Comparison of Bisphosphonate Treatment Regimens on Skeletal Growth & Biomechanics

描述（由申请方提供）：已证明双膦酸盐可安全有效地治疗与人体骨吸收增加相关的疾病。然而，这些研究集中在生长板融合的成人，因此没有纵向骨生长和很少/没有贴壁骨生长。虽然双膦酸盐给药在儿科人群中最初是为了同情地用于患有严重成骨障碍的儿童，但这些药物正越来越多地用于其他疾病，从预防受结缔组织、胃肠道和肺部疾病影响的非卧床儿童的类固醇诱导的骨质疏松症到预防高钙尿症儿童的骨丢失。低磷酸盐血症损害肥大软骨细胞的凋亡，在体内和体外，导致佝偻病的发展，在生长的动物。含氮二膦酸盐阿仑膦酸钠对磷酸盐介导的肥大软骨细胞凋亡的抑制作用。在双膦酸盐治疗的小鼠和兔体内研究表明，长骨生长减少，伴随着肥大软骨细胞层的扩张和皮质骨中软骨的保留。本提案中的研究将检查双膦酸盐对骨生长的影响。他们将解决的假设，选择双膦酸盐损害肥大软骨细胞凋亡在体外和体内，并减弱血管入侵的成熟软骨-骨交界处。他们还将解决这样的假设：对于某些药物，预防骨丢失所需的剂量与对生长板产生不利影响的剂量不平行。将检查双膦酸盐处理的小鼠骨骼的结构特征、组织性质和生物力学完整性，以确定治疗停止后干骺端骨的增加（其密度低于治疗期间增加的骨）和/或皮质骨中软骨的存在是否导致局部骨脆性区，从而导致生物力学完整性受损。将使用含氮和不含氮的双膦酸盐进行研究，并将使用不同的给药方案（每日一次、每两周一次或每两个月一次）检查急性和慢性双膦酸盐给药的后果。虽然这些研究预计不会改变双膦酸盐作为重度成骨障碍患者一线治疗的使用，但预计会影响选择用于保护骨量、骨生物力学完整性和儿童纵向生长的药理学药物和给药方法，这些疾病需要双膦酸盐治疗，以最大限度地降低骨骼发病率。

DESCRIPTION (provided by applicant): 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.