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Developmental Endocrinology Branch, National Institute of Child Health and Human Development (M.A., V.K.B., C.A.B.), and Warren G. Magnuson Clinical Center Radiology Department (S.H.), National Institutes of Health, Bethesda, Maryland 20892
Address all correspondence and requests for reprints to: Carolyn Bondy, M.D., Chief Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, BG10, Room 1E-3330, Rockville, Maryland 20892. E-mail: bondyc{at}mail.nih.gov.
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Abstract |
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Objective: The objective was to determine how GH treatment affects bone mineral density (BMD) and body composition in girls with TS.
Method: In a cross-sectional study, we compared measures of body composition and BMD by dual energy x-ray absorptiometry, and phalangeal cortical thickness by hand radiography in 28 girls with TS who had never received GH and 39 girls who were treated with GH for at least 1 yr. All girls were participants in a National Institutes of Health (NIH) Clinical Research Center (CRC) protocol between 2001 and 2006.
Results: The two groups were similar in age (12.3 yr, SD 2.9), bone age (11.5 yr, SD 2.6), and weight (42.8 kg, SD 16.6); but the GH-treated group was taller (134 vs. 137 cm, P = 0.001). The average duration of GH treatment was 4.2 (SD 3.2) yr (range 1–14 yr). After adjustment for size and bone age, there were no significant differences in BMD at L1–L4, 1/3 radius or cortical bone thickness measured at the second metacarpal. However, lean body mass percent was higher (P < 0.001), whereas body fat percent was lower (P < 0.001) in the GH-treated group. These effects were independent of estrogen exposure and were still apparent in girls that had finished GH treatment at least 1 yr previously.
Conclusions: Although GH treatment has little effect on cortical or trabecular BMD in girls with TS, it is associated with increased lean body mass and reduced adiposity.
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Introduction |
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Although it is well established that GH promotes longitudinal bone growth, its effects on bone density are less clear (4, 5, 6, 7, 8, 9). GH is known to increase bone turnover, but it is yet to be determined whether the increase in turnover increases bone density in growing children. Given that women with TS have cortical bone deficiency (10, 11), it is important to understand the effects of GH on bone density in this population. Furthermore, there is little information on the effect of GH on body composition in girls with TS. The existing studies had small numbers and no untreated TS controls (12, 13). Therefore, in the present study we examined body composition and bone mineral density (BMD) by dual energy x-ray absorptiometry (DXA), and also cortical thickness of the second metacarpal using hand radiographs, in GH-treated vs. untreated girls with TS.
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Subjects and Methods |
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Study subjects were participants in a TS natural history protocol, which was approved by the National Institute of Child Health and Human Development (NICHD) institutional review board. All adult participants and parents of minor children gave written informed consent, and minors informed assent. The protocol includes studies of BMD, metabolic function, and cardiovascular imaging. Study subjects with TS were recruited through notices on the NIH web site: http://turners.nichd.nih.gov/. Inclusion criteria were: 1) phenotypic females greater than 6 yr of age; and 2) a 50-cell peripheral karyotype in which more than 70% of cells demonstrated loss of all or part of the second sex chromosome.
For this study on the effect of GH on body composition and bone, all study participants aged 18 yr and under and their caregivers were queried about any history of GH use. There were 78 patients aged 7 to 18 yr for which we obtained information on history of GH use, including age of initiation and duration of treatment. In addition to a questionnaire and personal interview, medical records were reviewed to confirm GH history. As to the dose of GH used, we obtained reliable information mainly for those subjects currently using GH, and this was in the standard range for treating girls with TS, i.e. 0.03–0.05 mg/kg·d.
Hand radiography
Posterior-anterior view images of the left hand of all patients were obtained using a computerized radiography (CR) cassette system (GP storage phosphor screen; Kodak, Rochester, NY) with Kodak direct view CR 950 reader. In some patients, the radiographs were obtained by direct digital system (Axiom Aristos; Siemens, Munich, Germany) (film focus distance, 40 in.; small focus, 0.6 mm; tube voltage, 55 kVp; exposure, 2.5–3 mAs). The digitized CR images of the hands were then transferred to picture archive communication system (PACS, Kodak system 5). The cortical thickness of the second metacarpal shaft of the left hand was measured (in millimeters) using Kodak PACS workstation viewer to perform linear measurement. The metacarpal shaft was divided at the point of the proximal 1/3, the midpoint, and the distal 1/3. At each of these levels (proximal 1/3, 1/2, distal 1/3), the total width and the medullary width were measured using computer-drawn lines with automatic length values displayed. Combined cortical thickness (CCT) was obtained by subtracting the medullary width from the total width. The measurements at each point were averaged to come up with an average CCT. An average ratio was also calculated as the cortical thickness divided by the total width of the metacarpal, averaged from the three locations. Additional dependent measures included Metacarpal Index (MI) and Bending Breaking Resistance Index (BBRI) (14, 15). MI is calculated as (TW2 – MW2/TW2), and BBRI is calculated as (TW4–MW4/TW), where TW is total width and MW is medullary width.
DXA
All girls underwent measurement of areal BMD and body composition using a Hologic QDR-4500A DXA (Hologic, Inc., Bedford, MA) with fan-beam technology to obtain 1/3 radius, ultradistal radius, anteroposterior L1–L4, and total body BMD. Total BMC, total lean, total lean percent, total fat, and total fat percent were also used as measures of body composition. The lean tissue mass (LTM) ratio was also calculated as total BMC/total lean mass.
Statistics
Data are presented as means with SD or as proportions. Comparisons of age, height, and body mass index (BMI) between groups were by ANOVA. Comparison of measures of cortical thickness, DXA BMD, and body composition was done by post hoc analysis of covariance (ANCOVA) using as covariates the potentially confounding factors of bone age and BMI. Proportions were compared by 
2 test. The effects of GH treatment duration were assessed by multiple linear regression analysis. All analyses were performed on StatView, version 5.0.1; or JMP, version 5 (SAS Institute, Inc., Cary, NC).
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Results |
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The GH-treated and untreated groups were similar in age, although the treated group was significantly taller (Table 1
). Most subjects not taking GH had a very recent diagnosis of TS and planned to start GH treatment. The average duration of GH treatment was 4.2 (SD 3.2) yr, range 1–14 yr. The proportion of girls exposed to estrogen was 31% in the GH-treated group and 21% in the nontreated group. The karyotype distribution was similar in both groups: greater than 80% had either 45,X or 45,X with a second abnormal cell line with a fragmented X or Y chromosome. There was one subject in the untreated group and four subjects in the treated group with 45,X/46,XX karyotype, but the proportion of cells with normal karyotype was less than 30% in these girls. The remainder had karyotypes including 46,XiXq; 46,XdelXp; or 46,XdelXq. The majority of girls in both groups were Caucasian; however, the study did include Hispanic, African-American, and Asian girls.
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Because girls with TS seem to have a selective reduction in cortical bone (10, 11), and GH treatment was reported to increase cortical BMD in girls with TS (4), we first compared cortical bone thickness and BMD in our two groups (Table 2). The absolute phalangeal cortical thickness was greater in the GH-treated group, but after adjusting for the larger digital size in GH-treated girls by use of the cortical thickness to metacarpal diameter ratio and the MI, we found no significant difference between treated and untreated groups. We analyzed the contribution of duration of GH use in a multiple regression analysis including cortical thickness, age, and BMI. Cortical bone thickness was positively correlated to age (P = 0.03) but not duration of GH treatment (P = 0.44) or BMI. The BBRI was calculated as another parameter of cortical bone, and this index was greater in GH-treated vs. untreated groups, but the difference did not achieve statistical significance. DXA densitometry was similar in the two groups at the largely cortical 1/3 radius and at the mainly trabecular bone lumbar (anteroposterior L1–L4) spine. We also compared lumbar BMD after correction for somatic size difference using body surface area (16), and there was still no significant difference between GH-treated and untreated groups (P = 0.7). The untreated group, however, had slightly greater bone density at the ultradistal radius (Tables 2 and 3).
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GH-treated individuals had on average 15% less adipose tissue (P < 0.001) and approximately 8% more lean mass compared with untreated girls (Table 3
and Fig. 1). These salutary effects were similar in groups with no estrogen exposure (i.e. excluding girls with spontaneous puberty or estrogen treatment) (Table 4). To investigate the longevity of the effects of GH on body composition, we compared girls that had been off GH treatment for over 1 yr (n = 14, mean age 15.2 yr, SD 2.4) with age-matched girls that had never been treated with GH (n = 20, mean age 14.1 yr, SD 2.2). The percent lean body mass was 68.9 (sd 7.4) in the previously treated vs. 63.3 (SD 7.9) in the never-treated girls (P < 0.0001), whereas the percent body fat was 29.8 (SD 9.1) in the previously treated vs. 34.3 (SD 8.3) in the never-treated girls (P = 0.0004).
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Discussion |
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The present study has shown that GH treatment for an average duration of approximately 4 yr has little apparent effect on cortical or trabecular bone mineralization in girls with TS, but it does increase muscle mass and decrease adiposity. Because of the selective cortical bone deficit in TS (10, 11), we were particularly interested in the effects of GH on cortical bone. Cortical bone was measured by two methods: hand radiography and DXA of the radius. Metacarpal cortical thickness was slightly greater in the GH group, but after adjusting for metacarpal size, the difference was not significant. Also, the BBRI, a calculation of bone breaking point, indicated similar strength in the bones of the treated and untreated groups. DXA BMD measurements of the largely cortical radial shaft (1/3 radius) were also very similar in treated vs. untreated groups. Our sample size was sufficient enough to allow detection of an 8% difference in cortical bone thickness between groups, hence it is unlikely that we missed any clinically significant effect. These data suggest that GH treatment is without strong effect on cortical bone in TS.
The earlier Dutch study (4) that reported an increase of phalangeal bone density used significantly higher doses of GH (0.0675 mg/kg·d) compared with doses used in our patients, which ranged from 0.03 to 0.05 mg/kg·d. Also, the duration of treatment in the Dutch study was 7 yr, whereas our average duration was approximately 4 yr. Thus it is possible that GH does increase cortical bone density when used at higher doses over a longer period. Our present finding of no effect of GH treatment on lumbar spine BMD confirms previous small studies that also found no difference in lumbar spine with GH treatment (6, 7, 8).
GH treatment is well known to promote anabolism of lean tissue and reduce adiposity in adults, with or without GH deficiency (20). Our data confirm and extend two small longitudinal studies showing that GH treatment increased lean mass and decreased adiposity in girls with TS. Leger et al. (12) found increased thigh muscle volume in eight girls with TS over 12 months of GH treatment, and Gravholt et al. (13) observed increased muscle and decreased fat after 2 months of GH treatment. Although the salutary effects of GH on body composition "melt away" after a few months in adults (20), it is not known whether treatment of growing children may have more long-lasting effects. The present study is encouraging in this regard because the fat-to-lean ratio in the group of girls that had discontinued GH treatment at least 1 yr ago was still quite favorable compared with untreated girls. Further longitudinal study of these patient groups will be more informative on this important question.
A major limitation of the present study is that study subjects were not randomized as to treatment, and thus it is possible that the relation between GH use and lean body habitus does not represent cause and effect but only an association. This seems unlikely, however, because GH treatment has been shown to promote lean tissue and reduce adiposity in previous prospective studies. Moreover, the lack of GH treatment in our untreated group was due in most cases to a late diagnosis, and most of these girls were planning to begin GH treatment. Another limitation is that because IGF-I levels were not measured in the girls on GH treatment, we cannot exclude the possibility of supraphysiological exposure in some girls.
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Footnotes |
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Disclosure Statement: The authors have nothing to disclose.
First Published Online August 29, 2006
Abbreviations: ANCOVA, Analysis of covariance; BBRI, Bending Breaking Resistance Index; BMD, bone mineral density; BMI, body mass index; CCT, combined cortical thickness; CR, computerized radiography; DXA, dual energy x-ray absorptiometry; LTM, lean tissue mass; MI, Metacarpal Index; TS, Turner syndrome.
Received June 22, 2006.
Accepted August 21, 2006.
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