A prospective, randomized, placebo-controlled trial showed reduced retears after arthroscopic rotator cuff (RC) repair in patients without osteoporosis by a systemic single-dose of zoledronic acid. Distinct micro-ribonucleic acids (miRNAs) related to inflammation, fibrosis, and tendon-to-bone healing are associated with RC injuries.
Purpose:
To investigate the longitudinal effects of a single-dose of zoledronic acid in patients without osteoporosis undergoing arthroscopic RC repair on circulating miRNAs in order to explore the molecular mechanism of this treatment.
Study Design:
Controlled laboratory study.
Methods:
Data were collected in the course of a single-center, prospective, randomized, placebo-controlled, triple-blinded (investigator, surgeon, patient) phase II trial. A total of 80 patients underwent arthroscopic RC repair and were intraoperatively randomized to the zoledronic acid group (n = 40) or the control group (n = 40). Circulating plasma miRNAs were assessed preoperatively, 2 days postoperatively, and 3 months postoperatively using small RNA sequencing and reverse transcription quantitative polymerase chain reaction (RT-qPCR).
Results:
Six miRNAs were selected for validation by RT-qPCR based on small RNA-sequencing analysis. No statistical differences in miRNA plasma levels were observed preoperatively between the 2 study groups. Two days after surgery, plasma levels were significantly lower for miR-140-3p (P = .047) in the zoledronic acid group. In the control group, plasma levels were significantly lower for miR-29a-3p (P < .001), miR-21-5p (P = .036), miR-192-5p (P = .034), and miR-146a-5p (P < .001) 2 days after surgery. Three months after surgery, miRNA plasma levels of the 2 study groups equalized without any significant differences. Gene target analysis identified collagen type I alpha 1 chain, collagen type III alpha 1 chain, vascular endothelial growth factor, insulin-like growth factor 1, and transforming growth factor-β1 as targets of miRNAs impacted by zoledronic acid.
Conclusion:
Longitudinal plasma miRNA expressions suggest a molecular response to zoledronic acid, potentially indicating a reduction of inflammation and fibrosis at the enthesis as well as increased collagen synthesis and vascularization, possibly explaining improved tendon-to-bone healing.
Clinical Relevance:
Zoledronic acid is a safe and easy-to-apply augmentation technique for patients undergoing arthroscopic RC repair.
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