Comparison of Bisphosphonate Treatment Regimens on Skeletal Growth & Biomechanics

双膦酸盐治疗方案对骨骼生长的影响比较

• 批准号: 8135462
• 负责人: Marie Demay
• 金额: $ 30.59万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8135462
• 关键词: Acute; Address; Adult; Affect; Affinity; Aftercare; Alendronate; Animals; Apoptosis; Attenuated; Binding; Biomechanics; Blood Vessels; Bone Density; Bone Growth; Bone Matrix; Bone Resorption; Cartilage; Cerebrum; Characteristics; Child; Childhood; Chondrocytes; Chronic; Connective Tissue; Control Groups; Cytochromes; Data; Development; Disease; Dose; Epiphysial cartilage; Fracture; Gastrointestinal Diseases; Growth; Human; Hypophosphatemia; In Vitro; Individual; Investigation; Lead; Lung diseases; Mature Bone; Mediating; Methods; Morbidity - disease rate; Mus; Nitrogen; Oryctolagus cuniculus; Osteoclasts; Osteogenesis Imperfecta; Osteoporosis; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphorylation; Population; Prevention; Property; Randomized Clinical Trials; Rickets; Rodent; Schedule; Severities; Skeleton; Steroids; TNFSF11 gene; Testing; Therapeutic Index; Tissues; Torsion; Treatment Protocols; annexin A5; base; bisphosphonate; bone; bone loss; bone mass; caspase-9; clinical practice; design; effective therapy; hypercalciuria; in vivo; inhibitor/antagonist; inorganic phosphate; long bone; prevent; public health relevance; senescence; skeletal; skeletal disorder

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.

描述（由申请人提供）：双膦酸盐已被证明对于治疗与人类骨吸收增加相关的疾病是安全有效的。然而，这些研究主要针对生长板融合的成年人，因此没有纵向骨生长，并且很少/没有并置骨生长。尽管双膦酸盐在儿科人群中的应用最初是为了同情性地用于患有严重成骨不全的儿童，但这些药物越来越多地用于其他疾病，其严重程度包括预防受结缔组织、胃肠道影响的活动儿童类固醇引起的骨质疏松症。和肺部疾病，以预防高钙尿症儿童的骨质流失。低磷血症在体内和体外都会损害肥大软骨细胞的凋亡，导致生长动物患佝偻病。含氮双膦酸盐阿仑膦酸盐可在体外防止磷酸盐介导的肥大软骨细胞凋亡。双膦酸盐治疗的小鼠和兔子的体内研究表明，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。该提案中的研究将检查双膦酸盐对骨骼生长的影响。他们将提出这样的假设：选择双磷酸盐会在体外和体内损害肥大软骨细胞凋亡，并减弱成熟软骨-骨连接处的血管侵袭。他们还将提出这样的假设：对于某些药物来说，预防骨质流失所需的剂量与对生长板产生不利影响的剂量并不相同。将检查双膦酸盐治疗小鼠骨骼的结构特征、组织特性和生物力学完整性，以确定治疗停止后干骺端骨是否增长（其密度比治疗期间增长的骨密度低）和/或皮质中是否存在软骨。骨，导致局部骨脆性区域，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磷酸盐作为严重成骨不全患者一线治疗的使用，但预计它们会对为保持骨量、骨生物力学完整性和纵向生长而选择的药物和给药方法产生影响患有需要双磷酸盐治疗以尽量减少骨骼发病率的疾病的儿童。 公共卫生相关性：双磷酸盐是有效的抗骨吸收剂，可有效减少骨质疏松成人的骨折。它们率先用于同情性地用于患有骨骼衰弱疾病的儿童。它们目前正用于儿童的许多其他适应症。然而，它们对生长板的影响以及间歇性使用它们在骨骼生长中的生物力学后果尚未得到研究。该提案中的研究将检查这些药物对骨骼生长的影响。