Basic Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Orthop. Dec 18, 2019; 10(12): 434-445
Published online Dec 18, 2019. doi: 10.5312/wjo.v10.i12.434
Effect of clopidogrel in bone healing-experimental study in rabbits
Theodoros Lillis, Alexander Veis, Nikolaos Sakellaridis, Anastasios Tsirlis, Zoe Dailiana
Theodoros Lillis, Zoe Dailiana, Department of Orthopaedic Surgery, Faculty of Medicine, University of Thessaly, Biopolis, Larissa 41500, Greece
Theodoros Lillis, Alexander Veis, Anastasios Tsirlis, Department of Dentoalveolar Surgery, Implantology and Oral Radiology, Faculty of Dentistry, Aristotle University of Thessaloniki, Panepistimioupoli, Thessaloniki 54124, Greece
Nikolaos Sakellaridis, Department of Clinical Pharmacology, Faculty of Medicine, University of Thessaly, Biopolis, Larissa 41500, Greece
Author contributions: Lillis T, Veis A and Dailiana Z conceived the idea; Lillis T, Veis A, Sakellaridis N, Tsirlis A and Dailiana Z designed the study; Lillis T and Dailiana Z conducted the experiments; Lillis T collected and statistically analyzed the data; Lillis T, Veis A, Sakellaridis N, Tsirlis A and Dailiana Z interpreted the data; Lillis T and Dailiana Z drafted the manuscript; and Sakellaridis N, Tsirlis A and Daliana Z critically revised the manuscript; Veis A passed away before the preparation of the manuscript.
Institutional review board statement: The study was reviewed and approved by the Institutional Review Board of the Medical Faculty, University of Thessaly, Larissa, Greece.
Institutional animal care and use committee statement: The experiments were conducted in the Animal Care and Use facilities of the Department of Physiology, Faculty of Veterinary Medicine of the Aristotle University of Thessaloniki, Panepistimioupoli, 54636, Thessaloniki, Greece (EU Code: EL 54BIO10) and the study protocol was approved and authorized by the local Prefectural Veterinary Service, 64 26th October St, 54627, Thessaloniki, Greece, according to Directive 2010/63/EU and national law (Approval ID: 527888/4090).
Conflict-of-interest statement: All authors state that they have no conflicts of interest.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Zoe Dailiana, MD, PhD, Professor, Department of Orthopaedic Surgery, Faculty of Medicine, University of Thessaly, 3 Panepistimiou St, Biopolis, Larissa 41500, Greece. dailiana@med.uth.gr
Telephone: +30-2413-502723 Fax: +30-2413-501011
Received: June 11, 2019
Peer-review started: June 11, 2019
First decision: July 30, 2019
Revised: August 27, 2019
Accepted: September 13, 2019
Article in press: September 13, 2019
Published online: December 18, 2019
Processing time: 184 Days and 5.9 Hours
ARTICLE HIGHLIGHTS
Research background

Clopidogrel is a widely prescribed drug that inhibits platelet aggregation and, therefore, prevents thromboembolic events such as myocardial infarction and stroke. Clopidogrel acts by binding on the P2Y12 purinergic receptor on the platelet surface. Purinergic receptors also play an important role in bone homeostasis, and P2Y12, in particular, is expressed in osteoblasts and osteoclasts as well. The exact role of the P2Y12 receptor and the effect of clopidogrel treatment in bone metabolism have not been elucidated. The few existing studies demonstrate contrasting results, with some of them indicating a negative impact on bone turnover. The effect of clopidogrel treatment in bone healing has not yet been studied.

Research motivation

The presence of a drug that may negatively affect bone healing during the perioperative period when dealing with skeletal surgery raised our concerns and motivated us to conduct this study.

Research objectives

The main objective of the present study was to evaluate bone healing during continuous perioperative clopidogrel treatment.

Research methods

Our study used the well-described critical sized calvarial defect model. Sixteen male New Zealand rabbits were used and randomly divided into two groups; an experimental group taking clopidogrel 3 mg/kg/d per os and a control group taking the vehicle alone. The treatment began 1 wk before the surgical procedures and continued for 6 wk postoperatively. Surgical procedures were conducted to create two circular bony defects on the cranium of every animal. After a 6-wk postoperative period, the animals were euthanized, and postmortem radiographical and histological evaluation was conducted. Radiological evaluation was conducted using a five grade qualitative scale. Histological evaluation included measurements of the percentages of the defect regeneration, bridging and bone density.

Research results

The postoperative period was uneventful and without any complication for all animals. The radiological examination showed that the clopidogrel group had a statistically significant improved radiographic score in bone bridging and union. The histomorphometric analyses also revealed significantly greater percentage of bone regeneration and bridging in the clopidogrel group than in the control group. However, bone density was not statistically different between the groups.

Research conclusions

The present study results indicate that continuous perioperative clopidogrel treatment does not impair bone healing; instead, it promotes new bone formation. This finding is important when dealing with skeletal surgery in patients who use this drug chronically for cardiovascular indications.

Research perspectives

Future research may involve evaluation of the effect of other antiplatelet drugs of the same category, such as ticagrelor or prasugrel, and at different dosing and treatment duration. Moreover, further research is needed in order to evaluate if our findings have useful implications in bone healing improvement such as topically drug releasing vehicles or drug eluting orthopedic implants.