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Quantitative Ultrasound Measurements at Hand Phalanges in Children and Adolescents: A Longitudinal Study
Ultrasound in Med. & Biol., Vol. 34, No. 10, pp. 1547–1553, 2008 Copyright © 2008 World Federation for Ultrasound in Medicine & Biology Printed in the USA. All rights reserved 0301-5629/08/$–see front matter
doi:10.1016/j.ultrasmedbio.2008.03.007
● Original Contribution QUANTITATIVE ULTRASOUND MEASUREMENTS AT HAND PHALANGES IN CHILDREN AND ADOLESCENTS: A LONGITUDINAL STUDY ZENON P. HALABA Public Clinical Hospital No 1 in Zabrze, Zabrze, Poland (Received 21 September 2007; revised 1 March 2008; in final form 4 March 2008)
Abtract—The purpose of this longitudinal study was to characterize changes in quantitative ultrasound (QUS) values over a 1-y period in healthy boys and girls aged 7 to 12 y at baseline and assess the relation between the increase in anthropometric parameters and amplitude dependent speed of sound (Ad-SoS). A total of 269 children completed the study (139 girls and 130 boys). Ultrasound measurements were performed with a DBM Sonic 1200 device (IGEA, Carpi, Italy), which measures the Ad-SoS, m/s. Girls had significantly higher QUS values than boys at first and second measurements (p < 0.01 and p < 0.00001, respectively). Both girls and boys experienced statistically significant increases in Ad-SoS and all anthropometric parameters over a 1-y period. When the studied group was divided into age groups by year, the differences in QUS values between genders were significant only for 11 and 12 y groups at baseline (p < 0.02 and p < 0.01, respectively) and second visit (p < 0.00001 and p < 0.001, respectively). Stepwise regression analyses models with Ad-SoS at baseline and after 1 y as dependent variables showed a strong correlation between Ad-SoS and Tanner stage in girls but not in boys. In the entire survey group, only 21.5% of the boys and 41% of the girls experienced increases in Ad-SoS more than least significant change. This article suggests that QUS measurements allow the investigation of longitudinal changes and give reliable information about skeletal status in a manner similar to other methods. (E-mail: [email protected]) © 2008 World Federation for Ultrasound in Medicine & Biology. Key Words: Ultrasound, Bone quality, Children, Adolescents, Puberty, Longitudinal.
In recent years, the method of quantitative ultrasound (QUS) has been developed for assessing bone properties. Low-frequency ultrasound travels across bone with a velocity that is related to bone quality and density. Therefore, it seems QUS techniques may be less influenced by bone size (Falk et al. 2003). Furthermore, QUS can reveal physical properties of bone determined by bone composition and by structure (Njeh et al. 1997). QUS is also void of ionizing radiation, cost-effective, easy to use and portable so its features are beneficial in pediatrics. QUS systems exist for measurements at various skeletal sites such as calcaneus, phalanges, tibia and patella. Phalangeal QUS measurements have shown the ability to reveal changes due to skeletal growth (Halaba and Pluskiewicz 1997), aging (Ventura et al. 1996; Grampp et al. 1997) and diseases (Takada et al. 1997; Guglielmi et al. 1999). These assets caused many pediatricians to carry out some cross-sectional normal ranges for children and adolescents by means of a DBM Sonic 1200 machine (IGEA, Carpi, Italy) (Halaba and Pluskiewicz 1997, 2004; Wuster et al. 2000; Baroncelli
INTRODUCTION Although dual energy x-ray absorptiometry (DXA) is the method considered to be the gold standard in pediatrics, we must keep the disadvantages of this method in mind while trying to develop other more effective diagnostic tools used in the pediatric population. DXA has some essential limitations. First, DXA estimates only the level up to which a radiation beam is attenuated by bone tissue that depends not only on physical density, but on bone size as well. It means that a smaller bone may have a lower areal bone density than a larger bone (Nelson and Koo 1999; Prentice et al. 1994; Rauch and Schoenau 2002). Because of increases in bone size, not volumetric density, the changes in bone size during growth make the value of DXA less useful as an assessment tool in children than in adults. Second, DXA does not provide information about the quality of bone. Address correspondence to: Zenon Piotr Halaba, Public Clinical Hospital No 1 in Zabrze, Poland, Traugutt Square 6; 41-800 Zabrze, Poland. E-mail: [email protected] 1547
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Table 1. Mean and standard deviation of age, anthropometric parameters and Ad-SoS at the baseline and follow-up and their increments (⌬) during the study Girls [n ⫽ 139] Baseline, mean ⫾ SD Age, y Height, cm Weight, kg BMI, kg/m2 Leg length, cm Trunk length, cm Arm span, cm Ad-SoS, m/s
9.87 ⫾ 1.5 138.7 ⫾ 11.4 33.4 ⫾ 9.5 17.0 ⫾ 2.8 68.2 ⫾ 6.7 42.9 ⫾ 3.9 137.2 ⫾ 12.1 1959 ⫾ 43
Follow-up, mean ⫾ SD 11.05 ⫾ 1.52 145.7⫾11.7* 38.8 ⫾ 11.0* 17.9 ⫾ 3.1* 71.8 ⫾ 6.2* 45.4 ⫾ 4.6* 144.2⫾13.9* 1991 ⫾ 52*
Boys [n ⫽ 130] ⌬
Baseline, mean ⫾ SD
1.18 7.0 5.4 0.9 3.6 2.5 7.0 32
9.42 ⫾ 1.51 136.0 ⫾ 10.7 31.2 ⫾ 8.3 16.6 ⫾ 2.4 66.1 ⫾ 5.9 42.3 ⫾ 4.0 134.8 ⫾ 10.7 1944 ⫾ 35
Follow-up, mean ⫾ SD 10.56 ⫾ 1.49 142.8⫾10.8* 36.0 ⫾ 9.7* 17.4 ⫾ 2.7* 69.5 ⫾ 5.7* 45.3 ⫾ 4.3* 142.4⫾11.2* 1965 ⫾ 37*
⌬ 1.14 6.8 4.8 0.8 3.4 3.0 7.6 21
* p ⬍ 0.001
et al. 2001; Barkmann et al. 2002). Large child and adolescent populations from different European countries were measured and trends of changes in measured ultrasound parameter during childhood and puberty were comparable as shown in studies using DXA measurements (Bonjour et al 1991; Theintz 1992). Further, some studies were performed in young subjects with different diseases known to affect bone metabolism. In case-control studies, QUS proved its utility in the detection of skeletal changes in subjects with genetic disorders (Pluskiewicz et al. 2003a), renal osteodystrophy (Pluskiewicz et al. 2002a, 2003b), acute lymphoblastic leucaemia (Pluskiewicz et al. 2002b ) and in subjects treated by gonadotrophin-releasing hormone (Kapteijnsvan Kordelaar et al. 2003). There are also some longitudinal studies in healthy children and adolescents (Lappe at al. 2000, Vignolo et al. 2006) and in survivors of malignant bone tumors (Azcona et al. 2003) and acute lymphoblastic leucaemia (Pluskiewicz et al. 2004), in subjects with renal insufficiency (Pluskiewicz et al. 2005) and in subjects with genetic disorders (Halaba et al. 2006). Recently, phalangeal QUS and DXA measurements were compared in healthy subjects (Halaba et al. 2005) and have shown that QUS has the potential to express bone changes in measurements comparable to DXA. The purpose of the current longitudinal study was to characterize changes in QUS values over a 1-y period in healthy boys and girls aged 7 to 12 y at baseline. Furthermore, the relationship between the increase in anthropometric parameters and Ad-SoS was assessed. The second aim of the study was to establish the follow-up reference curves for children and adolescents aged 7 to 12 y. Intensive treatment in many diseases (corticosteroids, citotoxic agents, radiotherapy) may influence bone metabolism and skeletal growth. There is a need to monitor these changes longitudinally and we, therefore, should compare results with data obtained in a normal healthy population.
MATERIALS The children studied were randomly recruited from a number of primary schools in Zabrze selected on the basis of their location in different socioeconomic areas of the city. At the baseline of 427 total enrolled subjects, 376 (88%) positively answered the invitation and were accepted to enter the study. All were healthy Caucasian children (boys and girls) aged 7 to 12 y. At the follow-up, 107 were withdrawn from the study for the following reasons: (1) 27 had moved from the school district; (2) six were no longer in school because of suspension or dropout; and (3) 74 refused the follow-up measurements. The remaining 269 completed the study (139 girls and 130 boys). Therefore, the dropout total reached 37%. The examined subjects did not take any medication known to affect bone metabolism. Anthropometric parameters, pubertal development and Ad-SoS values were measured. After 1 y, all measurements were repeated (mean ⫺1.16 ⫾ 0.09 y). Anthropometric measurements: standing height (basis-vertex [b-v]), leg length (basis- symphysion [B-sy]), trunk length together with leg length (basis-suprasternale [B-sst]) and arm span (dactylion-dactylion [Da-Da]) were taken in a standard way with certified devices. Height and other anthropometric parameters were measured using Martin’s anthropometer. Weight was mea-
Table 2. Tanner stage in the studied group at baseline and follow-up At baseline %
Follow-up %
Tanner stage
Girls
Boys
Girls
Boys
T1 T2 T3 T4 T5
50.34 19.73 20.41 6.12 3.4
61.38 31.72 5.52 1.38 0
38.1 12.24 23.13 18.37 8.16
51.41 35.21 7.75 4.93 0.7
Table 3. Mean and standard deviation of Ad-SoS and anthropometric parameters in 1-y age groups at the baseline and follow-up in girls Girls [mean ⫾ SD] Ad-SoS, m/s Age class–
Height, cm
BMI, kg/m2
Leg length, cm
Trunk length, cm
Arm span, cm
Baseline
Follow-up
Baseline
Follow-up
Baseline
Follow-up
Baseline
Follow-up
Baseline
Follow-up
Baseline
Follow-up
Baseline
Follow-up
1924 ⫾ 27 1935 ⫾ 33 1961 ⫾ 31 1954 ⫾ 42 1988 ⫾ 34 2001 ⫾ 48
1951 ⫾ 33 1959 ⫾ 36 1988 ⫾ 31 1987 ⫾ 57 2030 ⫾ 42 2046 ⫾ 47
24.5 ⫾ 4.3 27.6 ⫾ 5.3 29.8 ⫾ 6.1 36.3 ⫾ 8.6 40.1 ⫾ 8.0 43.0 ⫾ 11.1
28.7 ⫾ 5.3 32.2 ⫾ 6.6 34.6 ⫾ 7.5 41.6 ⫾ 10.1 47.4 ⫾ 9.5 49.2 ⫾ 11.4
126.2 ⫾ 6.1 128.9 ⫾ 5.1 135.3 ⫾ 7.7 143.0 ⫾ 7.9 147.6 ⫾ 8.0 153.4 ⫾ 7.8
133.1 ⫾ 6.1 135.7 ⫾ 5.7 142.8 ⫾ 8.6 150.1 ⫾ 9.4 154.7 ⫾ 7.7 159.2 ⫾ 7.6
15.3 ⫾ 2.2 16.5 ⫾ 2.3 16.1 ⫾ 2.3 17.5 ⫾ 3.0 18.3 ⫾ 2.3 18.2 ⫾ 4.0
16.1 ⫾ 2.4 17.4 ⫾ 2.6 16.8 ⫾ 2.4 18.2 ⫾ 3.1 19.7 ⫾ 2.9 19.4 ⫾ 4.3
60.9 ⫾ 3.6 61.9 ⫾ 3.3 66.6 ⫾ 4.5 71.2 ⫾ 4.7 73.4 ⫾ 4.5 76.3 ⫾ 4.4
65.0 ⫾ 4.1 66.7 ⫾ 3.2 72.0 ⫾ 4.7 74.8 ⫾ 5.0 75.7 ⫾ 4.6 77.8 ⫾ 5.0
37.8 ⫾ 2.2 40.6 ⫾ 2.9 41.8 ⫾ 2.9 43.8 ⫾ 3.4 45.6 ⫾ 3.1 47.8 ⫾ 2.7
38.9 ⫾ 4.2 42.0 ⫾ 2.4 44.1 ⫾ 3.5 46.1 ⫾ 3.7 49.2 ⫾ 3.1 51.1 ⫾ 2.4
123.4 ⫾ 7.0 127.2 ⫾ 5.6 134.3 ⫾ 8.1 140.9 ⫾ 8.1 147.6 ⫾ 9.1 151.6 ⫾ 7.1
128.1 ⫾ 18.0 134.8 ⫾ 6.3 141.6 ⫾ 9.2 148.6 ⫾ 9.0 154.5 ⫾ 8.6 158.1 ⫾ 5.4
Table 4. Mean and standard deviation of Ad-SoS and anthropometric parameters in 1-y age groups at the baseline and follow-up in boys Boys [mean ⫾ SD] Ad-SoS, m/s Age class– 7 [27] 8 [30] 9 [29] 10 [17] 11 [21] 12 [6]
Weight, kg
Height, cm
BMI, kg/m2
Leg length, cm
Trunk length, cm
Arm span, cm
Baseline
Follow-up
Baseline
Follow-up
Baseline
Follow-up
Baseline
Follow-up
Baseline
Follow-up
Baseline
Follow-up
Baseline
Follow-up
1915 ⫾ 32 1939 ⫾ 31 1949 ⫾ 26 1967 ⫾ 33 1965 ⫾ 32 1943 ⫾ 26
1944 ⫾ 36 1961 ⫾ 37 1978 ⫾ 33 1983 ⫾ 35 1972 ⫾ 38 1951 ⫾ 28
23.2 ⫾ 3.4 28.0 ⫾ 6.9 30.4 ⫾ 4.9 35.9 ⫾ 8.7 38.7 ⫾ 7.7 42.5 ⫾ 6.3
27.5 ⫾ 3.4 34.1 ⫾ 8.4 34.7 ⫾ 6.3 39.9 ⫾ 10.2 44.6 ⫾ 9.0 49.4 ⫾ 9.2
123.6 ⫾ 4.8 131.6 ⫾ 5.3 136.1 ⫾ 6.2 142.5 ⫾ 6.3 147.5 ⫾ 7.2 154.0 ⫾ 8.7
131.6 ⫾ 4.8 138.4 ⫾ 5.6 142.0 ⫾ 6.8 148.6 ⫾ 6.7 154.6 ⫾ 8.0 161.6 ⫾ 11.2
15.2 ⫾ 0.8 16.5 ⫾ 2.9 16.3 ⫾ 2.0 17.5 ⫾ 2.9 17.7 ⫾ 2.7 17.8 ⫾ 1.6
15.9 ⫾ 1.3 17.6 ⫾ 3.1 17.1 ⫾ 2.5 17.9 ⫾ 3.1 18.6 ⫾ 2.9 18.8 ⫾ 2.4
59.7 ⫾ 3.2 61.9 ⫾ 3.3 66.6 ⫾ 4.5 71.2 ⫾ 4.7 73.4 ⫾ 4.5 76.3 ⫾ 4.4
63.3 ⫾ 2.7 66.7 ⫾ 3.2 71.0 ⫾ 4.7 74.8 ⫾ 5.0 75.7 ⫾ 4.6 77.8 ⫾ 5.0
37.8 ⫾ 2.2 41.4 ⫾ 2.6 42.0 ⫾ 2.7 44.6 ⫾ 2.5 46.4 ⫾ 2.8 48.0 ⫾ 2.6
41.4 ⫾ 2.3 43.9 ⫾ 2.4 44.6 ⫾ 3.8 46.8 ⫾ 2.8 49.9 ⫾ 3.2 52.2 ⫾ 3.9
122.8 ⫾ 5.2 129.8 ⫾ 5.8 135.5 ⫾ 6.4 142.2 ⫾ 8.8 145.9 ⫾ 7.5 151.5 ⫾ 8.1
131.3 ⫾ 5.2 136.9 ⫾ 5.9 142.3 ⫾ 7.5 148.5 ⫾ 7.3 154.3 ⫾ 9.0 161.7 ⫾ 9.8
Quantitative ultrasound for assessing bone properties ● Z. P. HALABA
7 [19] 8 [24] 9 [25] 10 [31] 11 [28] 12 [12]
Weight, kg
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Table 5. Number of subjects and increments (⌬) in Ad-SoS, height, weight, BMI, leg length, trunk length and arm span during different pubertal phases Classes Girls Pre-puberty Early-puberty Mid puberty Late puberty Boys Pre-puberty Early-puberty Mid puberty Late puberty
n
⌬ Ad-SoS, m/s
⌬ height, cm
⌬ weight, kg
⌬ BMI, kg/m2
⌬ leg length, cm
⌬ trunk length, cCm
⌬ arm span, cm
55 14 21 35
25* 33* 23* 49*
6.5* 7.5* 7.9* 6.5*
4.1* 5.7* 5.8* 7.1*
0.8* 1.0* 0.8* 1.3*
4.3* 4.1* 4.0* 2.1*
1.4* 3.4* 2.7* 3.3*
6.0* 8.2* 8.7* 6.7*
71 14 8 5
25* 24* 2 [NS] 15[NS]
6.9* 6.9* 7.5* 10.6*
4.6* 4.6* 6.3* 9.0*
0.9* 0.7* 0.8* 1.1 [NS]
3.7* 3.1* 3.0* 3.4*
2.8* 2.7* 4.4* 4.6*
7.5* 7.5* 8.7* 12.5*
NS ⫽ not significant. * p⬍ 0.001.
sured on an electronic scale (Seca, Hamburg, Germany). The trunk length (cm) was derived from the formula: trunk length (cm) ⫽ B-sst (cm) ⫺ B-sy (cm). The body mass index (BMI) was derived from the formula: BMI ⫽ weight (kg)/height2 (m2). Pubertal status was based on Tanner staging of pubertal development and was ascertained by the physician’s examination (Tanner and Whitehouse 1976). Pubertal development was assessed on genital (G1-5), mamma (M1-5) and pubic hair (P1-5) stages (with 1 being no development and 5 being the highest level of development). All participants completed a questionnaire relating to hand dominance. Informed written consent was obtained from all parents/ guardians of subjects. The study protocol was approved by the Committee of Ethics and Supervision of Research on Humans and Animals of the Medical University of Silesia, Katowice. In all subjects, ultrasound measurements were performed with a DBM Sonic 1200 device (IGEA), which measures the amplitude-dependent speed of sound (AdSoS) at the proximal phalanges (distal metaphysis) of the of II-V fingers in the dominant hand (Halaba and Pluskiewicz 1997, 2004). There is, however, no signifi-
Table 6. Percentage of the subjects that had increases of AdSoS more than LSC in 1-y age groups Percentage of the subject with ⌬ Ad-SoS ⬎ LSC Girls
Boys
Age class
n
%
n
%
7 8 9 10 11 12
4 8 9 15 15 11
21.1 33.3 36.0 48.4 53.6 91.7
10 4 11 3 2 0
37.0 13.3 37.9 17.7 9.52 0.0
cant difference between measurements in left and right hands (Schönau et al. 1994; Ventura et al. 1996; Baroncelli et al. 2001). The final result was the average Ad-SoS over four fingers. In vivo short-term precision was assessed based on mean coefficient of variation (CV) for the 75 measurements made in 15 healthy adolescents (eight boys and seven girls measured five times each). All measurements were made by the same operator repositioning the caliper; the CV% was 0.64% and was calculated according to the formula given by Gluer et al. (1995). All QUS measurements were carried out by the same investigator (ZPH). The device used was daily calibrated using plexiglass phantom according to the manufacturer’s recommendation. In the longitudinal study, the use of the concept of the least significant change (LSC) has great clinical importance. The LSC, or critical difference, denotes the minimum difference between two successive results in an individual that can be considered to reflect a real change. The LSC was calculated for AD-SoS by the formula: CV% x 2 x 1.41 x Ad-SOS of each individual at baseline, which would represent a statistical difference at the 95% confidence level (Gluer 1999). Statistical analysis The data was expressed as mean ⫾ standard deviations (SD). Statistical analysis was performed with the STATISTICA data analysis software system version 7.1. (StatSoft Polska, Inc., Krakow, Poland). Differences between mean values were established using Student’s t-test for dependent variables (for comparison of baseline and follow-up measurements). Relationships between Ad-SOS at baseline and 1 y later (as dependent variable) and age and anthropometric parameters and pubertal stage (as independent variables), were determined using stepwise multiple regression analyses. Correlation analyses were performed utilizing a Pearson’s test and Spear-
Quantitative ultrasound for assessing bone properties ● Z. P. HALABA
Table 7. Stepwise regression analysis model with Ad-SoS1 (at baseline) and Ad-SoS as dependent variables
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2
(after 1 y)
Equations of multivariate regression All at baseline All after 1 y Female at baseline Female after 1 y Males at baseline Males after 1 y
Ad-SoS1 ⫽ 5.4 x age ⫹ 9.9 x Tanner stage ⫺ 2.7 x weight ⫹ 2.3 x arm span ⫺ 7.3 x gender ⫹ 2387; R⫽0.64, F ⫽ 36.3, SEE ⫽ 31.0, Ad-SoS2 ⫽ 18.5 x Tanner stage ⫺ 2.4 weight ⫹ 1.8 height ⫺ 3.3 age ⫹1737; R⫽ 0.60, F ⫽ 37.4, SEE ⫽ 38,2, Ad-SoS1 ⫽ 6.6 x age ⫹ 16.0 x Tanner stage ⫺ 3.4 x weight ⫹ 2.1 x arm span ⫺ 3.5 x leg length ⫹ 2.2 x height ⫹1624; R⫽ 0.67, F ⫽ 19.6, SEE ⫽ 31.9 Ad-SoS2 ⫽ 15.4 x Tanner stage ⫺ 2.5 x weight ⫹ 4.5 x height ⫺ 4.4 x leg length ⫹ 7.2 x age ⫹ 1636; R⫽ 0.69, F ⫽ 24.6, SEE ⫽ 38.4 Ad-SoS1 ⫽ 2.5 x arm span ⫺ 2.6 x weight ⫹ 5.5 x age ⫹ 1633; R⫽ 0.59, F ⫽ 21.9, SEE ⫽ 28.8 Ad-SoS2 ⫽ 2.9 x arm span ⫺ 3.0 weight ⫹ 1650; R ⫽ 0.52, F ⫽ 23.5, SEE ⫽ 32.3
p ⬍ 0.00001
man’s rank correlation for data in ordinal scale. A priori p value of ⬍ 0.05 was considered statistically significant. RESULTS At baseline and after 1 y, in the entire studied group, girls were taller and heavier than boys but the mean BMI values did not differ significantly. Furthermore, there were no significant differences in the mean values of trunk length and arm span between genders at baseline and 1 y later. Girls had significantly higher QUS values than boys at first and second measurements (p ⬍ 0.01 and p ⬍ 0.00001, respectively). Both girls and boys experienced statistically significant increases in Ad-SoS and all anthropometric parameters over a 1-y period. Basic information on the study group is given in Table 1. At first and second visit, girls were much more mature than boys (Table 2). At baseline, seven girls had experienced menarche and after a year, 44 girls were postmenarchal. When the studied group was divided into age groups by year, the differences in QUS values between genders were significant only for the 11- and 12-y groups at baseline (p ⬍ 0.02 and p ⬍ 0.01, respectively). The same results were observed on the second visit (p ⬍ 0.00001 and p ⬍ 0.001, respectively). With regards to anthropometric parameters, there were no statistically significant differences between girls and boys in all 1-y age groups at baseline and 1 y later. In girls, the greatest rate of increase in Ad-SoS was apparent between 11 y of age at first and 12 y of age at second measurements; and 12 y of age at first and 13 y of age at second measurements. Similarly in boys between 7 y of age at first and 8 y of age at second measurements; 8 y of age at first and 9 y of age at second measurements; 9 y of age at first and 10 y of age at second measurements (Tables 3 and 4). The increments in Ad-SoS after a year were statistically significant between 8- and 11-y, and 8- and 12-y age groups (p ⬍ 0.02 and p ⬍ 0.04 respectively) in girls, and 7 and 11-y, 8-
and 11-y, and 9 and 11-y age groups in boys (p ⬍ 0.0001, p ⬍ 0.02, p ⬍ 0.0002, respectively). Subjects were grouped, similarly to Vignolo et al. (2006), according to the initial and final pubertal stages in the following classes: prepuberty at baseline from stage 1 and after a year to stage 1, early puberty at baseline from stage 1 and after a year to stage 2 or 3, mid-puberty at baseline from stage 2 and after a year to stage 3 or 4, late puberty at baseline from stage 3 and after a year to stage 4 or 5 (Table 5). Only in boys in midpuberty and late puberty were there no statistically significant differences between first and second measurements; however, the number of subjects in these groups was too small to analyze. In the entire survey group, only 21.5% of the boys and 41% of the girls experienced increases in Ad-SoS more than LSC over the period of study. The percentage of subjects that had increases of Ad-SoS more than LSC in 1-y age groups are shown in Table 6. Multivariate regression models with Ad-SoS1 (at baseline) and AdSoS2 (after 1 y) as dependent variables in all studied children and in girls and boys separately are shown in Table 7. DISCUSSION Skeletal growth in the course of many serious diseases may be affected and there is increasing interest in assessing the influence of treatment effects or disease state on bone quality. Quantitative ultrasound of the hand phalanges method, which is portable, easy to use, and free of ionizing radiation, has more than adequately met our needs in a pediatric population. Most studies in children and adolescents using phalangeal QUS are cross-sectional. Only a few studies are based on a longitudinal design (Lappe et al. 2000; Pluskiewicz et al. 2004, 2005; Vignolo et al. 2006). To assess changes in ill children and adolescents it becomes necessary to establish longitudinal data in this healthy group. Guesens et al. (1991) reported that girls and boys from 3 to 9 y have
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similar BMC and BMD values. Our prior cross-sectional studies (Halaba and Pluskiewicz 1997, 2004) have shown that up to the age of 11 y, there are no significant differences between girls and boys. This longitudinal study showed similar results. Moreover, our cross-sectional studies showed that in girls, the acceleration of Ad-SoS begins after 11 y and in boys after 13 y of age. In this study, the greatest rate of increase in Ad-SoS was apparent between 11 and 12 and 13 y in girls but the statistically significant differences were only between 8 and 11 and 8 and 12 y age groups (p ⬍ 0.02 and p ⬍ 0.04, respectively). Similar tendencies have been presented in the longitudinal studies using QUS method (Lappe et al. 2000; Vignolo et al. 2006) and with DXA (Theintz et al. 1992). Lappe et al. (2000) measured the longitudinally apparent velocity of ultrasound at the patella in the group of 328 children aged 8 to 15.5 y at baseline and found that females had significantly higher QUS values than males at baseline and at the second visit. In our study, girls had significantly higher QUS values than boys at first and second measurements too. The girls in the study had the greatest increase in QUS values from 10 to 12 y. Similar results have been reported by these authors. Our observations in longitudinal study may suggest that the QUS method of the phalanges is accurate and useful in a pediatric population. In like manner, Vignolo et al. (2006) assessing 589 children aged 3 to 16 y proved the accuracy and usefulness of the QUS method. The Ad-SoS increments in the pubertal stage are slightly different from the changes reported by Vignolo et al. (2006). In their study, QUS variables showed larger increments in the midpuberty class in girls and in late puberty in boys. This discrepancy is probably caused by the small number of subjects in our study group. It may also reflect the narrow range of pubertal development because this group was limited to 7- to 13-y-old subjects. Our results are rather similar to the follow-up study by Lappe et al. (2000) in which QUS values significantly increased in late puberty from Tanner stage 3 to 4 and to 5. In our study, the greatest increase occurred in girls whose Tanner stage changed from 3 to 4 to 5. It is well known that there is an asynchronism between linear growth and mineralization pubertal spurt, earlier in girls, later in boys (Parfitt 1994). In the present study, this tendency was seen in girls with height velocity spurt occurring in early and midpuberty and with larger increments in Ad-SoS values in late puberty. In boys, it is impossible to see these tendencies as a result of the limited range of age. In our studied group, the increment of Ad-SoS greater than LSC over the study duration was observed in about half of girls and only one fifth of boys. The percentage of girls in the 1-y age groups, who experi-
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enced increments of Ad-SoS greater than LSC, augmented with age. The largest number of subjects with the increment of Ad-SoS values over LSC was seen among girls at age class 11 and 12 in which the annual increases in Ad-SoS were the greatest. This tendency was not seen in boys. It may result from the fact that the girls studied had just started their process of maturation, while the boys had not yet started theirs. It suggests that QUS measurements allow investigation of longitudinal changes and give reliable information about skeletal status in a manner similar to the DXA method (Glisanz et al. 1988; Bonjour et al. 1991; Theintz et al. 1992). Stepwise regression analyses models with Ad-SoS at baseline and after 1 y as dependent variables show strong correlation between Ad-SoS and Tanner Stage in girls but not in boys. It is not surprising because the boys were less mature and more than 50% did not experience maturation. This study had some limitations. The main weakness was the narrow range of studied subjects. In a longitudinal study, it would be more appropriate to provide a long-term precision but such a procedure was not performed and only a short-term precision was used. This article includes only a short period of childhood and adolescence and studies extended from 2 y up to 18 y will be necessary to better our understanding of skeletal development and to monitor these changes with more longitudinal accuracy, especially in children and adolescents affected by impaired bone development. Another limitation of the study may have been the lack of measurements of bone transmission time (BTT, us) since our device did not have this option. In conclusion, this study suggests that QUS measurements allow easy, safe and accurate tracking of skeletal changes during growth periods. REFERENCES Azcona C, Burghard E, Ruza E. Reduced bone mineralization in adolescent survivors of malignant bone tumors: Comparison of quantitative ultrasound and dual-energy x-ray absorptiometry. J Pediatr Hematol Onc 2003;25:297–302. Barkmann R, Rohrschneider W, Vierling M, Troger J, de TF, Cadossi R, Heller M, Gluer CC. German pediatric reference data for quantitative transverse transmission ultrasound of finger phalanges. Osteoporos Int 2002;13:55– 61. Baroncelli GI, Federico G, Bertelloni S, de Terlizzi F, Cadossi R, Saggese G. Bone quality assessment by quantitative ultrasound of proximal phalanxes of the hand in healthy subjects aged 3-21 years. Pediatr Res 2001;49:713–718. Bonjour JP, Theintz G, Buchs B, Slosman D, Rizzoli R. Critical years and stages of puberty for spinal and femoral bone mass accumulation during adolescence. J Clin Endocrinol Metab 1991;73:555– 563. Falk B, Bronshtein Z, Zigel L, Constantini NW, Eliakim A. Quantitative ultrasound of the tibia and radius in prepubertal and earlypubertal female athletes. Arch Pediatr Adolesc Med 2003;157:139 – 143.
Quantitative ultrasound for assessing bone properties ● Z. P. HALABA Glisanz V, Gibbens DT, Roe TF, Carlson M, Senac MO, Boechat MI, Huang HK, Schulz EE, Libanati CR, Cann CC. Vertebral bone density in children: Effect of puberty. Radiology 1988; 166:847– 850. Gluer C, Blake G, Lu Y, Blunt BA, Jergas M, Genant HK. Accurate assessment of precision errors: How to measure the reproducibility of bone densitometry techniques. Osteoporos Int 1995;5:262–270. Gluer CC. Sense and sensitivity: Monitoring skeletal changes by radiological techniques. J Bone Miner Res 1999;14:1952–1962. Guesens P, Cantatore F, Nijas J, Proesmans W, Emma F, Dequeker J. Heterogeneity of growth of bone in children at spine, radius and total skeleton. Growth Dev Aging 1991;55:249 –256. Guglielmi G, Cammisa M, De Serio A, Scillitani A, Chiodini I. Phalangeal US-velocity discriminates between normal and vertebrally fractured subjects. Eur Radiol 1999;9:1632–1637. Grampp S, Genant HK, Mathur A, Lang P, Jergas M, Takada M, Gluer CC, Lu Y, Chavez M. Comparisons of noninvasive bone mineral measurements in assessing age-related loss, fracture discrimination, and diagnostic classification. J Bone Miner Res 1997;12:1954 – 1955. Halaba Z, Pluskiewicz W. The assessment of development of bone mass in children by quantitative ultrasound through the proximal phalanxes of the hand. Ultrasound Med Biol 1997;23:1331–1335. Halaba Z, Pluskiewicz W. Quantitative ultrasound in the assessment of skeletal status in children and adolescents. Ultrasound Med Biol 2004;30:239 –243. Halaba ZP, Konstantynowicz J, Pluskiewicz W, Kaczmarski M, Piotrowska-Jastrzebska J. Comparison of phalangeal ultrasound and dual energy x-ray absorptiometry in healthy male and female adolescents. Ultrasound Med Biol 2005;31:1617–1622. Halaba Z, Pyrkosz A, Adamczyk P, Drozdzowska B, Pluskiewicz W. Longitudinal changes in ultrasound measurements: A parallel study in subjects with genetic disorders and healthy controls. Ultrasound Med Biol 2006;4:523–528. Kapteijns-van Kordelaar S, Noordam K, Otten B, van den Bergh J. Quantitative calcaneal ultrasound parameters and bone mineral density at final height treated with depot gonadotrophin-releasing hormone agonist for central precocious puberty or idiopathic short stature. Eur J Pediatr 2003;162:776 –780. Lappe JM, Stegman MR, Davies KM, Barber S, Becker RR. A prospective study of quantitative ultrasound in children and adolescents. J Clin Densitom 2000;2:167–175. Nelson DA, Koo WW. Interpretation of absorptiometric bone mass measurements in the growing skeleton: Issue and limitations. Calcif Tissue Int 1999;65:1–3. Njeh CF, Boivin CM, Langton CM. The role of ultrasound in the assessment of osteoporosis: A review. Osteoporos Int 1997;7:7–22. Parfitt AM. The two faces of growth: benefits and risks to bone integrity. Osteoporos Int 1994;4:382–398. Pluskiewicz W, Adamczyk P, Drozdzowska B, Szprynger K, Szczepan´ska M, Halaba Z, Karasek D. Skeletal status in children, adolescents and young adults with end-stage renal failure treated with hemo- or peritoneal dialysis. Osteoporos Int 2002a;13:353– 357. Pluskiewicz W, Luszczyn´ska A, Halaba Z, Drozdzowska B, Son´taJakimczyk D. Skeletal status in survivors of childhood acute lym-
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phoblastic leukemia assessed by quantitative ultrasounds: A pilot cross-sectional study. Ultrasound Med Biol 2002b;10:1279 –1284. Pluskiewicz W, Pyrkosz A, Drozdzowska B, Halaba Z. Quantitative ultrasound of the hand phalanges in patients with genetic disorders: A pilot case-control study. Osteoporos Int 2003a;14:787–792. Pluskiewicz W, Adamczyk P, Drozdzowska B, Szprynger K, Szczepan´ska M, Halaba Z, Karasek D. Skeletal status in children and adolescents with chronic renal failure before onset dialysis of dialysis or on dialysis. Osteoporos Int 2003b;14:283–288. Pluskiewicz W, Halaba Z, Chełmecka L, Drozdzowska B, Son´taJakimczyk D, Karasek D. Skeletal status in survivors of acute lymphoblastic leukemia assessed by quantitative ultrasound at the hand phalanges: A longitudinal study. Ultrasound Med Biol 2004; 30:893– 898. Pluskiewicz W, Adamczyk P, Drozdzowska B, Szprynger K, Szczepan´ska M, Halaba Z, Karasek D. Skeletal status in adolescents with end-stage renal failure: A longitudinal study. Osteoporos Int 2005;16:289 –295. Prentice A, Parsons TJ, Cole TJ. Uncritical use of bone mineral density in absorptiometry may lead to size-related artifacts in the identification of bone mineral determinants. Am J Clin Nutr 1994;60:837– 842. Rauch F, Schoenau E. Skeletal development in premature infants: A review of bone physiology beyond nutritional aspects. Arch Dis Child Fetal Neonatal Ed 2002;86:F82–F85. Schönau E, Radermacher A, Wentzlik U, Klein K, Michalk D. The determination of ultrasound velocity in the os calcis, thumb and patella during childhood. Eur J Pediatr 1994; 153:252–256. Takada M, Engelke S, Hagiwara S, Grampp S, Jerga M, Gluer CC, Genant HK. Assessment of osteoporosis: comparison of radiographic absorptiometry of the phalanges and dual x-ray absorptiometry of the radius and lumbar spine. Radiology 1997;202: 759 – 763. Tanner JM, Whitehouse RH. Clinical longitudinal standard of height, weight, height velocity, weight velocity and the stages of puberty. Arch Dis Child 1976;51:170 –179. Theintz G, Buchs B, Rizzoli R, Slosman D, Clavien H. Longitudinal monitoring of bone mass accumulation in healthy adolescents: Evidence for a marked reduction after 16 years of age at the levels of lumbar spine and femoral neck in female subjects. J Clin Endocrinol Metab 1992;75:1060 –1065. Ventura V, Mauloni M, Mura M, Paltrinieri F, de Aloysio D. Ultrasound velocity changes at the proximal phalanges of the hand in pre-, peri- and postmenopausal women. Osteopor Int 1996;6:368 – 375. Vignolo M, Parodi A, Mascagni A, Torrisi C, De Terlizzi F, Aicardi G. Longitudinal assessment of bone quality by quantitative ultrasonography in children and adolescents. Ultrasound Med Biol 2006;7: 1003–1010. Wuster C, Albanese C, de Aloysio D, Duboeuf F, Gambacciani M, Gonnelli S, Gluer CC, Hans D, Joly J, Reginster JY, De Terlizzi F, Cadossi R. Phalangeal osteosonogrammetry study: Age-related changes, diagnostic sensitivity, and discrimination power. J Bone Miner Res 2000;15:1603–1614.
doi:10.1016/j.ultrasmedbio.2008.03.007
● Original Contribution QUANTITATIVE ULTRASOUND MEASUREMENTS AT HAND PHALANGES IN CHILDREN AND ADOLESCENTS: A LONGITUDINAL STUDY ZENON P. HALABA Public Clinical Hospital No 1 in Zabrze, Zabrze, Poland (Received 21 September 2007; revised 1 March 2008; in final form 4 March 2008)
Abtract—The purpose of this longitudinal study was to characterize changes in quantitative ultrasound (QUS) values over a 1-y period in healthy boys and girls aged 7 to 12 y at baseline and assess the relation between the increase in anthropometric parameters and amplitude dependent speed of sound (Ad-SoS). A total of 269 children completed the study (139 girls and 130 boys). Ultrasound measurements were performed with a DBM Sonic 1200 device (IGEA, Carpi, Italy), which measures the Ad-SoS, m/s. Girls had significantly higher QUS values than boys at first and second measurements (p < 0.01 and p < 0.00001, respectively). Both girls and boys experienced statistically significant increases in Ad-SoS and all anthropometric parameters over a 1-y period. When the studied group was divided into age groups by year, the differences in QUS values between genders were significant only for 11 and 12 y groups at baseline (p < 0.02 and p < 0.01, respectively) and second visit (p < 0.00001 and p < 0.001, respectively). Stepwise regression analyses models with Ad-SoS at baseline and after 1 y as dependent variables showed a strong correlation between Ad-SoS and Tanner stage in girls but not in boys. In the entire survey group, only 21.5% of the boys and 41% of the girls experienced increases in Ad-SoS more than least significant change. This article suggests that QUS measurements allow the investigation of longitudinal changes and give reliable information about skeletal status in a manner similar to other methods. (E-mail: [email protected]) © 2008 World Federation for Ultrasound in Medicine & Biology. Key Words: Ultrasound, Bone quality, Children, Adolescents, Puberty, Longitudinal.
In recent years, the method of quantitative ultrasound (QUS) has been developed for assessing bone properties. Low-frequency ultrasound travels across bone with a velocity that is related to bone quality and density. Therefore, it seems QUS techniques may be less influenced by bone size (Falk et al. 2003). Furthermore, QUS can reveal physical properties of bone determined by bone composition and by structure (Njeh et al. 1997). QUS is also void of ionizing radiation, cost-effective, easy to use and portable so its features are beneficial in pediatrics. QUS systems exist for measurements at various skeletal sites such as calcaneus, phalanges, tibia and patella. Phalangeal QUS measurements have shown the ability to reveal changes due to skeletal growth (Halaba and Pluskiewicz 1997), aging (Ventura et al. 1996; Grampp et al. 1997) and diseases (Takada et al. 1997; Guglielmi et al. 1999). These assets caused many pediatricians to carry out some cross-sectional normal ranges for children and adolescents by means of a DBM Sonic 1200 machine (IGEA, Carpi, Italy) (Halaba and Pluskiewicz 1997, 2004; Wuster et al. 2000; Baroncelli
INTRODUCTION Although dual energy x-ray absorptiometry (DXA) is the method considered to be the gold standard in pediatrics, we must keep the disadvantages of this method in mind while trying to develop other more effective diagnostic tools used in the pediatric population. DXA has some essential limitations. First, DXA estimates only the level up to which a radiation beam is attenuated by bone tissue that depends not only on physical density, but on bone size as well. It means that a smaller bone may have a lower areal bone density than a larger bone (Nelson and Koo 1999; Prentice et al. 1994; Rauch and Schoenau 2002). Because of increases in bone size, not volumetric density, the changes in bone size during growth make the value of DXA less useful as an assessment tool in children than in adults. Second, DXA does not provide information about the quality of bone. Address correspondence to: Zenon Piotr Halaba, Public Clinical Hospital No 1 in Zabrze, Poland, Traugutt Square 6; 41-800 Zabrze, Poland. E-mail: [email protected] 1547
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Table 1. Mean and standard deviation of age, anthropometric parameters and Ad-SoS at the baseline and follow-up and their increments (⌬) during the study Girls [n ⫽ 139] Baseline, mean ⫾ SD Age, y Height, cm Weight, kg BMI, kg/m2 Leg length, cm Trunk length, cm Arm span, cm Ad-SoS, m/s
9.87 ⫾ 1.5 138.7 ⫾ 11.4 33.4 ⫾ 9.5 17.0 ⫾ 2.8 68.2 ⫾ 6.7 42.9 ⫾ 3.9 137.2 ⫾ 12.1 1959 ⫾ 43
Follow-up, mean ⫾ SD 11.05 ⫾ 1.52 145.7⫾11.7* 38.8 ⫾ 11.0* 17.9 ⫾ 3.1* 71.8 ⫾ 6.2* 45.4 ⫾ 4.6* 144.2⫾13.9* 1991 ⫾ 52*
Boys [n ⫽ 130] ⌬
Baseline, mean ⫾ SD
1.18 7.0 5.4 0.9 3.6 2.5 7.0 32
9.42 ⫾ 1.51 136.0 ⫾ 10.7 31.2 ⫾ 8.3 16.6 ⫾ 2.4 66.1 ⫾ 5.9 42.3 ⫾ 4.0 134.8 ⫾ 10.7 1944 ⫾ 35
Follow-up, mean ⫾ SD 10.56 ⫾ 1.49 142.8⫾10.8* 36.0 ⫾ 9.7* 17.4 ⫾ 2.7* 69.5 ⫾ 5.7* 45.3 ⫾ 4.3* 142.4⫾11.2* 1965 ⫾ 37*
⌬ 1.14 6.8 4.8 0.8 3.4 3.0 7.6 21
* p ⬍ 0.001
et al. 2001; Barkmann et al. 2002). Large child and adolescent populations from different European countries were measured and trends of changes in measured ultrasound parameter during childhood and puberty were comparable as shown in studies using DXA measurements (Bonjour et al 1991; Theintz 1992). Further, some studies were performed in young subjects with different diseases known to affect bone metabolism. In case-control studies, QUS proved its utility in the detection of skeletal changes in subjects with genetic disorders (Pluskiewicz et al. 2003a), renal osteodystrophy (Pluskiewicz et al. 2002a, 2003b), acute lymphoblastic leucaemia (Pluskiewicz et al. 2002b ) and in subjects treated by gonadotrophin-releasing hormone (Kapteijnsvan Kordelaar et al. 2003). There are also some longitudinal studies in healthy children and adolescents (Lappe at al. 2000, Vignolo et al. 2006) and in survivors of malignant bone tumors (Azcona et al. 2003) and acute lymphoblastic leucaemia (Pluskiewicz et al. 2004), in subjects with renal insufficiency (Pluskiewicz et al. 2005) and in subjects with genetic disorders (Halaba et al. 2006). Recently, phalangeal QUS and DXA measurements were compared in healthy subjects (Halaba et al. 2005) and have shown that QUS has the potential to express bone changes in measurements comparable to DXA. The purpose of the current longitudinal study was to characterize changes in QUS values over a 1-y period in healthy boys and girls aged 7 to 12 y at baseline. Furthermore, the relationship between the increase in anthropometric parameters and Ad-SoS was assessed. The second aim of the study was to establish the follow-up reference curves for children and adolescents aged 7 to 12 y. Intensive treatment in many diseases (corticosteroids, citotoxic agents, radiotherapy) may influence bone metabolism and skeletal growth. There is a need to monitor these changes longitudinally and we, therefore, should compare results with data obtained in a normal healthy population.
MATERIALS The children studied were randomly recruited from a number of primary schools in Zabrze selected on the basis of their location in different socioeconomic areas of the city. At the baseline of 427 total enrolled subjects, 376 (88%) positively answered the invitation and were accepted to enter the study. All were healthy Caucasian children (boys and girls) aged 7 to 12 y. At the follow-up, 107 were withdrawn from the study for the following reasons: (1) 27 had moved from the school district; (2) six were no longer in school because of suspension or dropout; and (3) 74 refused the follow-up measurements. The remaining 269 completed the study (139 girls and 130 boys). Therefore, the dropout total reached 37%. The examined subjects did not take any medication known to affect bone metabolism. Anthropometric parameters, pubertal development and Ad-SoS values were measured. After 1 y, all measurements were repeated (mean ⫺1.16 ⫾ 0.09 y). Anthropometric measurements: standing height (basis-vertex [b-v]), leg length (basis- symphysion [B-sy]), trunk length together with leg length (basis-suprasternale [B-sst]) and arm span (dactylion-dactylion [Da-Da]) were taken in a standard way with certified devices. Height and other anthropometric parameters were measured using Martin’s anthropometer. Weight was mea-
Table 2. Tanner stage in the studied group at baseline and follow-up At baseline %
Follow-up %
Tanner stage
Girls
Boys
Girls
Boys
T1 T2 T3 T4 T5
50.34 19.73 20.41 6.12 3.4
61.38 31.72 5.52 1.38 0
38.1 12.24 23.13 18.37 8.16
51.41 35.21 7.75 4.93 0.7
Table 3. Mean and standard deviation of Ad-SoS and anthropometric parameters in 1-y age groups at the baseline and follow-up in girls Girls [mean ⫾ SD] Ad-SoS, m/s Age class–
Height, cm
BMI, kg/m2
Leg length, cm
Trunk length, cm
Arm span, cm
Baseline
Follow-up
Baseline
Follow-up
Baseline
Follow-up
Baseline
Follow-up
Baseline
Follow-up
Baseline
Follow-up
Baseline
Follow-up
1924 ⫾ 27 1935 ⫾ 33 1961 ⫾ 31 1954 ⫾ 42 1988 ⫾ 34 2001 ⫾ 48
1951 ⫾ 33 1959 ⫾ 36 1988 ⫾ 31 1987 ⫾ 57 2030 ⫾ 42 2046 ⫾ 47
24.5 ⫾ 4.3 27.6 ⫾ 5.3 29.8 ⫾ 6.1 36.3 ⫾ 8.6 40.1 ⫾ 8.0 43.0 ⫾ 11.1
28.7 ⫾ 5.3 32.2 ⫾ 6.6 34.6 ⫾ 7.5 41.6 ⫾ 10.1 47.4 ⫾ 9.5 49.2 ⫾ 11.4
126.2 ⫾ 6.1 128.9 ⫾ 5.1 135.3 ⫾ 7.7 143.0 ⫾ 7.9 147.6 ⫾ 8.0 153.4 ⫾ 7.8
133.1 ⫾ 6.1 135.7 ⫾ 5.7 142.8 ⫾ 8.6 150.1 ⫾ 9.4 154.7 ⫾ 7.7 159.2 ⫾ 7.6
15.3 ⫾ 2.2 16.5 ⫾ 2.3 16.1 ⫾ 2.3 17.5 ⫾ 3.0 18.3 ⫾ 2.3 18.2 ⫾ 4.0
16.1 ⫾ 2.4 17.4 ⫾ 2.6 16.8 ⫾ 2.4 18.2 ⫾ 3.1 19.7 ⫾ 2.9 19.4 ⫾ 4.3
60.9 ⫾ 3.6 61.9 ⫾ 3.3 66.6 ⫾ 4.5 71.2 ⫾ 4.7 73.4 ⫾ 4.5 76.3 ⫾ 4.4
65.0 ⫾ 4.1 66.7 ⫾ 3.2 72.0 ⫾ 4.7 74.8 ⫾ 5.0 75.7 ⫾ 4.6 77.8 ⫾ 5.0
37.8 ⫾ 2.2 40.6 ⫾ 2.9 41.8 ⫾ 2.9 43.8 ⫾ 3.4 45.6 ⫾ 3.1 47.8 ⫾ 2.7
38.9 ⫾ 4.2 42.0 ⫾ 2.4 44.1 ⫾ 3.5 46.1 ⫾ 3.7 49.2 ⫾ 3.1 51.1 ⫾ 2.4
123.4 ⫾ 7.0 127.2 ⫾ 5.6 134.3 ⫾ 8.1 140.9 ⫾ 8.1 147.6 ⫾ 9.1 151.6 ⫾ 7.1
128.1 ⫾ 18.0 134.8 ⫾ 6.3 141.6 ⫾ 9.2 148.6 ⫾ 9.0 154.5 ⫾ 8.6 158.1 ⫾ 5.4
Table 4. Mean and standard deviation of Ad-SoS and anthropometric parameters in 1-y age groups at the baseline and follow-up in boys Boys [mean ⫾ SD] Ad-SoS, m/s Age class– 7 [27] 8 [30] 9 [29] 10 [17] 11 [21] 12 [6]
Weight, kg
Height, cm
BMI, kg/m2
Leg length, cm
Trunk length, cm
Arm span, cm
Baseline
Follow-up
Baseline
Follow-up
Baseline
Follow-up
Baseline
Follow-up
Baseline
Follow-up
Baseline
Follow-up
Baseline
Follow-up
1915 ⫾ 32 1939 ⫾ 31 1949 ⫾ 26 1967 ⫾ 33 1965 ⫾ 32 1943 ⫾ 26
1944 ⫾ 36 1961 ⫾ 37 1978 ⫾ 33 1983 ⫾ 35 1972 ⫾ 38 1951 ⫾ 28
23.2 ⫾ 3.4 28.0 ⫾ 6.9 30.4 ⫾ 4.9 35.9 ⫾ 8.7 38.7 ⫾ 7.7 42.5 ⫾ 6.3
27.5 ⫾ 3.4 34.1 ⫾ 8.4 34.7 ⫾ 6.3 39.9 ⫾ 10.2 44.6 ⫾ 9.0 49.4 ⫾ 9.2
123.6 ⫾ 4.8 131.6 ⫾ 5.3 136.1 ⫾ 6.2 142.5 ⫾ 6.3 147.5 ⫾ 7.2 154.0 ⫾ 8.7
131.6 ⫾ 4.8 138.4 ⫾ 5.6 142.0 ⫾ 6.8 148.6 ⫾ 6.7 154.6 ⫾ 8.0 161.6 ⫾ 11.2
15.2 ⫾ 0.8 16.5 ⫾ 2.9 16.3 ⫾ 2.0 17.5 ⫾ 2.9 17.7 ⫾ 2.7 17.8 ⫾ 1.6
15.9 ⫾ 1.3 17.6 ⫾ 3.1 17.1 ⫾ 2.5 17.9 ⫾ 3.1 18.6 ⫾ 2.9 18.8 ⫾ 2.4
59.7 ⫾ 3.2 61.9 ⫾ 3.3 66.6 ⫾ 4.5 71.2 ⫾ 4.7 73.4 ⫾ 4.5 76.3 ⫾ 4.4
63.3 ⫾ 2.7 66.7 ⫾ 3.2 71.0 ⫾ 4.7 74.8 ⫾ 5.0 75.7 ⫾ 4.6 77.8 ⫾ 5.0
37.8 ⫾ 2.2 41.4 ⫾ 2.6 42.0 ⫾ 2.7 44.6 ⫾ 2.5 46.4 ⫾ 2.8 48.0 ⫾ 2.6
41.4 ⫾ 2.3 43.9 ⫾ 2.4 44.6 ⫾ 3.8 46.8 ⫾ 2.8 49.9 ⫾ 3.2 52.2 ⫾ 3.9
122.8 ⫾ 5.2 129.8 ⫾ 5.8 135.5 ⫾ 6.4 142.2 ⫾ 8.8 145.9 ⫾ 7.5 151.5 ⫾ 8.1
131.3 ⫾ 5.2 136.9 ⫾ 5.9 142.3 ⫾ 7.5 148.5 ⫾ 7.3 154.3 ⫾ 9.0 161.7 ⫾ 9.8
Quantitative ultrasound for assessing bone properties ● Z. P. HALABA
7 [19] 8 [24] 9 [25] 10 [31] 11 [28] 12 [12]
Weight, kg
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Table 5. Number of subjects and increments (⌬) in Ad-SoS, height, weight, BMI, leg length, trunk length and arm span during different pubertal phases Classes Girls Pre-puberty Early-puberty Mid puberty Late puberty Boys Pre-puberty Early-puberty Mid puberty Late puberty
n
⌬ Ad-SoS, m/s
⌬ height, cm
⌬ weight, kg
⌬ BMI, kg/m2
⌬ leg length, cm
⌬ trunk length, cCm
⌬ arm span, cm
55 14 21 35
25* 33* 23* 49*
6.5* 7.5* 7.9* 6.5*
4.1* 5.7* 5.8* 7.1*
0.8* 1.0* 0.8* 1.3*
4.3* 4.1* 4.0* 2.1*
1.4* 3.4* 2.7* 3.3*
6.0* 8.2* 8.7* 6.7*
71 14 8 5
25* 24* 2 [NS] 15[NS]
6.9* 6.9* 7.5* 10.6*
4.6* 4.6* 6.3* 9.0*
0.9* 0.7* 0.8* 1.1 [NS]
3.7* 3.1* 3.0* 3.4*
2.8* 2.7* 4.4* 4.6*
7.5* 7.5* 8.7* 12.5*
NS ⫽ not significant. * p⬍ 0.001.
sured on an electronic scale (Seca, Hamburg, Germany). The trunk length (cm) was derived from the formula: trunk length (cm) ⫽ B-sst (cm) ⫺ B-sy (cm). The body mass index (BMI) was derived from the formula: BMI ⫽ weight (kg)/height2 (m2). Pubertal status was based on Tanner staging of pubertal development and was ascertained by the physician’s examination (Tanner and Whitehouse 1976). Pubertal development was assessed on genital (G1-5), mamma (M1-5) and pubic hair (P1-5) stages (with 1 being no development and 5 being the highest level of development). All participants completed a questionnaire relating to hand dominance. Informed written consent was obtained from all parents/ guardians of subjects. The study protocol was approved by the Committee of Ethics and Supervision of Research on Humans and Animals of the Medical University of Silesia, Katowice. In all subjects, ultrasound measurements were performed with a DBM Sonic 1200 device (IGEA), which measures the amplitude-dependent speed of sound (AdSoS) at the proximal phalanges (distal metaphysis) of the of II-V fingers in the dominant hand (Halaba and Pluskiewicz 1997, 2004). There is, however, no signifi-
Table 6. Percentage of the subjects that had increases of AdSoS more than LSC in 1-y age groups Percentage of the subject with ⌬ Ad-SoS ⬎ LSC Girls
Boys
Age class
n
%
n
%
7 8 9 10 11 12
4 8 9 15 15 11
21.1 33.3 36.0 48.4 53.6 91.7
10 4 11 3 2 0
37.0 13.3 37.9 17.7 9.52 0.0
cant difference between measurements in left and right hands (Schönau et al. 1994; Ventura et al. 1996; Baroncelli et al. 2001). The final result was the average Ad-SoS over four fingers. In vivo short-term precision was assessed based on mean coefficient of variation (CV) for the 75 measurements made in 15 healthy adolescents (eight boys and seven girls measured five times each). All measurements were made by the same operator repositioning the caliper; the CV% was 0.64% and was calculated according to the formula given by Gluer et al. (1995). All QUS measurements were carried out by the same investigator (ZPH). The device used was daily calibrated using plexiglass phantom according to the manufacturer’s recommendation. In the longitudinal study, the use of the concept of the least significant change (LSC) has great clinical importance. The LSC, or critical difference, denotes the minimum difference between two successive results in an individual that can be considered to reflect a real change. The LSC was calculated for AD-SoS by the formula: CV% x 2 x 1.41 x Ad-SOS of each individual at baseline, which would represent a statistical difference at the 95% confidence level (Gluer 1999). Statistical analysis The data was expressed as mean ⫾ standard deviations (SD). Statistical analysis was performed with the STATISTICA data analysis software system version 7.1. (StatSoft Polska, Inc., Krakow, Poland). Differences between mean values were established using Student’s t-test for dependent variables (for comparison of baseline and follow-up measurements). Relationships between Ad-SOS at baseline and 1 y later (as dependent variable) and age and anthropometric parameters and pubertal stage (as independent variables), were determined using stepwise multiple regression analyses. Correlation analyses were performed utilizing a Pearson’s test and Spear-
Quantitative ultrasound for assessing bone properties ● Z. P. HALABA
Table 7. Stepwise regression analysis model with Ad-SoS1 (at baseline) and Ad-SoS as dependent variables
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2
(after 1 y)
Equations of multivariate regression All at baseline All after 1 y Female at baseline Female after 1 y Males at baseline Males after 1 y
Ad-SoS1 ⫽ 5.4 x age ⫹ 9.9 x Tanner stage ⫺ 2.7 x weight ⫹ 2.3 x arm span ⫺ 7.3 x gender ⫹ 2387; R⫽0.64, F ⫽ 36.3, SEE ⫽ 31.0, Ad-SoS2 ⫽ 18.5 x Tanner stage ⫺ 2.4 weight ⫹ 1.8 height ⫺ 3.3 age ⫹1737; R⫽ 0.60, F ⫽ 37.4, SEE ⫽ 38,2, Ad-SoS1 ⫽ 6.6 x age ⫹ 16.0 x Tanner stage ⫺ 3.4 x weight ⫹ 2.1 x arm span ⫺ 3.5 x leg length ⫹ 2.2 x height ⫹1624; R⫽ 0.67, F ⫽ 19.6, SEE ⫽ 31.9 Ad-SoS2 ⫽ 15.4 x Tanner stage ⫺ 2.5 x weight ⫹ 4.5 x height ⫺ 4.4 x leg length ⫹ 7.2 x age ⫹ 1636; R⫽ 0.69, F ⫽ 24.6, SEE ⫽ 38.4 Ad-SoS1 ⫽ 2.5 x arm span ⫺ 2.6 x weight ⫹ 5.5 x age ⫹ 1633; R⫽ 0.59, F ⫽ 21.9, SEE ⫽ 28.8 Ad-SoS2 ⫽ 2.9 x arm span ⫺ 3.0 weight ⫹ 1650; R ⫽ 0.52, F ⫽ 23.5, SEE ⫽ 32.3
p ⬍ 0.00001
man’s rank correlation for data in ordinal scale. A priori p value of ⬍ 0.05 was considered statistically significant. RESULTS At baseline and after 1 y, in the entire studied group, girls were taller and heavier than boys but the mean BMI values did not differ significantly. Furthermore, there were no significant differences in the mean values of trunk length and arm span between genders at baseline and 1 y later. Girls had significantly higher QUS values than boys at first and second measurements (p ⬍ 0.01 and p ⬍ 0.00001, respectively). Both girls and boys experienced statistically significant increases in Ad-SoS and all anthropometric parameters over a 1-y period. Basic information on the study group is given in Table 1. At first and second visit, girls were much more mature than boys (Table 2). At baseline, seven girls had experienced menarche and after a year, 44 girls were postmenarchal. When the studied group was divided into age groups by year, the differences in QUS values between genders were significant only for the 11- and 12-y groups at baseline (p ⬍ 0.02 and p ⬍ 0.01, respectively). The same results were observed on the second visit (p ⬍ 0.00001 and p ⬍ 0.001, respectively). With regards to anthropometric parameters, there were no statistically significant differences between girls and boys in all 1-y age groups at baseline and 1 y later. In girls, the greatest rate of increase in Ad-SoS was apparent between 11 y of age at first and 12 y of age at second measurements; and 12 y of age at first and 13 y of age at second measurements. Similarly in boys between 7 y of age at first and 8 y of age at second measurements; 8 y of age at first and 9 y of age at second measurements; 9 y of age at first and 10 y of age at second measurements (Tables 3 and 4). The increments in Ad-SoS after a year were statistically significant between 8- and 11-y, and 8- and 12-y age groups (p ⬍ 0.02 and p ⬍ 0.04 respectively) in girls, and 7 and 11-y, 8-
and 11-y, and 9 and 11-y age groups in boys (p ⬍ 0.0001, p ⬍ 0.02, p ⬍ 0.0002, respectively). Subjects were grouped, similarly to Vignolo et al. (2006), according to the initial and final pubertal stages in the following classes: prepuberty at baseline from stage 1 and after a year to stage 1, early puberty at baseline from stage 1 and after a year to stage 2 or 3, mid-puberty at baseline from stage 2 and after a year to stage 3 or 4, late puberty at baseline from stage 3 and after a year to stage 4 or 5 (Table 5). Only in boys in midpuberty and late puberty were there no statistically significant differences between first and second measurements; however, the number of subjects in these groups was too small to analyze. In the entire survey group, only 21.5% of the boys and 41% of the girls experienced increases in Ad-SoS more than LSC over the period of study. The percentage of subjects that had increases of Ad-SoS more than LSC in 1-y age groups are shown in Table 6. Multivariate regression models with Ad-SoS1 (at baseline) and AdSoS2 (after 1 y) as dependent variables in all studied children and in girls and boys separately are shown in Table 7. DISCUSSION Skeletal growth in the course of many serious diseases may be affected and there is increasing interest in assessing the influence of treatment effects or disease state on bone quality. Quantitative ultrasound of the hand phalanges method, which is portable, easy to use, and free of ionizing radiation, has more than adequately met our needs in a pediatric population. Most studies in children and adolescents using phalangeal QUS are cross-sectional. Only a few studies are based on a longitudinal design (Lappe et al. 2000; Pluskiewicz et al. 2004, 2005; Vignolo et al. 2006). To assess changes in ill children and adolescents it becomes necessary to establish longitudinal data in this healthy group. Guesens et al. (1991) reported that girls and boys from 3 to 9 y have
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similar BMC and BMD values. Our prior cross-sectional studies (Halaba and Pluskiewicz 1997, 2004) have shown that up to the age of 11 y, there are no significant differences between girls and boys. This longitudinal study showed similar results. Moreover, our cross-sectional studies showed that in girls, the acceleration of Ad-SoS begins after 11 y and in boys after 13 y of age. In this study, the greatest rate of increase in Ad-SoS was apparent between 11 and 12 and 13 y in girls but the statistically significant differences were only between 8 and 11 and 8 and 12 y age groups (p ⬍ 0.02 and p ⬍ 0.04, respectively). Similar tendencies have been presented in the longitudinal studies using QUS method (Lappe et al. 2000; Vignolo et al. 2006) and with DXA (Theintz et al. 1992). Lappe et al. (2000) measured the longitudinally apparent velocity of ultrasound at the patella in the group of 328 children aged 8 to 15.5 y at baseline and found that females had significantly higher QUS values than males at baseline and at the second visit. In our study, girls had significantly higher QUS values than boys at first and second measurements too. The girls in the study had the greatest increase in QUS values from 10 to 12 y. Similar results have been reported by these authors. Our observations in longitudinal study may suggest that the QUS method of the phalanges is accurate and useful in a pediatric population. In like manner, Vignolo et al. (2006) assessing 589 children aged 3 to 16 y proved the accuracy and usefulness of the QUS method. The Ad-SoS increments in the pubertal stage are slightly different from the changes reported by Vignolo et al. (2006). In their study, QUS variables showed larger increments in the midpuberty class in girls and in late puberty in boys. This discrepancy is probably caused by the small number of subjects in our study group. It may also reflect the narrow range of pubertal development because this group was limited to 7- to 13-y-old subjects. Our results are rather similar to the follow-up study by Lappe et al. (2000) in which QUS values significantly increased in late puberty from Tanner stage 3 to 4 and to 5. In our study, the greatest increase occurred in girls whose Tanner stage changed from 3 to 4 to 5. It is well known that there is an asynchronism between linear growth and mineralization pubertal spurt, earlier in girls, later in boys (Parfitt 1994). In the present study, this tendency was seen in girls with height velocity spurt occurring in early and midpuberty and with larger increments in Ad-SoS values in late puberty. In boys, it is impossible to see these tendencies as a result of the limited range of age. In our studied group, the increment of Ad-SoS greater than LSC over the study duration was observed in about half of girls and only one fifth of boys. The percentage of girls in the 1-y age groups, who experi-
Volume 34, Number 10, 2008
enced increments of Ad-SoS greater than LSC, augmented with age. The largest number of subjects with the increment of Ad-SoS values over LSC was seen among girls at age class 11 and 12 in which the annual increases in Ad-SoS were the greatest. This tendency was not seen in boys. It may result from the fact that the girls studied had just started their process of maturation, while the boys had not yet started theirs. It suggests that QUS measurements allow investigation of longitudinal changes and give reliable information about skeletal status in a manner similar to the DXA method (Glisanz et al. 1988; Bonjour et al. 1991; Theintz et al. 1992). Stepwise regression analyses models with Ad-SoS at baseline and after 1 y as dependent variables show strong correlation between Ad-SoS and Tanner Stage in girls but not in boys. It is not surprising because the boys were less mature and more than 50% did not experience maturation. This study had some limitations. The main weakness was the narrow range of studied subjects. In a longitudinal study, it would be more appropriate to provide a long-term precision but such a procedure was not performed and only a short-term precision was used. This article includes only a short period of childhood and adolescence and studies extended from 2 y up to 18 y will be necessary to better our understanding of skeletal development and to monitor these changes with more longitudinal accuracy, especially in children and adolescents affected by impaired bone development. Another limitation of the study may have been the lack of measurements of bone transmission time (BTT, us) since our device did not have this option. In conclusion, this study suggests that QUS measurements allow easy, safe and accurate tracking of skeletal changes during growth periods. REFERENCES Azcona C, Burghard E, Ruza E. Reduced bone mineralization in adolescent survivors of malignant bone tumors: Comparison of quantitative ultrasound and dual-energy x-ray absorptiometry. J Pediatr Hematol Onc 2003;25:297–302. Barkmann R, Rohrschneider W, Vierling M, Troger J, de TF, Cadossi R, Heller M, Gluer CC. German pediatric reference data for quantitative transverse transmission ultrasound of finger phalanges. Osteoporos Int 2002;13:55– 61. Baroncelli GI, Federico G, Bertelloni S, de Terlizzi F, Cadossi R, Saggese G. Bone quality assessment by quantitative ultrasound of proximal phalanxes of the hand in healthy subjects aged 3-21 years. Pediatr Res 2001;49:713–718. Bonjour JP, Theintz G, Buchs B, Slosman D, Rizzoli R. Critical years and stages of puberty for spinal and femoral bone mass accumulation during adolescence. J Clin Endocrinol Metab 1991;73:555– 563. Falk B, Bronshtein Z, Zigel L, Constantini NW, Eliakim A. Quantitative ultrasound of the tibia and radius in prepubertal and earlypubertal female athletes. Arch Pediatr Adolesc Med 2003;157:139 – 143.
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