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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 11 5266-5272
Copyright © 2003 by The Endocrine Society

Cortical Bone Density Is Normal in Prepubertal Children with Growth Hormone (GH) Deficiency, but Initially Decreases during GH Replacement due to Early Bone Remodeling

R. Schweizer, D. D. Martin, C. P. Schwarze, G. Binder, A. Georgiadou, J. Ihle and M. B. Ranke

Pediatric Endocrinology Section, University Children’s Hospital, University of Tuebingen D-72076, Germany

Address all correspondence and requests for reprints to: Dr. Roland Schweizer, Pediatric Endocrinology Section, University Children’s Hospital, Hoppe-Seyler Strasse 1, D-72076 Tuebingen, Germany. E-mail: roland.schweizer{at}med.uni-tuebingen.de.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Dual energy x-ray absorptiometry (DEXA) has revealed that GH- deficient adults gain in bone mineral density during GH therapy. Measurements of volumetric bone density (grams per cubic centimeter vs. grams per square centimeter) and structure, however, are achieved through peripheral quantitative computed tomography (pQCT). In 45 prepubertal GH-deficient children, we studied pQCT measurements before the start and for 12 months of GH treatment. Serum alkaline phosphatase (AP), procollagen I carboxyl-terminal propeptide (PICP), and deoxypyridinoline reflected bone metabolism status. Findings at the start of GH treatment were (mean SD score): bone area, -0.44; cortical density, -0.03; cortical area, -1.32; cortical thickness, -1.41; and marrow area, +0.66. At 12 months, cortical density had fallen to -0.73 (P < 0.001), whereas cortical area and thickness, and marrow area did not change. AP, PICP, and deoxypyridinoline increased significantly within the first 3 months (increase: AP, 66.5 U/liter; PICP, 72 µg/liter; DPD, 11.4 nmol/mmol creatinine). The pQCT showed that cortical density is not reduced in GH-deficient patients. Higher bone metabolism explains the lower cortical density after GH therapy commenced. Thus, the manifestation of GH deficiency is evidently similar in children and adults, and pQCT provides important information in addition to DEXA measurements, as DEXA does not take bone structure into account.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
CHANGES IN HEIGHT velocity are mainly attributed to the effectiveness of GH replacement therapy in children with GH deficiency (GHD). In adults with GHD, however, the efficacy of replacement is ascertained by observed changes in body composition and function. Characteristic of these adult patients is their low bone mineral density (BMD), reduced lean body mass, and substantially higher fat mass (1, 2, 3), but, under replacement therapy, a decrease in fat mass and an increase in muscle mass as well as higher BMD have consistently been observed (4, 5, 6, 7, 8, 9). Although the effects of GH on body composition, such as a decrease in skinfold thickness, were described more than a decade ago (10, 11), it is still not common practice to monitor compartments of the body during GH therapy in children and adolescents. In view of the fact that childhood-onset GHD requires life-long medical care and that distinct effects of GH, such as height increment, obviously cannot serve as identifiable parameters in adulthood, we support the view that body composition measurements should start at the time GH therapy is initiated in children and adolescents.

Several investigators have shown that GH therapy has an effect on bone metabolism in terms of both bone formation and bone resorption (12, 13, 14, 15, 16). There is, however, no consensus on the biochemical parameters that should be determined, nor is there clarity about the definitive techniques for investigating structural bone changes in children that are both safe and cost-effective as well as physiologically appropriate.

Dual energy x-ray absorptiometry (DEXA) is restricted to the measurement of a two-dimensional area density (grams per square centimeter), which is calculated by means of the x-ray absorption. In contrast, peripheral quantitative computed tomography (pQCT) allows the study of both volumetric bone density (grams per cubic centimeter) and bone structure (17). This is an important feature, because bone density alone is not the single parameter that determines bone stability: in fact, it has been shown that bone structure is also a relevant factor (18). Our objective was, therefore, to conduct a longitudinal study of biochemical parameters indicative of bone metabolism and bone structure by applying pQCT during the first year of GH replacement in prepubertal children with idiopathic GHD. We assumed that evidence would be found to corroborate reported findings associating an increase in bone metabolism with a significant increase in volumetric bone density during GH treatment.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
The investigations were conducted in our unit between March 1999 and April 2001. Of the primary population of 53 prospectively investigated children, 4 were excluded because of organic GHD, and 4 because they developed signs of puberty. The study population, therefore, consists of 45 (8 female) prepubertal (females, B1; males, G1; testis volume, <3 ml) children in whom GHD had been recently established based upon anthropometrical characteristics and biochemical tests (19). In all children, GH levels (measured by RIA) in 2 standard stimulation tests (insulin hypoglycemia and arginine) did not exceed 8 µg/liter, and basal levels of IGF-I were below -1.0 SD score (SDS) for age (19). In cases with additional pituitary hormone deficiencies (TSH and ACTH; n = 3), replacement of T4 (75 µg/m2·d, orally) and/or hydrocortisone (10 mg/m2·d) was given at least 3 months before and during GH therapy. In all patients, magnetic resonance imaging of the hypothalamic-pituitary and stalk-pituitary region was performed. In 10 patients (including the 3 with additional hormone deficiencies) we observed hypoplasia of the pituitary gland and/or stalk or an ectopic neuropituitary gland. All children were treated with a single daily evening injection of authentic recombinant human GH of various brands. The initial dosage was variable (median dose, 0.028 mg/kg·d; range, 0.018–0.047 mg/kg·d), but was kept constant during the observational phase. Children with additional chronic disorders and/or dysmorphological features were not included in the study.

Anthropometrical and biochemical parameters were measured before as well as 3, 6, and 12 months after initiation of GH replacement. A pQCT scan was performed before as well as 6 and 12 months after GH treatment started. After overnight fasting, samples of blood and urine were taken in the morning, between 0900–1100 h. The study was approved by the ethics committee of the Faculty of Medicine, University of Tuebingen, and informed written consent was given by the parents.

pQCT

Bone structure and volumetric bone density were measured using a pQCT device (XCT 2000, Stratec, Inc., Pforzheim, Germany). The scanner was equipped with a low energy (38 keV) x-ray tube. The radiation dose for a single scan was approximately 0.3 µSv, with an effective dose for the forearm of about 0.1 µSv. The radiation source was 45 kV at 150 µA. The machine was calibrated once a week with a standard phantom and once a month with a cone phantom provided by the manufacturer. The proximal radius of the nondominant arm was chosen, and cross-sectional measurements were taken at exactly 65% of the ulna length away from the radius growth plate. For this, the radius growth plate was precisely located with a scout-view scan. This position of measurement was chosen because it is the site comprising the biggest muscle area cross-section for which Neu et al. (20) established age-dependent reference values in 2001 using the same pQCT device for healthy German children. A relative (65%) distance was chosen because the arm is constantly growing in childhood. This ensured the measurement of the exactly corresponding site, regardless of changing arm lengths. A 2-mm-thick, single tomographic slice was taken at a voxel size of 0.4 mm. Image processing and calculation of numerical values were performed by means of the software package supplied by the manufacturer (version 5.4, Stratec, Inc.). The following parameters were determined: 1) total area (square millimeters), 2) cortical area (square millimeters), 3) marrow area (square millimeters), 4) cortical thickness (millimeters), and 5) cortical density (milligrams per cubic centimeter) of the radius as well as muscle area (square millimeters).

The entire cross-sectional area of the radius (total area) and the cross-sectional area of cortical bone (cortical area; square millimeters), were determined by detecting the outer and inner cortical bone contours at a threshold of 710 mg/cm3. Volumetric cortical BMD (cortical density) represents the mass of mineral per unit volume of the cortical bone mass (milligrams per cubic millimeters). Marrow area represents the difference between total area and cortical area. Cortical thickness (millimeters) was calculated as outer bone radius minus marrow radius [outer bone radius = (total area/{Pi})1/2 and marrow radius = (marrow area/{Pi})1/2]. This procedure was described by Neu et al. (20). Muscle area was measured at a threshold of 30–70 mg/cm3. The measurements were transformed into SDSs based on the age-specific references (20). Presuming height to be an important parameter influencing bone structure, we decided to establish the SDS by deriving height age, this being the age obtained by projecting a given patient’s height on to the corresponding median height of the reference population. To establish the variability of the measurements, 3 investigators measured the forearm of an adult volunteer 12 times. The coefficients of variation for total area, cortical area, marrow area, cortical thickness, cortical density, and muscle area were 2%, 0.9%, 6%, 1.6%, 0.3%, and 3%, respectively.

Biochemical parameters

From the large number of potential markers of bone metabolism, we chose total serum alkaline phosphatase (AP) and serum carboxyl-terminal propeptide of procollagen I (PICP) as markers of bone formation and the urinary deoxypyridinoline (DPD) as a marker of bone resorption (21, 22).

AP

Serum alkaline phosphatase was measured by the p-nitrophenylphosphate color method as provided by Roche (Mannheim, Germany). The measurement requires a sample volume of 150 µl serum. The sensitivity is 5 U/liter, and the intra- and interassay coefficients of variation were 0.5% and 0.4% at 458 and 579 U/liter, and 2.2% and 2.1% at 357 and 563 U/liter, respectively (information as given by the producer). For comparison, modified reference data for prepubertal children according to Lockitch et al. (23) were used. Reference values showed no age dependency for prepubertal children.

PICP

PICP was measured with a sandwich ELISA provided by Metra Biosystems GmbH (Osnabruck, Germany). The measurement requires a sample volume of 100 µl serum. The sensitivity was 0.2 µg/liter, and the intra- and interassay coefficients of variation were 6.8% and 5.0% at 80.8 and 296.7 µg/liter, and 8.8% and 7.8% at 51.1 and 437.9 µg/liter, respectively. Our own reference data, established on the basis of 268 healthy children (155 female) between 3 and 18 yr of age, were used to calculate the SDS. Reference values showed no age dependency for prepubertal children, and the median and 90% ranges were 274 and 154–486 µg/liter, respectively (ln mean, 5.61; ln SD, 0.35).

DPD

For the automated chemiluminescence assay employed to measure DPD (Imulite Pyrilinks-D, DPC Biermann, Bad Nauheim, Germany), a 75-µl urine volume was used. The measured DPD concentrations were normalized by means of the urinary creatinine concentrations by calculating a DPD/urinary creatinine ratio in nanomoles per millimoles of creatinine. The intraassay coefficients of variation in the DPD measurement were 9.3%, 5.9%, and 7.4% at 9.5, 22.3, and 50.1 nmol/mmol creatinine. The interassay coefficients of variation were 11.2%, 8.4%, and 8.8% at 9.3, 22.9, and 48.8 nmol/mmol creatinine. The sensitivity specified by the manufacturer was 4 nmol/liter (21).

The measured values were compared with the reference values for prepubertal children reported by Elmlinger et al. (21), which did not show any age dependency.

Statistical analyses

Statistical analysis was performed using the computed statistics program JMP. Results are expressed as the mean ± SD unless otherwise specified. The significance of changes was tested using a paired t test. To study the relationship between serum, urine, and pQCT parameters, regression analyses (Pearson’s coefficient of variation) were performed. SDSs were calculated as the patient value minus the mean of the age- and sex-matched reference value divided by the SD of the age- and sex-matched reference value. {Delta} values ({Delta} = change in) are expressed as the difference between a value at time t2 minus a value at time t1.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Patient characteristics at the start of GH therapy are shown in Table 1Go. At the start of GH treatment, patients were (median and range in parentheses) 7.5 yr old (3.3–14.4 yr) with a height (SDS) of -2.9 (-5.4 to -1.8 SD) and a serum IGF-I-level (SDS) of -3.5 (-14.7 to -0.8). Height velocity during the first year of GH therapy was 9.1 cm (5.5–12.4 cm), corresponding to a {Delta} height (SDS) of 0.8 SD (0.2–1.8 SD; see TableGo 1).


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  		TABLE 1. Patient characteristics (n = 45)

 
Biochemical markers

At the start of GH treatment bone metabolism parameters in almost all patients were within the reference range (Fig. 1Go). However, in four patients serum AP levels exceeded the 95th percentile; two patients had PICP serum levels below the 5th, and 3 had values above the 95th percentile. DPD values were in the lower normal range, with a median concentration of 23.2 nmol/mmol creatinine. Five patients had DPD levels below the 5th percentile. Median AP and PICP serum levels were normal, with concentrations of 293 U/liter and 281 µg/liter, respectively. Markers of bone metabolism increased significantly after the first 3 months of GH treatment (see Table 2Go). Thereafter, no significant further changes occurred.



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  		FIG. 1. Parameters of bone metabolism at the start of GH treatment.

 

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  		TABLE 2. Bone metabolism parameters at start and after 3, 6, and 12 months of GH treatment

 
Bone density and structure

At the onset of GH therapy. The following measurements are expressed in terms of median and range (see Table 3Go for mean and SD). Cortical density was normal at 991 mg/cm3 (849–1089 mg/cm3), corresponding to 0.03 SDS (-2.7 to 2.2). Total area was only slightly reduced, with an absolute area of 74.9 mm2 (24.0–133.8), corresponding to -0.43 SDS (-3.5 to 1.45). Cortical area was significantly reduced at 30 mm2 (8–62.5), corresponding to -1.38 SDS (-3.3 to 0.6), as was cortical thickness at 1.12 mm (0.25–1.88), corresponding to -1.32 SDS (-3.6 to 0.4). Bone marrow area was increased at 47.6 mm2 (7.7–97.0), corresponding to +0.51 SDS (-1.8 to 4.0). The SDSs of all parameters were higher when matched with height age. The total area as well as the marrow area were above normal, whereas the cortical area and cortical thickness were only slightly reduced (see Table 3Go for mean and SD values). Muscle area proved to be reduced when we compared it with age- as well as height age-matched controls (Table 3Go).


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  		TABLE 3. pQCT parameters at the start and after 6 and 12 months of GH treatment

 
During GH therapy. During GH treatment cortical density decreased significantly: {Delta} cortical density (SDS) = -0.32 ± 0.91 SD (mean ± SD) after 6 months, and -0.70 ± 0.96 SD after 12 months (see also Table 3Go and Fig. 2Go). Cortical area, marrow area, and cortical thickness did not change significantly (see Table 3Go). Total area increased significantly: {Delta} total area (SDS) = +0.27 ± 0.72 SD after 6 months, and +0.41 ± 1.00 SD after 12 months.



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  		FIG. 2. Changes in cortical density during GH treatment.

 
No significant correlations were found between changes in bone metabolism parameters and changes in bone structure. After 3 months of GH therapy, nearly all bone metabolism parameters had increased (AP at start vs. AP after 3 months: r = 0.77; P < 0.001; PICP at start vs. PICP after 3 months: r = 0.46; P < 0.001; DPD at start vs. DPD after 3 months: r = 0.51; P < 0.001). The correlation between the changes in AP and PICP over the first 3 months of GH treatment was highly significant (r = 0.47; P < 0.001). A weak correlation was found between {Delta}AP and {Delta}DPD over the 3-month period (r = 0.3; P = 0.03). {Delta}PICP and {Delta}DPD showed no correlation (Fig. 3Go). In the following 9 months, all three parameters showed no significant change.



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  		FIG. 3. Cross-correlations of changes in bone metabolism parameters after 3 months of GH treatment (A–C).

 
Height velocity during the first 6 months of GH treatment showed a correlation with the change in PICP in the sixth month of therapy (r = 0.34; P = 0.05), but showed a weak correlation with {Delta}AP over the initial 6 months (r = 0.23; P = 0.06) and no correlation with {Delta}DPD during the same period.

We observed a very strong correlation between cortical area (x-axis) and muscle area (y-axis) before and during GH treatment. The ratio between cortical area and muscle area decreased during GH treatment (from 0.030 to 0.026 to 0.025, at the start and after 6 and 12 months of GH treatment, respectively; see Fig. 4Go).



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  		FIG. 4. Correlation between muscle cross-sectional area and cortical area of the radius before (A) and after 6 (B) and 12 (C) months of GH treatment.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In GHD adults, the extent of loss in bone mass and BMD varies between patients whose disease had an adult onset and those with a childhood onset (2). The extent of bone mass loss evidently correlates with the duration of unsubstituted GHD, and most researchers reported a reduced BMD (1, 2, 3). Another important parameter influencing the loss of bone mass in adult GHD is the combination with other hormone deficiencies, such as sex steroids (8). For the determination of bone mineral status in these studies, DEXA or single photon absorptiometry were used. In one study with GHD children, Boot et al. (4) showed reduced area BMD of the lumbar spine and total body, as measured by DEXA. With reference to the interpretation of results in these studies, it must be remembered that two-dimensional methods such as DEXA or single photon absorptiometry do not measure a three-dimensional volumetric density; instead, only area density is calculated from the x-ray absorption.

One uniform finding in GHD adults and children is the increase in the levels of bone metabolism parameters, which is understood as an expression of increased bone turnover after the start of GH therapy (9, 12, 16). This is partly the result of direct GH effects, but is mainly caused by IGF-I, which has endocrine as well as para- and autocrine activity (24, 25, 26).

Our present study is the first to examine the relationship between changes in bone metabolism and direct changes in bone structure and volumetric cortical density during GH treatment in children with idiopathic GHD. As could be anticipated, the markers of bone metabolism increased significantly during the first 3 months of GH treatment. In contrast to the literature, however, and contrary to our initial hypothesis, we found a normal cortical density before the start of therapy, which decreased on treatment. There are two possible explanations for this finding. Firstly, there could be a difference in the manifestation of adult GHD compared with childhood GHD. In children, the most important indication of GHD is growth retardation and delayed bone age. In GHD adults, however, an increase in body fat and a simultaneous decrease in muscle mass are the most characteristic findings, and are occasionally accompanied by a reduced area BMD. It is likely, however, that the duration of insufficient GH secretion during childhood is comparatively too short to affect bone density. It is also relevant to mention here that 40–80% of children with idiopathic isolated GHD do not prove to have sustained GHD as adults.

Secondly, our study is the first to use a new method for determining bone density in GHD. The pQCT allows measurement of volumetric bone density as well as determination of bone structure. In comparison with a healthy reference population measured with exactly the same method (20), the cross-sectional pQCT measurement of the radius in our patients showed near-normal total area (mean, -0.35 SDS) and increased marrow area (mean, +0.57 SDS), but decreased cortical area (mean, -1.27 SDS) and cortical thickness (mean, -1.25 SDS) and normal cortical density (mean, 0.03 SDS). The normal findings for total area were unexpected, as the reference group was age-matched. Using stature-matched SDS, we observed that total area was markedly higher than normal. We assumed that our short patients would prove to have smaller bones with decreased bone area, cortical area, and cortical thickness. We thus conclude that the cortical bones in GHD children who do not receive GH therapy are wider than normal and have thinner walls than those of age- and stature-matched healthy children. The bone marrow enlargement is probably due to the fact that endocortical bone resorption is more pronounced than pericortical bone deposition. This presumably leads to a compensatory functional stability of bone during the state of GHD in children. In the light of our findings, which showed that cortical thickness and area are reduced, whereas cortical density itself is normal, it becomes possible to explain the lower area BMD (milligrams per square centimeter) found in DEXA studies of GHD adults (1, 2, 3) and children (4). In the two-dimensional projection used in DEXA, these changes lead to a reduction in absorption, which is then calculated as a reduced area bone density (milligrams per square centimeter) and total bone mass. Our results confirm other published reports on the issue of reduced bone mass. In addition, our results provide new information, as they demonstrate that cortical density is normal, whereas cortical proportions undergo change. Future pQCT studies of adults with GHD would presumably lead to the same results, but to our knowledge no published reports are yet available. Our findings thus indicate that the manifestation of childhood GHD is not different from that of adult GHD, except that growth retardation occurs additionally in childhood GHD.

In terms of bone health, both bone stability and solidity are more important than bone mass. A study by Schönau et al. (18) illustrated that the solidity of a bone is a function not only of its density but also of its geometry. Further parameters for bone solidity are trabecular density and alignment (27, 28), which, however, cannot yet be evaluated in vivo and thus require a bone biopsy. In summary, bone solidity is determined by material characteristics, mass (bone mineral content), architecture and geometry, and the three-dimensional organization of the trabecules. Further research is needed to establish the significance of each of these parameters for bone fracture prevention. A few studies have suggested that GHD in adults poses a higher risk for fractures (29). There are, however, no pQCT studies of the bones of GHD adults, nor is literature available on this subject with regard to children. It is worth mentioning that none of the children we studied suffered a bone fracture.

In our cohort of GHD children, cortical density was found to decrease during the first year of GH therapy. Studies with DEXA on GHD adults have also shown that bone density remains unchanged, or even decreases slightly, in the first 6 months of GH therapy (6, 7, 9, 14). Because DEXA was employed, however, these studies could not clearly determine whether cortical thickness or cortical density was affected by GH therapy.

The decrease in cortical density found in our study could be explained by the strong increase in bone remodeling and remodeling space (30). This is reflected in an increase in both osteoblastic (AP und PICP) and osteoclastic (DPD) parameters. The rise in DPD in our study was possibly underestimated, because we corrected urinary DPD concentrations according to urinary creatinine concentrations, which may increase during GH treatment due to increasing muscle mass. Further, bones grow rapidly during the first year of GH therapy (median growth velocity, 9 cm/yr). This may initially led to lower volumetric cortical bone density due to undermineralized, newly formed bone, associated with the higher bone turnover. There are no data indicating that the rate of fractures increases in GHD children during this catch-up phase; however, there is reportedly a higher incidence of slipped capital femoral epiphysis (31, 32).

Changes in bone metabolism do not correlate with changes in volumetric bone density and structure. It must be assumed that the relatively rapid changes in bone metabolism parameters, which are influenced by a multitude of environmental, behavioral, and nutritional factors, do not directly reflect the long-term bone changes.

It has been recently suggested that the major factor influencing bone mass is muscle mass (33). We, therefore, tested the correlation between muscle area and cortical area measured by means of pQCT, and our results showed a strong relationship for the period before and during GH treatment. During the course of GH treatment, however, the relation between muscle area and bone area changes, in that normalization in muscle area is higher than that in cortical area; therefore, the ratio between cortical area and muscle area decreased to normal, as in healthy prepubertal children it is approximately 0.023 (33).

The follow-up of our patients will clarify whether another increase in cortical density occurs and whether significant changes in bone structure are observable. The studies with DEXA show a significant increase in BMD and bone mass starting after 6 months of GH treatment in GHD adults (7, 8) and children (4).

The present study is the first to provide evidence that cortical bone density does not decrease in untreated GHD children and that an abnormal bone structure is the likely cause of the lower x-ray absorption reported in previous DEXA studies. The same is probably true in the case of GHD adults. The increase in bone modeling and remodeling together with the catch-up growth result in a decrease in cortical density during the first year of GH therapy in GHD children. The follow-up of this study population will provide further data on the influence of long-term GH treatment on volumetric bone density and bone structure in these children. Further, the results presented here support the proposal that the manifestation of GHD is not different in adults compared with children, and that pQCT is a precise, cheap, and quick tool that offers important information for the assessment of changes in bone in addition to DEXA measurements. We, therefore, recommend that measurements of bone density and structure should, in the future, be made by means of pQCT in addition to DEXA.


   Footnotes
 
This work was supported in part by an educational grant from Pharmacia GmbH (Erlangen, Germany) and Fortüne Forschungsförderung, a grant from University of Tuebingen.

Abbreviations: AP, Alkaline phosphatase; BMD, bone mineral density; {Delta}, change in; DEXA, dual energy x-ray absorptiometry; DPD, deoxypyridinoline; GHD, GH deficiency; PICP, procollagen I carboxyl-terminal propeptide; pQCT, peripheral quantitative computed tomography; SDS, SD score.

Received March 12, 2003.

Accepted August 1, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Amato G, Carella C, Fazio S, La Montagna, G, Citadini A, Sabatini D, Marciano-Mone C, Saccá L, Bellastella A 1993 Body composition, bone metabolism, and heart structure and function in growth hormone (GH)-deficient adults before and after GH replacement therapy at low doses. J Clin Endocrinol Metab 77:1671–1676[Abstract]
  2. Holmes SJ, Economou G, Whitehouse RW, Adams JE, Shalet SM 1994 Reduced bone mineral density in patients with adult onset growth hormone deficiency. J Clin Endocrinol Metab 78:669–674[Abstract]
  3. Rosen T, Hansson T, Granhed H, Szucs J, Bengtsson BA 1993 Reduced bone mineral content in adult patients with growth hormone deficiency. Acta Endocrinol (Copenh) 129:201–206[Medline]
  4. Boot AM, Engels MA, Boerma GJ, Krenning EP, De Muinck-Keizer S 1997 Changes in bone mineral density, body composition, and lipid metabolism during growth hormone (GH) treatment in children with GH deficiency. J Clin Endocrinol Metab 82:2423–2428[Abstract/Free Full Text]
  5. Janssen YJ, Doornbos J, Roelfsema F 1999 Changes in muscle volume, strength, and bioenergetics during recombinant human growth hormone (GH) therapy in adults with GH deficiency. J Clin Endocrinol Metab 84:279–284[Abstract/Free Full Text]
  6. Johannsson G, Rosen T, Bosaeus I, Sjostrom L, Bengtsson BA 1996 Two years of growth hormone (GH) treatment increases bone mineral content and density in hypopituitary patients with adult-onset GH deficiency. J Clin Endocrinol Metab 81:2865–2873[Abstract]
  7. Kann P, Piepkorn B, Schehler B, Andreas J, Lotz J, Prellwitz W, Beyer J 1998 Effect of long-term treatment with GH on bone metabolism, bone mineral density and bone elasticity in GH-deficient adults. Clin Endocrinol (Oxf) 48:561–568[CrossRef][Medline]
  8. Kaufman JM, Taelman P, Vermeulen A, Vandeweghe M 1992 Bone mineral status in growth hormone-deficient males with isolated and multiple pituitary deficiencies of childhood onset. J Clin Endocrinol Metab 74:118–123[Abstract]
  9. Valimaki MJ, Salmela PI, Salmi J, Viikari J, Kataja M, Turunen H, Soppi E 1999 Effects of 42 months of GH treatment on bone mineral density and bone turnover in GH-deficient adults. Eur J Endocrinol 140:545–554[Abstract]
  10. Rutherford OM, Jones DA, Round JM, Preece MA 1989 Changes in skeletal muscle after discontinuation of growth hormone treatment in young adults with hypopituitarism. Acta Paediatr Scand 356(Suppl):61–63
  11. Tanner JM, Whitehouse RH 1967 The effect of human growth hormone on subcutaneous fat thickness in hyposomatotrophic and panhypopituitary dwarfs. J Endocrinol 39:263–275[Medline]
  12. Baroncelli GI, Bertelloni S, Ceccarelli C, Cupelli D, Saggese G 2000 Dynamics of bone turnover in children with GH deficiency treated with GH until final height. Eur J Endocrinol 142:549–556[Abstract]
  13. Fujimoto S, Kubo T, Tanaka H, Miura M, Seino Y 1995 Urinary pyridinoline and deoxypyridinoline in healthy children and in children with growth hormone deficiency. J Clin Endocrinol Metab 80:1922–1928[Abstract]
  14. Hansen TB, Brixen K, Vahl N, Jørgensen JOL, Christiansen JS, Mosekilde L, Hagen C 1996 Effects of 12 months of growth hormone (GH) treatment on calciotropic hormones, calcium homeostasis, and bone metabolism in adults with acquired GH deficiency: a double blind, randomized, placebo-controlled study. J Clin Endocrinol Metab 81:3352–3359[Abstract]
  15. Rodriguez-Arnao J, James I, Jabbar A, Trainer PJ, Perrett D, Besser GM, Ross RJM 1998 Serum collagen crosslinks as markers of bone turn-over during GH replacement therapy in growth hormone deficient adults. Clin Endocrinol (Oxf) 48:455–462[CrossRef][Medline]
  16. Stracke H, Schulz A, Moeller D, Rossol S, Schatz H 1984 Effect of growth hormone on osteoblasts and demonstration of somatomedin-C/IGF I in bone organ culture. Acta Endocrinol (Copenh) 107:16–24[Medline]
  17. Schönau E 1998 Problems of bone analysis in childhood and adolescence. Pediatr Nephrol 12:420–429[CrossRef][Medline]
  18. Schönau E, Neu CM, Rauch F, Manz F 2001 The development of bone strength at the proximal radius during childhood and adolescence. J Clin Endocrinol Metab 86:613–618[Abstract/Free Full Text]
  19. Ranke MB, Schweizer R, Elmlinger MW, Weber K, Binder G, Schwarze CP, Wollmann HA 2000 Significance of basal IGF-I, IGFBP-3 and IGFBP-2 measurements in the diagnostics of short stature in children. Horm Res 54:60–68[CrossRef][Medline]
  20. Neu CM, Rauch F, Manz F, Schönau E 2002 Modeling of cross-sectional bone size, mass and geometry at the proximal radius: a study of normal bone development using peripheral quantitative computed tomography. Osteoporos Int 12:538–547
  21. Elmlinger M, Gässler N, Weber M 1999 Detection of free deoxypyridinoline (DPD) in urines of healthy individuals and patients with osteoporosis and osteogenesis imperfecta by an automated chemiluminescence immunoassay. Clin Lab 45:423–428
  22. Schönau E, Rauch F 1997 Markers of bone and collagen metabolism-problems and perspectives in paediatrics. Horm Res 48(Suppl 5):50–59
  23. Lockitch G, Halstead AC, Albersheim S, MacCallum C, Quigley G 1988 Age- and sex-specific pediatric reference intervals for biochemistry analytes as measured with the Ektachem-700 analyzer. Clin Chem 34:1622–1625[Abstract/Free Full Text]
  24. Bianda T, Glatz Y, Bouillon R, Froesch ER, Schmid C 1998 Effects of short-term insulin-like growth factor-I (IGF-I) or growth hormone (GH) treatment on bone metabolism and on production of 1,25-dihydroxycholecalciferol in GH-deficient adults. J Clin Endocrinol Metab 83:81–87[Abstract/Free Full Text]
  25. Langdahl BL, Kassem M, Moller MK, Eriksen EF 1998 The effects of IGF-I and IGF-II on proliferation and differentiation of human osteoblasts and interactions with growth hormone. Eur J Clin Invest 28:176–183[CrossRef][Medline]
  26. Laron Z, Klinger B 2000 Comparison of the growth-promoting effects of insulin-like growth factor I and growth hormone in the early years of life. Acta Paediatr 89:38–41[CrossRef][Medline]
  27. Homminga J, Weinans H, Gowin W, Felsenberg D, Huiskes R 2001 Osteoporosis changes the amount of vertebral trabecular bone at risk of fracture but not the vertebral load distribution. Spine 26:1555–1561[CrossRef][Medline]
  28. Lin JC, Grampp S, Link T, Kothari M, Newitt DC, Felsenberg D, Majumdar S 1999 Fractal analysis of proximal femur radiographs: correlation with biomechanical properties and bone mineral density. Osteoporos Int 9:516–524[Medline]
  29. Wüster C 2000 Fracture rates in patients with growth hormone deficiency. Horm Res 54(Suppl 1):31–35
  30. Bex M, Abs R, Maiter D, Beckers A, Lamberigts G, Bouillon R 2002 The effects of growth hormone replacement therapy on bone metabolism in adult-onset growth hormone deficiency: a 2-year open randomized controlled multicenter trial. J Bone Miner Res 17:1081–1094[CrossRef][Medline]
  31. Clayton PE, Cowell CT 2000 Safety issues in children and adolescents during growth hormone therapy: a review. Growth Horm IGF Res 10:306–317[CrossRef][Medline]
  32. Maneatis T, Baptista J, Connelly K, Blethen S 2000 Growth hormone safety update from the National Cooperative Growth Study. J Pediatr Endocrinol Metab 13(Suppl 2):1035–1044
  33. Schönau E, Neu CM, Mokov G, Wassmer G, Manz F 2000 Influence of puberty on muscle area and cortical bone area of the forearm in boys and girls. J Clin Endocrinol Metab 85:1095–1098[Abstract/Free Full Text]
  34. Greulich WW, Pyle SI 1959 Radiographic atlas of skeletal development of the hand and wrist. 2nd ed. Stanford, CA: Stanford University Press



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