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Purpose: Preventing fragility fractures by treating osteoporosis may reduce disability and mortality worldwide. Algorithms combining clinical risk factors with bone mineral density have been developed to better estimate fracture risk and possible treatment thresholds. This systematic review supported panel members of the Italian Fragility Fracture Guidelines in recommending the use of best-performant tool. The clinical performance of the three most used fracture risk assessment tools (DeFRA, FRAX, and FRA-HS) was assessed in at-risk patients. Methods: PubMed, Embase, and Cochrane Library were searched till December 2020 for studies investigating risk assessment tools for predicting major osteoporotic or hip fractures in patients with osteoporosis or fragility fractures. Sensitivity (Sn), specificity (Sp), and areas under the curve (AUCs) were evaluated for all tools at different thresholds. Quality assessment was performed using the Quality Assessment of Diagnostic Accuracy Studies-2; certainty of evidence (CoE) was evaluated using the Grading of Recommendations Assessment, Development and Evaluation approach. Results: Forty-three articles were considered (40, 1, and 2 for FRAX, FRA-HS, and DeFRA, respectively), with the CoE ranging from very low to high quality. A reduction of Sn and increase of Sp for major osteoporotic fractures were observed among women and the entire population with cut-off augmentation. No significant differences were found on comparing FRAX to DeFRA in women (AUC 59–88% vs. 74%) and diabetics (AUC 73% vs. 89%). FRAX demonstrated non-significantly better discriminatory power than FRA-HS among men. Conclusion: The task force formulated appropriate recommendations on the use of any fracture risk assessment tools in patients with or at risk of fragility fractures, since no statistically significant differences emerged across different prediction tools.

Purpose: Since vertebral fragility fractures (VFFs) might increase the risk of subsequent fractures, we evaluated the incidence rate and the refracture risk of subsequent vertebral and non-vertebral fragility fractures (nVFFs) in untreated patients with a previous VFF. Methods: We systematically searched PubMed, Embase, and Cochrane Library up to February 2022 for randomized clinical trials (RCTs) that analyzed the occurrence of subsequent fractures in untreated patients with prior VFFs. Two authors independently extracted data and appraised the risk of bias in the selected studies. Primary outcomes were subsequent VFFs, while secondary outcomes were further nVFFs. The outcome of refracture within ≥ 2 years after the index fracture was measured as (i) rate, expressed per 100 person-years (PYs), and (ii) risk, expressed in percentage. Results: Forty RCTs met our inclusion criteria, ranging from medium to high quality. Among untreated patients with prior VFFs, the rate of subsequent VFFs and nVFFs was 12 [95% confidence interval (CI) 9–16] and 6 (95% CI 5–8%) per 100 PYs, respectively. The higher the number of previous VFFs, the higher the incidence. Moreover, the risk of VFFs and nVFFs increased within 2 (16.6% and 8%) and 4 years (35.1% and 17.4%) based on the index VFF. Conclusion: The highest risk of subsequent VFFs or nVFFs was already detected within 2 years following the initial VFF. Thus, prompt interventions should be designed to improve the detection and treatment of VFFs, aiming to reduce the risk of future FFs and properly implement secondary preventive measures.

Purpose: We aimed to evaluate the near-final height (nFHt) in a large cohort of pediatricpatients with growth hormone deficiency (GHD) and to elaborate a new predictive method of nFHt. Methods: We recruited GHD patients diagnosed between 1987 and 2014 and followed-up until nFHt. To predict the values of nFHt, each predictor was run in a univariable spline. Results: We enrolled 1051 patients. Pre-treatment height was −2.43 SDS, lower than parental height (THt) (−1.09 SDS, p< 0.001). The dose of recombinant human GH (rhGH) was 0.21mg/kg/week at start of treatment. nFHt was −1.08 SDS (height gain 1.27 SDS), higher than pre-treatment height (p< 0.001) and comparable to THt. 1.6% of the patients were shorter than −2 SDS from THt. The rhGH dose at nFHt was 0.19 mg/kg/week, lower than at the start (p< 0.001). The polynomial regression showed that nFHt was affected by gender, THt, age at puberty, height at puberty, age at the end of treatment (F= 325.37, p< 0.0001, R287.2%). Conclusion: This large national study shows that GHD children can reach their THt. The rhGH/kg/day dose significantly decreased from the start to the end of the treatment. Our model suggests the importance of a timely diagnosis, possibly before puberty, the beneficial effect of long-term treatment with rhGH, and the key-role of THt. Our prediction model has a very acceptable error compared to the majority of other published studies.

Poor adherence to recombinant human growth hormone (r-hGH) therapy is associated with reduced growth velocity in children with growth hormone deficiency (GHD). This twelve-month observational study was to assess adherence in r-hGH patients treated with the easypod™, an electronic, fully automated injection device designed to track the time, date and dose administered. Ninety-seven prepubertal patients receiving r-hGH therapy were included in the study from ten Italian clinical sites and 88 completed the study. To avoid possible confounding effects, only GHD patients (79/88; 89.7 % of the overall study population) were considered in the final analysis. The primary endpoint—adherence to treatment—was calculated as the proportion of injections correctly administered during the observational period out of the expected total number of injections. The relevant information, tracked by the easypod™, was collected at months 6 (V1) and 12 (V2) after baseline (V0). At study termination, adherence data were partially available from 16 patients and fully available from 53 patients. As secondary endpoints, serum IGF-1 levels, fasting serum glucose and insulin levels and key anthropometric characteristics (height, waist circumference and BMI) were also determined. The easypod™data showed that 56.7 % of the patients were considered to be fully (≥92 %) adherent to their treatment throughout the period V0–V2. Treatment improved stature, significantly increased IGF-1 and produced a non-significant increase in blood glucose and insulin levels. The injection-recording system and other characteristics of easypod™could enhance the ability of physicians to monitor adherence to r-hGH treatment.

Treatment of adolescents with growth hormone deficiency (GHD) during the transition period is a controversial issue. This paper is a contribution from the Italian community of paediatric and adult endocrinologists surveyed in a Delphi panel. The Delphi method is a structured communication technique, originally developed as a systematic, interactive forecasting method that relies on a panel of experts. The experts answer questionnaires in two or more rounds. There was substantial agreement on the definition of the problems associated with the diagnosis and treatment of adolescents with GHD in the transition period, as well as on the identification of the controversial issues which need further studies. There is general consensus on the need of re-testing all isolated idiopathic GHD after at least 30-day withdrawn from treatment, while in patients with multiple pituitary deficiency and low IGF-I levels there is generally no need to re-test. In patients with permanent or confirmed GHD, a starting low rhGH dose (0.01–0.03 mg per day) to be adjusted according to IGF-I concentrations is also widely accepted. For those continuing treatment, the optimal therapeutic schedule to obtain full somatic maturation, normalization of body composition and bone density, cardiovascular function and Quality of Life, need to be evaluated.

Background:Congenital adrenal hyperplasia (CAH) is mainly caused by the deficiency of the 21-hydroxylase enzyme coded by the CYP21A2gene. However, some alleles in the non-classical form (NC-CAH) remain without identified mutations, suggesting the involvement of regulatory regions. Aim:Our objective was to study an allele carrying the variant *13 G>A in the 3’UTR of the CYP21A2gene identified in some patients with a mild form of NC-CAH in order to verify the possible implication of this variation with the phenotype observed. Subjects and methods:Among all the subjects in whom the CYP21A2gene was analyzed, 14 patients and 7 relatives heterozygous or homozygous for the *13 G>A substitution in 3’UTR were selected. Sequencing of DNA, genotyping, multiplex ligation-dependent probe amplification (MLPA), in vitrostudies and bioinformatic analysis were performed. Results:The haplotype of the *13 G>A allele was identical in all the subjects with a monomodular structure composed by one C4Agene and one CYP21A2gene without a second module with the CYP21A1Ppseudogene. No other concomitant mutations were found in the region extending from 3 kb in the promoter and encompassing the polyadenylation signal. Both bioinformatic analysis and in vitrostudies predicted an alteration of the RNA folding and expression, but no miRNA target sequences were found in this region. Conclusions:The identification of a substitution in the 3’UTR of the gene associated with a mild form of NC-CAH suggests the importance of analyzing the CYP21A2 untranslated regions to better characterize and treat this subgroup of patients.

Pseudohypoparathyroidism type Ia (PHP-Ia) is characterized by Albright’s hereditary osteodistrophy (AHO) and resistance to hormones that act viathe α subunit of the Gs protein (Gsα) protein, ie PTH, TSH, FSH/LH, and, as recently described in limited series, GHRH. However, the current lack of data on GHRH secretion, obesity and short stature included in the AHO phenotype hampers interpretation of GH secretory status and its effects on these subjects. We evaluated GH secretion after GHRH plus arginine (Arg) stimulus, IGF-I levels and anthropometric features in an exclusively pediatric population of 10 PHP-Ia subjects. Of our PHP-Ia children, 5 out of 10 (50%) showed impaired GH responsiveness to the provocative test, with a lower prevalence than the 75–100% previously reported. A negative correlation (p=0.024) was found between GH secretion and body mass index (BMI), whereas no correlation emerged between GH and IGF-I values (p=0.948). Height and growth velocity did not significantly differ between GH-deficient and GH-sufficient subjects. In the 5 GH-deficient patients, GHRH resistance could arguably be responsible for hormonal impairment; however, 3 of them were obese, showing normal stature and IGF-I levels: the increased BMI in these subjects could influence GH secretion and its effects. In conclusion, GH deficiency is frequent among PHP-Ia children and its prevalence is variable, two factors indicating that GH secretory testing should be part of the routine management of this patient group. It could be argued that GHRH resistance is the pathogenetic mechanism in most patients, but further studies on GHRH secretion are needed to define which values can be considered as raised. Lastly, because BMI has been indicated as a major determinant of evoked adult GH response to provocative testing, GH levels related to increased BMI also in childhood could be helpful in defining GH assessment in obese or overweight PHP-Ia children.

Prolonged QT intervals and a reduced fall of nocturnal blood pressure (BP) both predict an increased risk of cardiovascular events in obese subjects. We evaluated circadian BP variations (24-h ambulatory BP monitoring), autonomic function (power spectral analysis of RR interval oscillations) and cardiac repolarization times (QTc-dispersion and QTc interval) in 70 obese women, aged 25–44 yr, grouped by WHR into group A (WHR>0.85, no.=38) and group B (WHR≤0.85, no.=32). Compared with non-obese age-matched women (no.=25, BMI=23±1.8) and obese women of group B, obese women of group A had higher values of QTc-d (p<0.05) and QTc (p<0.05), an altered sympathovagal balance (ratio of low-frequency/high-frequency power, p<0.01), and a blunted nocturnal drop in BP (p<0.01). In group A, QTc-d and the QTc interval correlated with diastolic night BP (p<0.01) and sympathovagal balance (p<0.01). WHR and plasma insulin levels correlated with QT intervals, reduced nocturnal fall in diastolic BP and sympathovagal balance (p<0.01). Prolongation of cardiac repolarization times and the reduction of nocturnal fall in BP coexist in obese women with visceral obesity, and might contribute to their raised cardiovascular risk. Autonomic dysfunction may be the common mechanism for this association.

The effects of somatostatin-14 (SS-14) and the somatostatin-analog octreotide (SMS 201-995, Sandostatin) on proliferation of GH3pituitary tumor cells were investigated in vitro. SMS 201-995 exerted a significant, but transient, inhibition on GH3cell growth which reached a maximum at 24 h and was no longer detectable at 48 h. The concentration that evoked the strongest inhibitory effect was 10 nM SMS 201-995, while lower and higher doses resulted in a less pronounced effect. The inhibitory effect SMS 201-995 exerted on cell proliferation was associated with a dose- and time-related reduction in both c-myc and c-fos mRNA levels. SS-14 had no noteworthy influence on either cell proliferation or c-myc and c-fos protooncogene expression. These data demonstrate that SS-analogs transiently inhibit pituitary tumor cell proliferation in vitro.