X-linked hypophosphatemic rickets: an Italian experts' opinion survey.

BACKGROUND: X-linked hypophosphatemic rickets (XLH) is the first cause of inherited hypophosphatemia and is caused by mutation in the PHEX gene, resulting in excessive expression of the phosphaturic factor FGF23. Symptoms are mainly related to rickets in children and osteomalacia in adults and cause several complications that can be highly invalidating. Due to its rarity, XLH is poorly known and diagnosis is frequently delayed. Conventional treatment is based on oral phosphate salts supplementation and activated vitamin D analogs, which however, cannot cure the disease in most cases. OBJECTIVE: Due to the low prevalence of XLH, an experts' opinion survey was conducted across Italian centers to collect data on XLH and on its management. METHODS: A questionnaire was developed by a group of experts to collect data on XLH epidemiology, diagnosis and treatment in Italy. RESULTS: Data from 10 Italian centers (nine of which pediatric) on 175 patients, followed between 1998 and 2017, were included in the survey. Most patients were followed since childhood and 63 children became adults during the investigated period. The diagnosis was made before the age of 1 and between 1 and 5 years in 11 and 50% of cases, respectively. Clinically apparent bone deformities were present in 95% of patients. These were ranked moderate/severe in 75% of subjects and caused growth stunting in 67% of patients. Other frequent complications included bone pain (40%), dental abscesses (33%), and dental malpositions (53%). Treatment protocols varied substantially among centers. Nephrocalcinosis was observed in 34% of patients. Tertiary hyperparathyroidism developed in 6% of patients. CONCLUSIONS: XLH remains a severe condition with significant morbidities.

Significant association among growing pains, vitamin D supplementation, and bone mineral status: results from a pilot cohort study.

The aim of our study was to analyze the possible relationship between growing pains, vitamin D levels, and bone mineral status. We enrolled 33 children affected by growing pains. Their pain intensity was evaluated through a questionnaire using the Wong-Baker Faces Pain Rating Scale for pain assessment. Serum 25-hydroxyvitamin D (25-OH-D), parathyroid hormone (PTH), and alkaline phosphatase levels were measured as well. A quantitative ultrasound assessment (QUS) was also done, measuring both the amplitude-dependent speed of sound (AD-SOS) and the bone transmission time (BTT), correlating, respectively, with bone density and with cortical thickness. After 3 and 24 months of vitamin D supplementation, we re-evaluated pain intensity and laboratory results. After 24 months we re-assessed QUS parameters. At the beginning of the study the children reported a mean growing pain intensity of 7.5 ± 1.6 SD. The mean values of 25-OH-D and PTH levels were 15.7 ± 6.9 ng/ml and 57.3 ± 27.3 pg/ml, respectively. The AD-SOS Z score was -0.53 ± 1.19 SD, and the mean value of the BTT Z score was -0.72 ± 0.96 SD. After the first 3 months of vitamin D supplementation we observed an increase in 25-OH-D levels (34.1 ± 17.8, p < 0.001) and a reduction in both PTH levels (47.3 ± 30.6, p = 0.135) and pain intensity (2.7 ± 2.2, p < 0.001). After 24 months we observed a further significant reduction in the pain intensity (3.9 ± 3.4, p < 0.001) and in PTH levels (43.7 ± 28.5, p = 0.004) and an improvement in the QUS parameters, in particular in BTT Z scores (p = 0.014). Our study suggests an interesting relationship between growing pains, vitamin D levels and bone mineral status.

Calcium supplementation increases bone mass in GH-deficient prepubertal children during GH replacement.

BACKGROUND/AIMS: Since GH plays an important role in bone mineralization, and several studies demonstrated the positive influence of a higher calcium intake on bone mass, we studied the effect of calcium supplementation in GHD children during GH therapy. METHODS: 28 prepubertal GHD children, 5.0-9.9 years old, were assigned to two groups: group A (n = 14; 7 females) treated with GH, and group B (n = 14; 7 females) treated with GH + calcium gluconolactate and carbonate (1 g calcium/day per os). Auxological parameters, total bone mineral content (TBMC) and density (TBMD), leg BMC and BMD, lumbar BMD, fat mass (FM) and lean tissue mass (LTM), blood 25-hydroxyvitamin D (25-OHD), parathyroid hormone (PTH), osteocalcin (OC) and urinary N-terminal telopeptide of type I collagen (NTx) were determined at the start of therapy and after 1 and 2 years of treatment. RESULTS: During the 2 years of the study, TBMC, TBMD, leg BMC and BMD (but not lumbar BMD) increased in both groups of patients, however after 2 years of treatment they were significantly higher in the calcium-supplemented group B than in group A (p < 0.05, for all parameters). At the start of therapy, in both groups of patients percentage FM was higher and total and leg LTM lower than in controls (p < 0.05 for each parameter). Thereafter, FM decreased and LTM increased and after 2 years they were both different from baseline (p < 0.05). After 2 years of treatment, leg BMC and BMD were more positively correlated with regional leg LTM in patients of group B (r = 0.834 and r = 0.827, respectively; p < 0.001) than in patients of group A (r = 0.617 and r = 0.637, respectively; p < 0.05). 25-OHD and PTH levels were in the normal range in all patients at the start and during treatment. OC levels were lower and urinary NTx levels higher in patients than in controls (p < 0.05 for both parameters), either at the start and after 1 year of treatment. After 2 years of treatment, OC levels were significantly higher than at the start of the study (p < 0.05) in both groups of patients, but they were higher in group B than in group A (p < 0.05); on the contrary, urinary Ntx levels were lower in group B than in group A (p < 0.05). CONCLUSION: In GHD children, treated with GH, calcium supplementation improved bone mass; it may aid in reaching better peak bone mass and in protecting weight-bearing bones, usually completed in childhood to maximum levels, from risk of osteoporosis and fractures later in life.

Prevention of bone demineralization by calcium supplementation in precocious puberty during gonadotropin-releasing hormone agonist treatment.

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.

[Bone mass formation in childhood and risk of osteoporosis]. / La formazione di massa ossea nell'infanzia ed il rischio di osteoporosi.

The appearance of postmenopausal osteoporosis is correlated with the peak bone mass achieved during adolescence and the bone loss during adult life. The magnitude of the peak bone mass depends on genetic (race, sex, heredity), nutritional (calcium supplementation, obesity) and environmental factors as well as physical activity. Sex steroids and other hormonal factors involved in puberty, like growth hormone and insulin-like growth factors, are very important in the bone mass increase during this period. This is confirmed by studies in men with histories of constitutional delay of puberty, who have a decreased bone mineral density, and in children with precocious puberty treated with GnRH analogs, where the reduction in bone mineral density previously demonstrated seems at least completely reversible.

Influence of dietary taurine on vitamin D absorption.

To evaluate the influence of dietary taurine supplementation on vitamin D absorption, we studied three groups of infants: 21 (11 preterm) were fed a taurine-free formula, 21 (10 preterm) were fed a taurine-supplemented formula (50 mg/100 g of powder) and 20 (9 preterm) were fed human, not heat-treated milk. Taurine, total bile acids, glyco-(GBA) and tauro-(TBA) conjugated bile acids, 25-hydroxyvitamin D3 (25OHD3) and 1,25-dihydroxyvitamin D3 (1,25OH2D3) were determined in all infants at birth in blood cord and at one and three months of life. In preterm infants fed a taurine-free formula, we found lower plasma taurine levels than in infants of other groups at one and three months of life. In these infants, GBA predominated, with a G/T ratio of 1.1 and 1.4 at one and three months of life, whereas in all other infants TBA predominated with a G/T ratio always < 1. Also, 25OHD3 and 1,25OH2D3 levels were significantly lower in preterm infants fed a taurine-free formula than in infants fed a taurine-enriched formula or human milk. Term infants fed a taurine-free formula did not show differences in the parameters studied in comparison to infants of other groups. Low taurine dietary intake appears to compromise vitamin D absorption in preterm infants, and therefore taurine supplementation of preterm infant formulas should be encouraged.

Effects of 1,25-dihydroxyvitamin D3 and growth hormone therapy on serum osteocalcin levels in children with growth hormone deficiency.

In order to investigate the influence on bone metabolism of growth hormone (GH), we evaluated the response to an acute load of 1,25(OH)2D3 (Rocaltrol) (1.5 micrograms/day for 4 days) in 16 growth hormone-deficient prepubertal children (11 boys and 5 girls, aged from 6.2 to 9.6 years) both before and after 1 month of human GH (hGH) therapy (0.1 IU/kg/day, 6 times per week). Before and after the 1,25(OH)2D3 load, serum IGF-I, osteocalcin, Ca, P, alkaline phosphatase (ALP) and urinary excretion of Ca and P were measured. The serum levels of osteocalcin rose significantly after the first 1,25(OH)2D3 load, without an increase in IGF-I values and with a slight non-significant increase in serum Ca and P. Almost superimposable increases of osteocalcin, Ca and P were observed after 1 month of hGH therapy, with a significant increase of IGF-I, but they did not rise further after the second 1,25(OH)2D3 load. On the basis of our results, 1,25(OH)2D3 seems to have a stimulatory action on osteoblastic activity even in the absence of normal levels of GH. However, there is no apparent additional stimulatory activity after administration of hGH. Osteocalcin level behaviour during our study might suggest that GH and 1,25(OH)2D3 have a common and easily saturable stimulatory pathway on osteoblastic function.

Impaired response of free alpha-subunits after luteinizing hormone-releasing hormone and thyrotropin-releasing hormone stimulations in beta-thalassemia major.

In order to clarify whether the damage in gonadotropin secretion due to iron overload in patients with beta-thalassemia is of pituitary or hypothalamic origin, 14 euthyroid patients (8 females and 6 males, age 15-24 years) affected by beta-thalassemia major with hypogonadotropic hypogonadism were studied. Luteinizing-hormone (LH), follicle-stimulating hormone (FSH) and free alpha-subunit (FAS) were measured during LH-releasing hormone (LH-RH) stimulation test, and thyroid-stimulating hormone (TSH), prolactin (PRL) and FAS during thyrotropin-releasing hormone (TRH) stimulation test. During LH-RH stimulation, the mean basal LH, FSH and FAS levels were similar to those found in normal prepubertal children, but the peak values were lower than those found in such children. Also during TRH stimulation, the mean peak values of FAS were lower than those of normal prepubertal children, but the TSH response was normal. The lack of response of gonadotropins and FAS to LH-RH cannot exclude hypothalamic failure; however, the normal response of TSH to TRH, in spite of the poor response of FAS, indicates that the origin of hypogonadotropic hypogonadism is the pituitary damage concerning not only the gonadotroph but also the thyrotroph cells.