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Department of Biomedical Engineering (D.C.L., T.A.L.W.), University of Southern California, Los Angeles, California 90089; and Departments of Radiology and Orthopaedic Surgery (D.C.L., V.G., T.A.L.W.), Childrens Hospital Los Angeles, Los Angeles, California 90027
Address all correspondence and requests for reprints to: David C. Lee, Childrens Hospital Los Angeles, Department of Orthopaedic Surgery, Motion Lab, MS 69, 4650 Sunset Boulevard, Los Angeles, California 90027.E-mail: davidcle{at}usc.edu.
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Abstract |
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Objective: The objective of the study was to characterize the variability in trabecular bone density values along the length of the metaphysis.
Design: The design was an analysis of pQCT bone density data.
Setting: The study was conducted at a hospital radiology department.
Patients: The study included 35 children with cerebral palsy aged 6–12 yr.
Main Outcome Measure: Variations in cancellous bone density along the length of the proximal tibial metaphysis were measured.
Results: The patterns of decay in metaphyseal trabecular bone density were different in all subjects, and the density changed from the physis to the shaft at a rate of 16.8 ± 8.2% per 1 mm (range 8.6–37.9% per 1 mm). The slopes of the density curve drastically changed in some children over a short period of 6 months. Even with a high correlation (r2 = 0.88) between the density of a slice located a fixed distance from the growth plate and the overall mean metaphysis density, the respective changes in density over 6 months were only moderately correlated (r2 = 0.58).
Conclusions: These results underscore the difficulty in interpreting metaphyseal pQCT bone density measurements from a single slice and highlight the need for developing pQCT acquisition techniques that provide more representative bone density determinations in the appendicular skeleton of children.
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Introduction |
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Because of its porosity and large surface area, trabecular bone has greater turnover and is a better indicator of bone remodeling than cortical bone. Trabecular bone density determinations by pQCT are commonly obtained by a single scan at a relative location, such as 4 or 8% length of the radius or tibia (4, 5, 6, 7, 8), or a fixed location, such as 10 mm from the end of the growth plate (9).
Whereas available data indicate that the short-term reproducibility of these measurements is excellent (10, 11), positioning is critical, and due to the variability of trabecular bone density throughout the metaphysis, any offset in the location to be scanned would significantly influence the values obtained (12). Additionally, the large range of metaphyseal morphology among subjects, diseases, and ages limits comparative cross-sectional studies and interpretation of the same scan location in longitudinal examinations (13).
In this study, we characterized the variability in trabecular bone density values along the length of the proximal tibial metaphysis and the change in cancellous bone density over a 6-month period in a cohort of children with cerebral palsy who were participants in an ongoing study requiring longitudinal pQCT determinations.
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Subjects and Methods |
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This study examined existing pQCT data from 37 children with cerebral palsy. Two were excluded for motion artifacts, leaving 35 for analysis (five hemiplegic, 22 diplegic, two triplegic, six quadriplegic). The subjects were originally recruited for ongoing studies at Childrens Hospital Los Angeles, and informed consent was obtained for all subjects. All subjects were ambulatory either with or without assistive devices and were excluded if they had recently undergone any procedure or medication that could alter bone or muscle function. Of the 35 children, 19 returned for a 6-month follow-up measurement. Tanner stage was not evaluated at the time of the exams.
Data acquisition and processing
pQCT was performed on the proximal tibia of each subject using the same scanner (General Electric Hilite Advantage, Milwaukee, WI) and with the same K2HPO4 mineral reference phantom for simultaneous calibration (CT-T bone densitometry package; General Electric). The thickness of each cross-section was 1.25 mm, and the field of view was 345 mm. Data sets of at least 70 contiguous slices per subject were taken to ensure coverage of the metaphysis region (Fig. 1
). The same technician analyzed all images. Scans were evaluated and excluded if motion artifacts were found.
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). The circular cross-section of the core was determined by fitting the largest circle possible into the narrowest region of the proximal tibia, without coming into contact with the cortex. The length of the core from the metaphysis was defined as the region containing cancellous bone, specifically between the growth plate and where density values drop less than 0 mg/cm3, K2HPO4. Density values below zero, as calibrated by the phantom, were considered mainly fat or nonbone elements, as found in the intermedullary canal. Care was taken to ensure that the cylindrical core was placed in the same position relative to the growth plate in all subjects.
All image processing was performed with custom algorithms using MATLAB R2006a (MathWorks, Natick, MA).
Data analysis
The density data from the cylindrical core containing the metaphyseal cancellous bone can be depicted graphically (Fig. 2). For each cross-section along the length of the core, mean density and density variation are represented. Several parameters of interest can be extracted from the core data.
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Also, the length of the metaphysis can be found by observing the occurrence of cancellous bone, previously defined as between the growth plate and zero density values. The overall mean density of the metaphysis is the average of the mean densities from each cross-section. The area under the curve, which represents the total amount of cancellous bone in the metaphyseal core, is the product of the overall mean density and length of the metaphysis.
Additionally, the overall mean density was compared with density values along the length of the metaphysis by both relative and fixed distances. The percent length or fixed distance with the strongest correlation was then used to measure percent change in a period of 6 months and compared with the percent change using overall mean density.
Because the slice thickness used in this study (1.25 mm) differed from other pQCT studies (2.0–2.5 mm) (4, 5, 6, 7, 8, 14, 15), we also approximated a thicker slice (2.5 mm) by averaging two adjacent slices (2 x 1.25 mm) in an example subject. We compared the measurements using 1.25- and 2.5-mm slices.
Regression analysis was used to relate the metaphyseal bone measurements to the subject anthropometric measures. Regression was also used to compare the overall mean density and density from a single slice. Paired t tests were used to compare baseline and follow-up measurements. Wilcoxon sign rank tests were used to compare variables with skewness coefficients greater than 1. All statistical analysis was performed with Statistics Toolbox Version 5.2 (MathWorks).
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Results |
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). Follow-up data were available for 19 of the subjects (eight females and 11 males) (Table 2).
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). The length of the metaphysis, overall mean density of the entire metaphysis, and area under the curve (a measure of total bone in the metaphyseal core) all had wide ranges (Table 3). None of these measures from the metaphysis correlated strongly with anthropometric measures. The highest correlation was between metaphysis length and subject height (r2 < 0.14). The mean change in density also varied greatly between subjects. Among all subjects the mean change in density was 6.9 ± 2.7 mg/cm3·mm, ranging from 4.2 to 14.7 mg/cm3·mm. As a percentage, the mean change in density per millimeter was 16.8 ± 8.2%, ranging from 8.6 to 37.9% (Table 3). These results indicate that a 1-mm offset in positioning of a slice would result in errors averaging 6.9 mg/cm3 or 16.8%.
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), and area under the curve and overall mean density decreased (Table 4).
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When the percent change over a 6-month period was examined, regression strength between density from the 48% slice and overall mean density was weak (r2 = 0.36, P = 0.013). The range of percent change using a single slice at 48% length of metaphysis was wide, ranging from –50.2 to 31.3%, compared with a range of –32.8 to 11.9% for percent change using overall mean density (both ranges are without outliers, defined as points outside the fifth or 95th percentiles) (Fig. 4). The regression strength between the change in density over 6 months from the slice 1.25 away from the growth plate and overall mean density was stronger (r2 = 0.58, P < 0.001), but the range was even wider at –45.1 to 50.9% (Fig. 4).
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. The shape of the cancellous bone density curve has changed in a 6-month period during which the subject grew 4.3 cm. At the cross-section at which the curves intersect, there is no change in density. At the same time, it is possible to select a slice in which the change is a 25.3% decrease in density. For comparison, the percent change using the overall mean density of the entire metaphysis was –25.4%. When using a thicker slice of 2.5 mm, approximated by combining two 1.25-mm slices, the density curve was smoother, although the general shape of the curve did not change (Fig. 5B). There was a 24.0% decrease in the same location in which a 25.3% decrease was found using the 1.25-mm thickness data. The mean density slope and area under the curve remained the same using the two thicknesses.
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Discussion |
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Another significant limitation of this study is that tibia length was not measured, so assessments involving percentage of tibia length could not be done. We attempted to use percentage of metaphysis length as a surrogate for bone length. Whereas metaphysis length is theoretically useful, it would not be known by clinicians before a scan, and the relationship between metaphysis length and bone length is complex. Longitudinal growth of long bones occurs at the growth plate and is associated with extension of the metaphysis (18, 19). At the same time, the metaphysis gradually shortens as a proportion of bone length. This dynamic process is specific to each extremity of the long bone. The distal and proximal growth plates grow at disproportionate and varying rates (20), making exact locations difficult to track longitudinally. It is therefore likely that cross-sections based on a percentage of long bone length will not be measuring the same site over time.
In contrast, our results suggest that a scan location near the growth plate (1.25–2.5 mm) may be a promising measurement site. There was a strong correlation between trabecular density at this location and mean density of the entire metaphysis. Nevertheless, we observed tremendous variability in the percent change after 6 months at this location. At this site, some children showed a decrease of up to 45.1% in trabecular bone density, whereas others showed an increase of up to 50.9%. The unexpectedly large range suggests that even if we were able to choose the site that best reflects overall trabecular density in cross-sectional studies, longitudinal measures would still yield conflicting results. Additional studies are needed to determine whether mean density or a slice reflecting mean density is indeed superior to single slice measurements at other locations. Additional studies are also needed to discern which slice, if any, is the best choice and whether a single slice can provide sufficient information to infer any relation to bone strength or fracture risk.
Previous studies using pQCT in children have investigated the effects of age or maturity related growth, gender differences, physical activity, disease, geometry, and strength (5, 6, 7, 8, 14, 15, 21, 22, 23). These studies used a variety of methods, such as measurements at 4 or 10% length of the radius or tibia or at a fixed length 10 mm distal to the growth plate. More recent studies using high-resolution pQCT have scanned 9-mm-thick sections of long bones to assess trabecular microarchitecture (24, 25, 26, 27). Although this relatively new technique is promising, further evaluation is necessary to determine how measures from a 9-mm-thick section should be interpreted, especially across a growing population.
The results of this study highlight the limitations of current pQCT methodology using single scans as outcome measures in cross-sectional and longitudinal studies assessing trabecular bone density. We found a large variability in metaphyseal morphology among subjects; the length of the metaphysis, overall trabecular mean density, and slope of the density curve all had wide ranges. In addition, longitudinal assessments showed that the slopes of the density curve drastically changed in some children, even over a short period of 6 months. These results emphasize the need for developing pQCT acquisition techniques that provide more accurate bone density determinations in the appendicular skeleton of children.
The findings of this study corroborate the presence of a considerable gradient in trabecular bone density from the physeal plate, in which values are higher, to the shaft of the bone, in which no trabecular bone is present. The large intra- and intersubject variability in the bone density measures along the metaphysis highlights the limitations of assessments with a single scan. Subjects in this study showed a substantial range of variability from a 1-mm offset slice positioning with an average of 6.9 mg/cm3 or 16.8%.
Single-slice studies are also prone to error from the metaphysis’ changing morphology. In the case example (Fig. 5), the density slope or gradient changed over 6 months. Thus, any cross-section selected would yield a unique percent change.
Several issues regarding the design of this study need to be considered for the appropriate interpretation of the current results. First, because the image resolution of pQCT does not allow clear delineation between the inner margin of cortical bone and the outer margin of trabecular bone, especially near the growth plate, we chose to measure a defined cylindrical core of trabecular bone rather than sample all the trabecular bone in the metaphysis. Similar difficulties apply to histopathological studies because of the gradual transition from cortical to trabecular bone in the subcortical region along the endosteum. Second, the slice thickness (1.25 mm) used in this study differs from that typically used in other studies (2.3–2.5 mm) (4, 5, 6). The thinner slices enabled greater resolution in examining density variation, the main objective of this study. However, to better compare with other studies, we also simulated a 2.5-mm slice by averaging adjacent 1.25-mm slices. The thicker slice made the density curves slightly smoother but did not greatly reduce the effect of positioning errors. The slope of the density curve remained the same whether using 1.25- or 2.5-mm slices.
In summary, this study, which quantified the variability of trabecular bone density along the length of the metaphysis, underscores the difficulties in obtaining reproducible pQCT measures from a single scan in the appendicular skeleton of children. Future studies are needed to determine whether different acquisition methods could provide more representative measures of bone density.
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Footnotes |
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Disclosure Statement: The authors have nothing to declare.
First Published Online August 7, 2007
Abbreviation: pQCT, Peripheral quantitative computed tomography.
Received January 18, 2007.
Accepted July 31, 2007.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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