title: Botox induced muscle paralysis rapidly degrades bone.
abstract: The means by which muscle function modulates bone homeostasis is poorly understood. To begin to address this issue, we have developed a novel murine model of unilateral transient hindlimb muscle paralysis using botulinum toxin A (Botox). Female C57BL/6 mice (16 weeks) received IM injections of either saline or Botox (n = 10 each) in both the quadriceps and calf muscles of the right hindleg. Gait dysfunction was assessed by multi-observer inventory, muscle alterations were determined by wet mass, and bone alterations were assessed by micro-CT imaging at the distal femur, proximal tibia, and tibia mid-diaphysis. Profound degradation of both muscle and bone was observed within 21 days despite significant restoration of weight bearing function by 14 days. The muscle mass of the injected quadriceps and calf muscles was diminished -47.3% and -59.7%, respectively, vs. saline mice (both P < 0.001). The ratio of bone volume to tissue volume (BV/TV) within the distal femoral epiphysis and proximal tibial metaphysis of Botox injected limbs was reduced -43.2% and -54.3%, respectively, while tibia cortical bone volume was reduced -14.6% (all P < 0.001). Comparison of the contralateral non-injected limbs indicated the presence of moderate systemic effects in the model that were most probably associated with diminished activity following muscle paralysis. Taken as a whole, the micro-CT data implied that trabecular and cortical bone loss was primarily achieved by bone resorption. These data confirm the decisive role of neuromuscular function in mediating bone homeostasis and establish a model with unique potential to explore the mechanisms underlying this relation. Given the rapidly expanding use of neuromuscular inhibitors for indications such as pain reduction, these data also raise the critical need to monitor bone loss in these patients.
authors.affiliation: Department of Orthopaedics and Sports Medicine, University of Washington, 325 Ninth Ave, Box 359798, Seattle, WA 98104-2499, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Warner
authors.forename: David A
authors.initials: DA
authors.lastname: Sanford
authors.forename: Blair A
authors.initials: BA
authors.lastname: Becker
authors.forename: Steven D
authors.initials: SD
authors.lastname: Bain
authors.forename: Sundar
authors.initials: S
authors.lastname: Srinivasan
authors.forename: Ted S
authors.initials: TS
authors.lastname: Gross
mesh_terms: D000818:Animals; D001837:Body Weights and Measures; D015519:Bone Density; D001851:Bone Diseases, Metabolic; D019274:Botulinum Toxins, Type A / Q000009:adverse effects*; D004195:Disease Models, Animal; D004838:Epiphyses / Q000473:pathology; D005260:Female; D005269:Femur / Q000000981:diagnostic imaging / Q000473:pathology; D005684:Gait; D006132:Growth Plate / Q000502:physiology*; D006614:Hindlimb / Q000473:pathology; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects*; D010243:Paralysis / Q000139:chemically induced*; D013997:Time Factors; D014057:Tomography, X-Ray Computed
chemical_list: D019274:Botulinum Toxins, Type A