Hypercalcaemia after treatment with denosumab in children: bisphosphonates as an option for therapy and prevention?

BACKGROUND: Pharmacologic options for treatment of osteolytic diseases especially in children are limited. Although not licensed for use, denosumab, a fully humanized antibody to RANKL, is used in children with good effects. Among others, one possible indication are giant cell tumors and aneurysmatic bone cysts. However, there are reports of severe hypercalcemia during weeks to months after termination of denosumab, that are rarely seen in adults. METHODS: We collected data of four patients, aged 6-17 years, who experienced severe hypercalcemia after completion of treatment with denosumab for unresectable giant cell tumors of bone or aneurysmal bone cysts and methods of their treatment. The detailed case information were described. RESULTS: One patient was treated with long-term, high-dose steroid therapy, leading to typical Cushing's syndrome. Another patient was restarted on denosumab repeatedly due to relapses of hypercalcemia after every stop. Finally, in two patients, hypercalcemia ceased definitely after treatment with bisphosphonates. However, several applications were necessary to stabilize calcium levels. CONCLUSIONS: There is a considerable risk of hypercalcemia as an adverse effect after denosumab treatment in children. Therapeutic and, preferably, preventive strategies are needed. Bisphosphonates seem to be an option for both, but effective proceedings still remain to be established.

Evaluation of Changes in Insulin Sensitivity in Prepubertal Small for Gestational Age Children Treated with Growth Hormone.

BACKGROUND: Although growth hormone (GH) therapy for children born small for gestational age (SGA) has been approved for many years, there are still concerns about increasing their risk for insulin resistance and diabetes mellitus type 2. Monitoring of glucose homeostasis is therefore generally recommended, but there is no consensus on either the methods or consequences. METHODS AND AIMS: The aim of our study was to analyze the oral Glucose Tolerance Tests (oGTTs) which were performed yearly from baseline to 4 years of GH therapy in a collective of 93 SGA children, who were prepubertal during the whole follow-up. We looked for correlations with auxological and laboratory data as well as predictive baseline results for glucose homeostasis during further treatment. RESULTS: While glucose levels remained constant, insulin secretion increased from baseline to the first year of GH therapy. Insulin sensitivity index (ISI) showed no significant change afterwards; HOMA1, HOMA2, and QUICKI stabilized after the second year. For all indices mean values never reached pathological levels and no cases of diabetes mellitus were induced. Higher gestational age, lower birth length, and older age at start of GH therapy were associated with lower insulin sensitivity. No predictive factors for later insulin resistance could be found. CONCLUSION: As expected, in GH-treated prepubertal SGA children insulin resistance was induced, but not to pathological levels. No special risk factors for disturbed glucose homeostasis could be identified. Based on our opinion, performing oGTTs in GH-treated SGA children at baseline and in puberty should remain mandatory, but the current study recommendations regarding further surveillance of glucose homeostasis are questionable.

IRF-1 SNPs influence the risk for childhood allergic asthma: A critical role for pro-inflammatory immune regulation.

BACKGROUND: Allergic and non-allergic childhood asthma has been characterized by distinct immune mechanisms. While interferon regulating factor 1 (IRF-1) polymorphisms (SNPs) influence atopy risk, the effect of SNPs on asthma phenotype-specific immune mechanisms is unclear. We assessed whether IRF-1 SNPs modify distinct immune-regulatory pathways in allergic and non-allergic childhood asthma (AA/NA). METHODS: In the CLARA study, asthma was characterized by doctor's diagnosis and AA vs NA by positive or negative specific IgE. Children were genotyped for four tagging SNPs within IRF-1 (n = 172). mRNA expression was measured with qRT-PCR. Gene expression was analyzed depending on genetic variants within IRF-1 and phenotype including haplotype estimation and an allelic risk score. RESULTS: Carrying the risk alleles of IRF-1 in rs10035166, rs2706384, or rs2070721 was associated with increased risk for AA. Carrying the non-risk allele in rs17622656 was associated with lower risk for AA but not NA. In AA carrying the risk alleles, an increased pro-inflammatory expression of ICAM3, IRF-8, XBP-1, IFN-γ, RGS13, RORC, and TSC2 was observed. NOD2 expression was decreased in AA with risk alleles in rs2706384 and rs10035166 and with risk haplotype. Further, AA with risk haplotype showed increased IL-13 secretion. NA with risk allele in rs2070721 compared to non-risk allele in rs17622656 showed significantly upregulated calcium, innate, mTOR, neutrophil, and inflammatory-associated genes. CONCLUSION: IRF-1 polymorphisms influence the risk for childhood allergic asthma being associated with increased pro-inflammatory gene regulation. Thus, it is critical to implement IRF-1 genetics in immune assessment for childhood asthma phenotypes.

Needle-Free and Needle-Based Growth Hormone Therapy in Children: A Pooled Analysis of Three Long-Term Observational Studies.

BACKGROUND: Treatment with growth hormone (GH) is standard clinical practice in children with GH deficiency (GHD) or Turner syndrome (TS). Hitherto, no long-term data on auxological outcome and safety of Zomacton® have been published. Data comparing needle-free administration (NF) and needle injection (NI) of GH are very sparse. AIMS: To analyse longitudinal auxological outcome and safety data of GH treatment-naïve patients diagnosed with GHD or TS and to compare NF and NI in a real-life setting. METHODS: Pooled auxological data and safety information from three consecutive prospective observational Zomacton® studies covering 22 years of treatment were analysed and NF was compared to NI. RESULTS: The safety cohort comprised 1,595 patients who received at least one GH dose. The auxological outcome cohort comprised 856 treatment-naïve patients with follow-up data ≥12 months. Height-SDS and height velocity improved significantly during the first 3 years of treatment. Documented choice of device was available for 658 patients (NF 69.1%, NI 30.9%). NF administration was non-inferior to NI. No previously unknown safety signals occurred. CONCLUSION: Real-life data show that treatment with Zomacton® improves auxological outcome parameters without new safety concerns. NF administration of GH represents a useful alternative to NI in children with growth disorders.

Effect of antiandrogen treatment on bone density and bone geometry in adolescents with polycystic ovary syndrome.

STUDY OBJECTIVES: To determine the impact of antiandrogen treatment on bone density and geometry. DESIGN: Prospective cohort investigation. SETTING: Academic research institute. PARTICIPANTS: 38 (age 14.96 ± 1.42 yr) subjects with PCOS. INTERVENTIONS: Treated with metformin (n = 17) or metformin and antiandrogen (n = 21). MAIN OUTCOME MEASURE: Bone density and geometry parameters at baseline and after a mean duration of 1.92 ± 0.88 years using peripheral quantitative computed tomography of the forearm. RESULTS: At baseline, z-scores for trabecular (0.53 ± 1.02) and cortical BMD (0.79 ± 1.55) as well as total (0.62 ± 1.07) and medullary cross sectional area (CSA) (0.79 ± 1.29) were elevated. Cortical CSA (-0.01 ± 1.10) and bone strength strain index (SSI) z-scores (-0.01 ± 1.10) were normal. Muscle CSA z-score (0.12 ± 1.70) was normal, but grip strength (-1.60 ± 1.15) was significantly reduced. There were no significant changes within and between the two treatment options in respect to bone density and bone geometry parameters. With antiandrogen treatment, free androgen index (FAI) was significantly lower and grip strength further decreased (P < .001). CONCLUSIONS: No significant changes in bone mineral density and geometry parameters took place in PCOS women irrespective of treatment followed over a time of almost two years. General muscle weakness expressed as low grip strength may influence further bone development in PCOS.

The effect of cardiovascular risk factors on the longitudinal evolution of the carotid intima medial thickness in children with type 1 diabetes mellitus.

BACKGROUND: Type 1 diabetes mellitus is a generally accepted atherogenic risk factor. The aim of this prospective longitudinal study was to evaluate changes in carotid intima media thickness (cIMT) in children and adolescents with type 1 diabetes mellitus (T1DM) using standardized methods. METHODS: We re-evaluated cIMT in 70 (38 f) of initial 150 (80 f) patients with T1DM after 4 years. At re-evaluation, mean (±SD) age was 16.45±2.59 y, mean diabetes duration was 9.2±3.24 y and patients had a mean HbA1c of 8.14±1.06%. RESULTS: Mean cIMT z-scores increased significantly during 4 years (0.58±0.75, p<0.001) as well as BMI-z-score (0.41±0.81, p<0.01), systolic blood pressure (0.77±1.15, p<0.01) and HbA1c (0.90±1.07, <0.001). In a linear regression model systolic blood pressure z-score at first measurement (0.02, CI: 0.01, 0.04) was a significant predictor for the mean effect on cIMT z-score. In a logistic regression model significant risk factors for an increase in IMT of ≥1.5 z-scores were BMI z-scores (OR: 3.02, CI:1.11, 10.14), diabetes duration (OR:1.32, CI:1.04, 1.77) and systolic blood pressure (OR: 1.14, CI: 1.04, 1.27) at first measurement each. CONCLUSIONS: Longitudinal cIMT measurements revealed progression in subclinical atherosclerosis during a four year period in diabetic children and adolescents. Systolic blood pressure and BMI were related to cIMT increment. Control of these risk factors by lifestyle and medical intervention may prevent progression of cIMT in diabetic children.