Alpha-Ketoglutarate, a Natural Endogenous Metabolite, Enhances Rotator Cuff Tendon–to-Bone Healing by Mitigating Postmenopausal Osteoporosis

BACKGROUND: Compromised bone strength in proximal humerus osteoporosis predisposes patients with rotator cuff repair (RCR) to an increased anchor pull-out risk and healing failure. PURPOSE: To explore the potential of locally administered alpha-ketoglutarate (αKG), a natural metabolite in the tricarboxylic acid cycle, to enhance rotator cuff healing by mitigating osteoporosis. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 48 female Sprague-Dawley rats were assigned into 4 groups: normal control (sham surgery), ovariectomy (OVX) control, OVX-rotator cuff tear (RCT) (RCR with fibrin application after OVX), and OVX-RCT-αKG (RCR with αKG-enriched fibrin treatment after OVX). Bilateral RCR was performed on rats in 2 RCT groups, with the respective application of fibrin or αKG-enriched fibrin gel at the tendon-bone interface (TBI). At 6 weeks and 12 weeks postoperatively, bone quality was evaluated using micro-computed tomography (CT), while histology and immunohistochemistry were used to assess bone, TBI, and tendon quality. Biomechanical tests determined the strength of the tendon-to-bone complex. RESULTS: Micro-CT analysis confirmed proximal humerus osteoporosis after OVX. Alpha-KG-enriched fibrin leads to improved bone quality compared with OVX-RCT, more prominent at 12 weeks after surgery, as evidenced by the higher bone volume/total volume fraction, trabecular number, and trabecular thickness. Histological and immunohistochemical analyses demonstrated enhanced bone regeneration and improved TBI integrity in the OVX-RCT-αKG group, which could be explained by decreased osteoclastic and increased osteoblastic activity. Biomechanical testing showed improved tendon-bone resilience, with higher ultimate failure load and stress after αKG treatment. CONCLUSION: Local supplementation of αKG, a natural metabolite, along with the repair surgery could effectively improve proximal humerus osteoporosis, thereby enhancing RCR. It holds great potential for preventing anchor pullout and improving RCT outcomes in patients with osteoporosis. CLINICAL RELEVANCE: Alpha-KG supplementation along with surgery may enhance RCR for patients with osteoporosis complications.