This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Treatment options for children with severe osteogenesis imperfecta (OI) are limited. There is no FDA-labeled drug for treatment of OI, and until recently treatment focused on fracture management and surgical correction of deformity. All medical therapies other than those directed at symptomatic pain relief, including fluoride, magnesium, calcitonin and anabolic steroids have been ineffective(Engelbert et al. 1999; Engelbert et al. 1998). 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 with Paget's Disease of bone, cancer metastases to bone and tumor induced hypercalcemia. In one recent study, even a single treatment increased BMD for 12 months(Reid et al. 2002). 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(Rosen et al. 2001). 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. We propose a clinical trial to 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 efficacy of zoledronic acid will be demonstrated if it is shown to be not inferior to pamidronate (i.e. the percentage change from baseline in bone mineral density after 12 months is less than 13% inferior to pamidronate). 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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