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.
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.
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|Bajaj, Deepti; Allerton, Brianne M; Kirby, Joshua T et al. (2015) Muscle volume is related to trabecular and cortical bone architecture in typically developing children. Bone 81:217-27|
|Modlesky, C M; Whitney, D G; Singh, H et al. (2015) Underdevelopment of trabecular bone microarchitecture in the distal femur of nonambulatory children with cerebral palsy becomes more pronounced with distance from the growth plate. Osteoporos Int 26:505-12|
|Modlesky, Christopher M; Whitney, Daniel G; Carter, Patrick T et al. (2014) The pattern of trabecular bone microarchitecture in the distal femur of typically developing children and its effect on processing of magnetic resonance images. Bone 60:1-7|