Microcirculatory consequences of limb ischemia/reperfusion in ovariectomized rats treated with zoledronic acid

Levente Pócs,József Kaszaki,Imre Ocsovszki,Andrea Szabó,József Piffkó,Ágnes Janovszky

doi:10.1186/s13018-019-1117-x

Levente Pócs, József Kaszaki + Show 4 more

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https://doi.org/10.1186/s13018-019-1117-x

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Abstract

BackgroundNitrogen-containing bisphosphonates (BIS) are potent therapeutics in osteoporosis, but their use may result in osteonecrotic side-effects in the maxillofacial region. Periosteal microcirculatory reactions may contribute to the development of bone-healing complications, particularly in osteoporotic bones, where ischemia–reperfusion (IR) events often develop during orthopaedic/trauma interventions. The effect of BIS on the inflammatory reactions of appendicular long bones has not yet been evaluated; thus, we aimed to examine the influence of chronic zoledronate (ZOL) administration on the periosteal microcirculatory consequences of hindlimb IR in osteopenic rats.Materials and methodsTwelve-week-old female Sprague–Dawley rats were ovariectomized (OVX) or sham-operated, and ZOL (80 μg/kg iv, weekly) or a vehicle was administered for 8 weeks, 4 weeks after the operation. At the end of the pre-treatment protocols, 60-min limb ischemia was induced, followed by 180-min reperfusion. Leukocyte-endothelial interactions were quantitated in tibial periosteal postcapillary venules by intravital fluorescence videomicroscopy. CD11b expression of circulating polymorphonuclear leukocytes (PMN, flow cytometry) and plasma TNF-alpha levels (ELISA) were also determined. Two-way RM ANOVA followed by the Holm–Sidak and Dunn tests was used to assess differences within and between groups, respectively.ResultsLimb IR induced significant increases in PMN rolling and firm adhesion in sham-operated and OVX rats, which were exacerbated temporarily in the first 60 min of reperfusion by a ZOL treatment regimen. Postischemic TNF-alpha values showed a similar level of postischemic elevations in all groups, whereas CD11b expression only increased in rats not treated with ZOL.ConclusionsThe present data do not show substantial postischemic periosteal microcirculatory complications after chronic ZOL treatment either in sham-operated or OVX rats. The unaltered extent of limb IR-induced local periosteal microcirculatory reactions in the presence of reduced CD11b adhesion molecule expression on circulating PMNs, however, may be attributable to local endothelial injury/activation caused by ZOL.

Highlights

The unaltered extent of limb IR-induced local periosteal microcirculatory reactions in the presence of reduced CD11b adhesion molecule expression on circulating PMNs, may be attributable to local endothelial injury/activation caused by ZOL
Osteoporosis affects more than 75 million people worldwide [1], with every other woman and every fifth man over 50 years suffering an osteoporotic fracture of the extremities during her or his remaining lifetime [2]
Proinflammatory cytokines (e.g. TNF-alpha, IL-1 and IL-6) typically reach peak values after fracture operations [5], Pócs et al Journal of Orthopaedic Surgery and Research (2019) 14:95 and it is suggested that these proinflammatory reactions may critically influence the process of bone regeneration

Summary

Introduction

Osteoporosis affects more than 75 million people worldwide [1], with every other woman and every fifth man over 50 years suffering an osteoporotic fracture of the extremities during her or his remaining lifetime [2]. Bisphosphonates (BISs) are potent therapeutic agents that ameliorate the osteoporosis-induced decrease of bone mineral density [2, 6]. Chronic BIS treatment can effectively enhance the incorporation of bone implants in appendicular bones [8, 9], but the likelihood of osteonecrotic complications increases in parallel at the jaw bones [2, 10, 11]. Nitrogen-containing bisphosphonates (BIS) are potent therapeutics in osteoporosis, but their use may result in osteonecrotic side-effects in the maxillofacial region. Periosteal microcirculatory reactions may contribute to the development of bone-healing complications, in osteoporotic bones, where ischemia–reperfusion (IR) events often develop during orthopaedic/trauma interventions. The effect of BIS on the inflammatory reactions of appendicular long bones has not yet been evaluated; we aimed to examine the influence of chronic zoledronate (ZOL) administration on the periosteal microcirculatory consequences of hindlimb IR in osteopenic rats

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