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

描述（由申请人提供）：最近的动物研究表明肉毒杆菌毒素（Botox）会降解骨骼。这对患有痉挛性脑瘫（CP）的儿童来说可能是一个严重的问题，因为他们经常使用肉毒杆菌治疗，并且他们已经具有低骨量和下肢骨结构不发达的特点。长期目标是优化骨骼发育，减少残疾儿童的短期和长期骨折发生率。本应用程序的总体目标是收集初步数据，这些数据将用于更大规模的研究，旨在确定肉毒杆菌毒素治疗对CP儿童骨骼的有害影响程度、作用机制以及通过高频、低幅度振动（HLV）刺激减轻这种影响的程度。该应用的中心假设是，通过改变骨转换，肉毒杆菌素治疗下肢会损害骨矿物质含量（BMC）的增加以及股骨和胫骨骨小梁和皮质骨结构的发育，并且肉毒杆菌素诱导的骨退化可以通过每日HLV刺激来减轻。这一假设是基于最近的研究表明，在注射肉毒杆菌毒素的动物中，骨吸收增加，小梁结构明显丧失，骨膜扩张受到抑制。此外，已发表的研究表明，每日HLV刺激可以增加BMC并改善CP儿童下肢骨骼的骨结构。这项初步研究的基本原理是，它将使我们能够计划更大规模的研究，其结果将使我们能够确定是否需要重新评估肉毒杆菌毒素的安全性，以及HLV是否是一种有效的策略来抵消肉毒杆菌毒素对骨骼的预期负面影响。为了验证中心假设，将使用以下具体目标：1)确定肉毒杆菌毒素治疗结合每日HLV刺激对痉挛性CP儿童BMC和骨结构的影响；2)确定肉毒杆菌毒素对骨骼有害作用的机制，以及肉毒杆菌毒素作用被痉挛型CP儿童每日HLV刺激所抵消的机制。将采用两个随机治疗组（肉毒杆菌毒素和肉毒杆菌毒素+ HLV）和一个方便控制组的CP儿童（5 - 11岁）进行试点治疗试验，以实现目标。使用双能x线吸收仪评估BMC的变化，使用磁共振成像评估骨结构的变化，使用血清骨钙素评估骨形成的变化，使用I型胶原c端端肽（CTX-1）评估骨吸收的变化。HLV将在家中每天使用10分钟，持续6个月，并监测依从性。这项研究意义重大，因为肉毒杆菌毒素是治疗痉挛和其他慢性疾病的常用药物。这项提议的研究具有创新性，因为肉毒杆菌素对人体骨骼的影响尚未得到检验。此外，如果有迹象表明，肉毒杆菌毒素对骨骼的破坏性影响可以通过简单的HLV治疗来抵消，这将为未来的研究提供一个令人兴奋的方向。

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.