Intraoperative Zoledronic Acid for Arthroscopic Rotator Cuff Repair Results in Distinct Circulating Micro-RNA Profiles Indicating Improved Tendon-to-Bone Healing.

BACKGROUND

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.

REGISTRATION: NCT05677152 (ClinicalTrials.gov identifier).