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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 6 1992-1996
Copyright © 1999 by The Endocrine Society

Original Studies

Prevention of Bone Demineralization by Calcium Supplementation in Precocious Puberty during Gonadotropin-Releasing Hormone Agonist Treatment

Franco Antoniazzi, Francesco Bertoldo, Silvana Lauriola, Stefania Sirpresi, Elisabetta Gasperi, Giorgio Zamboni and Luciano Tatò

Clinica Pediatrica e Istituto di Medicina Interna (F.B., E.G.), Università degli Studi di Verona, Verona, Italy

Address all correspondence and requests for reprints to: Dott. Franco Antoniazzi, Clinica Pediatrica Università di Verona, Policlinico Borgo Roma, I-37134 Verona, Italy. E-mail: francoa{at}borgoroma.univr.it


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
We have previously demonstrated a negative impact on peak bone mass in girls with precocious puberty treated with GnRH agonist (GnRHa). Several studies have shown that a high calcium intake positively influences bone mass in prepubertal girls and leads to a higher peak bone mass. The aim of this study was to evaluate the effect of calcium supplementation in girls with precocious puberty during GnRHa treatment.

Forty girls affected by true central precocious puberty and treated with the GnRHa triptorelin were studied for 2 yr. After diagnosis, the patients were randomly assigned to three groups: group A, treated only with GnRHa; group B, treated for 12 months solely with GnRHa and then supplemented with calcium gluconolactate/carbonate (1 g calcium/day in two doses) for 12 months; and group C, treated from the beginning with combined GnRHa and calcium.

Bone mineral density (BMD) at the lumbar spine was measured by dual energy x-ray absorptiometry at the beginning of the study and after 12 and 24 months and was expressed as the calculated true volumetric density (BMDv) in milligrams per cm3.

Group A showed a decrease in absolute BMDv levels, in SD score for chronological age (CA), and even more in SD score for bone age (BA). Group B showed the same behavior during the first year, but this trend was reversed in the second year, when calcium supplementation was added to GnRHa treatment. Group C showed an increase in absolute BMDv levels and in SD score for CA and BA. BMDv variations (expressed as absolute values, SD score for CA, and SD score for BA) became statistically significant at 24 months between groups C and A (P = 0.036, P = 0.032, and P = 0.025, respectively).

The behavior of the lumbar spine BMDv in the three groups is consistent with a positive effect of calcium supplementation during GnRHa treatment. In calcium-supplemented patients, the normal process of bone mass accretion at puberty is preserved despite GnRHa treatment. Therefore, the reduction in BMD during GnRHa treatment in girls with precocious puberty is at least completely reversible and preventable if calcium supplementation is associated from the beginning.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
PUBERTY is a crucial period for bone development and the achievement of peak bone mass necessary to prevent postmenopausal osteoporosis (1). Bone mineral density (BMD) increases with age, and during puberty, the age-dependent increment is higher, also depending on skeletal age (2). Sex steroids play an important role in this acquisition of bone mass (3). In precocious puberty, bone age (BA) is advanced, and there is an enhancement of the increase in BMD (4, 5). GnRH agonists (GnRHa) are the treatment of choice for central precocious puberty (CPP) (6); the treatment arrests pubertal development and improves final height (7). GnRHa suppresses gonadotropin secretion and reduces sex steroid levels; this reduction of sex steroid levels during puberty may have a detrimental effect on bone mass. We and others have demonstrated, in fact, that GnRHa treatment reduces bone density in girls with CPP who before treatment had a bone mass that was high for chronological age (CA) (4, 5). On the other hand, it has been demonstrated that calcium supplementation above the recommended dietary allowances increases bone density in children (8, 9). Consequently, precocious puberty becomes an excellent model for studying the reciprocal rapport between calcium assumption and estrogen increase and decrease.

The aim of this study was to clarify the importance of calcium supplementation on bone density in girls affected by CPP and in normal puberty as well.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Forty Caucasian (Italian) girls (age range at diagnosis, 5.1–8.4 yr) affected by true CPP took part in the study. Informed consent was obtained from the parents of each girl before starting the study protocol.

Diagnosis was based on the appearance of pubertal signs (breast and pubic hair at stage 2 or above, according to Tanner) before 8 yr of age (age range, 4.7–7.5 yr), BA more than 1 yr beyond CA, uterus longitudinal diameter (detected by ultrasonography) greater than 3.5 cm, LH and FSH responses to the GnRH stimulation test (100 µg/m2, iv bolus dose), and estradiol concentrations in the pubertal range (10). None of the patients had any evidence of progressive organic disorders of the central nervous system at computed tomography or magnetic resonance imaging, identifiable adrenal or gonadal pathology, or thyroid deficiency or had previously been treated with inhibitory steroids. Renal and hepatic functions were normal.

After diagnosis of CPP, the patients were assigned to treatment with the long acting GnRH analog triptorelin (Decapeptyl, IPSEN, Milan, Italy) at a dose of 3.75 mg, im, every 28 days (0.123 ± 0.12 mg/kg; range, 0.10–0.15 mg/kg). Patients were randomly assigned to three groups (A, B, and C) comparable for age, BA, height, and weight. The time lapse from the appearance of pubertal signs to diagnosis was 0.61 ± 0.3 yr, with no difference among the groups.

Patients in group A were treated solely with GnRHa for 24 months. Patients in group B, after 12 months of GnRHa treatment, received a supplementation of calcium gluconolactate and carbonate (1 g calcium/day divided into two doses) for 12 months. Patients in group C from the start received a combined treatment with GnRHa and calcium. The girls were instructed to continue their usual physical activity and diet (investigated by nutritional recall), thereby ensuring adequate caloric (70–80 Cal/kg·day), protein (>1 g/kg·day), calcium (>800 mg/day), and phosphate (>800 mg/day) intake during treatment. Dietary calcium intake was evaluated by a weighed food record, and exercise was evaluated by an exercise diary; compliance in assumption of calcium supplementation was checked by a diary in groups B and C. No patient received other drugs known to interfere with bone mineral metabolism, except those included in the study protocol.

The patients were seen every 3 months to record standing height (by Harpenden stadiometer) and weight and to evaluate pubertal signs (according to Tanner). The suppression of pituitary gonadotropins was checked every 6 months (on the 26th day after im GnRHa administration) by measuring serum estradiol levels and repeating the GnRH stimulation test (100 µg/m2, iv bolus dose). Clinical data regarding patients at the start of treatment and after 12 and 24 months of treatment are reported in Table 1Go.


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  		Table 1. Clinical data regarding the three groups of patients: at the start of GnRHa treatment; after 12 months of GnRHa (groups A and B) or GnRHa plus calcium (group C) treatment; and after 24 months of GnRHa (group A), 12 months of GnRHa and 12 months of GnRHa plus calcium (group B), and 24 months of GnRHa plus calcium (group C) treatment

 
BA evaluation and bone mass measurements at the lumbar spine were carried out in the three groups at the beginning and after 12 and 24 months of treatment. BA was determined blindly by the same observer according to the Greulich and Pyle method (11) and expressed in years.

BMD at the lumbar spine was measured by dual energy x-ray absorptiometry (DXA; Sophos L-XRA 3.1, Sopha Medical S.N.I., Les Ullis, France). The second, third, and fourth lumbar vertebrae were scanned by antero-posterior projection (AP-BMD). Only the third lumbar vertebra was also measured by lateral scan (L-BMD) because of possible interference with the assessment of the second and fourth lumbar vertebrae by either overlying ribs or iliac crests, respectively. The instrument, equipped with a rotating detector, enabled us to carry out both scans while the subject was in a supine position. The DXA scan in the lateral position, excluding cortical bone in the posterior elements, allows more selective measurements of the trabecular-rich vertebral body than do antero-posterior scans, increasing the sensitivity of the technique to trabecular bone modifications, similar to those induced by hormonal therapy.

AP-BMD and L-BMD were expressed in milligrams per cm2; they represent bone mineral area density and are functions of both the density and volume of bone. Thus, differences in DXA measurements in growing children may reflect increases in bone volume rather than in true density. Therefore, we calculated true volumetric BMD (BMDv), expressed in milligrams per cm3, taking the vertebral body as an ellipsoid cylinder and dividing the bone mineral content obtained by lateral scan (in milligrams) by body vertebral volume (in cubic centimeters), calculated as follows: {pi} x width/2 x depth/2 x height. Vertebral dimensions (anterior width, depth, and height) were found using software data.

The coefficient of variation (CV) for duplicate measurements in normal children (mean age, 9.0 ± 0.8 yr) at an interval of 1 week was 1.2% for AP-BMD, 1.9% for L-BMD, and 3.1% for BMDv.

The densitometric instrument was calibrated daily, and a commercial phantom (Hologic, Inc., Waltham, MA) measurement was performed daily, which excluded appreciable measurement drifts during the study

The percent variation in the measured parameters were calculated as: (measured value - initial value/initial value) x 100.

Bone densitometric data were compared with those of a normal female population of 183 subjects, aged 5–11 yr, with BA appropriate for CA, body mass index (kilograms per m2) between 15–17.5, normal intake of calcium and phosphate, and normal physical activity (Table 2Go). SD scores from the normal population of the same age were calculated as: (measured value - mean population value)/SD of the normal population.


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  		Table 2. Bone mineral density (BMD) at the lumbar spine in a control group of 183 prepubertal female subjects, divided per yr of age with BA appropriate for CA, BMI (kilograms per m2) between 15 and 17.5, normal intake of calcium and phosphate and normal physical activity

 
LH and FSH levels were determined using chemiluminescence assays (Chiron Corp., East Walpole, MA; intra- and interassay CVs, 5.0% and 6.3%, respectively, for LH and 2.8% and 4.7% for FSH); estradiol levels were measured using RIA (Sorin Biomedica, Saluggia, Italy; CV, 4.2% and 4.9%).

The results are expressed as the mean ± SD. Statistical analysis was performed using a data analysis system (StatView 4.5, Abacus Concepts, Inc., Cal) run on a Macintosh computer; the significance of changes during therapy was determined using ANOVA for repeated measures and the nonparametric Wilcoxon signed rank test. Statistical significance was set at P < 0.05.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Complete arrest of pubertal development was observed in patients during GnRHa treatment. In each patient, serum estradiol levels decreased from pubertal to prepubertal levels (<75 pmol/L), and LH and FSH responses after GnRH stimulation test were lower than 2 U/L. The growth velocity rate decreased from 8.4 ± 1.4 cm/yr before treatment to 5.7 ± 0.8 and 4.9 ± 0.9 cm/yr after 12 and 24 months of treatment, respectively (Table 1Go).

The compliance in assumption of calcium supplementation was more than 91% for group B (in the second year) and more than 89% and more than 86% in the first and second years, respectively, for group C.

There were no differences in exercise levels or in exposure to sunlight among the three groups of subjects, as reported in each patient’s food and exercise diary.

At the beginning of the study protocol, AP-BMD was significantly higher in patients (with no significant difference among the groups) compared to controls of the same CA (AP-BMD SD score for CA, +1.79 ± 1.36; P = 0.04); L-BMD and BMDv levels were higher, but not significantly, in patients (L-BMD SD score for CA, +0.33 ± 1.18; BMDv SD score for CA, +0.25 ± 0.54; P = NS) compared to those in the control group of the same CA. If compared with the control group with the same BA, AP-BMD was higher, but not significantly (AP-BMD SD score for BA, +0.91 ± 1.11; P = NS); L-BMD and BMDv in patients did not differ from those in the control group of the same BA (L-BMD SD score for BA, -0.09 ± 0.74; BMDv SD score for BA, +0.11 ± 0.43; P = NS).

After 12 months of therapy, we found a slight increase in absolute levels of AP-BMD in the three groups, whereas in L-BMD and BMDv a slight increase was found only in group C (+5.97 ± 3.23% and +3.30 ± 3.04%, respectively; P = NS). If corrected for CA, AP-BMD SD scores tended to diminish in all groups, whereas L-BMD and BMDv SD scores showed a slight decrease in groups A and B, and group C tended to have an increase. If corrected for BA, SD scores tended to diminish for all the three variables studied in groups A and B, whereas they tended to increase, although not significantly, in Group C.

From 12–24 months, group A showed a decrease in absolute densitometric levels of AP-BMD, L-BMD, and BMDv; group B showed an insignificant increase, whereas group C continued to show increases in all parameters studied. The cumulative absolute densitometric changes from 0–24 months between groups C and A became significantly different for AP-BMD (P = 0.041), L-BMD (P = 0.039; data not shown), and BMDv (P = 0.036; Table 3Go).


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  		Table 3. BMD at the lumbar spine (L3) in the three groups of patients affected by precocious puberty: at the start of GnRHa treatment; after 12 months of GnRHa (groups A and B) or GnRHa plus calcium (group C) treatment; and after 24 months of GnRHa (group A), 12 months of GnRHa and 12 months of GnRHa plus calcium (group B), and 24 months of GnRHa plus calcium (group C) treatment

 
If corrected for CA, group A had a decrease in SD score in all three measures; groups B and C showed a slight decrease in AP-BMD SD score and an increase in L-BMD and BMDv SD scores, which were more pronounced in group B, but not significantly different. The cumulative CA SD score changes from 0–24 months became statistically significant in group C compared to group A for AP-BMD (P = 0.038), L-BMD (P = 0.043; data not shown), and BMDv (P = 0.032; Table 3Go and Fig. 1Go).



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  		Figure 1. Changes in three-dimensional calculated volumetric vertebral BMD ({Delta} BMDv; L3) in SD scores for CA ({Delta} BMDv SD score CA) and for BA ({Delta} BMDv SD score BA) in the three groups of patients in the first year, in the second year, and as cumulative change in the 2 yr of the study. Group A, Twenty-four months of GnRHa; group B, 12 months of GnRHa and thereafter 12 months of GnRHa plus calcium; group C, 24 months of GnRHa plus calcium. P < 0.05, in group C the difference is statistically significant compared with the group A values.

 
If corrected for BA, there was a decrease in group A and an increase in groups B and C in AP-BMD SD score, L-BMD SD score, and BMDv SD score. The cumulative BA SD score changes between groups C and A became significant at 24 months for AP-BMD (P = 0.037), L-BMD (P = 0.027; data not shown), and BMDv (P = 0.025; Table 3Go and Fig. 1Go).

If treated with nonparametric tests, the data became significant also at the end of the first year between group C on one side and groups A and B on the other, whereas a significant difference was present between groups A and group B in the second year of the study protocol.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Long acting GnRH analogs are the therapy of choice when precocious puberty is GnRH dependent (6); treatment is effective in arresting both the progression of secondary sexual characteristics and the rates of linear growth and bone maturation, thus improving final adult height (7).

Peak bone mass, which can be defined as the amount of bony tissue present at the time of skeletal maturation, is an important determinant for postmenopausal osteoporosis and fracture risk (1). BMD increases with age, and during puberty, the age-dependent increment is higher (2, 12). In fact, about half of adult peak bone mass is accumulated during the adolescent growth spurt (13). In girls, the maximum increase in BMD at the lumbar spine occurs between 11–14 yr and approaches its peak at age 16 yr (14). Contrary to area BMD, volumetric BMD seems to be less dependent on age and growth variables (15), but this fact is disputed (12).

The magnitude of the peak bone mass achieved during adolescence in different subjects depends on genetic-ethnic (race, sex, heredity) (16, 17), nutritional [calcium supplementation (8, 9, 12), body composition (18)], and environmental factors as well as physical activity (19, 20) and muscle strength (21). A number of studies published to date seem to offer overall evidence that calcium intake above the recommended dietary allowances is positively associated with bone mass in prepubertal (22, 23), premenopausal (24), and postmenopausal (25, 26) females. Calcium supplementation seems to be important to reach a higher peak bone mass, as the best time for bone calcium deposition is during the premenarcheal and perimenarcheal time periods (27).

Sex steroids and other hormonal factors, such as GH and insulin-like growth factors, increase considerably during puberty, and their synergistic actions are amplified mutually, as they control growth, increase muscle mass, and affect mineralization of the skeleton (3). Observations of delayed skeletal maturation and deficient bone mineralization in individuals with estrogen receptor defects (28) or mutations of the aromatase gene (29) demonstrate the role of estrogen in promoting normal bone maturation, in the accrual and maintenance of BMD, and in control of the rate of bone turnover (30). This has been confirmed by studies of men with histories of untreated constitutional delay in puberty, who have a significant reduction in trabecular and cortical BMD (31). Moreover, hypoestrogenic conditions, such as natural menopause and GnRHa administration in premenopausal women (32), are characterized by bone mass reduction. GH also plays an important role, and GH deficiency is associated with decreased bone density in both growing (33) and adult individuals (34).

The spinal BMD of patients with untreated precocious puberty has been reported to be high for CA (35) but appropriate for the advanced BA (4, 5, 36, 37) or, in one study, lower than the normal mean for BA (38), probably because bone maturation and bone mineralization do not necessarily advance simultaneously.

During GnRHa treatment, we observed complete arrest of pubertal development, and serum estradiol levels decreased from pubertal to prepubertal levels in each patient. This is a situation of estrogen deprivation and resembles that of estrogen receptor defects, where there is delayed skeletal maturation and deficient bone mineralization. In fact, estrogen, even if at low levels, augments skeletal growth and maturation in boys (39) as well as girls.

A reduction in BMD during GnRHa treatment was demonstrated by our group and others (4, 5, 37), whereas in one study BMD values increased, and the BMD SD score for age and skeletal age did not change during treatment (36). It is obvious that at such a critical age, a decrease in BMD, instead of an increase as expected in normal growing girls, might have a negative impact on peak bone mass and produce a higher risk for postmenopausal osteoporosis.

To study the possibility of reversing or preventing the reduction of BMD, we studied the effect of calcium supplementation during GnRHa treatment in three groups of girls with true precocious puberty: group A, GnRHa for 24 months; group B, GnRHa for 12 months and then both GnRHa and calcium supplementation; and group C, GnRHa and calcium combined treatment.

Our data at the beginning of the study confirmed a higher BMD in all groups compared to the control group of the same chronological age. If compared for BA, our patients show levels above normal in AP-BMD, whereas BMDv levels did not differ from normal values.

In group A, there was a decrease in the BMDv SD score for CA and BA: these data further confirmed the results of our study and other studies (4, 5). The same behavior occurred during the first year in group B, but this trend was completely reversed in the second year when calcium supplementation was added. Group C showed an increase in absolute BMDv levels that became significant in BMDv SD score for CA and BA. The behavior of the lumbar BMDv in the three groups is consistent with an effect of calcium supplementation during GnRHa treatment. In effect, in calcium-supplemented subjects the normal process of bone mass accretion is preserved despite GnRHa treatment.

The mechanism by which oral calcium increases bone density remains speculative. In adults, it was demonstrated that short and long term calcium supplementations are able to reduce bone resorption (40) and increase bone mass, inhibiting serum PTH levels (41). There are no similar data in children, but the mechanism is probably the same.

On the basis of these data, we hypothesized that a reduction in BMD, previously demonstrated in girls with precocious puberty (4, 5) due to a decrease in estrogens and the reduction of GH-insulin-like growth factor I axis activity (42), can be prevented when calcium supplementation is associated with GnRHa treatment from the beginning and can be reversed when calcium is added to treatment later. Moreover, these data agree with the influence of calcium quantity in the diet for the determination of peak bone mass at puberty; in fact, calcium supplementation enhanced the rate of increase in BMD in our girls, whose average dietary intake of calcium approximated the recommended dietary allowance. Also, in normal growing girls current calcium intake during the pubertal growth period may not result in maximal mineral retention, and increased calcium intakes should be considered (43). Based on our results, we suggest adding a calcium supplement in patients with precocious puberty from the beginning of GnRHa treatment and increasing calcium consumption during puberty for all children. Further studies will be necessary to identify the final peak bone mass of girls with precocious puberty and to clarify the mechanism by which oral calcium supplementation increases bone density.

Received August 21, 1998.

Revised March 2, 1999.

Accepted March 11, 1999.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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