Gi Baroncelli

Effect of central precocious puberty and gonadotropin-releasing hormone analogue treatment on peak bone mass and final height in females

To evaluate the effect of central precocious puberty (CPP) and its treatment with gonadotropin-releasing hormone (GnRH) analogues on final height and peak bone mass (PBM), we measured lumbar bone mineral density (BMD) in 23 girls at final height. Patients were distributed in two groups. Group 1: 14 patients with progressive CPP were treated with GnRH analogues; seven patients received buserelin (1600 μg/daily), subsequently switched to depot triptorelin (60 μg/kg/26–28 days); seven patients were treated with depot triptorelin (60 μg/kg/26–28 days); mean age of treatment was 6.2 years (range 2.7–7.8 years); the treatment was discontinued at the mean age of 10.1 years (range 8.7–11.3 years); final height was reached at the mean age 13.4 years (range 12.0–14.9 years). Group 2: 9 patients (mean age 6.5 years, range 4.8–7.7 years) with a slowly progressing variant of CPP were followed without treatment; final height was reached at the mean age 13.6 years (range 12.5–14.8 years). Lumbar BMD (L2–L4 by dual energy X-ray absorptiometry) was measured in all patients at final height. In group 1, final height (158.9 ± 5.4 cm) was significantly greater than the pre-treatment predicted height (153.5 ± 7.2 cm, P < 0.001), but significantly lower than mid-parental height (163.2 ± 6.2 cm, P < 0.005). Subdividing the girls of group 1 according to the bone age at discontinuation of therapy (i.e. ≤11.5 years, n = 5, or ≥12.0 years, n = 9), the former patients had a final height significantly higher than the latter (163.7 ± 3.9 cm vs 156.5 ± 4.6 cm, P < 0.02). In group 2, final height (161.8 ± 4.6 cm) was similar to the pre-treatment predicted height (163.1 ± 6.2 cm, P = NS) and was not significantly different from mid-parental height (161.0 ± 5.9 cm). BMD values (group 1: 1.11 ± 0.14 g/cm2, group 2: 1.22 ± 0.08 g/cm2) were not significantly different from those of a control group (1.18 ± 0.10 g/cm2; n = 20, age 16.3–20.5 years) and the patients’ mothers (group 1: 1.16 ± 0.07 g/cm2, n = 11, age 32.9–45.1 years; group 2: 1.20 ± 0.08 g/cm2, n = 7, age 33.5–46.5 years). In group 1, the girls who stopped therapy at a bone age ≤11.5 years had significantly higher BMD (1.22 ± 0.10 g/cm2) compared to those who discontinued therapy at a bone age ≥12.0 years (1.04 ± 0.12 g/ cm2, P < 0.05).ConclusionIn girls with progressive CPP, long-term treatment with GnRH analogues improves final height. A subset of patients with CPP does not require treatment because good statural outcome (slowly progressing variant). In CPP, the abnormal onset of puberty and the long-term GnRH analogue treatment do not impair the achievement of PBM. In GnRH treated patients, the discontinuation of therapy at an appropriate bone age for pubertal onset may improve both final height and PBM.

Twenty-four-Hour Osteocalcin, Carboxyterminal Propeptide of Type I Procollagen, and Aminoterminal Propeptide of Type III Procollagen Rhythms in Normal and Growth-Retarded Children

ABSTRACT: The relationships between spontaneous variations in serum 24-h osteocalcin (OC), carboxyterminal propeptide of type I procollagen (PICP), and aminoterminal propeptide of type III procollagen (PIIINP) concentrations and GH secretion, measured as GH response to provocative pharmacologic stimuli and spontaneous GH secretion during 24 h, were evaluated in prepubertal normal children and in GH-deficient and GH-secreting short normal children (SNC). All the subjects showed a circadian rhythm in smoothed 24-h OC and PICP mean data with higher nocturnal values in comparison with diurnal values. Conversely, serum PIIINP concentrations did not vary throughout the day. In children with classic GH deficiency and nonclassic GH deficiency, mean 24-h serum levels and smoothed 24-h mean data for OC, PICP, and PIIINP were significantly reduced (p < 0.001) with respect to age-matched controls. SNC showed mean 24-h OC concentrations similar (p = NS) to those we found in age-matched controls, but they had significantly lower (p < 0.001) diurnal 12-h mean data in comparison with controls. SNC also showed both 24-h PICP and PIIINP mean data and smoothed 24-h PICP and PIIINP mean data significantly lower (from p < 0.02 to p < 0.001) at all the time points of measurement in comparison with controls. Twenty-four-hour PICP and PIIINP mean data were positively related to spontaneous 24-h GH concentrations (r = 0.77, p < 0.005 and r = 0.69, p < 0.005, respectively) and growth velocity (r = 0.85, p < 0.005, and r = 0.70, p < 0.005, respectively), whereas 24-h OC mean data were not. Our study suggests that circadian serum PICP and PIIINP concentrations show GH dependency in children with classic GH deficiency and those with nonclassic GH deficiency, but this was less evident in SNC. Serum PICP and PIIINP concentrations may reflect somatic growth in children with short stature that is or is not related to GH deficiency.

Bone turnover in children with vitamin D deficiency rickets before and during treatment

Biochemical markers of bone formation [alkaline phosphatase, osteocalcin, and carboxyterminal propeptide of type I procollagen (PICP)] and bone resorption [cross‐linked carboxyterminal telopeptide of type I collagen (ICTP) and cross‐linked N‐telopeptides of type I collagen (NTX)] were measured in 14 children aged 8.5–10.5 mo with vitamin D deficiency rickets before and longitudinally during vitamin D treatment (3000–4000 IU/daily). Forty‐four healthy children aged 8–10.5 mo were enrolled as sex‐ and age‐matched controls. Before treatment, serum levels of alkaline phosphatase, PICP, and ICTP, and urinary excretion values of NTX were significantly higher, and serum osteocalcin levels significantly lower than controls (31.4 ± 3.5 mμkat/L and 9.8 ± 2.9 μkat/L, p < 0.001; 1025 ± 89 μg/L and 952 ± 97.4 μg/L, p < 0.02; 15.6 ± 2.6 μg/L and 14.2 ± 1.3 μg/L, p< 0.01 370.7 ± 109.4 nmol BCE and 201.8 ± 69.2 nmol BCE, p < 0.001; 17.6 ± 9.1 μg/L and 22.5 ± 7.6 μg/L, p <0.05, respectively). During treatment, serum alkaline phosphatase levels progressively declined in association with the radiographic healing of the skeletal lesions. Serum levels of osteocalcin, PICP, and ICTP, and urinary excretion values of NTX showed a transient but significant (p < 0.05 to p < 0.001) increase in comparison with baseline values during the first 2–4 wk of treatment, and decreased slowly thereafter. They were within the mean 2 SD of controls before the recovery of the skeletal lesions.

Parathyroid hormone-related protein in healthy pregnant women

The object of this study was to determine whether increased circulating levels of parathyroid hormone-related protein (PTH-rp) may explain the increased parathyroid hormone (PTH) bioactivity in pregnancy. In 41 healthy pregnant women (age 19–41 years), PTH-rp and corrected calcium levels were measured and compared with those of nonpregnant control women (n=18, age 20–39 years). PTH-rp and corrected calcium levels were significantly higher in pregnant women (PTH-rp 21.9±7.9 pg/ml, P<0.001; corrected calcium 2.38±0.07 mmol/liter, P=0.001) than in nonpregnant women (PTH-rp 10.3±7.8 pg/ml; corrected calcium 2.30±0.10 mmol/liter). Our data indicate that circulating PTH-rp levels may significantly increase in pregnancy, suggesting a possible role of this peptide in the modification of calcium homeostasis in pregnant women.

Evaluation of a peptide family encoded by the calcitonin gene in selected healthy pregnant women. A longitudinal study.

We conducted a longitudinal study on serum levels of peptides encoded by the calcitonin gene before conception, every month during pregnancy, and 24 h and 5 days after delivery in 26 healthy women. Only subjects fulfilling optimality criteria according to the literature were included. Blood samples for ionized calcium, total (tCT) and extractable (exCT) calcitonin, katacalcin, and calcitonin gene-related peptide (CGRP) were collected. We found no significant changes of ionized calcium, tCT, exCT, and katacalcin levels, while CGRP serum levels showed a significant increase during pregnancy and a fall to preconceptional values after delivery. Since variations of calcitonin levels did not occur in our selected pregnant women, we conclude that thyroidal C cell secretion is not increased during pregnancy. Our data suggest that calcitonin is not involved in the modifications of mineral homeostasis occurring in pregnancy. In addition, the variations of CGRP serum levels we found suggest that such a hormone participates in circulation modifications of pregnant women.

Androgen-Receptor Blockade Does Not Impair Bone Mineral Density in Adolescent Females

Abstract. The effect of peripheral androgen hypersensitivity on bone mineral density (BMD) was investigated in a group of adolescent women with idiopathic hirsutism (n= 17; mean age 17.0 ± 1.7 years). The effect of long-term androgen-receptor blockade with flutamide (500 mg daily in two divided doses for 12 months) on BMD was assessed too. BMD was measured at lumbar spine (L2–L4) by a dual energy X-ray densitometer. Before flutamide treatment, patient BMD (1.14 ± 0.07 g/cm2) was not significantly different from that of the control group (1.16 ± 0.12 g/cm2, n= 22), and was normal for age and sex (BMD 0.14 ± 0.69 SDS, P= NS vs. 0). After 12 months of treatment, absolute BMD in patients increased (1.18 ± 0.08 g/cm2, P < 0.002), but SDS BMD did not change (0.21 ± 0.72, P= NS vs. baseline). Flutamide treatment determined a clinical, marked improvement of androgen hypersensitivity (Ferriman–Gallwey score: before 22.0 ± 6.2; 6 months: 13.2 ± 6.4, P < 0.003; 12 months; 7.6 ± 4.1, P < 0.001; acne score: before 3.8 ± 0.8; 3 months 0.8 ± 0.5, P < 0.001; later disappeared). The serum levels of 3α-androstenediol-glucoronide decreased (before: 8.6 ± 1.1 μg/liter; 12 months: 7.2 ± 1.0 μg/liter, P < 0.02), whereas the other endocrinological parameters did not change. No relationship was found between BMD and clinical or biochemical parameters of hyperandrogenism. We concluded that in adolescent women, peripheral hyperandrogenism is not associated with abnormal BMD; long-term treatment with flutamide, which blocks the androgen receptor, does not alter their BMD.

Bone Mineral Density and Biochemical Parameters of Bone Turnover in Children with Growth Hormone Deficiency

Growth hormone (GH) is a crucial factor in the build-up and in the maintenance of peak bone mass. Children with GH deficiency have osteopenia and a concomitant reduction in bone turnover. On the other hand, GH therapy improves bone mineral density and stimulates bone turnover. These data suggest that GH treatment may have a beneficial effect on peak bone mass. In children with GH deficiency, the values of some biochemical markers of bone turnover may be closely related to growth response during GH therapy. However, further studies are needed to define the usefulness of bone markers in order to optimize the treatment and to predict the growth outcome in GH-treated children.

Calcitonin secretion in children with insulin-dependent diabetes-mellitus

To test the hypothesis that calcitonin (CT) deficiency may contribute to bone mineral loss in insulin-dependent diabetes mellitus (IDDM), we studied basal and calcium stimulated (2 mg/kg body wt. in 5 min) CT levels in 15 children with IDDM and osteopenia. Ten age-sex matched healthy children were studied as controls. Since extractable CT (exCT) allows more sensitive and specific measurement of CT monomer, we measured both total serum CT (tCT) and exCT. Diabetic children had slightly but significantly (P<0.05) higher basal levels of both tCT (24.5±7.1 ng/l) and exCT (5.6±1.6 ng/l) than controls (tCT: 18.7±5.4 ng/l; exCT: 4.3±1.2 ng/l). Calcium stimulation test pointed out significant increase (P<0.001) of tCT and exCT in both groups with peak values not significantly different in IDDM in respect to controls. However, diabetic children showed a reduced CT reserve evidenced by a lower peak/basal ratio (diabetics: tCT 1.68, exCT 1.84; controls: tCT 2.49, exCT 2.88) and by a more rapid decrease in CT levels. We conclude that CT deficiency is not a causative factor of diabetic osteopenia. The slightly higher basal CT values suggest that an increased bone reabsorption may be operative in IDDM and it stimulates CT secretion. This chronic “C” cell stimulation may induce the reduction in CT reserve observed employing the calcium infusion test.

Growth hormone secretion in poorly growing children with renal hypophosphataemic rickets.

We evaluated growth hormone (GH) secretion and baseline serum free insulin-like growth factor-I (IGF-I) levels in 12 poorly growing patients (5 males and 7 females; age 1.6–12.5 years, median 6.4) with renal hypophosphataemic rickets treated with 1,25-dihydroxy-vitamin D3 plus inorganic oral phosphate salts. Eleven healthy normally growing children (6 males and 5 females age 3.1–10.8 years, median 6.6) were studied as control group. All patients had a normal GH response (GH peak ≥ 10 μg/l) to at least one provocative pharmacological stimulus (levodopa or insulin tolerance test), as well as all the controls. Mean growth hormone concentrations (MGHC), mean pulse amplitude, number of GH peaks above 5 μg/l, and IGF-I values overlapped between patients and controls, even though four patients had MGHC below the lower limit of MGHC of controls. In these patients, however, height-SDS, serum calcium, phosphate, alkaline phosphatase, intact parathyroid hormone, 1,25-dihydroxyvitamin D concentrations and maximum tubular phosphate reabsorption/glomerular filtration rate ratio did not differ in respect to the patients who showed MGHC in the range of controls (n = 6). MGHC, IGF-I and biochemical parameters of phospho-calcium metabolism did not differ when the patients were subdivided in two groups on the basis of the median (−2.4) of height-SDS. No relationship was found between MGHC or IGF-I and height-SDS or growth velocity-SDS. Height-SDS and years of treatment or age at which therapy was started were not related.

Indications and strategies for continuing GH treatment during transition from late adolescence to early adulthood in patients with GH deficiency: The impact on bone mass

GH plays an important role in longitudinal bone growth and maturation during childhood and adolescence. However, GH has important metabolic functions other than bone growth, which become more apparent during young adulthood, when growth has been completed. Indeed, GH deficiency (GHD) in adult life is a recognized clinical syndrome which includes symptoms such as increased central adiposity, decreased lean body mass, reduced bone mineral density (BMD), increased atherogenic risk, cerebrovascular and cardiac morbidity and mortality, and reduced quality of life. As approximately one quarter of the children with GHD should continue GH administration in adulthood, it is important to reconfirm GHD at the end of growth in order to select patients with severe GHD who need to resume GH therapy with an appropriate age-related dosage. Some evidence indicates that most peak bone mass (PBM) is achieved by the end of adolescence but small increases in BMD continue during the period of transition from late adolescence to young adulthood. Some young adults with GHD show a persistent increase of lumbar BMD after the completion of growth even after discontinuation of treatment suggesting a spontaneous progression towards lumbar PBM or a continuing effect of the treatment. The data indicates that adolescents with GHD who do not reach lumbar PBM at the time of discontinuation of GH treatment can achieve a BMD lower than their genetic potential if they are not treated during the transition to young adulthood.