This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Treatment options for children with severe osteogenesis imperfecta (OI) are limited. Bisphosphonates, the synthetic analogs of pyrophosphate, have been widely used for the treatment of adults suffering from bone loss and bone fragility. Recent studies of the bisphosphonate, pamidronate, in children with severe osteogenesis imperfecta show an increase in BMD evident as early as six weeks after the start of treatment. Without exception, this gain in BMD has been greater than the increase expected in healthy children. Signs of bone pain disappear within days of receiving the bisphosphonate and a marked decrease in fracture rate is observed despite a higher risk of injury due to increased mobility. Though not yet used in the treatment of osteogenesis imperfecta, the bisphosphonate zoledronic acid has been shown to be safe and efficacious in the treatment of adults. Comparison with pamidronate infusion in adult patients with tumor-induced hypercalcemia shows zoledronic acid to be more effective than pamidronate when approximate adult doses of the two medications were administered. Additionally, pamidronate administration requires 4-hour infusions over 3 consecutive days per treatment cycle while zoledronic acid dosing is a single 30-minute infusion per treatment cycle of the same length. Indeed, once safety and efficacy are established, zoledronate may prove to be a superior alternative to pamidronate for the treatment of severe osteogenesis imperfecta in children. Through this clinical trial, we will evaluate the efficacy and safety of zoledronic acid in the treatment of severe osteogenesis imperfecta in children. A non-inferiority design has been chosen due to the ethical difficulty of conducting a placebo-controlled trial in this patient population. Since pamidronate is the currently known off-label therapy for treating these children, study objectives will compare changes in zoledronic acid treated patients with changes in pamidronate treated patients. The safety of zoledronic acid for the treatment of severe osteogenesis imperfecta in children will be shown through the monitoring of tolerability, renal safety, general safety and adverse events.
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