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
Abstract
BACKGROUND

Clopidogrel is a widely prescribed drug for prevention of myocardial infarction and stroke in patients at risk. It inhibits thrombus formation via inhibition of the P2Y12 purinergic receptor on platelets, which is important in their activation by ADP. However, the P2Y12 receptor has also been found to be expressed in both osteoblasts and osteoclasts. Accumulated evidence suggests that purinergic receptors regulate important functions of bone turnover. Previous studies on the effect of clopidogrel on bone metabolism indicated potential harmful effects, but their results remain conflicting. Thus, clopidogrel treatment may affect bone healing, but it has not yet been studied.

AIM

To evaluate if continuous perioperative clopidogrel treatment has any negative effect on bone healing in the rabbit calvarial defect model.

METHODS

Sixteen male white New Zealand rabbits were randomly assigned in two groups: One group received daily 3 mg/kg of clopidogrel per os and the other group received the vehicle alone for a week prior to the surgical procedures; the treatments were continued for another 6 wk postoperatively. The surgical procedures included generation of two circular calvarial defects 11 mm in diameter in every animal. After the 6-wk period of healing, postmortem radiographic and histomorphometric evaluation of the defects was performed.

RESULTS

Both the surgical procedures and the postoperative period were uneventful and well tolerated by all the animals, without any surgical wound dehiscence, signs of infection or other complication. New bone was formed either inwards from the defect margins or in the central portion of the defect as separated bony islets. While defect healing was still incomplete in both groups, the clopidogrel group had significantly improved radiographic healing scores. Moreover, the histomorphometric analysis showed that bone regeneration (%) was 28.07 ± 7.7 for the clopidogrel group and 19.47 ± 4.9 for the control group, showing a statistically significant difference between them (P = 0.018). Statistically significant difference was also found in the defect bridging (%), i.e. 72.17 ± 21.2 for the clopidogrel group and 41.17 ± 8.5 for the control group, respectively (P = 0.004), whereas there was no statistical difference in bone tissue density between the groups.

CONCLUSION

Our results indicate that maintenance of perioperative clopidogrel treatment does not negatively affect bone healing but rather promotes it. Further research is needed in order to find useful applications of this finding.

Keywords: Clopidogrel; Bone healing; Purinergic signaling; Calvarial defect; Rabbit

Core tip: To our knowledge, the present study is the first to evaluate the effect of clopidogrel treatment on bone healing. Clopidogrel is an antithrombotic drug that inhibits platelet aggregation through inhibition of the P2Y12 purinergic receptor on their surface. The P2Y12 is also expressed in osteoblasts and osteoclasts, and previous studies have raised concerns about clopidogrel’s possible effect on bone metabolism. We report our results on the effect of clopidogrel on bone healing using the rabbit calvarial defect model. Our results indicate that clopidogrel treatment does not negatively affect bone healing but rather promotes it.