Reduced bone formation markers, and altered trabecular and cortical bone mineral densities of non-paretic femurs observed in rats with ischemic stroke: A randomized controlled pilot study.

Karen N Borschmann,Peta N Skeers,Rachel A Davey,Julie Bernhardt,Heidi Ho,Ali Ghasem-Zadeh,David W Howells,Sandra Iuliano,Sarah S Rewell,Joseph M Wallace

doi:10.1371/journal.pone.0172889

Abstract

BackgroundImmobility and neural damage likely contribute to accelerated bone loss after stroke, and subsequent heightened fracture risk in humans.ObjectiveTo investigate the skeletal effect of middle cerebral artery occlusion (MCAo) stroke in rats and examine its utility as a model of human post-stroke bone loss.MethodsTwenty 15-week old spontaneously hypertensive male rats were randomized to MCAo or sham surgery controls. Primary outcome: group differences in trabecular bone volume fraction (BV/TV) measured by Micro-CT (10.5 micron istropic voxel size) at the ultra-distal femur of stroke affected left legs at day 28. Neurological impairments (stroke behavior and foot-faults) and physical activity (cage monitoring) were assessed at baseline, and days 1 and 27. Serum bone turnover markers (formation: N-terminal propeptide of type 1 procollagen, PINP; resorption: C-terminal telopeptide of type 1 collagen, CTX) were assessed at baseline, and days 7 and 27.ResultsNo effect of stroke was observed on BV/TV or physical activity, but PINP decreased by -24.5% (IQR -34.1, -10.5, p = 0.046) at day 27. In controls, cortical bone volume (5.2%, IQR 3.2, 6.9) and total volume (6.4%, IQR 1.2, 7.6) were higher in right legs compared to left legs, but these side-to-side differences were not evident in stroke animals.ConclusionMCAo may negatively affect bone formation. Further investigation of limb use and physical activity patterns after MCAo is required to determine the utility of this current model as a representation of human post-stroke bone loss.

Highlights

Within 12 months of stroke, human adult fracture risk is increased up to 7-fold that of agematched controls[1], and recovery from fracture is poorer in those with history of stroke[2]
No effect of stroke was observed on BV/TV or physical activity, but PINP decreased by -24.5% (IQR -34.1, -10.5, p = 0.046) at day 27
Further investigation of limb use and physical activity patterns after middle cerebral artery occlusion (MCAo) is required to determine the utility of this current model as a representation of human post-stroke bone loss

Summary

Introduction

Within 12 months of stroke, human adult fracture risk is increased up to 7-fold that of agematched controls[1], and recovery from fracture is poorer in those with history of stroke[2]. In non-stroke animal models, measurable site-specific bone loss [5,6,7] occurs within days of hind-limb immobilization. In contrast with humans who are often sedentary after stroke [15], physical activity has been reported to stay the same[16] or increase [17,18] in rats after stroke The aim of this pilot study was to examine the utility of MCAo in rats as a model of the skeletal effects of stroke in humans. The primary hypothesis was that stroke would lead to a reduction in trabecular bone volume fraction (BV/TV) at the ultra-distal femur site in the paretic hindlimb 28 days after MCAo. Immobility and neural damage likely contribute to accelerated bone loss after stroke, and subsequent heightened fracture risk in humans. Editor: Joseph M Wallace, Indiana University Purdue University at Indianapolis, UNITED STATES Received: September 13, 2016 Accepted: February 10, 2017

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