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.

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.

A recessive mutation resulting in a disabling amino acid substitution (T194R) in the LHX3 homeodomain causes combined pituitary hormone deficiency.

BACKGROUND/AIMS: Recessive mutations in the LHX3 homeodomain transcription factor gene are associated with developmental disorders affecting the pituitary and nervous system. We describe pediatric patients with combined pituitary hormone deficiency (CPHD) who harbor a novel mutation in LHX3. METHODS: Two female siblings from related parents were examined. Both patients had neonatal complications. The index patient had CPHD featuring deficiencies of GH, LH, FSH, PRL, and TSH, with later onset of ACTH deficiency. She also had a hypoplastic anterior pituitary, respiratory distress, hearing impairment, and limited neck rotation. The LHX3 gene was sequenced and the biochemical properties of the predicted altered proteins were characterized. RESULTS: A novel homozygous mutation predicted to change amino acid 194 from threonine to arginine (T194R) was detected in both patients. This amino acid is conserved in the DNA-binding homeodomain. Computer modeling predicted that the T194R change would alter the homeodomain structure. The T194R protein did not bind tested LHX3 DNA recognition sites and did not activate the α-glycoprotein and PRL target genes. CONCLUSION: The T194R mutation affects a critical residue in the LHX3 protein. This study extends our understanding of the phenotypic features, molecular mechanism, and developmental course associated with mutations in the LHX3 gene.