Comparison of Bisphosphonate Treatment Regimens on Skeletal Growth & Biomechanics

描述(由申请人提供)：双膦酸盐已被证明是安全有效的，用于治疗与人类骨吸收增加相关的疾病。然而，这些研究主要集中在生长板融合的成年人身上，因此没有纵向骨生长，很少或没有对位骨生长。虽然双膦酸类药物最初在儿科人群中的应用是为了对患有严重成骨不全的儿童进行同情治疗，但这些药物正越来越多地用于其他疾病，从预防患有结缔组织、胃肠道和肺部疾病的门诊儿童的类固醇诱发的骨质疏松症，到预防患有高钙尿的儿童的骨丢失。无论在体内还是在体外，低磷血症都会损害肥大的软骨细胞的凋亡，从而导致生长动物软骨病的发生。含氮双磷酸盐，阿伦磷酸，在体外可阻止磷酸盐介导的肥大软骨细胞的凋亡。双磷酸盐治疗的小鼠和兔的体内研究表明，长骨生长减少，伴随着肥大的软骨细胞层的扩张和皮质骨中软骨的保留。这项提案中的研究将检验双膦酸盐对骨骼生长的影响。他们将提出这样的假设，即选择双膦酸盐在体外和体内都会损害肥大的软骨细胞凋亡，并减少成熟的软骨-骨连接处的血管侵袭。他们还将解决这样的假设，即对于一些药物来说，防止骨丢失所需的剂量不会与对生长板产生不利影响的剂量相匹配。将对双膦酸盐处理的小鼠骨骼的结构特征、组织特性和生物力学完整性进行检测，以解决治疗后干骺端骨的堆积是否导致局部骨脆性区域，从而导致生物力学完整性受损。干骺端骨的密度低于治疗期间堆积的骨密度，和/或皮质骨中存在软骨。将对含氮和非含氮双膦酸盐进行研究，并将使用不同的给药时间表(每天、每两周或每隔一个月)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严重成骨不全患者的一线治疗方法，但它们预计将影响为保护骨量、骨的生物力学完整性和纵向生长而选择的药理学制剂和给药方法，这些儿童患有需要双膦酸盐治疗以将骨骼发病率降至最低的疾病。 公共卫生相关性：双膦酸盐是一种有效的抗吸收药物，可有效减少骨质疏松成人的骨折。它们被率先用于患有衰弱骨骼疾病的儿童的同情用途。它们目前正被用于儿童的其他一些适应症。然而，它们对生长板的影响以及间歇性使用它们在生长骨中的生物力学后果还没有得到检验。这项提案中的研究将检验这些制剂对生长骨骼的影响。

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. PUBLIC HEALTH RELEVANCE: 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.