Effect of botulinum toxin plus vibration on bone in children with cerebral palsy

肉毒毒素联合振动对脑瘫患儿骨骼的影响

• 批准号: 8232897
• 负责人: CHRISTOPHER M MODLESKY
• 金额: $ 46.42万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-15 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8232897
• 关键词: Affect; Animals; Bone Development; Bone Mineral Contents; Bone Resorption; Botulinum Toxins; C-terminal type I collagen telopeptide; Cerebral Palsy; Child; Chronic; Cyclophosphamide; Data; Deterioration; Development; Disabled Children; Disease; Dual-Energy X-Ray Absorptiometry; Femur; Fracture; Frequencies; Goals; Home environment; Human; Incidence; Individual; Intervention; Lower Extremity; Magnetic Resonance Imaging; Monitor; Muscle; Muscle Spasticity; Muscle Tonus; Neuromuscular Diseases; Osteocalcin; Osteogenesis; Outcome; Paralysed; Pilot Projects; Public Health; Publishing; Randomized; Research; Safety; Serum; Spastic Cerebral Palsy; Stimulus; Structure; Testing; Therapy Clinical Trials; Work; arm; base; bone; bone mass; bone turnover; common treatment; disability; improved; innovation; insight; lower limb bone structure; skeletal; tibia; vibration

DESCRIPTION (provided by applicant): Recent animal studies suggest Botulinum toxin (Botox) degrades bone. This may pose a significant problem for children with spastic cerebral palsy (CP) because they are often treated with Botox and they already feature low bone mass and underdeveloped bone structure in the lower extremities. The long-term goal is to optimize bone development and minimize short and long-term fracture incidence in children with disabilities. The overall objective of this application is to gather preliminary data that will be used to inform a larger-scale study aimed at determining the extent to which Botox treatment has a deleterious effect on bone in children with CP, the mechanism(s) of action and the degree to which this effect can be mitigated by a high-frequency, low- magnitude vibration (HLV) stimulus. The central hypothesis of this application is that Botox treatment of the lower extremities impairs the accretion of bone mineral content (BMC) and the development of trabecular and cortical bone structure in the femur and tibia through alterations in bone turnover and that the Botox-induced deterioration of bone can be mitigated by a daily HLV stimulus. This hypothesis is based on recent studies demonstrating increased bone resorption, a remarkable loss of trabecular structures and an inhibition of periosteal expansion in animals injected with Botox. Furthermore, published studies indicate that a daily HLV stimulus can increase BMC and improve bone structure in the lower extremity bones of children with CP. The rationale for this pilot study is that it will allow us to plan a larger scale study, the findings of which will enable us to determine if the safety of Botox needs to be reevaluated and if HLV is an effective strategy for counteracting the expected negative effects of Botox on bone. To test the central hypothesis, the following specific aims will be used: 1) to determine the effect of Botox treatment in conjunction with a daily HLV stimulus on BMC and bone structure in children with spastic CP; and 2) to identify the mechanism that underlies the deleterious effect of Botox on bone and the mechanism by which the Botox effect is offset by a daily HLV stimulus in children with spastic CP. A pilot therapeutic trial with two randomized treatment arms (Botox and Botox + HLV) and a convenience control arm of children with CP (5 - 11 y) will be used to accomplish the aims. Changes in BMC will be assessed using dual-energy x-ray absorptiometry, changes in bone structure will be assessed using magnetic resonance imaging, changes in bone formation will be assessed using serum osteocalcin, and changes in bone resorption will be assessed using C-terminal telopeptide of type I collagen (CTX-1). The HLV will be administered at home 10 min/d for 6 months and compliance will be monitored. The proposed study is significant because Botox is a common treatment for spasticity and other chronic conditions. The proposed study is innovative because the effect of Botox on human bone has not been examined. Furthermore, if there are signs that the expected devastating effect of Botox on bone is offset by a simple HLV treatment, it would provide an exciting direction for future research. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because botulinum toxin (Botox) is commonly used to treat muscle spasticity and other disorders. A more complete understanding of the skeletal consequences of Botox treatment on human bone is needed. If Botox is found to degrade the bones of children with cerebral palsy and if the expected degradation can be offset by a mild vibration treatment each day, it would have a dramatic effect on the approach used to manage spasticity and other disorders in which Botox is a common treatment.

描述（由申请人提供）：最近的动物研究表明肉毒杆菌毒素（肉毒杆菌毒素）降解了骨骼。这可能对患有痉挛性脑瘫（CP）的儿童构成一个重大问题，因为他们经常接受肉毒杆菌毒素治疗，并且已经以低骨量和下肢中的骨质欠发达骨结构为特征。长期目标是优化骨骼发育并最大程度地减少残疾儿童的短期和长期骨折发生率。该应用程序的总体目的是收集初步数据，该数据将用于告知一项较大规模的研究，旨在确定肉毒杆菌治疗对CP儿童的骨骼，动作机制的有害作用，以及这种效果可以通过高频率，低尺度振动（HLV）刺激性来缓解这种效果的程度。该应用的核心假设是，下肢的肉毒杆菌治疗会损害骨矿物质含量的吸收（BMC），以及通过改变骨骼转换的改变，股骨和胫骨的小梁和皮质骨结构的发展，并且肉毒杆菌毒素诱导的每日HLV刺激可以降低骨骼的恶化。该假设基于最近的研究表明骨吸收增加，小梁结构的显着丧失以及注射肉毒杆菌毒素的动物骨膜扩张的抑制作用。此外，已发表的研究表明，每天的HLV刺激可以增加BMC并改善CP儿童下肢骨骼的骨骼结构。这项试验研究的基本原理是，它将允许我们计划进行大规模研究，其发现将使我们能够确定肉毒杆菌毒素的安全是否需要重新评估，以及HLV是否是抵消肉毒杆菌毒素对骨骼的预期负面影响的有效策略。为了检验中心假设，将使用以下特定目的：1）确定肉毒杆菌毒素治疗与每日HLV刺激对痉挛性CP儿童的BMC和骨结构的影响； 2）确定肉毒杆菌毒素对骨骼的有害作用的机制以及肉毒杆菌毒素效应被痉挛性CP儿童的每日HLV刺激所抵消的机制。一项具有两个随机治疗组（肉毒杆菌毒素和肉毒杆菌毒素 + HLV）和CP儿童（5-11 Y）的便利控制臂的试验治疗试验将用于实现目标。 BMC的变化将使用双能X射线吸收法评估，骨结构的变化将使用磁共振成像进行评估，将使用血清骨钙素评估骨形成的变化，并将使用I型I型collagen（CTX-1）的C端端肽（CTX-1）评估骨吸收的变化。 HLV将在家里进行10分钟/d的持续6个月，并将监控合规性。拟议的研究很重要，因为肉毒杆菌毒素是痉挛和其他慢性疾病的常见治疗方法。拟议的研究具有创新性，因为尚未研究肉毒杆菌毒素对人骨的影响。此外，如果有迹象表明肉毒杆菌毒素对骨骼的预期破坏作用被简单的HLV处理所抵消，它将为未来的研究提供一个令人兴奋的方向。 公共卫生相关性：拟议的研究与公共卫生有关，因为肉毒杆菌毒素（肉毒杆菌素）通常用于治疗肌肉痉挛和其他疾病。需要更完整地了解肉毒杆菌毒素治疗对人骨的骨骼后果。如果发现肉毒杆菌毒素会降解脑瘫儿童的骨骼，并且每天可以通过轻度的振动治疗来抵消预期的降解，则它将对管理痉挛和其他肉毒杆菌毒素的方法具有巨大影响。

项目成果

The pattern of trabecular bone microarchitecture in the distal femur of typically developing children and its effect on processing of magnetic resonance images.

典型发育儿童股骨远端骨小梁微结构的模式及其对磁共振图像处理的影响。

• DOI: 10.1016/j.bone.2013.11.009
• 发表时间: 2014
• 期刊: Bone
• 影响因子: 4.1
• 作者: Modlesky,ChristopherM;Whitney,DanielG;Carter,PatrickT;Allerton,BrianneM;Kirby,JoshuaT;Miller,Freeman
• 通讯作者: Miller,Freeman

Site-Specific Transmission of a Floor-Based, High-Frequency, Low-Magnitude Vibration Stimulus in Children With Spastic Cerebral Palsy.

痉挛性脑瘫儿童基于地板的高频、低强度振动刺激的特定部位传输。

• DOI: 10.1016/j.apmr.2015.08.434
• 发表时间: 2016
• 期刊: Archives of physical medicine and rehabilitation
• 影响因子: 4.3
• 作者: Singh,Harshvardhan;Whitney,DanielG;Knight,ChristopherA;Miller,Freeman;Manal,Kurt;Kolm,Paul;Modlesky,ChristopherM
• 通讯作者: Modlesky,ChristopherM