the patient. (B) Rightdsmaller QCT calibration phantom [QRM GmbH, M€ ohrendorf, Germany]) with water equivalent and 100 and 200 mg hydroxyapatite allows for the use of smaller reconstruction field of views, which has advantages in children. of ionizing radiation. This issue will be discussed in the next section. The third reason is the lack of available QCT analysis software. Third-party software implemented on external workstations must be used, and there is only 1 commercial package available, QCTPro from Mindways, Inc., in addition to research software developed at individual universities.

Radiation Exposure Radiation exposure levels for bone densitometry in children have rarely been published. Effective doses for DXA scans of the hip or spine in children are between 4 and 27 mSv, depending on scanner manufacturer and model, scan length and body size, and which equate to only a few days of natural background radiation (15). Effective dose of total body DXA in children is even lower (1.5e10 mSv) (16), similar to those of pQCT using the Stratec (!1.0 mSv) or the XtremeCT (3.0 mSv) devices. For 3 CT slices through the forearm using the Stratec XCT 2000, the radiation dose is 1.4 mSv (17). Based on values in adults (2), one can estimate that pQCT radiation exposure in children using current XCT and XtremeCT scanners will be comparable to, if not slightly lower than, those for DXA. Table 1 shows effective dose values simulated for children using the ImpactDose 2.0 (CT Imaging GmbH, Erlangen) software package (18,19).

for evaluation. The methods used to develop, and the grading system applied to the ISCD Official Positions, are presented in the Executive Summary that accompanies this article. In brief, all positions were rated by the Expert Panel on quality of evidence (good; fair; poor: where good is evidence that includes results from well-designed and well-conducted studies in representative populations; fair is evidence sufficient to determine effects on outcomes, but the strength of the evidence is limited by the number, quality, or consistency of the individual studies; and poor is evidence that is insufficient to assess the effects on outcomes because of limited number or power of studies, important flaws in their design or conduct, gaps in the chain of evidence, or information), strength of the recommendation (A; B; C: where A is a strong recommendation supported by Table 1 Central QCT; Effective Dose Values (Calculated for a Helical 64-Detector Row Siemens Definition Flash Scanner Using the Pediatric Body Scan Mode Using 80 kV X-ray Tube Voltage and 100 mAs With a Slice Thickness of 0.6 mm and a Pitch of 1) Age (yr)

Scan length (cm)

Sex

Effective dose (mSv)

15

10

10

8

5

6

M F M F M F

0.59 0.61 0.80 0.84 1.02 1.09

Methodology The task force developed a comprehensive bibliography of the QCT literature in children. A literature search using PubMed was performed using the keywords, ‘‘quantitative comput* tomography children’’ to identify references. Further information was obtained from searching the abstracts from the American Society for Bone Mineral Research over the past 3 yr. Based on the literature review, preliminary position statements were developed by the task force and presented to an expert panel

Note: The scan length depended on age. Tissue weighing factors were taken from International Commission on Radiological Protection 103 (19). Abbr: F, female; M, male; QCT, quantitative computed tomography.

Journal of Clinical Densitometry: Assessment & Management of Musculoskeletal Health

Volume 17, 2014

Quantitative CT in Children and Adolescents the evidence; B is a recommendation supported by the evidence; and C is a recommendation supported primarily by expert opinion), and applicability (worldwide 5 W or variable, according to local requirements 5 L). Necessity was also considered with a response of ‘‘necessary’’ indicating that the indication or procedure is ‘‘necessary’’ because of the health benefits outweighing the risk to such an extent that it must be offered to all patients and the magnitude of the expected benefit is not small.

ISCD Official Positions ISCD Official Position: There is no preferred QCT method for clinical application in children and adolescents. Grade: Fair-C-W.

Rationale There are 3 different rationales supporting this position. First, there are various medical situations that require the use of different quantitative skeletal techniques, which may provide complimentary research information. Second, for many medical problems, comparative studies using different techniques have not been published. Third, major components that would be required to justify recommending the clinical application of QCT methods are largely absent for QCT in children, such as consensus on optimal measurement sites and outcomes, data on normative ranges, precision and accuracy errors, and on least significant changes and relative risk for fracture. With respect to the first rationale, the metaphyseal regions of long bones are rich in trabecular bone and the diaphyseal regions are almost entirely cortical bone. Most childhood fractures occur in the long bones, making pQCT measurements in the metaphysis and diaphysis of these bones relevant to the study of bone strength and fracture prediction. The use of oral glucocorticoids in many chronic diseases in children such as inflammatory bowel and arthritic disorders, nephrotic syndrome, Duchenne muscular dystrophy, and asthma can lead to increased risk of peripheral and vertebral fractures (20,21) and of detrimental changes particularly in vertebral trabecular BMD in longitudinal studies (22,23). In such clinical scenarios, QCT (24) of the spine, in particular of the trabecular compartment, which is more adversely affected by glucocorticoids, could be the method of choice, but studies in children are sparse. With respect to the second rationale, Stratec XCT scanners (worldwide distribution: 1100 XCT 900/960 and 600 XCT 2000/3000/Research devices) are the most widely used for peripheral measurements in pediatric studies, and a few studies have emerged using HR-pQCT, of which there are currently approx 50 devices worldwide. However, despite fairly standardized CT acquisition and reconstruction parameters, there is no agreed scan protocol in children. In particular, the location of the measurement varies considerably. Thus, comparative studies are difficult. Whole body CT scanners can be used to image peripheral bone (25). Scan times on modern machines are rapid, and the

261 child may be more comfortable in a supine position on a full length table, especially those with disabilities (e.g., cerebral palsy (CP) or Duchenne muscular dystrophy) (26). A volume covering larger limb sections can be scanned in less than 30 s, offering the possibility of a true 3D analysis or of the retrospective selection of single or multiple 2D slices. Also, this technique may lend itself to more standardized reference line placement in growing children. Last, existing reference data for XCT scanners are site and technique specific and limited in scope with respect to population, age, country, ethnicity, and others. This limits the use of reference data and makes combining data from different sites and centers almost impossible. Precision data for pQCT in children have been published as an abstract (27) and are shown in Table 2. There are no published pQCT cross-calibration studies in children, but unpublished data using cortical phantoms show significant differences among scanners in cortical vBMD (B. Zemel, personal communication). Cross-calibration studies in adults report good agreement between XCT devices, with no necessity for cross calibration (17). One study investigated agreement between the XCT 2000 and XCT 3000 in adults (28) with tibia measurements at the 8%, 50%, and 66% sites. Extremely high correlations (0.90e0.99) were reported, and precision in both devices was high (0.4%e2.4%). As precision errors were much lower than the longitudinal change in growing children, the authors concluded that the devices could be used interchangeably in children (28). However,

Table 2 Precision Estimates (Within-Subject CV) for pQCT Measurements of the Distal Tibia in Children (Zemel et al (27))

Site

Measure

3%

Trabecular density, mg/cm3 Trabecular density, mg/cm3 Cortical thicknessa, mm2 Cortical density, mg/cm3 Endosteal circumferencea, mm Periosteal circumferencea, mm Strain strength index, mm3

8 mm 38% 38% 38% 38% 38%

All ages

6e10 yr

11e18 yr

CV% (n)

CV% (n)

CV% (n)

1.4 (56) 1.5 (26) 1.3 (30) 2.5 (51) 2.7 (28) 2.5 (27) 1.4 (55) 1.3 (25) 1.5 (30) 0.5 (55) 0.5 (25) 0.5 (30) 1.6 (55) 1.7 (25) 1.5 (30) 0.4 (55) 0.5 (25) 0.3 (30) 2.8 (53) 2.8 (24) 2.8 (29)

Abbr: CV, coefficient of variation; pQCT, peripheral quantitative computed tomography. a Uses the circular ring mode.

Journal of Clinical Densitometry: Assessment & Management of Musculoskeletal Health

Volume 17, 2014

262 the variable nature of longitudinal changes and age-specific differences of pQCT outcomes on the various scanners available implies that this conclusion must be interpreted with caution. For XtremeCT scanners, a comprehensive assessment of multicenter precision and signal-to-noise ratio using phantoms demonstrated significant intrascanner variability between sites (29). Multicenter phantom precision was significantly worse than short-term and single-center precision. Further studies are needed to establish cross calibration between devices, precision for children and adolescents, and scanner cross compatibility. This is particularly important in multicenter studies and in the use of reference data that is developed on a single scanner.

Discussion Currently, standardization of scan location is challenging. The anatomy of the radius, tibia, and femur is extremely heterogeneous along its length, so it is imperative to define exactly the region of interest (ROI) or VOI to be scanned. Most pediatric protocols use sites that are a percent distance from the distal end of the radius or tibia as well as require accurate and consistent technique for measuring bone length. In addition, the changing appearance of the growth plate as children develop can make it difficult to achieve consistent reference line positioning between individuals, and within the same individual, over time unless acquired by highly experienced and well-trained technical staff. For the Stratec XCT and Scanco XtremeCT devices, the position of the measurement ROI/VOI is defined relative to a reference line. However, the position of the reference line is not standardized. For the XCT models, reference line placement is at either the distal growth plate or varying parts of the distal surface of the metaphysis. Anatomical measurement sites (Fig. 2AeF) reported using the XCT 2000 include in the radius 4%, 20%, and 66% and in the tibia 3%, 4%, 14%, 20%, 38%, and 66% from the distal end of the bone. For the XCT 3000, most tibia measurements are acquired at 4% and 66% sites; for the distal femur, 4% and 20% sites are scanned. For the XtremeCT (Fig. 3AeD), 4 protocols have been published, which use either the proximal edge of the growth plate or different positions on the end plate to define the reference line (Table 3) (30e39). The location of the VOI (at standard voxel size: 82 mm, 110 slices) is fixed relative to the reference line. The lack of standardization for XCT and XtremeCT devices has limited the use of reference data and made it impossible to pool data from multiple centers. There should ideally be proposed standardized protocols for new users so as to avoid the current variability of techniques that are applied, but such do not exist currently. New users should therefore follow existing protocols regarding reference line placement, ROI selection, and segmentation thresholds to minimize the variability in measurement sites and in analysis results using pQCT.

Adams et al. Because of the lack of standardization, the following technical details should be included when reporting study results: 1. The pQCT device model and manufacturer. 2. Full description of the reference point selection criteria, including how the differing appearance of the growth plate is taken into account. 3. The method of limb length measurement if a percent rule of bone length is used to locate the ROI/VOI analysis. 4. Slice thickness because it may differ among XCT devices. 5. The segmentation thresholds used for image analysis. 6. For the XtremeCT device, whether the standard control file is used must be reported. If a custom control file is used, all parameters specified in this control file must be reported. 7. The image quality is often impaired by motion artifacts, so the grading of image quality and procedure of scan exclusion because of poor image quality must be reported (40e43). ISCD Official Position: It is imperative that QCT protocols in children using whole body CT scanners use appropriate exposure factors, calibration phantoms, and software to optimize results and minimize radiation exposure. Grade: Good-B-W.

Rationale and Discussion Appropriate Radiation Exposure Radiation exposure should be kept as low as reasonably achievable (ALARA principle), as with all imaging in children (44e46). In general, scan protocols typically used in adults need to be adapted and optimized in children because of their smaller body size. All modern whole body CT scanners can adapt the exposure to the individual patient (automatic exposure control, AEC). However, AEC algorithms are CT manufacturer specific, and caution must be exercised when applying them in children. There is ongoing innovation in AEC, and newer scanners typically offer more advanced AEC options.

Tomographic Acquisition and Reconstruction In children, scan sites using whole body CT devices are usually the lumbar spine, forearm, calf, and midfemur. Table 4 (47e49) lists acquisition and reconstruction protocols used by Mindways, Inc.

Analysis Software The QCT analysis software is typically not integrated in the software of whole body clinical CT scanners, and thirdparty programs must be used. One commercial option is QCTPro from Mindways, Inc., for analysis of the traditional elliptical ROI in the anterior trabecular compartment of the vertebra (2). Total vertebral body VOIs can be analyzed with existing research software developed for adults such as the Medical Image Analysis Framework (50), but no pediatric studies using this analysis have been reported to date. QCTPro also offers modules for peripheral scans but again no studies have yet been reported.

Journal of Clinical Densitometry: Assessment & Management of Musculoskeletal Health

Volume 17, 2014

Quantitative CT in Children and Adolescents

263

Fig. 2. Peripheral quantitative computed tomography is performed in (A) nondominant radius in distal 4%, mid 50%, and between 60% and 66% proximal shaft sites and (B) in tibia in distal 4%, 14%, 38%, 50%, and proximal 66% sites. There are variations in where the distal reference line is placed using distal metaphysis (top image) or distal joint margin (lower image) as visualized in CT scout views of (C) radius and (D) tibia. Parameters measured at (E) distal 4% tibial site include total and trabecular bone mineral content, bone mineral density (BMD), and cross-sectional area (CSA). (F) In the tibia shaft, cortical BMD and geometric measurements are made from which biomechanical parameters of bone can be extracted. Using simple thresholding techniques, CSA of muscle and fat can be measured, as can muscle density.

Quality Assurance and Cross Calibration As in DXA, well-trained and meticulous technical staff are essential to optimize the precision of QCT scans. Quality assurance protocols are also important to ensure consistency of measurements (51,52). Common phantoms available for cross calibrating between scanners and for quality assurance testing in CT are the European Forearm phantom for appendicular sites (53,54) and the European Spine phantom for the spine (QRM GmbH, Moehrendorf, Germany) (55).

ISCD Official Position: QCT, pQCT, and HR-pQCT are primarily research techniques used to characterize bone deficits in children. They can be used clinically in children where appropriate reference data and expertise are available. Grade: Fair-B-W.

Rationale Because of the extensive flexibility of QCT modalities in terms of measurement site, scan acquisition protocols, and

Journal of Clinical Densitometry: Assessment & Management of Musculoskeletal Health

Volume 17, 2014

264

Adams et al.

Fig. 3. High-resolution peripheral quantitative computed tomography acquired on the Scanco XtremeCT, which provides high-resolution (isotropic voxel size 82mm; isotropic spatial resolution 130–150 mm) images of the distal radius and distal tibia. Scout view of (A) distal radius and (B) distal tibia, with placement of reference lines at the growth plate in (A) and distal tibial joint surface in (B). Three-dimensional volume images of (C) distal tibia and in more (D) proximal site, from which structural parameters of both trabecular and cortical bones are extracted. the many bone outcomes, these modalities are ideal tools in the research setting to address a variety of clinical issues in children. QCT-based studies have provided substantial insights into the development of the growing skeleton, as well as disease and treatment effects on cortical and trabecular bone compartments. However, research using QCT has rarely addressed important issues related to clinical application, such as optimal scan acquisition sites and outcome measures that can be universally applied across disease groups to characterize bone deficits, fracture risk, or disease/treatment effects. Other important requirements for clinical application of QCT are pediatric reference data and knowledge of precision and least significant change. Because these latter elements are available in some local centers with appropriate expertise, QCT may be used clinically in some locations.

Discussion Outcome Measures The standard outcome measurements of Stratec XCT devices were given in the previous ISCD position statement (7). Standard measures include BMC, vBMD, and cortical

dimensions. Derived measures include cortical thickness at the distal site (derived from CSA, total BMD, trabecular BMD, and cortical BMD), bone strength indices (the product of total vBMD and total area at distal site and includes relative measure of cortical BMD in the diaphyseal sites), and a measure of metaphyseal in-waisting (comparison of areas in adjacent slices) (56). Diaphyseal-fracture load is calculated combining stress strain indices (SSIs), ultimate load, and the deflection of the bone in bending. Additional XCT outcome measures include the combination of muscle and bone parameters to assess whether an individual has deficits in bone, muscle, or a combination of both (57,58). Cross-sectional muscle area is commonly reported. Muscle density may be a more sensitive measure of muscle status than cross-sectional muscle area alone (59). However, muscle density is reported as a calcium hydroxyapatite equivalent density. Thus, ‘‘muscle density’’ as measured on XCT devices is not the physical density of muscle tissue, and the clinical value of the XCT ‘‘muscle density’’ measurement requires further investigation and validation. The XtremeCT has many outcome measures, many of which have been derived to be equivalent to histomorphometric

Journal of Clinical Densitometry: Assessment & Management of Musculoskeletal Health

Volume 17, 2014

Quantitative CT in Children and Adolescents

265

Table 3 Various Studies Illustrate Differences in Placement of Reference Lines in HR-pQCT Scanning in Children Reference

Research center

Kirmani et al (34,35)

United States (Mayo)

Chevalley et al (33)

Switzerland

Nishiyima et al (37), Burrows et al (30e32), Liu et al (36) Wang et al (38,39)

Canada (University of British Columbia) Australia

parameters (60,61). Only trabecular number (Tb.N) is measured directly (60). Bone volume/total volume, trabecular thickness, and trabecular spacing are derived from combinations of Tb.N and trabecular BMD (62). It is important to note that a fixed bone mineralization of 1200 mg/cm3 is assumed. Violation of this assumption affects all parameters of trabecular structure apart from Tb.N. Diseases or treatments that cause alterations in bone composition will have accuracy errors in the parameters measured (63). Advanced cortical analysis software (12) from Scanco expands the variety of cortical measurements provided. Cortical porosity and mineralization parameters are limited by the spatial resolution; smaller pores are not detected, so cortical porosity and cortical mineralization may be underestimated (29). Accuracy errors of these parameters are undetermined.

Reference Data Since 2007, published reference data for XCT devices are limited to local studies of healthy children and may not be generalizable in other locations. Three published studies can be used to calculate age-, height-, and gender-matched Zscores for the radius (17,64) or the tibia (65). These samples are limited to children of European ancestry. Evidence suggests that height or bone lengths are important considerations in the assessment of cortical bone geometry and strength, whereas age and gender are the key determinants of vBMD results (64,66).

Placement of reference line Unfuseddproximal limit of epiphyseal growth plate; fused still used epiphyseal line Proximal limit of the epiphyseal growth plate of the radius. For subjects whose radial epiphyseal plates had fused, the remnant of the plate was still visible, enabling us to set the reference line Medial edge of distal radius Tibial plafond Proximal to the lateral edge of the radial joint surface of the wrist Proximal to the center of the tibial joint surface of the ankle

Distances from reference line 1 mm proximal to the reference line

1 mm proximal to the reference line

7% ulnar length 8% tibial plafond 4% of the forearm length

7% of the lower leg length

The Manchester Healthy Children study measured (Stratec XCT-2000) the nondominant distal (4%) and proximal (50%) radius in individuals aged 5e25 yr (n 5 629, 380 males) (17). Reference data for age (6e19 yr inclusive) and height (males: 120e190 cm and females: 120e175 cm) were produced using the LMS method (67). Outcome measures were 4% sitedtotal and trabecular vBMD and total CSA; 50% sitedcortical CSA, total CSA, cortical thickness, cortical bone mineral content (BMC), axial moment of inertia, and SSI. The Dortmund Nutritional and Anthropometric Longitudinally Designed study (64) measured (Stratec XCT-2000) the proximal (65%) and distal (4%) radius (n 5 250, 166 males: 6e20.9 yr). Previously published data were reanalyzed using the LMS method (67). Equations to calculate gender- and ageor height-matched Z-scores were provided for 65% site; genderand age-matched Z-scores for 4%. Measurements included total and trabecular vBMD and total CSA, cortical thickness, and total BMC. For assessment of the muscle-bone unit, reference ranges are given for BMC relative to muscle CSA. A US study published data (Stratec XCT-2000, Novotec Medical; Pforzheim, Germany) for the nondominant tibia (n 5 416, 197 males). Trabecular vBMD is reported at the distal site (4%), and at the diaphysis (66%), total, cortical, and medullary CSAs, cortical BMC, vBMD (not stated whether total or cortical), cortical thickness, SSI, crosssectional moment of inertia, and muscle CSA are reported (65). Reference ranges were generated for gender and height interval (boys: 105e184 cm and girls: 105e174 cm).

Journal of Clinical Densitometry: Assessment & Management of Musculoskeletal Health

Volume 17, 2014

266

Adams et al. Table 4 Acquisition and Reconstruction Protocols Used By Mindways, Inc

QCT protocols for children used by Mindways, Inc. Tube voltage (kV)a,b Tube current
rotation time (mAs) Pitch Slice thickness (mm)e Scan range

FOV (cm)g Reconstruction kerneli

Lumbar spine

Forearm

Lower leg

80 Auto exposure with noise index of 25c 1 2e3f L1 þ L2

80

80

d

d

38h Medium

1 1e2 Typically 10 cm for adults, shorter for pediatric applications, to cover the distal 30%e50% of the radius and the distal joint space of the radius and ulna

25h Medium

1 1e2 Typically 10 cm for adults, shorter for pediatric applications, to cover approximately the distal 20% of the tibia through the distal end of the fibuladregion between the red lines in the image to the right 25h Medium

Abbr: FOV, field of view; QCT, quantitative computed tomography. a The tube voltage used should be reduced from the 120 kV currently used in adult QCT protocols to 80 kV, although in existing studies a protocol change is not advised. Originally, 80 kV was used in adults because of the lower impact of fat in single-energy mode (47,48). A recent publication based on scans in cadavers concluded that even in adults, the use of 80 kV has advantages over 120 kV from the perspective of radiation exposure in CT osteodensitometry (49). b Once the tube voltage is selected, the effective dose is determined by the mAs value and the pitch (50). Ideally, automatic exposure control should be used to individually minimize the mAs product to obtain diagnostically acceptable signal-to-noise ratios in the CT images. However, as described previously, it is not clear whether current CT scan software is adequate to automatically perform this minimization of dose in children. Nevertheless, it is essential that the mAs product should be smaller than in adults, assuming that the other scan parameters are unchanged. c Apply to GE scanners only. d No pediatric values given, 100 mAs suggested for adults, medium kernel is standard on GE and a B40s or B30s on Siemens scanner. e In the spine, a slice thickness of 2e3 mm is adequate for the quantification of vBMD in the trabecular compartment in the center of the vertebral body. If cortical information is of interest, then the slice thickness should be reduced to 1 mm. f Applies if only the central trabecular volume of interest is measured. g The field of view (FOV) of the spine should be reduced to below 20 cm to optimize the spatial resolution. However, this requires the use of other than the Mindways calibration phantom or 2 reconstructions. The FOV should also be considerably smaller for the scans of peripheral sites unless both arms and legs are to be included in the analysis. In this situation, 2 separate individual reconstructions should be considered of each limb. Some scanners offer separate options for scan and reconstruction FOV. The scan FOV must always be large enough to include the complete body cross section. h Applies if the Mindways phantom is used, should be smaller for other phantoms. i The reconstruction kernels are manufacturer specific. A medium kernel corresponds for example to Standard (GE), B30s or B40s (Siemens), and to B or C (Philips).

For the XCT 3000, no reference data have been published, although few centers have used the XCT 3000 in healthy children (57,68e75). Presently, there are 8 studies using HR-pQCT in healthy children (30e39), but they were not designed for the collection of reference data. The largest is a longitudinal study of Canadian children (37); with data for the tibia and radius in females and males aged 9e22 yr presented by pubertal stage. Standard evaluation parameters (total vBMD, TB/bone volume, trabecular thickness, trabecular separation, and Tb.N; cortical analysis to give cortical porosity, cortical thickness, cortical vBMD; CSAs of the total, cortical, and trabecular compartments based on customized segmentation [no

reference provided/detail of protocol]); finite element analysis (FAIM, version 4.0; Numerics88 Solutions, Calgary, Canada) to estimate bone strength, failure load in the radius and tibia, and a load-to-strength ratio in the ultradistal radius are included. Kirmani et al (35) assessed cortical and trabecular bone parameters using standard evaluation parameters and finite element analysis. Another study reported cortical thickness and vBMD in midpuberty compared with prepuberty (37). As a research tool, HR-pQCT shows promise for describing the changes in cortical and trabecular bone architecture with skeletal maturation. None of these studies meet all the criteria for optimal reference data, but they provide important reference ranges

Journal of Clinical Densitometry: Assessment & Management of Musculoskeletal Health

Volume 17, 2014

Quantitative CT in Children and Adolescents for healthy children. Some sources include height-based reference ranges for calculation of Z-scores relative to height. However, this approach needs to be validated because it may lead to an overcorrection when applied to children with growth failure. Further studies are required to determine the optimal approach for size adjustment of cortical geometry measures. Based on these considerations, the working group advises that, in general, reference data are not sufficient for the use of pQCT for fracture prediction or diagnosis of low BMD. However, local reference data for pQCT XCT 2000 may be sufficient in some centers for diagnosis of low BMD.

Use of the Nondominant vs Dominant Limb Since the previous report, there are no new data regarding which limb should be measured. Most studies measured the nondominant limb (17,57,64,68e80) or the left limb (66,81e85). Others measured the noninjured arm (86), or the side measured was not stated (87e89). For HR-pQCT, the nondominant side was measured in all studies. For consistency, it is suggested that in all pQCT studies the nondominant forearm should be used unless there has been previous fracture or surgical intervention on that side.

Ethnicity and Puberty-Related Differences Studies from the United States (66) and South Africa (79) have described population ancestry differences in pQCT bone outcomes. Leonard et al (66) described greater cortical BMC and vBMD, periosteal and endosteal circumferences, and section modulus at the 38% tibia in African American compared with non-African American youth before Tanner stage 5 (66), after adjustment for tibia length and muscle CSA. Mickelsfield et al (79) examined 13 yr-old black and white children in South Africa and found greater vBMD of the radius, and greater tibia midshaft (38% site) total area, endosteal diameter, periosteal circumference, and polar strength-strain index in black children compared with whites. These studies support the need for reference data that account for expected differences between children of African vs European ancestry.

Fracture Studies in Healthy Children A number of QCT-based fracture studies, using retrospective, prospective, and case-controlled study designs, have been published since the previous positions statement. These have the potential to identify optimal outcomes for clinical application of QCT; therefore, they are described here. A retrospective population-based study of men (age: 18.9 yr, n 5 991) in Sweden found that 31% had a history of previous fracture with peak age of fracture at 14 yr (77). The fracture group had lower trabecular vBMD of the radius (6.6%) and tibia (94.5%) than the nonfracture group at age 19 yr. Cortical vBMD was modestly lower (radius: 0.4% and tibia: 0.3%). There were no differences in cortical CSA. Each standard deviation (SD) decrease in trabecular vBMD of the radius and tibia was associated with 1.46 times increased fracture prevalence. A retrospective school-based study of 465 girls, 8e13 yr in the United States (75), found

267 that every 1 SD decrease in trabecular vBMD at the distal femur and tibia was associated with increased risk of fracture (1.4 [1.1e1.9] for tibia and 1.3 [1.0e1.7] for femur). CSA and other pQCT outcomes were not associated with fracture. In the prospective study of 220 children, 5e17 yr, in the Dortmund Nutritional and Anthropometric Longitudinally Designed study (90), fractures (n 5 78) in the subsequent 5 yr were ascertained by questionnaire. They found no differences in age, height, weight, body mass index, or any bone outcome between children who experienced a fracture and those who did not. However, a study of 396 girls (10e13 yr at baseline) in Finland obtained both retrospective and prospective fracture data for up to 8 yr after enrollment (91). Distal total vBMD of the radius by pQCT was associated with upper limb fracture at baseline and up to 7 yr later. Girls in the fracture group had significantly lower distal radius vBMD than the nonfracture group at each time point measured, and this was the only pQCT outcome that was a significant predictor ( p 5 0.001) of upper limb fracture in logistic regression models. No other differences were observed. A well-designed case-controlled study (86) compared healthy children with forearm fractures (5e16 yr, n 5 224) with matched controls who experienced a forearm injury without fracture (n 5 200). At the distal radius (4%), total vBMD (3.2%) was lower, and at the midshaft (20%), total BMC (3.4%), cortical vBMD (0.9%), cortical area (2.8%), and strain-strength index (4.6%) were lower in fracture cases compared with controls, adjusted for age, sex, race, height, and Tanner stage. The odds ratio associated with 1 SD decrease in adjusted bone Z-scores was 1.28 (95% confidence interval: 1.03, 1.59) to 1.41 (95% confidence interval: 1.07, 1.85) for all bone outcomes including DXA and pQCT, similar to those described by Farr et al (75) and Cheng et al (91). The evidence regarding the relationship between pQCT outcomes and fracture in children with chronic disease is limited by small sample sizes and cross-sectional study designs. Among girls with Turner syndrome (n 5 67) (92), 21% had a positive fracture history associated with lower total vBMD (distal radius) than girls without a history of fracture (Z-scores: 1.7  1.1 vs 0.9  1.3, respectively). Armstrong et al (93) did not find a difference in fracture history among 18 subjects with neurofibromatosis type 1 compared with controls, despite their lower tibia trabecular vBMD, bone strength, and SSI. Other studies of adolescents and young adults with cystic fibrosis (CF) (n 5 64) (94) and boys with hemophilia (n 5 41) (95) did not find differences in pQCT outcomes based on fracture history. In summary, the studies examining associations between pQCT and fracture in healthy children suggest that distal vBMD measures (trabecular vBMD or total vBMD) of the radius or tibia are associated with fracture, and 1 study reported differences in cortical parameters. The findings were not consistent with respect to the optimal bone to study (radius, tibia, or femur) measurement site or pQCT outcome that best predicts fracture. Studies in children with chronic diseases are too limited to draw conclusions. Therefore, there is insufficient evidence at this time to establish

Journal of Clinical Densitometry: Assessment & Management of Musculoskeletal Health

Volume 17, 2014

268 the ability of pQCT outcomes to predicted fracture risk in children.

Bone Deficits in Children With Chronic Diseases Over the past 6 yr, the literature has been enriched by reports characterizing bone deficits in children with chronic illnesses that potentially threaten bone health. These include cancer survivors (96e98), children with diabetes (99), a variety of genetic disorders (CF (94,100), HutchinsonGilford Progeria Syndrome (101), neurofibromatosis 1 (93,102), Prader-Willi syndrome (103), Turner syndrome (92,104), X-linked hypophosphatemic rickets (105)), growth hormone deficiency (106,107), heart-lung transplant recipients (108), hematologic disorders (hemophilia (109), thalassemia (110), inflammatory bowel disease (IBD) (111e113), juvenile rheumatoid arthritis (114,115)), renal disease (chronic kidney disease (CKD) (116e119), glucocorticoid sensitive nephrotic syndrome (120)), and conditions that affect mobility (spinal cord injury (121,122), amputees (123)). Most of these studies have been cross sectional, but many demonstrate associations between pQCT bone outcomes and disease or treatment characteristics. A smaller number of studies have been longitudinal and describe changes in bone characteristics over time, often in relation to changes in disease characteristics or treatments. There are virtually no published studies of children with chronic illnesses that have used pQCT outcomes in randomized placebo controlled trials or prospective fracture studies. Many studies have considered the impact of growth and/or body composition deficits on bone, although there is no consensus on how to account for, and interpret the effects of, these important factors. Most studies included measures of trabecular vBMD at the distal radius and/or tibia. The technique for measuring bone length and landmarks for reference line placement were not consistently reported and can impact on the comparability of results to published reference data and interstudy comparisons. Some studies also used separate reference ranges for African Americans and non-African Americans, whereas others did not report population ancestry. Trabecular vBMD deficits were reported for survivors of acute lymphatic leukemia (ALL) (96,97), hematopoietic stem cell transplantation (98), Prader-Willi syndrome (103), CF (males (100)), neurofibromatosis type 1 (93,102), heart-lung transplant recipients on glucocorticoids (108), older children with thalassemia (110), IBD (111,113), especially Crohn disease (112), juvenile idiopathic arthritis (114,115), and children with psychiatric disorders on selective serotonin reuptake inhibitors treatment (124). Normal trabecular vBMD was reported for patients with CF after adjustment for age and weight (100), Turner syndrome (104), growth hormone deficiency (106), and heart-lung transplant recipients on immunosuppressive agents (108). Increased trabecular vBMD was reported for type 1 diabetes (125), males with CF (94), X-linked hypophosphatemic rickets (105), CKD (119,126), and younger renal transplant recipients (116). Declines in trabecular vBMD were associated with glucocorticoid use in renal transplant recipients (116).

Adams et al. Cortical vBMD results were variable across disease states. It was low in acute lymphoblastic leukemia (97), type 1 diabetes (125), CF (94), Turner syndrome (104), X-linked hypophosphatemic rickets (105), and advanced CKD (119); and normal in some ALL patients (96), Prader-Willi syndrome (relative to age and sex peers) (103), growth hormone deficiency (106), thalassemia (110), CKD stages 2e3 and 5D (119), and renal transplant recipients (116). High cortical vBMD was reported in Prader-Willi syndrome (relative to height- and sex-matched peers) (103), heart-lung transplant recipients on glucocorticoids (108), hemophilia (109), and IBD (113). Increasing cortical vBMD was associated with glucocorticoid use (108,112,116) and, in renal transplant recipients, parathyroid hormone (PTH) levels (116); declining cortical vBMD was associated with PTH levels in CKD. These reports suggest the sensitivity of cortical vBMD to disease and treatment effects. The implications of low and high cortical vBMD for risk of fracture remain to be determined. Numerous interrelated measures of cortical dimensions and structural strength in the diaphysis of the radius or tibia were also reported, including total CSA, periosteal circumference, cortical CSA, medullary CSA (or endosteal circumference), cortical thickness, section modulus, and polar moment of inertia. Cortical dimensions and structural strength are strongly associated with both bone length and muscle mass on cortical dimensions and structural strength. Wetzsteon et al (82) demonstrated that bone length and muscle mass have independent and equally strong effects on section modulus of the tibia. So, interpretation of results depends on the presence and method for adjusting for altered growth and body composition. Nearly all the disease states described previously were associated with deficits in cortical dimensions and structural strength, as well as growth deficits and altered body composition. Outcomes adjusted for growth and body composition sometimes demonstrated normal (e.g., hemophilia (109), diabetes (125)), or increased Z-scores (e.g., Turner (92)). However, different adjustment techniques were used, and the value of adjusted Z-scores to predict fracture has not been determined. In summary, many serious childhood disorders impact on bone accretion. Recent pQCT studies have continued to identify the nature of deficits in trabecular and cortical vBMD and cortical dimensions and strength. Treatments such as glucocorticoid therapy have distinct and opposing effects on cortical and vBMD that could be masked when using other densitometric methods such as DXA. Consensus and evidence-based guidelines are needed with respect to measurement methods and analytic techniques to make pQCT methodology clinically useful in the assessment of children with chronic diseases.

Whole Body General-Purpose CT Scanners Whole body CT scanners have not been widely used for QCT in children. Most studies have been performed using single 10-mm sections in the lumbar spine (L1 and L2 or L1eL3) using nonspiral step-and-scan CT technology in

Journal of Clinical Densitometry: Assessment & Management of Musculoskeletal Health

Volume 17, 2014

Quantitative CT in Children and Adolescents healthy children addressing effects of puberty and age (127e131) and influence of gender (132) and ethnicity (133) on BMD and bone size. Later studies have used more modern helical CT scanners with similar scan and acquisition protocols and applied to a central (L1eL3) and peripheral (tibia) sites (26,134,135). Reports also measured vertebral vBMD in children with diabetes (136) (reduced cortical vBMD), HIV-1 infection (137) (reduced vertebral CSA, which was thought to account for reduced DXA aBMD), and Turner Syndrome (138) (reduced CSA of vertebrae and femur and reduced vertebral vBMD), and midfemoral vBMD in children with congenital hypothyroidism (139) and untreated hyperthyroidism (140). Gilsanz et al (133,141) also used whole body CT scanners to quantify cortical bone. They measured cortical thickness in the midfemur where the cortex is considerably thicker than in the spine (133,141,142). Bacchetta et al (143) measured both the lumbar spine and the midfemur to show deficits in both trabecular and cortical vBMD in patients with idiopathic juvenile rheumatoid arthritis. Recently, Ward et al (26) studied 20 pre- or postpubertal disabled, ambulatory, children with disabling conditions ranging from CP to severe epilepsy (14 males, 6 females; mean age: 9.1  4.3 yr; range: 4e19 yr) who participated in a randomized controlled trial of whole body vibration. Outcomes were lumbar spine and proximal tibial vBMD using a Philips Medical Systems SR-4000 Tomoscan (Best, Netherlands) scanner. A significant change in proximal tibia trabecular vBMD was reported in the children standing on active devices compared with controls. No differences were detected for change in spine vBMD, bone size. or cortical thickness. In a similar study, Caulton et al (134) studied a heterogeneous group of 26 nonambulatory prepubertal children with CP (14 boys, age: 4.3e10.8 yr) in a randomized controlled trial of a standing program but found no change in proximal tibial vBMD. Another study of 31 children, 6e12 yr, with CP comparing whole body vibration vs standing, showed a greater increase in the cortical bone area and moments of inertia of the tibia in the vibration group but no difference in vBMD (135). The disabilities of the children in these studies would have made scanning on dedicated pQCT scanners impossible because of longer scanning time, increasing movement artifact, and positioning problems because of disability and safety concerns with the small gantry. A limitation in the use of QCT is the paucity of reference data. In an earlier publication, Gilsanz et al (132) published cortical and trabecular vBMD values, separately for nonblack healthy boys and girls. For cortical vBMD assessment, a threshold of 350 HU was applied to the vertebral body. More recently, vBMD data from 1222 healthy children and adolescents were pooled (age: 5e21) (144) for L1eL3, using an exposure of 140 mAs. The trabecular bone density (TBD) results were approx 1.5 times higher than the trabecular vBMD results previously reported (132). When related

269 to trabecular vBMD data in adults, in other spinal QCT studies in children and data contained in the International Commission on Radiation Units report that the newer spinal QCT reference databases (144) are not comparable. No information was provided as to how TBD was derived, in contrast to the well-defined trabecular vBMD parameter. Thus, without further information, the reference data published in 2009 should be treated with caution. Newer reference data for children and adolescents, which are used by the QCTPro software from Mindways, Inc., are shown in Fig. 4 (unpublished data, courtesy Alan Brett, Mindways). Although there is no consensus on scan procedures, on the basis of the current literature in adults and children, and the expert opinion of the working group, the following general recommendations should be considered. The most common sites scanned on whole body CT scanners are the lumbar spine (L1eL3), midfemoral shaft, and the tibia. In the long bones, a metaphyseal and diaphyseal site should be scanned, and ideally the whole bone should be included in the scan.

Fig. 4. Reference data for children for lumbar spine quantitative computed tomography. Trabecular volumetric bone mineral density reference data for (A) girls/young females and (B) boys/young males used by Mindways QCTPro software (unpublished data, courtesy Alan Brett, Mindways).

Journal of Clinical Densitometry: Assessment & Management of Musculoskeletal Health

Volume 17, 2014

270 The proximal femur (hip) should not be scanned as in adults as the ionizing radiation dose is relatively high (3 mSv). Currently, adult scan protocols are being used in children, and there is an urgent need for the development of pediatric protocols to minimize radiation dose.

Adams et al.

7. 8.

Questions for Future Research 9.

1. What are the optimum measurement sites, data acquisition procedures, and outcome measures for pQCT in children? 2. Which measures best characterize bone deficits and monitor response to therapy? 3. Can QCT (central or peripheral) predict fracture in health children and children with chronic diseases? 4. What training requirements, quality control procedures, and reporting features are necessary for clinical use of QCT and pQCT in children? In summary, QCT measurements have many advantages over standard bone densitometry techniques in the evaluation of pediatric bone health; unlike DXA, it is not influenced by size artifacts, and it is able to provide distinct measures of cortical and trabecular bone, with quantitation of vBMD, architecture, and biomechanical properties. However, because of the absence of standardized scan acquisition techniques, paucity of reference data, and uncertainty about optimal outcome measures, QCT is not recommended for clinical application except in local centers. Evidence is accumulating of the value of pQCT in identifying bone deficits and studying the effects of disease and therapy in children with complex medical problems. HR-pQCT is an emerging technology that is only recently being used in children. The use of general-purpose CT scanners for quantitative assessment of bone outcomes is now possible with lower radiation exposures and may be the preferred technique for children with physical disabilities. Future studies are needed to standardize the use of QCT for pediatric bone health assessment and address the needs identified in this review so that QCT can be used in the diagnosis of bone fragility in children.

References 1. Blake G, Adams JE, Bishop N. 2013 DXA in adults and children. In: Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. Rosen CJ, ed. 8th ed. Ames, IA: John Wiley & Sons, Inc., 251e263. 2. Leonard MB, Zemel BS. 2002 Current concepts in pediatric bone disease. Pediatr Clin North Am 49(1):143e173. 3. Crabtree N, Ward K. 2009 Bone densitometry: current status and future perspectives. Endocr Dev 16:58e72. 4. Fewtrell MS. 2003 Bone densitometry in children assessed by dual x ray absorptiometry: uses and pitfalls. Arch Dis Child 88(9):795e798. 5. Prentice A, Parsons TJ, Cole TJ. 1994 Uncritical use of bonemineral density in absorptiometry may lead to size-related artifacts in the identification of bone-mineral determinants. Am J Clin Nutr 60(6):837e842. 6. Engelke K, Adams JE, Armbrecht G, et al. 2008 Clinical use of quantitative computed tomography and peripheral quantitative computed tomography in the management of osteoporosis in

10. 11.

12.

13. 14. 15. 16. 17.

18. 19. 20. 21. 22. 23. 24. 25.

26.

adults: the 2007 ISCD Official Positions. J Clin Densitom 11(1): 123e162. Zemel B, Bass S, Binkley T, et al. 2008 Peripheral quantitative computed tomography in children and adolescents: the 2007 ISCD Pediatric Official Positions. J Clin Densitom 11(1):59e74. Engelke K. 2012 Assessment of bone quality and strength with new technologies. Curr Opin Endocrinol Diabetes Obes 19(6): 474e482. Gluer CC, Genant HK. 1989 Impact of marrow fat on accuracy of quantitative CT. J Comput Assist Tomogr 13(6):1023e1035. Rittweger J, Moller K, Bareille MP, et al. 2013 Muscle X-ray attenuation is not decreased during experimental bed rest. Muscle Nerve 47(5):722e730. Tjong W, Kazakia GJ, Burghardt AJ, Majumdar S. 2012 The effect of voxel size on high-resolution peripheral computed tomography measurements of trabecular and cortical bone microstructure. Med Phys 39(4):1893e1903. Burghardt AJ, Pialat JB, Kazakia GJ, et al. 2010 Reproducibility of direct quantitative measures of cortical bone microarchitecture of the distal radius and tibia by HR-pQCT. Bone 47(3):519e528. Gilsanz V. 1998 Bone density in children: a review of the available techniques and indications. Eur J Radiol 26(2):177e182. Kaste SC, Rai SN, Fleming K, et al. 2006 Changes in bone mineral density in survivors of childhood acute lymphoblastic leukemia. Pediatr Blood Cancer 46(1):77e87. Damilakis J, Adams JE, Guglielmi G, Link TM. 2010 Radiation exposure in X-ray-based imaging techniques used in osteoporosis. Eur Radiol 20(11):2707e2714. Blake GM, Naeem M, Boutros M. 2006 Comparison of effective dose to children and adults from dual X-ray absorptiometry examinations. Bone 38(6):935e942. Ashby RL, Ward KA, Roberts SA, et al. 2009 A reference database for the Stratec XCT-2000 peripheral quantitative computed tomography (pQCT) scanner in healthy children and young adults aged 6-19 years. Osteoporos Int 20(8):1337e1346. Kalender WA, Schmidt B, Zankl M, Schmidt M. 1999 A PC program for estimating organ dose and effective dose values in computed tomography. Eur Radiol 9(3):555e562. ICRP, 2007. 2007 Recommendations of the International Commission on Radiological Protection (Users Edition). ICRP Publication 103 (Users Edition). Ann. ICRP 37 (2-4). Kalpakcioglu BB, Engelke K, Genant HK. 2011 Advanced imaging assessment of bone fragility in glucocorticoid-induced osteoporosis. Bone 48(6):1221e1231. Kaste SC, Tong X, Hendrick JM, et al. 2006 QCT versus DXA in 320 survivors of childhood cancer: association of BMD with fracture history. Pediatr Blood Cancer 47(7):936e943. Feber J, Gaboury I, Ni A, et al. 2012 Skeletal findings in children recently initiating glucocorticoids for the treatment of nephrotic syndrome. Osteoporos Int 23(2):751e760. Rousseau-Nepton I, Lang B, Rodd C. 2013 Long-term bone health in glucocorticoid-treated children with rheumatic diseases. Curr Rheumatol Rep 15(3):315. Engelke K, Libanati C, Fuerst T, et al. 2013 Advanced CT based in vivo methods for the assessment of bone density, structure, and strength. Curr Osteoporos Rep 11(3):246e255. Engelke K, Libanati C, Liu Y, et al. 2009 Quantitative computed tomography (QCT) of the forearm using general purpose spiral whole-body CT scanners: accuracy, precision and comparison with dual-energy X-ray absorptiometry (DXA). Bone 45(1): 110e118. Ward K, Alsop C, Caulton J, et al. 2004 Low magnitude mechanical loading is osteogenic in children with disabling conditions. J Bone Miner Res 19(3):360e369.

Journal of Clinical Densitometry: Assessment & Management of Musculoskeletal Health

Volume 17, 2014

Quantitative CT in Children and Adolescents 27. Zemel BS, Paulhamus D, Dilzer C, et al. 2004 Precision of peripheral quantitative computed tomography measures of the tibia in children. J Bone Miner Res 19(Suppl 1):S232. 28. Burrows M, Cooper DM, Liu D, McKay HA. 2009 Bone and muscle parameters of the tibia: agreement between the XCT 2000 and XCT 3000 instruments. J Clin Densitom 12(2): 186e194. 29. Burghardt AJ, et al. 2013 Multicenter precision of cortical and trabecular bone quality measures assessed by high-resolution peripheral quantitative computed tomography. J Bone Miner Res 28(3):524e536. 30. Burrows M, Liu D, McKay H. 2010 High-resolution peripheral QCT imaging of bone micro-structure in adolescents. Osteoporos Int 21(3):515e520. 31. Burrows M, Liu D, Moore S, McKay H. 2010 Bone microstructure at the distal tibia provides a strength advantage to males in late puberty: an HR-pQCT study. J Bone Miner Res 25(6): 1423e1432. 32. Burrows M, Liu D, Perdios A, et al. 2010 Assessing bone microstructure at the distal radius in children and adolescents using HR-pQCT: a methodological pilot study. J Clin Densitom 13(4):451e455. 33. Chevalley T, Bonjour JP, Ferrari S, Rizzoli R. 2011 Pubertal timing and body mass index gain from birth to maturity in relation with femoral neck BMD and distal tibia microstructure in healthy female subjects. Osteoporos Int 22(10): 2689e2698. 34. Kirmani S, Amin S, McCready LK, et al. 2012 Sclerostin levels during growth in children. Osteoporos Int 23(3):1123e1130. 35. Kirmani S, Christen D, van Lenthe GH, et al. 2009 Bone structure at the distal radius during adolescent growth. J Bone Miner Res 24(6):1033e1042. 36. Liu D, Burrows M, Egeli D, McKay H. 2010 Site specificity of bone architecture between the distal radius and distal tibia in children and adolescents: an HR-pQCT study. Calcif Tissue Int 87(4):314e323. 37. Nishiyama KK, Macdonald HM, Moore SA, et al. 2012 Cortical porosity is higher in boys compared with girls at the distal radius and distal tibia during pubertal growth: an HRpQCT study. J Bone Miner Res 27(2):273e282. 38. Wang Q, Ghasem-Zadeh A, Wang XF, et al. 2011 Trabecular bone of growth plate origin influences both trabecular and cortical morphology in adulthood. J Bone Miner Res 26(7): 1577e1583. 39. Wang Q, Wang XF, Iuliano-Burns S, et al. 2010 Rapid growth produces transient cortical weakness: a risk factor for metaphyseal fractures during puberty. J Bone Miner Res 25(7): 1521e1526. 40. Engelke K, Stampa B, Timm W, et al. 2012 Short-term in vivo precision of BMD and parameters of trabecular architecture at the distal forearm and tibia. Osteoporos Int 23(8): 2151e2158. 41. Pauchard Y, Ayres FJ, Boyd SK. 2011 Automated quantification of three-dimensional subject motion to monitor image quality in high-resolution peripheral quantitative computed tomography. Phys Med Biol 56(20):6523e6543. 42. Pauchard Y, Liphardt AM, Macdonald HM, et al. 2012 Quality control for bone quality parameters affected by subject motion in high-resolution peripheral quantitative computed tomography. Bone 50(6):1304e1310. 43. Pialat JB, Liphardt AM, Macdonald HM, et al. 2012 Visual grading of motion induced image degradation in high resolution peripheral computed tomography: impact of image quality on measures of bone density and micro-architecture. Bone 50(1):111e118.

271 44. Miglioretti DL, Johnson E, Williams A, et al. 2013 The use of computed tomography in pediatrics and the associated radiation exposure and estimated cancer risk. JAMA Pediatr 167(8):700e707. 45. Paterson A, Frush DP. 2007 Dose reduction in paediatric MDCT: general principles. Clin Radiol 62(6):507e517. 46. Zacharias C, Alessio AM, Otto RK, et al. 2013 Pediatric CT: strategies to lower radiation dose. AJR Am J Roentgenol 200(5):950e956. 47. Cann CE. 1988 Quantitative CT for determination of bonemineral densityda review. Radiology 166(2):509e522. 48. Cann CE, Genant HK. 1980 Precise measurement of vertebral mineral-content using computed-tomography. J Comput Assist Tomogr 4(4):493e500. 49. Museyko O, Heinemann A, Krause M, et al. 2014 A low radiation exposure protocol for 3D QCT of the spine. Osteoporos Int 25(3):983e992. 50. Engelke K, Mastmeyer A, Bousson V, et al. 2009 Reanalysis precision of 3D quantitative computed tomography (QCT) of the spine. Bone 44(4):566e572. 51. Damilakis J, Guglielmi G. 2010 Quality assurance and dosimetry in bone densitometry. Radiol Clin North Am 48(3): 629e640. 52. Guglielmi G, Damilakis J, Solomou G, Bazzocchi A. 2012 Quality assurance of imaging techniques used in the clinical management of osteoporosis. Radiol Med 117(8):1347e1354. 53. Pearson J, Rueqsegger P, Dequeker J, et al. 1994 European semi-anthropomorphic phantom for the cross-calibration of peripheral bone densitometers: assessment of precision accuracy and stability. Bone Miner 27(2):109e120. 54. Reeve J, et al. 1996 Radial cortical and trabecular bone densities of men and women standardized with the European Forearm Phantom. Calcif Tissue Int 58(3):135e143. 55. Kalender WA, Felsenberg D, Genant HK, et al. 1995 The European Spine Phantomda tool for standardization and quality control in spinal bone mineral measurements by DXA and QCT. Eur J Radiol 20(2):83e92. 56. Rauch F, Neu C, Manz F, et al. 2001 The development of metaphyseal cortexdimplications for distal radius fractures during growth. J Bone Miner Res 16(8):1547e1555. 57. Anliker E, Toigo M. 2012 Functional assessment of the musclebone unit in the lower leg. J Musculoskelet Neuronal Interact 12(2):46e55. 58. Schoenau E. 2005 The ‘‘functional muscle-bone unit’’: a twostep diagnostic algorithm in pediatric bone disease. Pediatr Nephrol 20(3):356e359. 59. Veilleux LN, Cheung M, Ben Amor M, et al. 2012 Abnormalities in muscle density and muscle function in hypophosphatemic rickets. J Clin Endocrinol Metab 97(8): E1492eE1498. 60. Bouxsein ML. 2011 Bone structure and fracture risk: do they go arm in arm? J Bone Miner Res 26(7):1389e1391. 61. Parfitt AM, Drezner MK, Glorieux FH, et al. 1987 Bone histomorphometrydstandardization of nomenclature, symbols, and units. J Bone Miner Res 2(6):595e610. 62. Leib A, Ruegsegger P. 1999 Calibration of trabecular bone structure measures of in vivo three-dimensional peripheral quantitative computed tomography with 28-microm-resolution microcomputed tomography. Bone 24(1):35e39. 63. Donnelly E. 2011 Methods for assessing bone quality: a review. Clin Orthop Relat Res 469(8):2128e2138. 64. Rauch F, Schoenau E. 2008 Peripheral quantitative computed tomography of the proximal radius in young subjectsdnew reference data and interpretation of results. J Musculoskelet Neuronal Interact 8(3):217e226.

Journal of Clinical Densitometry: Assessment & Management of Musculoskeletal Health

Volume 17, 2014

272 65. Moyer-Mileur LJ, Quick JL, Murray MA. 2008 Peripheral quantitative computed tomography of the tibia: pediatric reference values. J Clin Densitom 11(2):283e294. 66. Leonard MB, Elmi A, Mostoufi-Moab S, et al. 2010 Effects of sex, race, and puberty on cortical bone and the functional muscle bone unit in children, adolescents, and young adults. J Clin Endocrinol Metab 95(4):1681e1689. 67. Cole TJ, Green PJ. 1992 Smoothing reference centile curves: the LMS method and penalized likelihood. Stat Med 11(10): 1305e1319. 68. Anliker E, Dick C, Rawer R, et al. 2012 Effects of jumping exercise on maximum ground reaction force and bone in 8- to 12year-old boys and girls: a 9-month randomized controlled trial. J Musculoskelet Neuronal Interact 12(2):56e67. 69. Anliker E, Rawer R, Boutellier U, et al. 2011 Maximum ground reaction force in relation to tibial bone mass in children and adults. Med Sci Sports Exerc 43(11):2102e2109. 70. Ducher G, Bass SL, Naughton GA, et al. 2009 Overweight children have a greater proportion of fat mass relative to muscle mass in the upper limbs than in the lower limbs: implications for bone strength at the distal forearm. Am J Clin Nutr 90(4):1104e1111. 71. Farr JN, Blew RM, Lee VR, et al. 2011 Associations of physical activity duration, frequency, and load with volumetric BMD, geometry, and bone strength in young girls. Osteoporos Int 22(5):1419e1430. 72. Farr JN, Chen Z, Lisse JR, et al. 2010 Relationship of total body fat mass to weight-bearing bone volumetric density, geometry, and strength in young girls. Bone 46(4):977e984. 73. Farr JN, Funk JL, Chen Z, et al. 2011 Skeletal muscle fat content is inversely associated with bone strength in young girls. J Bone Miner Res 26(9):2217e2225. 74. Farr JN, Lee VR, Blew RM, et al. 2011 Quantifying bonerelevant activity and its relation to bone strength in girls. Med Sci Sports Exerc 43(3):476e483. 75. Farr JN, Tomas R, Chen Z, et al. 2011 Lower trabecular volumetric BMD at metaphyseal regions of weight-bearing bones is associated with prior fracture in young girls. J Bone Miner Res 26(2):380e387. 76. Ashby RL, Adams JE, Roberts SA, et al. 2011 The musclebone unit of peripheral and central skeletal sites in children and young adults. Osteoporos Int 22(1):121e132. 77. Darelid A, Ohlsson C, Rudang R, et al. 2010 Trabecular volumetric bone mineral density is associated with previous fracture during childhood and adolescence in males: the GOOD study. J Bone Miner Res 25(3):537e544. 78. Dowthwaite JN, Flowers PP, Scerpella TA. 2011 Agreement between pQCT- and DXA-derived indices of bone geometry, density, and theoretical strength in females of varying age, maturity, and physical activity. J Bone Miner Res 26(6): 1349e1357. 79. Micklesfield LK, Norris SA, Pettifor JM. 2011 Determinants of bone size and strength in 13-year-old South African children: the influence of ethnicity, sex and pubertal maturation. Bone 48(4):777e785. 80. Warden SJ, Hill KM, Ferira AJ, et al. 2013 Racial differences in cortical bone and their relationship to biochemical variables in Black and White children in the early stages of puberty. Osteoporos Int 24(6):1869e1879. 81. Erlandson MC, Kontulainen SA, Baxter-Jones AD. 2011 Precompetitive and recreational gymnasts have greater bone density, mass, and estimated strength at the distal radius in young childhood. Osteoporos Int 22(1):75e84.

Adams et al. 82. Wetzsteon RJ, Zemel BS, Shults J, et al. 2011 Mechanical loads and cortical bone geometry in healthy children and young adults. Bone 48(5):1103e1108. 83. Wey HE, Binkley TL, Beare TM, et al. 2011 Cross-sectional versus longitudinal associations of lean and fat mass with pQCT bone outcomes in children. J Clin Endocrinol Metab 96(1):106e114. 84. Xu L, Nicholson P, Wang QJ, et al. 2010 Fat mass accumulation compromises bone adaptation to load in Finnish women: a cross-sectional study spanning three generations. J Bone Miner Res 25(11):2341e2349. 85. Xu L, Wang Q, Lyytikainen A, et al. 2011 Concerted actions of insulin-like growth factor 1, testosterone, and estradiol on peripubertal bone growth: a 7-year longitudinal study. J Bone Miner Res 26(9):2204e2211. 86. Kalkwarf HJ, Laor T, Bean JA. 2011 Fracture risk in children with a forearm injury is associated with volumetric bone density and cortical area (by peripheral QCT) and areal bone density (by DXA). Osteoporos Int 22(2):607e616. 87. Cole ZA, Harvey NC, Kim M, et al. 2012 Increased fat mass is associated with increased bone size but reduced volumetric density in pre pubertal children. Bone 50(2):562e567. 88. Deere K, Sayers A, Rittweger J, et al. 2012 A cross-sectional study of the relationship between cortical bone and highimpact activity in young adult males and females. J Clin Endocrinol Metab 97(10):3734e3743. 89. Sayers A, Tobias JH. 2010 Fat mass exerts a greater effect on cortical bone mass in girls than boys. J Clin Endocrinol Metab 95(2):699e706. 90. Beccard R, Land C, Semler O, et al. 2010 Do bone mineral density, bone geometry and the functional muscle-bone unit explain bone fractures in healthy children and adolescents? Horm Res Paediatr 74(5):312e318. 91. Cheng SL, Xu LT, Nicholson PHF, et al. 2009 Low volumetric BMD is linked to upper-limb fracture in pubertal girls and persists into adulthood: a seven-year cohort study. Bone 45(3): 480e486. 92. Soucek O, Lebl J, Snajderova M, et al. 2011 Bone geometry and volumetric bone mineral density in girls with Turner syndrome of different pubertal stages. Clin Endocrinol (Oxf) 74(4):445e452. 93. Armstrong L, Jett K, Birch P, et al. 2013 The generalized bone phenotype in children with neurofibromatosis 1: a sibling matched case-control study. Am J Med Genet A 161(7): 1654e1661. 94. De Schepper J, Roggen I, Van Biervliet S, et al. 2012 Comparative bone status assessment by dual energy X-ray absorptiometry, peripheral quantitative computed tomography and quantitative ultrasound in adolescents and young adults with cystic fibrosis. J Cyst Fibros 11(2):119e124. 95. Soucek O, Komrska V, Hlavka Z, et al. 2012 Boys with haemophilia have low trabecular bone mineral density and sarcopenia, but normal bone strength at the radius. Haemophilia 18(2): 222e228. 96. Kohler JA, Moon RJ, Sands R, et al. 2012 Selective reduction in trabecular volumetric bone mineral density during treatment for childhood acute lymphoblastic leukemia. Bone 51(4):765e770. 97. Mostoufi-Moab S, Brodsky J, Isaacoff EJ, et al. 2012 Longitudinal assessment of bone density and structure in childhood survivors of acute lymphoblastic leukemia without cranial radiation. J Clin Endocrinol Metab 97(10):3584e3592. 98. Mostoufi-Moab S, Ginsberg JP, Bunin N, et al. 2012 Bone density and structure in long-term survivors of pediatric allogeneic

Journal of Clinical Densitometry: Assessment & Management of Musculoskeletal Health

Volume 17, 2014

Quantitative CT in Children and Adolescents

99. 100. 101. 102.

103. 104. 105. 106.

107.

108. 109.

110.

111. 112. 113.

114.

115.

116.

hematopoietic stem cell transplantation. J Bone Miner Res 27(4):760e769. Saha MT, Sievanen H, Salo MK, et al. 2009 Bone mass and structure in adolescents with type 1 diabetes compared to healthy peers. Osteoporos Int 20(8):1401e1406. Gronowitz E, Lorentzon M, Ohlsson C, et al. 2008 Docosahexaenoic acid is associated with endosteal circumference in long bones in young males with cystic fibrosis. Br J Nutr 99(1):160e167. Gordon CM, Gordon LB, Snyder BD, et al. 2011 HutchinsonGilford progeria is a skeletal dysplasia. J Bone Miner Res 26(7):1670e1679. Stevenson DA, Viskochil DH, Carey JC, et al. 2009 Tibial geometry in individuals with neurofibromatosis type 1 without anterolateral bowing of the lower leg using peripheral quantitative computed tomography. Bone 44(4):585e589. Edouard T, Deal C, Van Vliet G, et al. 2012 Muscle-bone characteristics in children with Prader-Willi syndrome. J Clin Endocrinol Metab 97(2):E275eE281. Holroyd CR, Davies JH, Taylor P, et al. 2010 Reduced cortical bone density with normal trabecular bone density in girls with Turner syndrome. Osteoporos Int 21(12):2093e2099. Cheung M, Roschger P, Klaushofer K, et al. 2013 Cortical and trabecular bone density in X-linked hypophosphatemic rickets. J Clin Endocrinol Metab 98(5):954e961. Bechtold S, Bachmann S, Putzker S, et al. 2011 Early changes in body composition after cessation of growth hormone therapy in childhood-onset growth hormone deficiency. J Clin Densitom 14(4):471e477. Schweizer R, Martin DD, Haase M, et al. 2007 Similar effects of long-term exogenous growth hormone (GH) on bone and muscle parameters: a pQCT study of GH-deficient and smallfor-gestational-age (SGA) children. Bone 41(5):875e881. Bechtold S, Putzker S, Birnbaum J, et al. 2010 Impaired bone geometry after heart and heart-lung transplantation in childhood. Transplantation 90(9):1006e1010. Ranta S, Viljakainen H, Makipernaa A, et al. 2012 Peripheral quantitative computed tomography (pQCT) reveals alterations in the three-dimensional bone structure in children with haemophilia. Haemophilia 18(6):955e961. Fung EB, Vichinsky EP, Kwiatkowski JL, et al. 2011 Characterization of low bone mass in young patients with thalassemia by DXA, pQCT and markers of bone turnover. Bone 48(6): 1305e1312. Bechtold S, Alberer M, Arenz T, et al. 2010 Reduced muscle mass and bone size in pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis 16(2):216e225. Dubner SE, Shults J, Baldassano RN, et al. 2009 Longitudinal assessment of bone density and structure in an incident cohort of children with Crohn’s disease. Gastroenterology 136(1):123e130. Werkstetter KJ, Pozza SB, Filipiak-Pittroff B, et al. 2011 Longterm development of bone geometry and muscle in pediatric inflammatory bowel disease. Am J Gastroenterol 106(5): 988e998. Bechtold S, Ripperger P, Dalla Pozza R, et al. 2010 Dynamics of body composition and bone in patients with juvenile idiopathic arthritis treated with growth hormone. J Clin Endocrinol Metab 95(1):178e185. Burnham JM, Shults J, Dubner SE, et al. 2008 Bone density, structure, and strength in juvenile idiopathic arthritis: importance of disease severity and muscle deficits. Arthritis Rheum 58(8):2518e2527. Terpstra AM, Kalkwarf HJ, Shults J, et al. 2012 Bone density and cortical structure after pediatric renal transplantation. J Am Soc Nephrol 23(4):715e726.

273 117. Tsampalieros A, Kalkwarf HJ, Wetzsteon RJ, et al. 2013 Changes in bone structure and the muscle-bone unit in children with chronic kidney disease. Kidney Int 83(3):495e502. 118. Wesseling-Perry K, Bacchetta J. 2011 CKD-MBD after kidney transplantation. Pediatr Nephrol 26(12):2143e2151. 119. Wetzsteon RJ, Kalkwarf HJ, Shults J, et al. 2011 Volumetric bone mineral density and bone structure in childhood chronic kidney disease. J Bone Miner Res 26(9):2235e2244. 120. Wetzsteon RJ, Shults J, Zemel BS, et al. 2009 Divergent effects of glucocorticoids on cortical and trabecular compartment BMD in childhood nephrotic syndrome. J Bone Miner Res 24(3):503e513. 121. Biggin A, Briody JN, Ramjan KA, et al. 2013 Evaluation of bone mineral density and morphology using pQCT in children after spinal cord injury. Dev Neurorehabil 16(6):391e397. 122. Ooi HL, Briody J, McQuade M, et al. 2012 Zoledronic acid improves bone mineral density in pediatric spinal cord injury. J Bone Miner Res 27(7):1536e1540. 123. Sherk VD, Bemben MG, Bemben DA. 2008 BMD and bone geometry in transtibial and transfemoral amputees. J Bone Miner Res 23(9):1449e1457. 124. Calarge CA, Zimmerman B, Xie D, et al. 2010 A crosssectional evaluation of the effect of risperidone and selective serotonin reuptake inhibitors on bone mineral density in boys. J Clin Psychiatry 71(3):338e347. 125. Bechtold S, Putzker S, Bonfig W, et al. 2007 Bone size normalizes with age in children and adolescents with type 1 diabetes. Diabetes Care 30(8):2046e2050. 126. Griffin LM, Kalkwarf HJ, Zemel BS, et al. 2012 Assessment of dual-energy X-ray absorptiometry measures of bone health in pediatric chronic kidney disease. Pediatr Nephrol 27(7): 1139e1148. 127. Gilsanz V, Varterasian M, Senac MO, Cann CE. 1986 Quantitative spinal mineral analysis in children. Ann Radiol (Paris) 29(3e4):380e382. 128. Gilsanz V, Gibbens DT, Roe TF, et al. 1988 Vertebral bone density in children: effect of puberty. Radiology 166(3):847e850. 129. Mora S, Goodman WG, Loro ML, et al. 1994 Age-related changes in cortical and cancellous vertebral bone density in girls: assessment with quantitative CT. AJR Am J Roentgenol 162(2):405e409. 130. Mora S, Pitukcheewanont P, Kaufman FR, et al. 1999 Biochemical markers of bone turnover and the volume and the density of bone in children at different stages of sexual development. J Bone Miner Res 14(10):1664e1671. 131. Loro ML, Sayre J, Roe TF, et al. 2000 Early identification of children predisposed to low peak bone mass and osteoporosis later in life. J Clin Endocrinol Metab 85(10):3908e3918. 132. Gilsanz V, Boechat MI, Roe TF, et al. 1994 Gender differences in vertebral body sizes in children and adolescents. Radiology 190(3):673e677. 133. Gilsanz V, Skaggs DL, Kovanlikaya A, et al. 1998 Differential effect of race on the axial and appendicular skeletons of children. J Clin Endocrinol Metab 83(5):1420e1427. 134. Caulton JM, Ward KA, Alsop CW, et al. 2004 A randomised controlled trial of standing programme on bone mineral density in non-ambulant children with cerebral palsy. Arch Dis Child 89(2):131e135. 135. Wren TAL, Lee DC, Hara R, et al. 2010 Effect of highfrequency, low-magnitude vibration on bone and muscle in children with cerebral palsy. J Pediatr Orthop 30(7): 732e738. 136. Roe TF, Mora S, Costin G, et al. 1991 Vertebral bone density in insulin-dependent diabetic children. Metabolism 40(9):967e971.

Journal of Clinical Densitometry: Assessment & Management of Musculoskeletal Health

Volume 17, 2014

274 137. Pitukcheewanont P, Safani D, Church J, et al. 2005 Bone measures in HIV-1 infected children and adolescents: disparity between quantitative computed tomography and dual-energy X-ray absorptiometry measurements. Osteoporos Int 16(11): 1393e1396. 138. Pitukcheewanont P, Numbenjapon N, Safani D, et al. 2011 Bone size and density measurements in prepubertal children with Turner syndrome prior to growth hormone therapy. Osteoporos Int 22(6):1709e1715. 139. Pitukcheewanont P, Safani D, Gilsanz V, et al. 2004 Quantitative computed tomography measurements of bone mineral density in prepubertal children with congenital hypothyroidism treated with L-thyroxine. J Pediatr Endocrinol Metab 17(6): 889e893. 140. Numbenjapon N, Costin G, Gilsanz V, et al. 2007 Low cortical bone density measured by computed tomography in children

Adams et al.

141. 142.

143.

144.

and adolescents with untreated hyperthyroidism. J Pediatr 150(5):527e530. Gilsanz V, Kovanlikaya A, Costin G, et al. 1997 Differential effect of gender on the sizes of the bones in the axial and appendicular skeletons. J Clin Endocrinol Metab 82(5):1603e1607. Mora S, Pitukcheewanont P, Nelson JC, Gilsanz V. 1999 Serum levels of insulin-like growth factor I and the density, volume, and cross-sectional area of cortical bone in children. J Clin Endocrinol Metab 84(8):2780e2783. Bacchetta J, Wesseling-Perry K, Gilsanz V, et al. 2013 Idiopathic juvenile osteoporosis: a cross-sectional single-centre experience with bone histomorphometry and quantitative computed tomography. Pediatr Rheumatol Online J 11(1):6. Gilsanz V, Perez FJ, Campbell PP, et al. 2009 Quantitative CT reference values for vertebral trabecular bone density in children and young adults. Radiology 250(1):222e227.

Journal of Clinical Densitometry: Assessment & Management of Musculoskeletal Health

Volume 17, 2014