Effect of clopidogrel in bone healing-experimental study in rabbits

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.