Dataset Information

Rodent model of disuse-induced bone loss by hind limb injection with botulinum toxin A.

ABSTRACT: Bone loss materializes rapidly after immobilization or mechanical unloading. Hind limb injection with botulinum toxin A (BTX) is a highly reproducible animal model for disuse-induced bone loss. Here we describe an easy-to-use and enhanced version of the method employing multiple hind limb injections with BTX to induce a pervasive muscle paralysis and thereby disuse of the hind limb. Thirty-six 12-14-week-old female Wistar rats were stratified into three groups: Baseline (Base), Control (Ctrl), and BTX. Disuse was achieved by injecting BTX directly into the right quadriceps femoris muscle, the hamstring muscles, and the posterior calf muscles. The rats were sacrificed after six weeks, and the right rectus femoris muscle and femur were isolated and analyzed. Hind limb disuse resulted in a significant and substantial loss of both muscle mass and bone mass. The loss of bone mass was accompanied by a reduction of trabecular bone mass and a deterioration of the trabecular micro-architecture with a reduction of trabecular thickness and trabecular number compared to Ctrl. In addition, the trabeculae changed from a more plate-like towards a more rod-like shape as indicated by an increase in the structure model index.•Multiple injections with BTX targeting muscles on both the anterior and posterior thigh and the calf ensure a uniform and pervasive muscle paralysis and hind limb disuse.•Hind limb injections with BTX results in a substantial loss of muscle and bone mass and deterioration of the trabecular micro-architecture.•The induction of hind limb disuse with BTX is highly reproducible.

SUBMITTER: Brent MB

PROVIDER: S-EPMC7551361 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Rodent model of disuse-induced bone loss by hind limb injection with botulinum toxin A.

Brent Mikkel Bo MB Lodberg Andreas A Thomsen Jesper Skovhus JS Brüel Annemarie A

MethodsX 20201003

Bone loss materializes rapidly after immobilization or mechanical unloading. Hind limb injection with botulinum toxin A (BTX) is a highly reproducible animal model for disuse-induced bone loss. Here we describe an easy-to-use and enhanced version of the method employing multiple hind limb injections with BTX to induce a pervasive muscle paralysis and thereby disuse of the hind limb. Thirty-six 12-14-week-old female Wistar rats were stratified into three groups: Baseline (Base), Control (Ctrl), a ...[more]

PMID: 33083241

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Project description:Repeated injection cycles with abobotulinumtoxinA, a botulinum toxin type A, are recommended in current clinical guidelines as a treatment option for adults with upper limb spastic paresis. However, the magnitude of the maximal therapeutic effect of repeated abobotulinumtoxinA treatment across different efficacy parameters and the number of injection cycles required to reach maximal effect remain to be elucidated. Here, we present a post hoc exploratory analysis of a randomized, double-blind, placebo-controlled trial (12-24 weeks; NCT01313299) and open-label extension study (up to 12 months; NCT0131331), in patients aged 18-80 years with hemiparesis for ≥6 months after stroke/traumatic brain injury. Two inferential methods were used to assess the changes in efficacy parameters after repeat abobotulinumtoxinA treatment cycles: Mixed Model Repeated Measures analysis and Non-Linear Random Coefficients analysis. Using the latter model, the expected maximal effect size (not placebo-controlled) and the number of treatment cycles to reach 90% of this maximal effect were estimated. Treatment responses in terms of passive and perceived parameters (i.e. modified Ashworth scale in primary target muscle group, disability assessment scale for principal target for treatment or limb position, and angle of catch at fast speed) were estimated to reach near-maximal effect in two to three cycles. Near-maximal treatment effect for active parameters (i.e. active range of motion against the resistance of extrinsic finger flexors and active function, assessed by the Modified Frenchay Scale) was estimated to be reached one to two cycles later. In contrast to most parameters, active function showed greater improvements at Week 12 (estimated maximal change from baseline-modified Frenchay Scale overall score: +0.8 (95% confidence interval, 0.6; 1.0) than at Week 4 (+0.6 [95% confidence interval, 0.4; 0.8]). Overall, the analyses suggest that repeated treatment cycles with abobotulinumtoxinA in patients chronically affected with upper limb spastic paresis allow them to relearn how to use the affected arm with now looser antagonists. Future studies should assess active parameters as primary outcome measures over repeated treatment cycles, and assess efficacy at the 12-week time-point of each cycle, as the benefits of abobotulinumtoxinA may be underestimated in the studies of insufficient duration. Abbreviated summary In this post hoc analysis of repeated abobotulinumtoxinA injection cycles in upper limb spastic paresis, Gracies et al. used statistical modelling to elucidate the maximal therapeutic effect of abobotulinumtoxinA. Notably, the number of injections required to reach this maximal effect was higher for active (e.g. active function) compared with passive (e.g. tone) parameters.

Project description:ObjectivesThe therapeutic effects of botulinum neurotoxin (BoNT) are well documented in upper limb spasticity. However, several factors may influence treatment efficacy, including targeting of neuromuscular junctions (NMJs). We examined whether NMJ-targeted BoNT injections were non-inferior, in terms of efficacy, to current injection practices.DesignOpen-label prospective evaluator-blinded study.SettingConducted across 20 medical centres in Denmark, Finland, Norway and Sweden (24 September 2012 to 11 March 2015).ParticipantsAged ˃18 years with upper limb spasticity (Modified Ashworth Scale [MAS] score of 2 or 3) following stroke or traumatic brain injury, had received ≥2 consecutive BoNT-A treatment cycles (the latest of which was abobotulinumtoxinA [aboBoNT-A]) and needed BoNT-A retreatment (same modality as previous cycle). Patients requiring aboBoNT-A doses >800units were excluded. In total, 88 patients were randomised (intention-to-treat [ITT] population), most were male (n=58/88, 65.9%) and 54/88 (61.4%) completed the study (per protocol [PP] population).InterventionsRandomisation (1:1) to receive a single dose of aboBoNT-A (≤800 U) according to either current clinical practice (300 U/mL) or as an NMJ-targeted injection (100 U/mL).Primary outcome measureProportion of patients with a ≥1 level reduction from baseline in MAS score at week 4 post-injection (responders).ResultsIn the ITT population, the proportion of responders at elbow flexors was 72.7% in the current practice group and 56.8% in the NMJ-targeted group (adjusted difference -0.1673 [95% CIs: -0.3630 to 0.0284]; p=0.0986). Similar results were observed in the PP population (69.0% vs 68.0%, respectively, adjusted difference 0.0707 [-0.1948 to 0.3362]; p=0.6052).ConclusionsOwing to the limited number of participants, non-inferiority of NMJ-targeted injections could not be determined. However, there was no statistical difference between groups. Larger studies are needed confirm whether the two techniques offer comparable efficacy.Trial registration numberNCT01682148.

Dataset Information

Rodent model of disuse-induced bone loss by hind limb injection with botulinum toxin A.

Publications

Rodent model of disuse-induced bone loss by hind limb injection with botulinum toxin A.

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