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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 2 370-373
Copyright © 1998 by The Endocrine Society

Original Studies

Bone Mineral Density and Body Composition before and during Treatment with Gonadotropin-Releasing Hormone Agonist in Children with Central Precocious and Early Puberty1

Annemieke M. Boot, Sabine M. P. F. de Muinck Keizer-Schrama, Huibert A. P. Pols, Eric P. Krenning and Stenvert L. S. Drop

Department of Pediatrics, Division of Endocrinology, Sophia Children’s Hospital; and Department of Internal Medicine and Department of Nuclear Medicine, Dijkzigt Hospital, Erasmus University, 3015 GJ Rotterdam, The Netherlands

Address all correspondence and requests for reprints to: A. M. Boot, Division of Endocrinology, Sophia Children’s Hospital, dr Molewaterplein 60, 3015 GJ Rotterdam, The Netherlands. E-mail: boot{at}alkg.azr.nl


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Major changes in bone mineral density (BMD) and body composition occur during puberty. In the present longitudinal study, we evaluated BMD and calculated volumetric BMD [bone mineral apparent density (BMAD)], bone metabolism, and body composition of children (32 girls and 2 boys) with central precocious and early puberty before and during treatment with GnRH agonist (GnRH). Patients were studied at baseline and during treatment for 6 months (n = 34), 1 yr (n = 33), and 2 yr (n = 16). Lumbar spine and total body BMD and body composition were measured with dual-energy x-ray absorptiometry. The variables were compared with age- and sex-matched reference values of the same population and expressed as SD score (SDS). Bone age was assessed. Serum calcium, phosphate, alkaline phosphatase, osteocalcin, the carboxyterminal propeptide of type I collagen (PICP), cross-linked telopeptide of collagen I (ICTP), 1,25 dihydroxyvitamin D and urinary hydroxyproline/creatinine, and calcium/creatinine ratios were measured.

Mean lumbar spine BMD SDS was significantly higher than zero at baseline (P < 0.02) and did not differ from normal, after 2 yr of treatment. Mean spinal BMAD SDS and total body BMD SDS were not significantly different from zero at baseline and had not changed significantly after 2 yr of treatment. During therapy, fat mass and percentage body fat SDS increased, whereas lean tissue mass SDS decreased. Mean lumbar spine BMD and BMAD and total body BMD SDS, calculated for bone age, were all lower than zero at baseline (BMD P < 0.001 and BMAD P < 0.05) and also after 2 yr treatment (respectively, P < 0.001, P < 0.05, and P < 0.01). Biochemical bone parameters were significantly higher than prepubertal values at baseline, and they decreased during treatment. In conclusion, patients with central precocious and early puberty had normal BMD for chronological age but low BMD for bone age, after 2 yr of treatment with GnRH. Bone turnover decreased during treatment. Changes in body composition resembled those seen in patients with GH deficiency.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
DURING puberty, bone mineral density (BMD) and height increase, and body composition changes markedly (1, 2, 3, 4). In central precocious puberty, the hythalamus-pituitary-gonadal axis is activated before the age of 8 yr in girls and before the age of 9 yr in boys. Precocious puberty is associated with premature and rapid skeletal maturation, leading to decreased final height, compared with target height, in most patients (5, 6). GnRH agonist (GnRH) can be supplied to arrest pubertal development to improve final height and avoid psychosocial problems (7, 8, 9). In children with central early puberty, final adult height may be slightly improved with GnRH treatment (9). In the present study, both children with central precocious puberty and children with central early puberty who started treatment with GnRH were included. Treatment with GnRH causes a decline in gonadal sex steroids, which may affect BMD, bone metabolism, and body composition. Some studies in children with central precocious puberty showed a decrease of BMD after 6 and 12 months of treatment with GnRH (10, 11); another study reported no change during treatment (12). In women with endometriosis and in elderly men with benign prostatic hyperplasia, BMD decreased, and biochemical markers of bone turnover increased during treatment with GnRH (13, 14).

The aim of the present study was to investigate BMD, bone metabolism, and body composition of children with central precocious or early puberty (CPP) before and during treatment with GnRH.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patients

At diagnosis all patients had a history of increased growth velocity, girls had breast development Tanner stage 2 or more and boys genital development Tanner stage 2 or more and testis volume 4 mL or more, bone age was advanced more than 1 yr beyond chronological age, and a GnRH-stimulated serum LH concentration greater than 10 IU/L. Thirty-four patients participated in the study. Twenty-three girls and 2 boys had true idiopathic central precocious puberty. Seven girls had idiopathic central early puberty: in 3 girls the appearance of pubertal signs started before the age of 9 yr and in 4 girls before the age of 10 yr. Two girls had organic CPP: one had a meningomyelocele and the other a hydrocephalus with a start of puberty before the age of respectively 9 and 8 yr. Median age at start of treatment was 8.7 yr (range 2.8 to 10.8). All patients received therapy with depot leuprolide-acetate 3.75 mg (Lucrin depot, Abbott, Amsterdam, The Netherlands) given subcutaneously every 4 weeks. During the first month it was given every 2 weeks. Puberty suppression was evaluated by clinical evaluation, repeating GnRH stimulation test after 3 months, by measuring basal serum levels of LH, follicle stimulating hormone and estradiol/testosterone every 6 months, and bone age assessment. All children had complete suppression of plasma concentrations of LH and follicle stimulating hormone during the GnRH test after 3 months of treatment (levels below 5 IU/L). During treatment with GnRH all children except one girl had basal sex steroids concentrations equal or less than prepubertal levels (estradiol below 50 pmol/L, testosterone below 1 nmol/L). In the girl with incomplete suppression the dose of leuprolide-acetate was doubled. In the first year the mean ratio of the change of bone age and change of chronological age was 0.72 and in the second year, 0.47.

Thirty-four patients had baseline and half-year measurements, 33 of them had 1-yr measurements and 16 children (15 girls and 1 boy) had 2-yr follow-up. One girl stopped treatment after 6 months, and one stopped after 1 yr. The other children are still included in this ongoing study. No BMD SD for chronological age could be calculated for 1 girl, 2.8 yr old, because our reference data start from the age of 4 yr. Her data could be used in the evaluation of BMD SD calculated for bone age.

Methods

Anthropometry, BMD, and body composition measurements and assessment of biochemical bone parameters were performed at baseline and during GnRH treatment for 6 months, 1 yr, and 2 yr. Height was measured with a Harpenden stadiometer (Holtain Ltd., Crymmyth, UK). Height was compared with age- and sex-matched reference values (15) and expressed as SD score (SDS). Body mass index was calculated as weight/(height)2 (kg/m2) and compared with age- and sex-matched reference values (16) and expressed as SDS. Pubertal development was determined according to Tanner (17).

BMD (g/cm2) of the lumbar spine and total body was measured by dual-energy x-ray absorptiometry (DXA) (Lunar, DPXL/PED, Lunar Radiation Corporation, Madison, WI). The coefficient of variation has been reported as 1.04% for lumbar spine and 0.64% for total body (18). The coefficient of variation (SD) for lumbar spine in our setting is 1.1 (0.2)%. Ancillary DXA-derived data were used to calculate lumbar spine volumetric BMD [bone mineral apparent density (BMAD)] with the model BMAD = BMD x [4/({pi} x width)], as validated before (19). BMD and BMAD results were compared with our age- and sex-matched Dutch reference values (2) and expressed as SDS. With the total body measurement by DXA, the body composition was measured as lean tissue mass, fat mass, and bone mineral content. The coefficients of variation have been reported as 2.2% for fat mass, 1.1% for lean tissue mass, and 0.6% for bone mineral content (18). Bone mineral content, lean tissue mass, fat mass, and percentage body fat were compared with our age- and sex-matched Dutch reference values and expressed as SDS (3).

Bone age was assessed by one investigator using an x-ray of the left hand, according to the Greulich and Pyle method (20), at baseline in 34 patients, after 6 months in 21 patients, after 1 yr in 32 patients, and after 2 yr in 16 patients.

Blood samples were taken for the assessment of calcium, phosphate, alkaline phosphatase, 1,25 dihydroxyvitamin D, osteocalcin, the carboxyterminal propeptide of type I collagen (PICP), and cross-linked telopeptide of collagen I (ICTP) in the afternoon (between 1330 h and 1600 h). Samples were not collected on 2 patients at baseline and 2 other patients at 1 yr. Osteocalcin was measured by RIA (Incstar Corporation, Stillwater, ), and 1,25 dihydroxyvitamin D was measured by RIA of Immuno Diagnostic Systems (Boldon, United Kingdom). PICP and ICTP were measured with an RIA kit (Orion Diagnostica, Espoo, Finland). Our own reference values for prepubertal healthy children for osteocalcin, PICP, and ICTP (respectively n = 25, n = 82, and n = 88) were used. In the first morning void of urine, the ratio of hydroxyproline/creatinine (OHP/creat) and the ratio of calcium/creatinine (CA/creat) were evaluated. Reference values of Wolthers et al. (21) were used for OHP/creat. LH and FSH were assessed by RIA (Medgenix, Fleurus, Belgium), and estradiol and testosterone were assessed by RIA of Orion Diagnostica.

Statistical analysis

One-sample t tests were performed to compare the mean SDS values with normal. We tested to determine whether the average within-patient change differed from zero (with one-sample t test). Pearson correlation coefficient was calculated to test the association between two variables with a normal distribution. Spearman’s rank correlation coefficient was used, in case of a nonnormal distribution.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The results of BMD, BMAD, body composition, height, and body mass index measurements, before and during GnRH treatment, are shown in Table 1Go.


View this table:
[in this window]
[in a new window]
  		Table 1. Mean (SD) of variables at baseline and during treatment with GnRH (Rx) in children with CPP

 
At baseline, mean lumbar spine BMD SDS was significantly higher than zero, which is the mean SDS of age-and sex-matched healthy controls. Lumbar spine BMD SDS increased during the first 6 months of therapy and decreased between 6 months and 1 yr of treatment (P < 0.01). After 2 yr, lumbar spine BMD SDS was not significantly different from normal. Mean lumbar spine BMAD SDS and total body BMD SDS were not significantly different from normal at baseline. Lumbar spine BMAD SDS showed a transient increase after 6 months of treatment. Total body BMD SDS remained stable during treatment.

Mean total body bone mineral content SDS, lean tissue mass SDS, fat mass SDS, and percentage body fat SDS were significantly higher than zero at baseline. Total body bone mineral content SDS had increased after 6 months and 1 yr of treatment, compared with baseline. Lean tissue mass SDS decreased significantly during treatment, whereas fat mass SDS and percentage body fat SDS increased.

Mean height SDS and body mass index SDS were higher than zero at baseline. Mean height SDS had decreased after 2 yr of treatment. Body mass index SDS increased during treatment.

The two boys did not have lumbar spine BMD SDS higher than zero at baseline. During treatment, all the variables showed the same pattern as that seen in the girls.

When SDS was calculated for bone age instead of chronological age (SDSBA), mean lumbar spine BMD SDSBA was -0.82 (SD 0.91), mean BMAD SDSBA was -0.46 (SD 1.11), and mean total body BMD SDSBA was -1.07 (SD 1.05) at baseline, all significantly lower than zero (lumbar spine and total body BMD P < 0.001, BMAD P < 0.05). Mean lumbar spine BMD and BMAD SDSBA and total body BMD SDSBA, after 2 yr of treatment, were still significantly lower than zero (lumbar spine BMD P < 0.001, total body BMD P < 0.01, BMAD P < 0.05) and did not differ significantly from baseline.

The results of biochemical markers of bone metabolism are shown in Table 2Go. Mean osteocalcin, PICP, and ICTP at baseline were significantly higher than those of prepubertal controls (all P < 0.001). These values and alkaline phosphatase had decreased after 6 months. Mean PICP and ICTP at 6 months and osteocalcin at 12 months were not significantly different from those of prepubertal controls. Urine CA/creat had increased after 6 months, and OHP/creat had diminished after 1 yr. Serum calcium and phosphate were normal at baseline and did not change significantly during time.


View this table:
[in this window]
[in a new window]
  		Table 2. Mean (SD) of biochemical parameters at baseline and during GnRH (Rx) in children with CPP

 
At baseline, lumbar spine BMD SDS correlated with lean tissue mass SDS (r = 0.46, P < 0.01) and body mass index SDS (r = 0.46, P < 0.01). Total body BMD SDS correlated with fat mass SDS (r = 0.44, P < 0.02), percentage body fat SDS (r = 0.37, P < 0.02), and body mass index SDS (r = 0.42, P < 0.02). Height SDS, Tanner stage, or biochemical bone parameters were not related to lumbar spine BMD or BMAD or total body BMD SDS. Height SDS correlated with lean tissue mass SDS (r = 0.76, P < 0.001) and total body bone mineral content SDS (r = 0.58, P < 0.001).

The change between baseline and 2-yr treatment of height SDS correlated with the change in lumbar spine BMD SDS (r = 0.57, P < 0.05), the change in lean tissue mass SDS (r = 0.77, P < 0.001), and the change in bone mineral content SDS (r = 0.69, P < 0.01), and not with the change in total body BMD SDS or lumbar spine BMAD SDS. The change in levels of biochemical markers of bone turnover did not correlate with the change of BMD or BMAD SDS or height SDS.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In children with CPP, mean lumbar spine BMD was high, and spinal BMAD and total body BMD were normal for chronological age. After 2 yr of treatment with GnRH, mean lumbar spine BMD and BMAD and total body BMD were normal. Lumbar spine BMD and BMAD and total body BMD for bone age were low, before and after 2 yr of treatment with GnRH. During treatment, fat mass and percentage body fat SDS increased, whereas lean tissue mass SDS decreased. Biochemical markers of bone formation and of bone resorption decreased.

Previous studies reported increased lumbar spine (measured with DXA) or radius (measured with single photon absorptiometry) BMD for chronological age, but appropriate for bone age in girls with CPP (10, 11, 12). The higher spinal BMD at baseline is in agreement with our findings, but we found decreased BMD for bone age. The discrepancy may be caused by differences in reference values, differences in assessment of bone age, or differences in timing of start of treatment. In the present study, reference values of a large cohort of healthy children, of the same population and measured on the same DXA apparatus, were used.

Mean spinal BMAD (corrected for estimated bone volume) was not increased. BMD is an areal density and does not adjust for bone size completely. Therefore, the high spinal BMD could be caused by an increase of bone size.

During puberty, estrogens and GH play an important role in bone mineralization and bone metabolism in girls. In early puberty, low levels of estradiol stimulate growth and GH production. A significant increase of GH is seen during early puberty, with maximal levels at stage III in girls (22). Bone modeling of new bone and bone remodeling of existing mineralized tissue are each ongoing processes in growing children. The biochemical markers are not specific for either the process of bone modeling or remodeling (23). Markers of bone metabolism are related to growth velocity and increase maximally during midpuberty (24, 25). From stage III to V (late puberty), estradiol levels increase significantly, GH levels decrease, and markers of bone formation and markers of bone resorption decrease (26). In postmenopausal women and in adults treated with GnRH, the decline of estrogens is associated with an increase of bone turnover, the opposite of what happens during late puberty (13, 14). At baseline, the patients had bone turnover comparable with that of adolescents in early puberty. Bone formation and bone resorption markers were higher than prepubertal values, probably because of the increased growth related to early puberty. The markers of bone turnover decreased to prepubertal levels during treatment. This mainly reflects a decrease in bone modeling.

Increased GH and/or estrogens levels, associated with early puberty, may have caused the increase of lumbar spine BMD at baseline in the girls. Lumbar spine consists of more trabecular bone than bone of the total body, which is for 80% cortical bone (27). Bone turnover is higher in trabecular bone (28), which may explain the differences found between lumbar spine and total body BMD. Also, in postmenopausal women, change in BMD is faster in trabecular bone than in cortical bone (29). The initial increase of lumbar spine BMD and BMAD SDS may be explained by incomplete suppression of puberty during the first months. The decrease in spinal BMD, thereafter, is probably caused by the decline of estrogens and GH. A decrease in nocturnal GH secretion and subnormal response to GH stimulation tests were described after 3–12 months treatment with GnRH in children with CPP (10, 30, 31, 32). However, no relation was found between the subnormal GH levels and growth velocity during treatment with GnRH (32). The decline of GH may explain the decrease of lean tissue mass SDS and the increase of fat mass and percentage fat SDS. GH is known to have lipolytic and anabolic effects. Children and adults with GH deficiency have decreased lean tissue mass and increased fat mass, which improve during treatment (33, 34, 35, 36).

In conclusion, children with CPP have normal BMD for chronological age but decreased BMD, for bone age, after 2 yr of treatment with GnRH. Puberty is an important period for bone accretion. In patients with CPP, pubertal development is temporarily inhibited by GnRH. It is unknown whether BMD increases normally after cessation of GnRH and whether the patients reach a normal peak bone mass. Long-term longitudinal studies, till peak bone mass is achieved, are needed to evaluate BMD and body composition after cessation of treatment.


   Acknowledgments
 
The authors thank Jopie Hensen, of the Department of Nuclear Medicine, for her assistance in DXA measurements; Manon van Paasen, Sophie Dumas, and Ingrid Beukers (of the out-patient department); Dick Mul, for the bone age assessments; and Melanie Engels for her assistance in data collection.


   Footnotes
 
1 This work was supported by Novo Nordisk Farma BV. Back

Received August 8, 1997.

Revised October 17, 1997.

Accepted October 27, 1997.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Is Obesity an Outcome of Gonadotropin-Releasing Hormone Agonist Administration? Analysis of Growth and Body Composition in 110 Patients with Central Precocious Puberty
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Long-Term Outcome after Depot Gonadotropin-Releasing Hormone Agonist Treatment of Central Precocious Puberty: Final Height, Body Proportions, Body Composition, Bone Mineral Density, and Reproductive Function
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