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Longitudinal changes in ultrasound measurements: A parallel study in subjects with genetic disorders and healthy controls
Ultrasound in Med. & Biol., Vol. 32, No. 3, pp. 409 – 413, 2006 Copyright © 2006 World Federation for Ultrasound in Medicine & Biology Printed in the USA. All rights reserved 0301-5629/06/$–see front matter
doi:10.1016/j.ultrasmedbio.2005.11.009
● Original Contribution LONGITUDINAL CHANGES IN ULTRASOUND MEASUREMENTS: A PARALLEL STUDY IN SUBJECTS WITH GENETIC DISORDERS AND HEALTHY CONTROLS ZENON HALABA,* ANTONI PYRKOSZ,† PIOTR ADAMCZYK,‡ BOGNA DROZDZOWSKA,§ and WOJCIECH PLUSKIEWICZ储 *Outpatient Medical Care, Zabrze, Poland; †Department and Chair of Molecular Biology and Medical Genetics, Katowice, Poland; ‡Department and Clinic of Pediatrics, Pediatric Nephrology and Endocrinology, Zabrze, Poland; § Department and Chair of Pathomorphology, Zabrze, Poland; and 储Silesian School of Medicine in Katowice, Poland, Department and Clinic of Internal Diseases, Diabetology and Nephrology, Metabolic Bone Disease Unit, Zabrze, Poland (Received 25 July 2005; revised 26 October 2005; in final form 11 November 2005)
Abstract—Disturbances in skeletal status in subjects with genetic disorder may increase their fracture risk. The aim of the study was longitudinal observation of phalangeal speed of sound changes across the bone over a period of 2 y in 24 patients (14 boys and 10 girls, mean age 9.63 ⴞ 1.8 y.) and 24 age-matched healthy controls (14 boys and 10 girls, mean age 9.65 ⴞ 1.71 y.). Weight and height did not differ between patients and controls at baseline and follow-up. Patients with the following disorders were evaluated: 7 with Down syndrome, 6 nonspecific mental retardations of unknown etiology, 5 Martin-Bell syndrome and 6 with other diseases. In patients and controls, no factors potentially influencing bone metabolism (except for genetic disorder) were present. Bone status was assessed by quantitative ultrasound at hand phalanges using DBM Sonic 1200 (IGEA, Carpi, Italy), which measures amplitude-dependent speed of sound (Ad-SoS [m/s]). At baseline, Ad-SoS and Z-score were significantly lower in patients than in controls (1892 ⴞ 51 m/s versus 1936 ⴞ 43 m/s, p < 0.01 and ⴚ1.47 ⴞ 1.43 versus ⴚ0.14 ⴞ 1.04, p < 0.001, respectively. In follow-up, Ad-SoS and Z-score increased significantly in patients (1892 ⴞ 51m/s to 1934 ⴞ 48 m/s, p < 0.0001 and ⴚ1.47 ⴞ 1.43 to ⴚ0.76 ⴞ 1.00, p < 0.01, respectively) and in controls (1936 ⴞ 43 m/s to 1976 ⴞ 60 m/s and ⴚ0.14 ⴞ 1.04 to 0.31 ⴞ 1.08, p < 0.05, respectively). Follow-up Ad-SoS and Z-sScore were significantly lower in patients (p < 0.01). Longitudinal changes in Ad-SoS, Z-score weight did not differ between patients and control, and height increased more in controls (13.2 ⴞ 2.8 cm versus 11.4 ⴞ 5.9 cm, p < 0.05)ⴙ). In patients, Ad-SoS increased by 42 m/s (2.22%), and in controls increased by 40 m/s (2.07%). Difference in Ad-SoS between patients and controls was 44 m/s at baseline and 42 m/s at follow-up. Using the value of the least significant change (LSC ⴝ 20.5 m/s), in 16 patients (67%) and in 18 controls (75%) Ad-SoS showed an increase greater than the LSC, in one control (4%) a decrease greater than the LSC and in rest of subjects studied remained unchanged (33% patients and 19% controls) over a period of observation. In conclusion, despite comparable improvement in measured ultrasound parameter in patients and controls observed over a study duration, the difference between them remained stable. © 2006 World Federation for Ultrasound in Medicine & Biology. Key Words: Follow-up, Genetic disorders, Hand phalanges, Quantitative ultrasound.
INTRODUCTION
to the increase in fracture risk. In some studies performed in subjects with genetic disorders, spine bone mineral density (BMD) was significantly decreased in comparison with healthy controls (Kao et al. 1992; Sepulveda et al. 1995; Angelopoulou et al. 1999; Angelopoulou et al. 2000; van der Bergh et al. 2001; Sakadamis at al. 2002; Baptista et al. 2005). In some studies, other skeletal sites were also measured: pelvis (Sepulveda et al. 1995) and proximal femur (van der Bergh et al. 2001; Baptista et al. 2005).
Due to progress in management of subjects with genetic disorders, life expectancy in this group of patients increased significantly. Among many health complications commonly present in individuals with genetic disorders are also skeletal disturbances leading Address correspondence to: Prof. Wojciech Pluskiewicz, Ph.D., M.D., Metabolic Bone Diseases Unit, 3 Maja 13/15 str., 41-800 Zabrze, Poland. E-mail: [email protected] 409
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Table 1. Clinical characteristics and QUS variables in patients and controls (mean, ⫹/⫺ SD and range)
Age [years] Height [m] Weight [kg] Ad-SoS [m/s] Z-score
Baseline patients n ⫽ 24
Baseline controls n ⫽ 24
Follow-up patients n ⫽ 24
Follow-up controls n ⫽ 24
9.63 ⫹/⫺ 1.83 6.4–13.3 1.32 ⫹/⫺ 0.15 1.05–1.60 31.2 ⫹/⫺ 11.5 17.0–57.5 1892 ⫹/⫺ 51 1787–1978 ⫺1.47 ⫹/⫺ 1.43 ⫺4.44 to 0.70
9.65 ⫹/⫺ 1.71 6.9–12.3 1.35 ⫹/0.12 1.14–1.58 31.8 ⫹/⫺ 9.7 17.3–54.5 1936 ⫹/⫺ 43* 1838–2024 ⫺0.14 ⫹/⫺ 1.04** ⫺2.87 to 2.02
11.63 ⫹/⫺ 1.83 8.4–15.3 1.44 ⫹/0.16 1.13–1.73 40.8 ⫹/⫺ 12.4 18.0–63.0 1934 ⫹/⫺ 48 1837–2018 ⫺0.76 ⫹/⫺ 1.00 ⫺3.19 to 1.19
11.84 ⫹/⫺ 1.69 8.9–14.3 1.48 ⫹/⫺ 0.12 1.26–1.70 41.7 ⫹/⫺ 12.2 23.7–70.0 1976 ⫹/⫺ 60*** 1873–2147 0.31 ⫹/⫺ 1.08*** ⫺1.69 to 2.65
Mean values of age, height and weight did not differ between patients and controls at baseline and the follow-up * Significant difference vs. baseline with P ⬍.01. ** Significant difference vs. baseline with P ⬍.001. *** Significant difference vs. follow-up with P ⬍.001.
Recently, in the armentarium of bone measurements are also some other methods like peripheral quantitative computed tomography or magnetic resonance imaging, and among them is also quantitative ultrasound (QUS). Several skeletal sites may be evaluated, such as calcaneus, patella, radius or phalanges. In some studies, calcaneal (Hans et al. 1996; Drozdzowska and Pluskiewicz 2002; Huopio et al. 2004) and phalangeal (Wuster et al. 2000; Drozdzowska et al. 2003; Mele et al. 1997) QUS measurements proved an ability to predict and to discriminate fracture risk. However, Ekman et al. (2000) did not confirm an ability of QUS phalangeal measurements to discriminate patients with and without past hip fracture, and Krieg et al. (2003) showed that discrimination power of Ad-SoS was weaker than heel QUS variables. There are also some data showing that the values of QUS parameters were decreased in patients with genetic disorders for calcaneus (Aspray et al. 1998; van der Bergh 2001) and hand phalanges (Pluskiewicz et al. 2003). The aim of this study was longitudinal observation of phalangeal speed of sound changes across the bone over a period of 2 y in subjects with genetic disorders and in healthy controls. MATERIALS In the study were evaluated 24 patients (14 boys and 10 girls) and 24 age and gender-matched healthy controls (14 boys and 10 girls). Table 1 presents clinical characteristics of patients and controls at baseline and the follow-up. Patients were recruited from Outpatient Genetic Clinic and controls were randomly selected from pupils of a local school. At baseline, body size did not differ between patients and controls. Patients with the following disorders were evaluated:
7 with Down syndrome, 6 with nonspecific mental retardations of unknown etiology, 5 with Martin-Bell syndrome, 2 with Williams syndrome, 2 with MarfanMass syndrome, one with Turner and one with other chromosomal aberration. In patients and controls, no factors were present, except for genetic disorder potentially influencing bone metabolism (either prolonged medication using corticosteroids, thyroid hormones, anticonvulsants etc., or chronic diseases of thyroid gland, liver, kidney, intestine or stomach surgery etc.). Permission for the study was given by the local ethics committee. METHODS Skeletal status was assessed by ultrasound measurements of proximal phalanges using DBM Sonic 1200 device (IGEA, Carpi, Italy). The device measures amplitude-dependent speed of sound (Ad-SoS [m/s]) in the distal metaphyses of the proximal phalanges of the second through the fifth finger of the nondominant hand. Methodology was described in our previous study (Drozdzowska et al. 2003). All measurements were taken by the same operator. Device was calibrated daily according to manufacturers’ recommendations. In vivo precision was assessed by RMS_CV (rms coefficient of variation) calculated accordingly to proposition by Gluer et al. (1995). Seventy measurements were taken in 14 healthy persons aged 8 to 15 y (measured 5 times each) by the same operator. RMS_CV was 0.38% (Drozdzowska et al. 2003). Statistical analysis Calculations of means and standard deviations were performed using the Statistica program (Tulsa, OK, USA). Data distribution was established using the Shapiro-Wilk test. Differences between mean values
Longitudinal changes in ultrasound measurements ● Z. HALABA et al.
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Fig. 1. Changes in Ad-SoS values in subjects examined and controls over a period of observation.
in patients versus controls were established using Student’s t-test for independent samples or Mann-Whitney U test according to data distribution. Differences between baseline and follow-up examinations in patients and controls were checked with t-test for dependent samples or with Wilcoxon matched pairs test, according to data distribution. Statistical analyses were performed in all patients and all controls. Differences of values in Ad-SoS and x-score between baseline and the follow-up (⌬Ad-SoS and ⌬Z-score) were correlated with longitudinal changes in weight and height separately in patients and controls using Pearson or Spearman correlation analysis when appropriate. To follow reliable changes of Ad-SoS in individual subjects, the least significant change (LSC) was calculated. 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 using the formula: CV% × 2 × 1.41, which would represent a statistical difference at the 95% confidence level (Gluer et al. 1996). Ad-SoS measured at baseline in the entire group examined (patients and controls) was used to calculate the LSC. All results were considered as statistically significant at p ⬍ 0.05. RESULTS Longitudinal changes in weight did not differ between patients and control, and height increased more in controls (13.2 ⫾ 2.8 cm versus 11.4 ⫾ 5.9 cm, p ⬍ 0.05, Mann-Whitney U test).
Table 1 presents QUS values. At baseline, Ad-SoS and Z-score were significantly lower in patients than in controls (1892 ⫾ 51 m/s versus 1936 ⫾ 43 m/s, p ⬍ 0.01 and ⫺1.47 ⫾ 1.43 versus ⫺0.14 ⫾ 1.04, p ⬍ 0.001, t-test for independent samples). Baseline difference in Ad-SoS between patients and controls was 44 m/s. In the follow-up, Ad-SoS and Z-score increased significantly in patients (1892 ⫾ 51m/s to 1934 ⫾ 48 m/s, p ⬍ 0.0001 and ⫺1.47 ⫾ 1.43 to ⫺0.76 ⫾ 1.0, p ⬍ 0.01, (t-test for dependent samples) and in controls (1936 ⫾ 43 m/s to 1976 ⫾ 60 m/s and ⫺0.14 ⫾ 1.04 to 0.31 ⫾ 1.08, p ⬍ 0.05, t-test for dependent samples). In patients Ad-SoS increased by 42 m/s (2.22%), and in controls increased by 40 m/s (2.07%). The follow-up difference in Ad-SoS between patients and controls was 42 m/s. The follow-up Ad-SoS and Zscore values were significantly lower in patients (p ⬍ 0.01&mdash Mann-Whitney U test in the case of Ad-SoS and t-test for independent samples in case of Z-score). In patients, ⌬Ad-SoS and ⌬Z-score correlated with ⌬height (r ⫽ 0.42 and 0.51, p ⬍ 0.05). In controls, ⌬Ad-SoS correlated with ⌬weight (r ⫽ ⫺0.44, p ⬍ 0.05, Spearman correlation analysis). The trends of changes in gender subgroups were the same as in the whole group (data not shown). The value of LSC for Ad-SoS was 20.5 m/s (1.07%). Using the value of the LSC, in 16 patients (67%) and in 18 controls (75%) Ad-SoS showed an increase greater than the LSC, in one control (4%) a decrease greater than the LSC and in rest of the subjects studied remained unchanged (33% patients and 19% controls) over a period of observation (Fig. 1).
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DISCUSSION To our knowledge, the current study is the first observation of longitudinal changes of skeletal status, using quantitative ultrasound measurements, in patients with genetic disorders. The most important finding of the study is that skeletal disturbances, at least in age of measured patients, did not disappear. General positive trends of improvement in longitudinal skeletal changes were comparable in patients and controls but due to lower baseline values of Ad-SoS in patients the differences between them remained stable. Important are the values in Z-scores; negative value at baseline improved significantly but remained negative. Longitudinal studies are now in progress that would show whether, during adolescence, differences disappear, remain stable or increase. Data given in previous study (Pluskiewicz et al. 2003) suggest that, with age, we may expect an increase in difference in comparison with normal individuals. Cross-sectional data comparing Ad-SoS values in a group of 50 patients and 528 healthy controls have shown that in the age range 9 to 15 y, the difference was about 50 m/s, and at the age of 16 to 18 y, reached about 100 m/s. Current results cannot be compared with other data since longitudinal studies of skeletal status in subjects with genetic disorders are not available. Previously published studies had a case-control design and commonly used bone mineral density measurements (Kao et al. 1992; Sepulveda 1995; Angelopoulou et al. 1999; Angelopoulou et al. 2000; van der Bergh et al. 2001; Sakamidis et al. 2002; Baptista et al. 2005). Only in some articles, skeletal status was assessed using QUS (Aspray et al. 1998; van der Bergh 2001; Pluskiewicz et al. 2003). Generally, older individuals were evaluated; there is a lack of longitudinal data. However, all studies, using BMD parameters and QUS values, have shown that skeletal status in subjects with genetic disorder was affected. DXA is widely accepted as a gold standard of bone densitometry, but often DXA measurements are available in major hospital only. Therefore, QUS measurements could be proposed as a screening tool. Due to medical progress and prolonged life expectancy in this group of patients, the knowledge of increased fracture risk is of significant clinical value. Global fracture risk is attributed mainly to skeletal status. There are two main factors influencing current skeletal status: peak bone mass and a rate of loss observed in adults. Therefore, the knowledge on the nature of skeletal changes during adolescence should improve management of patients. We are conducting further observations, and longitudinal results will be available in the future.
Volume 32, Number 3, 2006
The current study has several limitations: relatively small group of patients studied, and lack of data on pubertal status or bone age; these factors were not evaluated in the study. However, the majority of patients studied were before the onset of sexual maturation. Another weakness of our trial is the lack of data concerning the ultrasound bone profile index (UBPI), the parameter of which the software of our older device cannot calculate. In conclusion, despite comparable improvement in measured ultrasound parameter in patients and controls observed over the study duration, the difference between them remained stable. REFERENCES Angelopoulou N, Souftas V, Sakadamis A, Mandroukas K. Bone mineral density in adults with Down’s syndrome. Eur Radiol 1999; 9:648 – 651. Angelopoulou N, Matziari C, Tsimaras V, Sakadamis A, Souftas V, Mandroukas K. Bone mineral density and muscle strength in young men with mental retardation (with and without Down syndrome). Calcif Tissue Int 2000;66:176 –180. Aspray TJ, Francis RM, Thompson A, Quilliam SJ, Rawlings DJ, Tyrer SP. Comparison of ultrasound measurements at the heel between adults with mental retardation and control subjects. Bone 1998;22: 665– 668. Baptista F, Varela A, Sardinha LB. Bone mineral mass in males and females with and without Down syndrome. Osteoporos Int 2005; 16:380 –388. Drozdzowska B, Pluskiewicz W. The ability of quantitative ultrasound at the calcaneus to identify postmenopausal women with different types of non-traumatic fractures. Ultrasound Med Biol 2002;28: 1491–1497. Drozdzowska B, Pluskiewicz W, de Terlizzi F. The usefulness of quantitative ultrasound at the hand phalanges in the detection of the different types of non-traumatic fractures. Ultrasound Med Biol 2003;29:1545–1550. Ekman A, Michaelsson K, Petren-Mallmin M, Ljunghall S, Mallmin H. DXA of the hip and heel ultrasound but not densitometry of the fingers can discriminate female hip fracture patients from controls: A comparison between four different methods. Osteopros Int 2000; 11:185–191. Gluer CC, 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 1996;4:262–270. Hans D, Dargent-Molina P, Schott AM., et al. Ultrasonographic heel measurements to predict hip fracture in elderly women: The EPIDOS prospective study. Lancet 1996;348:511–514. Huopio J, Kroger H, Honkanen R, Jurvelin J, Saarikoski S, Alhava E. Calcaneal ultrasound predicts early postmenopausal fractures as well as axial BMD. A prospective study of 422 women. Osteoopros Int 2004;15:190 –195. Kao Ch, Chen CC, Wang SJ, Yeh SH. Bone mineral density in children with Down’s syndrome detected by dual photon absorptiometry. Nucl Med Commun 1992;13:773–775. Krieg MA, Cornuz J, Ruffieux C et al. Comparison of three bone ultrasound for the discriminating of subjects with and without osteoporotic fractures among 7562 elderly women. J Bone Miner Res 2003;18:1261–1266. Mele R, Masci G, Ventura V et al. Three-year longitudinal study with quantitative ultrasound at the hand phalanx in a female population. Osteoporos Int 1997;7:550 –557. Pluskiewicz W, Pyrkosz A, Drozdzowska B, Halaba Z. Quantitative ultrasound at the hand phalanges in patients with genetic disorders: a pilot case-control study. Osteoporos Int 2003;14:787–792.
Longitudinal changes in ultrasound measurements ● Z. HALABA et al. Sakadamis A, Angelopoulou N, Matziari C, Papameletiou V, Souftas V. Bone mass, gonadal function and biochemical assessment in young men with trisomy 21. Eur J Obstet Gynecol Reprod Biol 2002;100:208––212. Sepulveda D, Allison DB, Gomez JE, et al. Low spinal and pelvic bone mineral density among individuals with Down syndrome. Am J Ment Ret 1995;100:109 –114.
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Van der Bergh JPW, Hermus ARMM, Spruyt AI, Sweep CGJ, Corstens FHM, Smals AGH. Bone mineral density and quantitative ultrasound parameters in patients with Klinefelter’s syndrome after long-term testosterone substitution. Osteoporos Int 2001;12:55– 62. Wuster C, Albanese C, De Aloysio D et al. Phalangeal osteosonogrammetry study: Age-related changes, diagnostic sensitivity, and discrimination power. J Bone Miner Res 2000;15(8):1603–1614.
doi:10.1016/j.ultrasmedbio.2005.11.009
● Original Contribution LONGITUDINAL CHANGES IN ULTRASOUND MEASUREMENTS: A PARALLEL STUDY IN SUBJECTS WITH GENETIC DISORDERS AND HEALTHY CONTROLS ZENON HALABA,* ANTONI PYRKOSZ,† PIOTR ADAMCZYK,‡ BOGNA DROZDZOWSKA,§ and WOJCIECH PLUSKIEWICZ储 *Outpatient Medical Care, Zabrze, Poland; †Department and Chair of Molecular Biology and Medical Genetics, Katowice, Poland; ‡Department and Clinic of Pediatrics, Pediatric Nephrology and Endocrinology, Zabrze, Poland; § Department and Chair of Pathomorphology, Zabrze, Poland; and 储Silesian School of Medicine in Katowice, Poland, Department and Clinic of Internal Diseases, Diabetology and Nephrology, Metabolic Bone Disease Unit, Zabrze, Poland (Received 25 July 2005; revised 26 October 2005; in final form 11 November 2005)
Abstract—Disturbances in skeletal status in subjects with genetic disorder may increase their fracture risk. The aim of the study was longitudinal observation of phalangeal speed of sound changes across the bone over a period of 2 y in 24 patients (14 boys and 10 girls, mean age 9.63 ⴞ 1.8 y.) and 24 age-matched healthy controls (14 boys and 10 girls, mean age 9.65 ⴞ 1.71 y.). Weight and height did not differ between patients and controls at baseline and follow-up. Patients with the following disorders were evaluated: 7 with Down syndrome, 6 nonspecific mental retardations of unknown etiology, 5 Martin-Bell syndrome and 6 with other diseases. In patients and controls, no factors potentially influencing bone metabolism (except for genetic disorder) were present. Bone status was assessed by quantitative ultrasound at hand phalanges using DBM Sonic 1200 (IGEA, Carpi, Italy), which measures amplitude-dependent speed of sound (Ad-SoS [m/s]). At baseline, Ad-SoS and Z-score were significantly lower in patients than in controls (1892 ⴞ 51 m/s versus 1936 ⴞ 43 m/s, p < 0.01 and ⴚ1.47 ⴞ 1.43 versus ⴚ0.14 ⴞ 1.04, p < 0.001, respectively. In follow-up, Ad-SoS and Z-score increased significantly in patients (1892 ⴞ 51m/s to 1934 ⴞ 48 m/s, p < 0.0001 and ⴚ1.47 ⴞ 1.43 to ⴚ0.76 ⴞ 1.00, p < 0.01, respectively) and in controls (1936 ⴞ 43 m/s to 1976 ⴞ 60 m/s and ⴚ0.14 ⴞ 1.04 to 0.31 ⴞ 1.08, p < 0.05, respectively). Follow-up Ad-SoS and Z-sScore were significantly lower in patients (p < 0.01). Longitudinal changes in Ad-SoS, Z-score weight did not differ between patients and control, and height increased more in controls (13.2 ⴞ 2.8 cm versus 11.4 ⴞ 5.9 cm, p < 0.05)ⴙ). In patients, Ad-SoS increased by 42 m/s (2.22%), and in controls increased by 40 m/s (2.07%). Difference in Ad-SoS between patients and controls was 44 m/s at baseline and 42 m/s at follow-up. Using the value of the least significant change (LSC ⴝ 20.5 m/s), in 16 patients (67%) and in 18 controls (75%) Ad-SoS showed an increase greater than the LSC, in one control (4%) a decrease greater than the LSC and in rest of subjects studied remained unchanged (33% patients and 19% controls) over a period of observation. In conclusion, despite comparable improvement in measured ultrasound parameter in patients and controls observed over a study duration, the difference between them remained stable. © 2006 World Federation for Ultrasound in Medicine & Biology. Key Words: Follow-up, Genetic disorders, Hand phalanges, Quantitative ultrasound.
INTRODUCTION
to the increase in fracture risk. In some studies performed in subjects with genetic disorders, spine bone mineral density (BMD) was significantly decreased in comparison with healthy controls (Kao et al. 1992; Sepulveda et al. 1995; Angelopoulou et al. 1999; Angelopoulou et al. 2000; van der Bergh et al. 2001; Sakadamis at al. 2002; Baptista et al. 2005). In some studies, other skeletal sites were also measured: pelvis (Sepulveda et al. 1995) and proximal femur (van der Bergh et al. 2001; Baptista et al. 2005).
Due to progress in management of subjects with genetic disorders, life expectancy in this group of patients increased significantly. Among many health complications commonly present in individuals with genetic disorders are also skeletal disturbances leading Address correspondence to: Prof. Wojciech Pluskiewicz, Ph.D., M.D., Metabolic Bone Diseases Unit, 3 Maja 13/15 str., 41-800 Zabrze, Poland. E-mail: [email protected] 409
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Table 1. Clinical characteristics and QUS variables in patients and controls (mean, ⫹/⫺ SD and range)
Age [years] Height [m] Weight [kg] Ad-SoS [m/s] Z-score
Baseline patients n ⫽ 24
Baseline controls n ⫽ 24
Follow-up patients n ⫽ 24
Follow-up controls n ⫽ 24
9.63 ⫹/⫺ 1.83 6.4–13.3 1.32 ⫹/⫺ 0.15 1.05–1.60 31.2 ⫹/⫺ 11.5 17.0–57.5 1892 ⫹/⫺ 51 1787–1978 ⫺1.47 ⫹/⫺ 1.43 ⫺4.44 to 0.70
9.65 ⫹/⫺ 1.71 6.9–12.3 1.35 ⫹/0.12 1.14–1.58 31.8 ⫹/⫺ 9.7 17.3–54.5 1936 ⫹/⫺ 43* 1838–2024 ⫺0.14 ⫹/⫺ 1.04** ⫺2.87 to 2.02
11.63 ⫹/⫺ 1.83 8.4–15.3 1.44 ⫹/0.16 1.13–1.73 40.8 ⫹/⫺ 12.4 18.0–63.0 1934 ⫹/⫺ 48 1837–2018 ⫺0.76 ⫹/⫺ 1.00 ⫺3.19 to 1.19
11.84 ⫹/⫺ 1.69 8.9–14.3 1.48 ⫹/⫺ 0.12 1.26–1.70 41.7 ⫹/⫺ 12.2 23.7–70.0 1976 ⫹/⫺ 60*** 1873–2147 0.31 ⫹/⫺ 1.08*** ⫺1.69 to 2.65
Mean values of age, height and weight did not differ between patients and controls at baseline and the follow-up * Significant difference vs. baseline with P ⬍.01. ** Significant difference vs. baseline with P ⬍.001. *** Significant difference vs. follow-up with P ⬍.001.
Recently, in the armentarium of bone measurements are also some other methods like peripheral quantitative computed tomography or magnetic resonance imaging, and among them is also quantitative ultrasound (QUS). Several skeletal sites may be evaluated, such as calcaneus, patella, radius or phalanges. In some studies, calcaneal (Hans et al. 1996; Drozdzowska and Pluskiewicz 2002; Huopio et al. 2004) and phalangeal (Wuster et al. 2000; Drozdzowska et al. 2003; Mele et al. 1997) QUS measurements proved an ability to predict and to discriminate fracture risk. However, Ekman et al. (2000) did not confirm an ability of QUS phalangeal measurements to discriminate patients with and without past hip fracture, and Krieg et al. (2003) showed that discrimination power of Ad-SoS was weaker than heel QUS variables. There are also some data showing that the values of QUS parameters were decreased in patients with genetic disorders for calcaneus (Aspray et al. 1998; van der Bergh 2001) and hand phalanges (Pluskiewicz et al. 2003). The aim of this study was longitudinal observation of phalangeal speed of sound changes across the bone over a period of 2 y in subjects with genetic disorders and in healthy controls. MATERIALS In the study were evaluated 24 patients (14 boys and 10 girls) and 24 age and gender-matched healthy controls (14 boys and 10 girls). Table 1 presents clinical characteristics of patients and controls at baseline and the follow-up. Patients were recruited from Outpatient Genetic Clinic and controls were randomly selected from pupils of a local school. At baseline, body size did not differ between patients and controls. Patients with the following disorders were evaluated:
7 with Down syndrome, 6 with nonspecific mental retardations of unknown etiology, 5 with Martin-Bell syndrome, 2 with Williams syndrome, 2 with MarfanMass syndrome, one with Turner and one with other chromosomal aberration. In patients and controls, no factors were present, except for genetic disorder potentially influencing bone metabolism (either prolonged medication using corticosteroids, thyroid hormones, anticonvulsants etc., or chronic diseases of thyroid gland, liver, kidney, intestine or stomach surgery etc.). Permission for the study was given by the local ethics committee. METHODS Skeletal status was assessed by ultrasound measurements of proximal phalanges using DBM Sonic 1200 device (IGEA, Carpi, Italy). The device measures amplitude-dependent speed of sound (Ad-SoS [m/s]) in the distal metaphyses of the proximal phalanges of the second through the fifth finger of the nondominant hand. Methodology was described in our previous study (Drozdzowska et al. 2003). All measurements were taken by the same operator. Device was calibrated daily according to manufacturers’ recommendations. In vivo precision was assessed by RMS_CV (rms coefficient of variation) calculated accordingly to proposition by Gluer et al. (1995). Seventy measurements were taken in 14 healthy persons aged 8 to 15 y (measured 5 times each) by the same operator. RMS_CV was 0.38% (Drozdzowska et al. 2003). Statistical analysis Calculations of means and standard deviations were performed using the Statistica program (Tulsa, OK, USA). Data distribution was established using the Shapiro-Wilk test. Differences between mean values
Longitudinal changes in ultrasound measurements ● Z. HALABA et al.
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Fig. 1. Changes in Ad-SoS values in subjects examined and controls over a period of observation.
in patients versus controls were established using Student’s t-test for independent samples or Mann-Whitney U test according to data distribution. Differences between baseline and follow-up examinations in patients and controls were checked with t-test for dependent samples or with Wilcoxon matched pairs test, according to data distribution. Statistical analyses were performed in all patients and all controls. Differences of values in Ad-SoS and x-score between baseline and the follow-up (⌬Ad-SoS and ⌬Z-score) were correlated with longitudinal changes in weight and height separately in patients and controls using Pearson or Spearman correlation analysis when appropriate. To follow reliable changes of Ad-SoS in individual subjects, the least significant change (LSC) was calculated. 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 using the formula: CV% × 2 × 1.41, which would represent a statistical difference at the 95% confidence level (Gluer et al. 1996). Ad-SoS measured at baseline in the entire group examined (patients and controls) was used to calculate the LSC. All results were considered as statistically significant at p ⬍ 0.05. RESULTS Longitudinal changes in weight did not differ between patients and control, and height increased more in controls (13.2 ⫾ 2.8 cm versus 11.4 ⫾ 5.9 cm, p ⬍ 0.05, Mann-Whitney U test).
Table 1 presents QUS values. At baseline, Ad-SoS and Z-score were significantly lower in patients than in controls (1892 ⫾ 51 m/s versus 1936 ⫾ 43 m/s, p ⬍ 0.01 and ⫺1.47 ⫾ 1.43 versus ⫺0.14 ⫾ 1.04, p ⬍ 0.001, t-test for independent samples). Baseline difference in Ad-SoS between patients and controls was 44 m/s. In the follow-up, Ad-SoS and Z-score increased significantly in patients (1892 ⫾ 51m/s to 1934 ⫾ 48 m/s, p ⬍ 0.0001 and ⫺1.47 ⫾ 1.43 to ⫺0.76 ⫾ 1.0, p ⬍ 0.01, (t-test for dependent samples) and in controls (1936 ⫾ 43 m/s to 1976 ⫾ 60 m/s and ⫺0.14 ⫾ 1.04 to 0.31 ⫾ 1.08, p ⬍ 0.05, t-test for dependent samples). In patients Ad-SoS increased by 42 m/s (2.22%), and in controls increased by 40 m/s (2.07%). The follow-up difference in Ad-SoS between patients and controls was 42 m/s. The follow-up Ad-SoS and Zscore values were significantly lower in patients (p ⬍ 0.01&mdash Mann-Whitney U test in the case of Ad-SoS and t-test for independent samples in case of Z-score). In patients, ⌬Ad-SoS and ⌬Z-score correlated with ⌬height (r ⫽ 0.42 and 0.51, p ⬍ 0.05). In controls, ⌬Ad-SoS correlated with ⌬weight (r ⫽ ⫺0.44, p ⬍ 0.05, Spearman correlation analysis). The trends of changes in gender subgroups were the same as in the whole group (data not shown). The value of LSC for Ad-SoS was 20.5 m/s (1.07%). Using the value of the LSC, in 16 patients (67%) and in 18 controls (75%) Ad-SoS showed an increase greater than the LSC, in one control (4%) a decrease greater than the LSC and in rest of the subjects studied remained unchanged (33% patients and 19% controls) over a period of observation (Fig. 1).
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DISCUSSION To our knowledge, the current study is the first observation of longitudinal changes of skeletal status, using quantitative ultrasound measurements, in patients with genetic disorders. The most important finding of the study is that skeletal disturbances, at least in age of measured patients, did not disappear. General positive trends of improvement in longitudinal skeletal changes were comparable in patients and controls but due to lower baseline values of Ad-SoS in patients the differences between them remained stable. Important are the values in Z-scores; negative value at baseline improved significantly but remained negative. Longitudinal studies are now in progress that would show whether, during adolescence, differences disappear, remain stable or increase. Data given in previous study (Pluskiewicz et al. 2003) suggest that, with age, we may expect an increase in difference in comparison with normal individuals. Cross-sectional data comparing Ad-SoS values in a group of 50 patients and 528 healthy controls have shown that in the age range 9 to 15 y, the difference was about 50 m/s, and at the age of 16 to 18 y, reached about 100 m/s. Current results cannot be compared with other data since longitudinal studies of skeletal status in subjects with genetic disorders are not available. Previously published studies had a case-control design and commonly used bone mineral density measurements (Kao et al. 1992; Sepulveda 1995; Angelopoulou et al. 1999; Angelopoulou et al. 2000; van der Bergh et al. 2001; Sakamidis et al. 2002; Baptista et al. 2005). Only in some articles, skeletal status was assessed using QUS (Aspray et al. 1998; van der Bergh 2001; Pluskiewicz et al. 2003). Generally, older individuals were evaluated; there is a lack of longitudinal data. However, all studies, using BMD parameters and QUS values, have shown that skeletal status in subjects with genetic disorder was affected. DXA is widely accepted as a gold standard of bone densitometry, but often DXA measurements are available in major hospital only. Therefore, QUS measurements could be proposed as a screening tool. Due to medical progress and prolonged life expectancy in this group of patients, the knowledge of increased fracture risk is of significant clinical value. Global fracture risk is attributed mainly to skeletal status. There are two main factors influencing current skeletal status: peak bone mass and a rate of loss observed in adults. Therefore, the knowledge on the nature of skeletal changes during adolescence should improve management of patients. We are conducting further observations, and longitudinal results will be available in the future.
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The current study has several limitations: relatively small group of patients studied, and lack of data on pubertal status or bone age; these factors were not evaluated in the study. However, the majority of patients studied were before the onset of sexual maturation. Another weakness of our trial is the lack of data concerning the ultrasound bone profile index (UBPI), the parameter of which the software of our older device cannot calculate. In conclusion, despite comparable improvement in measured ultrasound parameter in patients and controls observed over the study duration, the difference between them remained stable. REFERENCES Angelopoulou N, Souftas V, Sakadamis A, Mandroukas K. Bone mineral density in adults with Down’s syndrome. Eur Radiol 1999; 9:648 – 651. Angelopoulou N, Matziari C, Tsimaras V, Sakadamis A, Souftas V, Mandroukas K. Bone mineral density and muscle strength in young men with mental retardation (with and without Down syndrome). Calcif Tissue Int 2000;66:176 –180. Aspray TJ, Francis RM, Thompson A, Quilliam SJ, Rawlings DJ, Tyrer SP. Comparison of ultrasound measurements at the heel between adults with mental retardation and control subjects. Bone 1998;22: 665– 668. Baptista F, Varela A, Sardinha LB. Bone mineral mass in males and females with and without Down syndrome. Osteoporos Int 2005; 16:380 –388. Drozdzowska B, Pluskiewicz W. The ability of quantitative ultrasound at the calcaneus to identify postmenopausal women with different types of non-traumatic fractures. Ultrasound Med Biol 2002;28: 1491–1497. Drozdzowska B, Pluskiewicz W, de Terlizzi F. The usefulness of quantitative ultrasound at the hand phalanges in the detection of the different types of non-traumatic fractures. Ultrasound Med Biol 2003;29:1545–1550. Ekman A, Michaelsson K, Petren-Mallmin M, Ljunghall S, Mallmin H. DXA of the hip and heel ultrasound but not densitometry of the fingers can discriminate female hip fracture patients from controls: A comparison between four different methods. Osteopros Int 2000; 11:185–191. Gluer CC, 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 1996;4:262–270. Hans D, Dargent-Molina P, Schott AM., et al. Ultrasonographic heel measurements to predict hip fracture in elderly women: The EPIDOS prospective study. Lancet 1996;348:511–514. Huopio J, Kroger H, Honkanen R, Jurvelin J, Saarikoski S, Alhava E. Calcaneal ultrasound predicts early postmenopausal fractures as well as axial BMD. A prospective study of 422 women. Osteoopros Int 2004;15:190 –195. Kao Ch, Chen CC, Wang SJ, Yeh SH. Bone mineral density in children with Down’s syndrome detected by dual photon absorptiometry. Nucl Med Commun 1992;13:773–775. Krieg MA, Cornuz J, Ruffieux C et al. Comparison of three bone ultrasound for the discriminating of subjects with and without osteoporotic fractures among 7562 elderly women. J Bone Miner Res 2003;18:1261–1266. Mele R, Masci G, Ventura V et al. Three-year longitudinal study with quantitative ultrasound at the hand phalanx in a female population. Osteoporos Int 1997;7:550 –557. Pluskiewicz W, Pyrkosz A, Drozdzowska B, Halaba Z. Quantitative ultrasound at the hand phalanges in patients with genetic disorders: a pilot case-control study. Osteoporos Int 2003;14:787–792.
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