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Division of Pediatric Endocrinology, University Children’s Hospital (S.B., W.B., R.D.P., H.P.S.), Munich, Germany; and Children’s Rheumatology Clinic (P.R., R.H.), Garmisch-Partenkirchen, Germany
Address all correspondence and requests for reprints to: Dr. Susanne Bechtold, University Children’s Hospital, Lindwurmstrasse 4, D-80337 Munich, Germany. E-mail: susanne.bechtold{at}med.uni-muenchen.de.
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Abstract |
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Introduction |
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Studies of recombinant human GH treatment in patients with JIA showed, in addition to an increase in height, a positive effect of GH on bone metabolism and body composition (6, 7). Over a period of 4 yr we demonstrated that GH treatment increases growth velocity and height in JIA patients (8) as well as height-corrected bone mineral density (BMD), measured by dual energy x-ray absorptiometry (9).
The aim of the present study was to investigate the influence of GH on bone mass, density, geometry, bone strength, and the muscle-bone relation at the radius; as well as body composition determined by forearm muscle and fat size in a group of patients with JIA compared with those in an untreated control group of JIA patients.
Interpretation of bone density measurements is incomplete without taking account of the interrelationship with muscle mass. Some insight into the muscle-bone relationship can be gained by performing peripheral quantitative computed tomography (pQCT) analyses. In a single measurement run, both muscle cross-sectional area (CSA) and bone mass and geometry can be assessed. Cortical area is the main parameter to evaluate the muscle-bone relationship, which is affected by puberty (10).
We have used pQCT technique, which is not influenced by size-related artifacts, and have studied the muscle-bone relationship and body composition.
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Subjects and Methods |
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The study population comprised 34 Caucasian children and adolescents with polyarticular or systemic JIA according to the International League of Associations for Rheumatology criteria (11). Mean age was 15.3 ± 2.5 yr, and mean disease duration was 8.2 ± 4.4 yr. All patients had a delay of pubertal development; the mean Tanner stage was 2.8 ± 1.2 (12). Seventeen patients (nine males and eight females) were treated with GH over a mean period of 3.8 ± 1.1 yr and were part of a controlled study of the efficacy and safety of GH (8, 13). They were compared with 17 age- and sex-matched patients (seven males and 10 females) of a cross-sectional study of pQCT in JIA patients, who had never been treated with GH. All patients had been and still were, apart from two patients (one in each group), receiving treatment with GC when the pQCT measurement took place. Anthropometric data were compared with the longitudinal growth data of the Swiss longitudinal growth study (14). The pQCT results were compared with those in a German reference population using identical methodology. The reference population consisted of participants in the Dortmund Nutritional and Anthropometric Longitudinally Designed study, an observational study investigating the interrelations of nutrition, growth, and metabolism in healthy children. The results in this reference population have been described previously (15, 16).
Height was measured in a standing position to the next 1 mm using a digital, telescopic, wall-mounted stadiometer (Prof. E. Heinze, Ulmer Stadiometer, Ulm, Germany). Weight was determined to the nearest of 0.1 kg using an electronic scale (Seca 753 E, Vogel and Hanke, Hamburg, Germany) with the children clothed in underwear. The stage of sexual development was determined in all study participants by the same experienced endocrinologist using the grading system of Tanner for breast development in girls and genital status in boys (12). Age at testing was calculated to two decimals. Forearm length was measured at the nondominant forearm as the distance between the ulnar styloid process and the olecranon, using a caliper. Functional status of the joints as an indirect activity score of the overall disease course was determined by an experienced pediatric rheumatologist, using stages 1–4 following the functional Steinbrocker criteria (17). Patients received daily sc GH in a dose of 0.036–0.047 mg/kg body weight. GH was supplied by Pfizer (Karlsruhe, Germany). The study protocol was approved by the university’s ethics committee, and informed consent was obtained from all patients and/or their parents.
pQCT
Two sites of the nondominant radius were analyzed by pQCT, the distal metaphysis (4% site) and the proximal diaphysis (65% site), as described previously (15, 16, 18). An XCT scanner (Stratec, Inc., Pforzheim, Germany), equipped with a low energy (38 keV) x-ray tube, was used. The effective radiation dose is about 0.1 µSv from a radiation source of 45 kV at 150 µA. For the measurement, the scanner was positioned on the distal forearm, and a scout view was made to position the scanner at the site on the radius at which the distance to the radial articular surface corresponded to 4% and 65% of the forearm length. The diaphyseal site of measurement was chosen to analyze the forearm at its maximum circumference. At both sites, a 2-mm-thick single tomographic slice was sampled at a voxel size of 0.4 mm. Image processing and calculation of numerical values were performed using the manufacturer’s software package (version 5.40, Stratec, Inc.).
For analysis of the distal radius, the outer contour was detected using a threshold of 280 mg/cm3. The CSA, bone mineral content (BMC), and total and trabecular BMD were calculated using the manufacturer’s software (Stratec, Inc.). BMC represents the mass of mineral per millimeter slice thickness. Total BMD is defined as the mean mineral density of the total CSA. Using the equipment default settings, trabecular BMD was determined as the mean BMD of the 45% core area of the bone’s cross-section. To assess the bone strength strain index (SSI), a threshold of 480 mg/cm3 was used. It is calculated as a product of section modulus and cortical density normalized to the maximal physiological cortical density of human bones (18, 19).
At the diaphyseal site, detecting the outer and inner cortical bone contours at a threshold of 710 mg/cm3 determined the total CSA of the radius and the cortical CSA. Voxels peripheral of the bone’s outer edges with an absorptiometric density between 20 and 80 mg/cm3 were interpreted as representing muscle, and less than 20 mg/cm3 were interpreted as representing fat mass. Relative fat mass was defined as the percentage of fat CSA to total forearm CSA. Total CSA, cortical CSA, total BMC, total and cortical BMD, and muscle CSA were calculated using the manufacturer’s software (Stratec, Inc.). Cortical thickness and relative cortical CSA, the percentage of cortical CSA to total CSA, were derived from these primary measures (16) (Fig. 1
). Calibration of the machine was performed every other day (single slice) or once a month (multiple slices), with phantoms provided by the manufacturer.
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Results in JIA patients were converted into sex-, age-, and height-specific SD scores using the formula: SD score = [(test result for a patient) – (age- or height-specific mean in reference population)]/(age- or height-specific SD in reference population).
To evaluate whether a parameter was significantly different from the results of an age-matched healthy population, the difference of the mean SD score from zero was assessed. A significant difference was assumed when the 95% confidence interval of the mean SD score did not include zero. For the difference between the two investigated groups, the nonparametric Mann-Whitney test was used. Throughout, a value of P < 0.05 (two-sided) was defined as significant. Pearson’s product-moment correlation was used to determine r values. To evaluate the effect of covariance, we used a general univariate linear regression analysis. All statistical analyses were performed using the SPSS software package (version 11.5 for Windows, SPSS, Inc., Chicago, IL).
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Results |
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. Most of the patients had entered puberty at the time of pQCT measurements. Four patients in the GH-treated group and three patients in the control group were prepubertal. Eight patients in the GH-treated group and six in the control group were at Tanner stage 4; the remaining patients were at Tanner stages 2 (6) and 3 (7). All patients showed a delay of pubertal development. The Steinbrocker functional classification (17) correlated significantly with the present GC dose (r = 0.5; P < 0.05).
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There were more female patients (n = 10 vs. 8) in the control group. After correction for sex, there was no significant influence of the sex imbalance between the groups on bone and muscle parameters (P > 0.05). The GC dose correlated significantly (P < 0.01) with total diaphyseal BMD (r = –0.45), cortical thickness (r = –0.5), and the ratio of cortical CSA to muscle CSA (r = –0.5).
Bone parameters of the metaphyseal and diaphyseal sites are shown in Table 2.
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The total CSA of the radius was lower in both groups compared with that in a healthy control population (P < 0.01); however, there was a significant difference between the JIA groups, with higher total CSA in the GH-treated group (P < 0.05). Because BMC is influenced by bone size and total BMD, it is not surprising that this parameter is also significantly higher in the GH-treated group. There was no significant difference between the JIA groups with regard to total and trabecular BMD, but both parameters were significantly reduced compared with those in a healthy reference population. The consequence was a lower SSI (P < 0.01) compared with the reference population. There was a mild, but significant, correlation of total and trabecular BMD with the duration of illness (r = –0.4; P < 0.05).
pQCT at the radial diaphysis (65% site)
Similar to the metaphyseal site, total CSA and BMC were lower in both JIA groups (P < 0.01). However, total CSA, cortical CSA, and BMC were significantly higher in the GH-treated group compared with the JIA control group. In a subanalysis for Tanner stages, only in patients with Tanner stage 4 was there a significant difference between GH-treated and control JIA patients with regard to diaphyseal total, cortical, and muscle CSA (P < 0.05). In an additional separation of patient groups due to sex and Tanner stages, no significant difference could be found between GH-treated and untreated patients. There was also no significant difference between the JIA groups with regard to total BMD, cortical BMD, cortical thickness, and relative cortical CSA. All of these parameters were significantly lower compared with those in the reference population. Muscle CSA was 1.5 times higher in the GH-treated group compared with the untreated control group (P < 0.01) and correlated positively with the duration of GH treatment (r = 0.5; P < 0.01). Muscle CSA correlated significantly (P < 0.01) with metaphyseal BMC (r = 0.8), total BMD (r = 0.5), and trabecular BMD (r = 0.6) as well as with diaphyseal total CSA (r = 0.8), cortical CSA (r = 0.8), cortical thickness (r = 0.6), and BMC (r = 0.7). As a consequence of having a body composition of higher muscle mass, fat CSA at the proximal radius was also lower in the GH-treated group than in the untreated control group, but the difference was not significant. However, relative fat mass, the percentage of fat CSA of the total forearm CSA, was significantly different (P < 0.05); GH-treated patients had a relative fat mass of 20.8 ± 12%, whereas patients in the control group had a relative fat mass of 30.1 ± 15%.
Height-corrected normative data of pQCT (Table 3)
Because patients with severe forms of rheumatic disease are compromised in height, CSA has to be corrected for body size. In the JIA control group, there was a significantly lower metaphyseal total CSA, diaphyseal total and cortical CSA, and muscle CSA compared with those in a healthy reference population. In the GH-treated group, these parameters were not significantly lower compared with the reference population. The difference between the JIA groups was significant for diaphyseal total, medullary, cortical, and muscle CSA (P < 0.05). Separating the sexes, there was a significant difference between groups for height-corrected cortical and muscle areas only in male patients. Height-corrected cortical CSA SD score and muscle CSA SD score between male patients with and without GH treatment were 0.7 ± 1.8 vs. –1.1 ± 2.1 and 1.0 ± 1.3 vs. –0.9 ± 0.9 (P < 0.05), respectively. There was no such difference in female patients.
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Muscle CSA for a given cortical CSA was higher in the GH-treated JIA patients than in the control JIA patients (Fig. 3). Twelve GH-treated patients had a muscle CSA for a given cortical CSA above the regression line, and five GH-treated patients had a muscle CSA for a given cortical CSA below the regression line, whereas in the control JIA patients, six had values above and 11 had values below the regression line. From a functional point of view, a ratio of cortical CSA to muscle CSA has to be built. Cortical CSA per muscle CSA was significantly lower in all JIA patients in relation to that in a healthy reference population (P < 0.01), but there was no significant difference between the two JIA groups. The ratio of cortical CSA to muscle CSA was significantly (P < 0.01) influenced by the GC dose (r = –0.5).
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Discussion |
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The observation of increased bone strength and bone mass in gigantism and acromegaly raises the expectation that GH treatment might help, besides increasing statural height, to cure or prevent osteoporosis (24, 25). In a longitudinal study we showed a mild, but significant, increase in volumetric BMD, measured by dual energy x-ray absorptiometry over 4 yr in GH-treated JIA patients (9). In a study by Simon et al. (26) of GH treatment in JIA patients, a significant increase in BMD was seen during 3 yr of GH treatment. The researchers speculated that GH treatment might restore normal peak bone mass during puberty. In a more experimental approach, Sanchez et al. (27) demonstrated, by iliac crest biopsies, that GH treatment for 1 yr increased osteoblastic activity, bone formation, and bone turnover despite ongoing long-term GC treatment.
Comparing the results of the pQCT measurement of the GH treated and the control JIA group several important observations were made. Metaphyseal and diaphyseal total CSA values were significantly greater in the GH-treated group. As a consequence, the bone strength parameter, BMC, was also significantly greater. Another parameter of bone strength, the SSI, which combines architectural and material components of bone stability (18), was also greater in the GH-treated group than in the control group, but not significantly. Because cortical CSA is greater in the GH-treated group, but relative cortical CSA and cortical thickness were not different between the JIA patients, a greater expansion of the medullary cavity with periosteal bone apposition must have occurred. The consequence of this cortical drift, the greater bone diameter by periosteal cortical bone apposition and endosteal bone resorption, is again a greater bone stability (18, 28). Subdividing the groups according to Tanner stage, only in late puberty was the difference between the groups for cortical and muscle area significant. There might be a potentially beneficial effect of GH treatment in this developmental period (29). Using height-corrected reference data in male patients receiving GH treatment, cortical and muscle CSA were significantly higher than those in untreated JIA patients. In female patients, there was only a tendency for higher cortical and muscle CSA in patients with JIA who were receiving GH treatment. This greater effect of GH on cortical and muscle CSA in male patients could be due to an additional effect of testosterone. Overall, after correction for height, only patients with JIA and GH therapy showed normal values for total, cortical, and muscle CSA compared with a reference population.
Total, trabecular, and cortical BMD were not different in the two groups, but were significantly lower compared with those in a healthy reference population. As expected, influencing factors for total and trabecular BMD were the duration of illness and the GC dose. However, in a study by Häkkinen et al. (30) in adult patients with rheumatoid arthritis, the bone loss due to active disease was noted before GC therapy was initiated, putting more emphasis on the disease activity than on the often necessary GC therapy.
The largest bone loads come from muscle force, so the amount of physical activity in which a child is engaged is an important predictor of bone mass and strength (31). Consequently, chronically reduced muscle forces result in disuse osteopenia. GH and growth factors help to increase muscle strength (32). Increased muscle strength increases the thickness of tendons and fascia and the bone strength. However, this process is much slower than the increase in muscle size (25). We could show a dramatic difference in muscle CSA in the GH-treated group (1.5 times) compared with the untreated control JIA group. Muscle size was negatively affected by the necessary GC dose. The larger the muscle CSA, the higher the total and trabecular BMD and the higher the total and cortical CSA, resulting in a higher BMC. Unfortunately, we could not evaluate the dynamic muscle force by grip strength, because most of our patients had severe involvement of their joints. Cortical CSA for muscle CSA, a functional index of the muscle-bone unit, was not different between groups. However, compared with the reference population, the index was significantly reduced in both groups. A primary bone problem might be present.
Alterations in body composition have been described in patients with rheumatoid arthritis. Lean mass is decreased, whereas fat mass is increased (33). During 1 yr of GH treatment, Touati et al. (6) demonstrated a reduction in fat mass and an increase in lean mass. After discontinuation of GH treatment, this effect was reversible. In a recent study by Simon et al. (26), lean mass, measured by total body dual x-ray absorptiometry, steadily increased. In our GH-treated patients, there was a significantly higher lean or muscle mass compared with that in the control group. Additionally, the relative fat mass was significantly lower. A similar effect was observed in kidney transplant recipients (34).
In conclusion, this study showed greater muscle size and total and cortical CSA as well as lower relative fat mass after GH therapy in children with JIA receiving long-term GC compared with an age- and sex-matched control JIA group. These effects are compatible with an anabolic effect of GH on bone and body composition. The periosteal apposition of cortical bone in our GH-treated patients may result from a greater muscle mass and may lead to a better bone stability. However, follow-up of patients to final height and attainment of peak bone mass is necessary to better understand the potential beneficial effect of GH treatment in JIA patients.
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Acknowledgments |
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Footnotes |
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Abbreviations: BMC, Bone mineral content; BMD, bone mineral density; CSA, cross-sectional area; GC, glucocorticoid; JIA, juvenile idiopathic arthritis; pQCT, peripheral quantitative computed tomography; SSI, strength strain index.
Received August 11, 2004.
Accepted March 7, 2005.
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, Control JIA patients; 
, JIA patients receiving GH treatment.