Silvano Bertelloni

Effects of long-term treatment with growth-hormone on bone and mineral metabolism in children with growth-hormone deficiency

The effects of growth hormone (GH) deficiency and recombinant human GH replacement (0.6 IU/kg per week) on bone and mineral metabolism in 26 GH-deficient children were studied for 12 months. Before therapy, all children had significantly reduced serum levels of osteocalcin, carboxyl-terminal propeptide of procollagen type I, and 1,25-dihydroxyvitamin D, whereas serum ionized calcium, phosphate, intact parathyroid hormone, calcitonin, and 25-hydroxyvitamin D concentrations were in the normal range. All children had significant reduction of bone density for their chronologic, statural, and bone ages. During therapy with recombinant human GH, a decrease of serum ionized calcium levels and increases of phosphate, osteocalcin, carboxyl-terminal propeptide of procollagen type I, and intact serum levels of parathyroid hormone were found. A significant increase of serum levels of 1,25-dihydroxyvitamin D was found at 12 months. The urinary phosphate/urinary creatinine ratio decreased, whereas values for nephrogenous cyclic adenosine monophosphate and the ratio of the maximum rate of renal tubular reabsorption of phosphate to the glomerular filtration rate increased. Bone density significantly improved at 12 months, with a complete recovery in 12 children (46.2%). Significant relationships were found among growth velocity, bone density, maximum tubular reabsorption/glomerular filtration rate ratio, and serum levels of carboxyl-terminal propeptide of type I procollagen. The changes in serum levels of this propeptide during the first week of recombinant human GH treatment were positively related to growth velocity at 6 and 12 months and to bone density at 12 months of treatment, whereas the changes in osteocalcin levels were not. We conclude that recombinant human GH treatment caused significant modifications of mineral metabolism and significantly increased bone density, and that measurement of serum levels of the propeptide during the first week of recombinant human GH administration may be a useful tool in predicting improved growth velocity and bone density during long-term recombinant human GH replacement.

Bone quality assessment by quantitative ultrasound of proximal phalanxes of the hand in healthy subjects aged 3-21 years

Bone quality by quantitative ultrasound was assessed in 1083 (587 males) healthy white subjects aged 3–21 y. Amplitude-dependent speed of sound (AD-SoS) through the distal end of the first phalanx diaphysis of the last four fingers of the hand was measured by an ultrasound device (DBM Sonic 1200, IGEA, Carpi, Italy). Mean AD-SoS values increased progressively from 3 to 21 y (males, 1845.9–2119.1 m/s, p < 0.0001; females, 1842.3–2098.8 m/s, p < 0.0001). They did not differ (p = NS) between sexes up to age 11, but females showed higher (p < 0.05 –p < 0.0001) AD-SoS values than males in age groups 12, 13, and 14 y. There was no difference (p = NS) of AD-SoS values between sexes in pubertal stages 1, 2, and 5, but females had higher mean AD-SoS values than males in stages 3 (p < 0.01) and 4 (p < 0.001). Independent predictors of AD-SoS were weight, body mass index, pubertal stage, and mean width of fingers in males, and age, pubertal stage, and mean width of fingers in females (p < 0.01 –p < 0.0001). However, 7.8% in males and 3.6% in females of the increment of AD-SoS values can be related to the finger anatomy alone. AD-SoS values probably reflect the architectural organization of growing bone or changes in bone elasticity. Increased bone density and size may be additional factors influencing AD-SoS. Measurement of AD-SoS at the hand phalanxes may be a simple, noninvasive, and radiation-free technique to assess bone quality in children.

Assessment of bone quality by quantitative ultrasound of proximal phalanges of the hand and fracture rate in children and adolescents with bone and mineral disorders

Bone quality by quantitative ultrasound and fracture rate were assessed in 135 (64 males) children and adolescents aged 3-21 y with bone and mineral disorders such as chronic anticonvulsants or glucocorticoids treatment, juvenile rheumatoid arthritis, celiac disease, paucity of intrahepatic bile ducts, autoimmune hepatitis, genetic diseases, idiopathic juvenile osteoporosis, disuse osteoporosis, β-thalassemia major, survivors of acute lymphoblastic leukemia, liver transplantation, calcium deficiency, and nutritional or X-linked hypophosphatemic rickets. Amplitude-dependent speed of sound through the distal end of the first phalangeal diaphysis of the last four fingers of the hand was measured by an ultrasound device. In the majority of patients cortical area to total area ratio by metacarpal radiogrammetry (n=120) and lumbar bone mineral density (BMD) by dual-energy x-ray absorptiometry (n=99) were also assessed. In patients with X-linked hypophosphatemic rickets radial BMD by single-photon absorptiometry instead of lumbar BMD was measured. Mean values of amplitude-dependent speed of sound, cortical area to total area ratio, lumbar BMDarea, or lumbar BMD corrected for bone sizes estimated by a mathematical model (BMDvolume), as well as mean values of radial BMD in patients with X-linked hypophosphatemic rickets, expressed as z score, were significantly reduced (p < 0.0001) in comparison with their reference values (−1.7 ± 1.0, −2.0 ± 0.9, −3.0 ± 1.3, −1.9 ± 1.0, −2.7 ± 0.7, respectively). A positive relationship was found between amplitudedependent speed of sound and cortical area to total area ratio (r = 0.90, p < 0.0001), lumbar BMDarea (r = 0.62, p < 0.0001), or lumbar BMDvolume (r = 0.66, p < 0.0001). Fifty-two patients (38.5%) had suffered fractures in the 6 mo preceding the bone measurements, the radial distal metaphysis being the most frequent fracture site (28.8%). Mean values of amplitude-dependent speed of sound, cortical area to total area ratio, lumbar BMDarea, or lumbar BMDvolume, expressed as z score, of fractured patients were significantly lower (p < 0.0001) than those of fracture-free patients (−2.2 ± 1.0 and −1.4 ± 0.8, −2.6 ± 0.9 and −1.7 ± 0.7, −3.5 ± 1.2 and −2.5 ± 1.0, −2.5 ± 1.0 and −1.3 ± 0.7, respectively). Phalangeal quantitative ultrasound may be a useful method to assess bone quality and fracture risk in children and adolescents with bone and mineral disorders.

Bone demineralization in cystic fibrosis : Evidence of imbalance between bone formation and degradation

Bone turnover, collagen metabolism, and bone mineral status were investigated in 59 patients with cystic fibrosis and in 72 sex- and age-matched control subjects. In all patients and control subjects serum concentrations of osteocalcin (OC), carboxy-terminal propeptide of type I procollagen (PICP), amino-terminal propeptide of type III procollagen(PIIINP), and cross-linked carboxy-terminal telopeptide of type I collagen(ICTP), and urinary values of cross-linked N-telopeptides of type I collagen (NTX), as well as total body bone mineral content (TBBM) were measured. Higher ICTP (μg/L) and NTX (bone collagen equivalent/urinary creatinine (nmol/mmol) values were found in prepubertal, pubertal, and young adult patients than in control subjects (ICTP: 15.4 ± 2.1 and 13.2± 1.8, p < 0.001; 23.3 ± 5.3 and 20.1 ± 4.1,p < 0.02; 4.8 ± 1.1 and 4.0 ± 1.0, p < 0.05, respectively; NTX: 1047.5 ± 528.6 and 227.8 ± 71.8,p < 0.01; 997.8 ± 391.7 and 376.3 ± 91.0,p < 0.01; 993.2 ± 398.0 and 73.9 ± 28.5,p < 0.01, respectively). Lower OC and PICP levels (μg/L) were showed in pubertal patients in comparison with control subjects (OC: 20.2± 12.3 and 39.0 ± 15.1, p < 0.01; PICP: 305.8± 130.4 and 436.2 ± 110.1, p < 0.02, respectively). Lower OC and higher PIIINP levels (μg/L) were found in young adult patients than in control subjects (OC: 4.4 ± 3.0 and 7.0 ± 3.1,p < 0.05; PIIINP: 4.8 ± 1.1 and 3.1 ± 1.0,p < 0.001, respectively). TBBM (z score) was reduced in prepubertal, pubertal, and young adult patients (-0.8 ± 0.4, -1.0± 0.4, -1.1 ± 0.5, respectively). Patients with cystic fibrosis have bone demineralization and imbalance between bone formation and degradation.

Pamidronate treatment of bone fibrous dysplasia in nine children with McCune-Albright syndrome

McCune‐Albright syndrome is a rare genetic disorder consisting of skin and bone dysplasia and peripheral endocrinopathies. Little data have been collected regarding bisphosphonate treatment of bone fibrous dysplasia in paediatric patients with this syndrome. The aim of our study was to investigate the therapeutic efficacy of pamidronate in these patients. Nine patients with moderate to severe forms of bone fibrous dysplasia were treated with pamidronate intravenously (0.5‐1 mg/ kg/daily for 2‐3 d) at 0.5‐1‐y intervals. Patients were treated over a time period of 0.5‐3.5 y. During treatment no spontaneous fracture occurred. Bone pain and gait abnormality due to pain disappeared after 2‐3 therapeutic cycles. Cranial asymmetry and limb length discrepancy remained unchanged. Elevated serum alkaline phosphatase and urine hydroxyproline values were reduced by the treatment, demonstrating drug activity at the lesional level. The effectiveness of pamidronate was also seen at the non‐lesional level through an increase in bone density. Radiographic and scintigraphic evidence of lesion healing was not attained. Pamidronate treatment can ameliorate the course of bone fibrous dysplasia in children and adolescents with McCune‐Albright syndrome.

Osteoporosis in Children and Adolescents: Diagnosis, Risk Factors, and Prevention

Bone mass acquired during childhood and adolescence is a key determinant of adult bone health. Peak bone mass, which is achieved in late adolescence, is a main determinant of osteoporosis in adulthood. Therefore, any factor adversely impacting on bone acquisition during childhood or adolescence can potentially have long-standing detrimental effects on bone health predisposing to osteoporosis and fracture risk. Thus, osteoporosis can well have its origin in childhood and adolescence. Pediatricians should be playing an active role in osteoporosis diagnosis and prevention. It is increasingly recognized that osteoporosis may occur in some disorders of children and adolescents. In this paper we review the diagnostic criteria of osteopenia/osteoporosis by densitometric assessment of bone mineral density, the contributing factors, and the mechanisms whereby several disorders may affect the acquisition of bone mass in children and adolescents. Finally, some recommendations to optimize peak bone mass in order to prevent osteopenia/osteoporosis are suggested.

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.

Altered Bone Mineral Density in Patients with Complete Androgen Insensitivity Syndrome

Androgens have major influences on the regulation of bone mineralization. Because of their unique peripheral metabolism androgens may act on bone via activation of the androgen and/or estrogen receptor. Patients with complete androgen insensitivity syndrome (cAIS) are natural models to assess androgen actions on bone. We studied bone mineral density (BMD) in 10 patients with cAIS (mean age 13.70, range 4.7–19.8 years); 3 patients were studied before gonadectomy; the others were castrated and 6 were on hormonal replacement therapy. The BMD area (aBMD) was measured by dual energy X-ray; lumbar ‘apparent’ volumetric density (vBMD) was calculated using the formula vBMD = aBMD × [4/(π × width)]. In the patients, aBMD (0.72 ± 0.16 g/cm2) and vBMD (0.23 ± 0.04 g/cm3) were significantly (p < 0.001) reduced in comparison with those of a control group (n = 15, age 5.0–20.5 years: aBMD 1.028 ± 0.20 g/cm2; vBMD 0.35 ± 0.04 g/cm3). Both aBMD and vBMD were also reduced in comparison with normal values for males (aBMD –2.66 ± 0.99 SDS, p < 0.001; vBMD –3.08 ± 1.53 SDS, p < 0.0005) and females (aBMD –2.88 ± 1.05 SDS, p < 0.001; vBMD –2.84 ± 1.18 SDS, p < 0.0007). Real lumbar bone density, assessed by computed tomography in 1 patient, was also reduced (–6.2 SDS and –3.5 SDS for male and female normal values, respectively). Biochemical markers of bone metabolism were normal and not significantly different in patients and controls. Girls with cAIS did not have more fractures than controls. In conclusion, both aBMD and vBMD are reduced in cAIS patients, while bone turnover and the fracture risk seem not to be increased. Our data indicate that both androgens and estrogens may be required for acquisition of bone density during childhood.

Osteoporosis in children and adolescents: etiology and management

Bone mass increases progressively during childhood, but mainly during adolescence when approximately 40% of total bone mass is accumulated. Peak bone mass is reached in late adolescence, and is a well recognised risk factor for osteoporosis later in life. Thus, increasing peak bone mass can prevent osteoporosis.The critical interpretation of bone mass measurements is a crucial factor for the diagnosis of osteopenia/osteoporosis in children and adolescents. To date, there are insufficient data to formally define osteopenia/osteoporosis in this patient group, and the guidelines used for adult patients are not applicable. In males and females aged <20 years the terminology ‘low bone density for chronologic age’ may be used if the Z-score is less than −2. For children and adolescents, this terminology is more appropriate than osteopenia/osteoporosis. Moreover, the T-score should not be used in children and adolescents.Many disorders, by various mechanisms, may affect the acquisition of bone mass during childhood and adolescence. Indeed, the number of disorders that have been identified as affecting bone mass in this age group is increasing as a consequence of the wide use of bone mass measurements. The increased survival of children and adolescents with chronic diseases or malignancies, as well as the use of some treatment regimens has resulted in an increase in the incidence of reduced bone mass in this age group.Experience in treating the various disorders associated with osteoporosis in childhood is limited at present. The first approach to osteoporosis management in children and adolescents should be aimed at treating the underlying disease. The use of bisphosphonates in children and adolescents with osteoporosis is increasing and their positive effect in improving bone mineral density is encouraging. Osteoporosis prevention is a key factor and it should begin in childhood. Pediatricians should have a fundamental role in the prevention of osteoporosis, suggesting strategies to achieve an optimal peak bone mass.

Long-term growth hormone treatment in children with renal hypophosphatemic rickets : effects on growth, mineral metabolism, and bone density

OBJECTIVE To evaluate the effects of treatment with recombinant human growth hormone (rhGH) on growth, mineral metabolism, and bone density in children with renal hypophosphatemic rickets (RHR). DESIGN Long-term rhGH treatment combined with conventional therapy with 1,25-dihydroxyvitamin D3 plus inorganic phosphate salts. SETTING Endocrine unit, department of pediatrics, university hospital. SUBJECTS Twelve patients (5 boys; age range 4.6 to 12.5 years, median 7.0 years) were subdivided into two groups of six patients on the basis of the median of height z score (-2.41) and the median bone age/statural age (BA/SA) ratio (1.23). Group A included patients with a severe degree of short stature (height z score -3.4 +/- 0.5) (mean +/- SD) and altered BA/SA ratio (1.26 +/- 0.08); group B included patients with a lesser degree of short stature (height z score -2.1 +/- 0.6, p < 0.001 vs group A) and more normal BA/SA ratio (1.04 +/- 0.15, p < 0.01 vs group A). INTERVENTION Group A received rhGH treatment (0.6 IU/kg per week subcutaneously) combined with conventional therapy; group B received conventional therapy alone. MEASUREMENTS Height, growth velocity, predicted adult height, serum values of calcium, phosphate, bone alkaline phosphatase isoenzyme, osteocalcin, propeptides of type I and type III procollagen, intact parathyroid hormone, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and urinary calcium/urinary creatinine ratio and tubular maximum for phosphate reabsorption normalized to the glomerular filtration rate (TmP/GFR), as well as radial bone density, were measured at baseline and for 3 years. RESULTS Height z score, growth velocity z score, predicted adult height, serum values of phosphate, bone alkaline phosphatase isoenzyme, osteocalcin, propeptides of type I and type III procollagen, intact parathyroid hormone 1,25-dihydroxyvitamin D, and TmP/GFR, as well as radial bone density, improved significantly only in group A. Serum calcium and 25-hydroxyvitamin D, and urinary calcium/urinary creatinine ratio did not change in either group. CONCLUSIONS Long-term rhGH administration may benefit growth, phosphate retention, and bone density in patients with RHR, without evidence of side effects.