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

Abstract

Background 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, 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 methods Twelve-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. Results Limb 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. Conclusions The 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.

Alendronate reduces periosteal microperfusion in vivo

“…Periosteal activity is believed to be of crucial importance in bone physiology and pathophysiology, and therefore, in the healing process [ 13 ]. A basic requirement for the preservation of periosteal function is the presence of adequate blood flow in periosteal vessels, because normal healing seems to be critically linked to the reestablishment of periosteal microcirculation [ 14 , 15 ]. Bisphosphonates are known to affect periosteal perfusion by inducing leukocyte-endothelial cell interactions [ 15 , 16 ].…”

“…A basic requirement for the preservation of periosteal function is the presence of adequate blood flow in periosteal vessels, because normal healing seems to be critically linked to the reestablishment of periosteal microcirculation [ 14 , 15 ]. Bisphosphonates are known to affect periosteal perfusion by inducing leukocyte-endothelial cell interactions [ 15 , 16 ]. A previous study demonstrated an increased number of adherent and rolling leukocytes in the postcapillary venules of the mandibular periosteum of bisphosphonate-treated mice compared with that in non-treated animals [ 12 ].…”