Bisphosphonates have been shown to be safe and effective for the treatment of disorders associated with increased bone resorption in humans. However, these studies have focused on adults in whom the growth plate is fused, thus there is no longitudinal bone growth and little/no appositional bone growth. Although bisphosphonate administration in the pediatric population was initially pioneered for compassionate use in children with severe osteogenesis imperfecta, these medications are being increasingly used for other disorders, ranging in severity from the prevention of steroid-induced osteoporosis in ambulatory children affected with connective tissue, gastrointestinal and pulmonary diseases, to prevention of bone loss in children with hypercalciuria. Hypophosphatemia impairs apoptosis of hypertrophic chondrocytes, both in vivo and in vitro, leading to the development of rickets in growing animals. The nitrogen-containing bisphosphonate, alendronate, prevents phosphate-mediated apoptosis of hypertrophic chondrocytes in vitro. In vivo studies in bisphosphonate-treated mice and rabbits demonstrate decreased long bone growth, accompanied by expansion of the hypertrophic chondrocyte layer and retention of cartilage in cortical bone. The studies in this proposal will examine the effects of bisphosphonates on growing bone. They will address the hypothesis that select bisphosphonates impair hypertrophic chondrocyte apoptosis in vitro and in vivo and attenuate vascular invasion of the maturing chondro-osseous junction. They will also address the hypothesis that for some agents, the doses required for prevention of bone loss will not parallel that which adversely effects the growth plate. The structural characteristics, tissue properties and biomechanical integrity of the skeleton of bisphosphonate treated mice will be examined to address whether the accrual of metaphyseal bone after treatment discontinuation, which has lower density than bone accrued during treatment, and/or the presence of cartilage in cortical bone, result in zones of localized bone fragility leading to impaired biomechanical integrity. Investigations will be performed with nitrogen and non-nitrogen containing bisphosphonates and will examine the consequences of acute and chronic bisphosphonate administration using different administration schedules (daily, bi-weekly or every other month). While these investigations are not expected to change the use of bisphosphonates as the first line of therapy for patients with severe osteogenesis imperfecta, they are expected to impact on the pharmacological agent and delivery method selected to preserve bone mass, biomechanical integrity of bone and longitudinal growth in children with disorders that require bisphosphonate treatment to minimize skeletal morbidity.
Bisphosphonates are potent antiresorptive agents that are effective in decreasing fractures in osteoporotic adults. They were pioneered for compassionate use in children with debilitating skeletal disorders. They are currently being used for a number of other indications in children. However, their effect on the growth plate and the biomechanical consequences of their intermittent use in growing bone has not been examined. The studies in this proposal will examine the effects of these agents on the growing skeleton.