Recurrent Proximal Femur Fractures in a Teenager With Osteogenesis Imperfecta on Continuous Bisphosphonate Therapy: Are We Overtreating?

Long-term bisphosphonate (BP) therapy in adults with osteoporosis is associated with atypical femoral fractures, caused by increased material bone density and prolonged suppression of bone remodeling which may reduce fracture toughness. In children with osteogenesis imperfecta (OI), long-term intravenous BP therapy improves bone structure and mass without further increasing the already hypermineralized bone matrix, and is generally regarded as safe. Here we report a teenage girl with OI type IV, who was started on cyclical intravenous pamidronate therapy at age 6 years because of recurrent fractures. Transiliac bone biopsy revealed classical structural features of OI but unusually low bone resorption surfaces. She made substantial improvements in functional ability, bone mass, and fracture rate. However, after 5 years of pamidronate therapy she started to develop recurrent, bilateral, nontraumatic, and proximal femur fractures, which satisfied the case definition for atypical femur fractures. Some fractures were preceded by periosteal reactions and prodromal pain. Pamidronate was discontinued after 7 years of therapy, following which she sustained two further nontraumatic femur fractures, and continued to show delayed tibial osteotomy healing. Despite rodding surgery, and very much in contrast to her affected, untreated, and normally mobile mother, she remains wheelchair-dependent. The case of this girl raises questions about the long-term safety of BP therapy in some children, in particular about the risk of oversuppressed bone remodeling with the potential for microcrack accumulation, delayed healing, and increased stiffness. The principal concern is whether there is point at which benefit from BP therapy could turn into harm, where fracture risk increases again. This case should stimulate debate whether current adult atypical femoral fracture guidance should apply to children, and whether low-frequency, low-dose cyclical, intermittent, or oral treatment maintenance regimens should be considered on a case-by-case basis. © 2016 American Society for Bone and Mineral Research.

Neonatal Diabetes in a Singapore Children's Hospital: Molecular Diagnoses of Four Cases.

INTRODUCTION: Neonatal diabetes (ND) presents below 6 months of age, and is caused by a genetic defect in glucose homeostasis. Molecular genetic diagnosis can identify the exact molecular aetiology and guide clinical management. The objective of this study was to identify ND among children with diabetes in a major children's hospital in Singapore and to characterise their molecular and clinical features. MATERIALS AND METHODS: The study identified all infants below 6 months of age who presented with diabetes to our centre from January 2008 to December 2010. It also reviewed diabetes database comprising 662 patients, to identify those who were diagnosed with diabetes below 6 months of age between January 1997 and December 2010. Four patients (3 females and 1 male) were identified and their molecular aetiology was investigated. RESULTS: A molecular aetiology was found in each of the 4 patients identified. Two patients (Patient 1 and 2) had permanent ND (PND). Patient 1 who has KCNJ11/R201H mutation was successfully switched from insulin to oral glibenclamide and Patient 2 who has a novel mutation INS/C109Y continues to be treated with insulin. Two patients (Patient 3 and 4) had transient ND (TND) and no longer require insulin or any other intervention to maintain normoglycaemia. Patient 3 has a novel mutation ABCC8/F1182S and Patient 4 has a paternal duplication on chromosome 6q24. CONCLUSION: This study identified 4 cases of ND in our cohort of diabetes children and confirmed their molecular diagnosis. Molecular genetic testing for these children led to accurate diagnosis and appropriate management.