Abaloparatide Improves Rotator Cuff Healing via Anabolic Effects on Bone Remodeling in a Chronic Rotator Cuff Tear Model of Rat With Osteoporosis: A Comparison With Denosumab

Abstract

Background: Because of poor clinical outcomes, rotator cuff healing in patients with osteoporosis has recently gained attention. Antiresorptive therapy for osteoporosis has been reported to improve healing after repair. However, the comparative effectiveness of anabolic and antiresorptive agents has not been investigated. Hypothesis: Anabolic therapy with abaloparatide (ABL) would outperform antiresorptive therapy with denosumab (Dmab) to improve rotator cuff healing in the osteoporotic status. Study Design: Controlled laboratory study. Methods: A chronic rotator cuff tear model was established in ovariectomy-induced postmenopausal osteoporotic rats. Then, bilateral rotator cuff repairs were conducted in all experimental rats, which were randomly divided into control (CON), Dmab, and ABL groups to receive the corresponding subcutaneous injections. The rats sacrificed at 2 weeks (the early healing period) were used to detect osteoblast and osteoclast activities, related gene expression (osteoclastogenesis, osteogenesis, and chondrogenesis), new bone formation, and mineralization. In the rats sacrificed at 4 and 8 weeks, the bone mineral density and bone architecture at the repaired site were assessed by micro–computed tomography, and rotator cuff healing was evaluated using histological and biomechanical analyses. Results: At 8 weeks, significantly higher failure load and stiffness were observed in the ABL (25.13 ± 3.54 N, P < .001; 21.65 ± 3.08 N/mm, P < .001; respectively), and Dmab (21.21 ± 2.55 N, P < .001; 16.15 ± 2.07 N/mm, P = .008; respectively) groups than in the CON group (13.36 ± 1.70 N; 11.20 ± 2.59 N/mm; respectively), whereas the ABL treatment provided better failure load and stiffness than Dmab ( P = .019; P = .003). Although tendon-to-bone healing was improved by Dmab, the most mature tendon insertion at the interface was observed in the ABL group, including a more organized collagen and fibrocartilage and higher bone quality. ABL significantly promoted bone remodeling via coupling between osteoclasts and osteoblasts (osteoblast to osteoclast ratio: 4.80 ± 0.39; P = .022), thereby stimulating more new bone formation and mineralization at the tendon-to-bone healing interface than Dmab (osteoblast to osteoclast ratio: 3.21 ± 0.75) at 2 weeks. Moreover, ABL had significant effects on gene expression [Runt-realted transcription factor 2 ( Runx2, collagen type I-alpha 1 ( Col1A1]), and sclerostin for osteogenesis; aggrecan and collagen type II ( Col2) for chondrogenesis] in mineralized tissues, indicative of enhanced bone and fibrocartilage formation when compared with the CON and Dmab groups. Conclusion: ABL promoted rotator cuff healing in osteoporotic rats by significantly increasing the mineralized tissue quality and collagen maturity at the reattachment site, leading to improved biomechanical properties, and was superior to Dmab in both biomechanical and histological analyses. Clinical Relevance: Anabolic therapy with ABL may outperform antiresorptive therapy with Dmab in improving outcomes after rotator cuff repair in osteoporotic patients.

Abaloparatide Improves Rotator Cuff Healing Via Anabolic Effects on Bone Remodeling in a Chronic Rotator Cuff Tear Model of Rat With Osteoporosis: A Comparison With Denosumab: Letter to the Editor

“…This also translated to biomechanical properties of the enthesis, as at 8 weeks after rotator cuff repair, a significantly higher failure load and stiffness were observed in the intervention groups treated either with abaloparatide or denosumab compared to the nontreated control group. 15 Although the presented results concerning abaloparatide are encouraging, biomechanical, bone morphometric, and histological findings concerning denosumab are questionable in this experimental setting. For drug application and dose, the authors referred to a previous study on anti-RANKL treatment in rats.…”

“…Based on that, the effects of different anti-osteoporotic treatments after rotator cuff repair have previously been published by several authors. 4,5,10,11,12,14,15 Bisphosphonates such as zoledronic acid or risedronate strongly bind to mineralized surfaces, especially hydroxyapatite. They are incorporated into osteoclasts, where they inhibit a key enzyme in osteoclast function and survival.…”

“…However, at final follow-up, no differences in biomechanical properties were observed between both study groups. 4 A new approach of adjuvant bone augmentation after rotator cuff repair was recently published by Xu et al 15…”

“…In conclusion, OPG-Fc can be seen as a surrogate marker for denosumab in rats and therefore be used for investigations of anti-RANKL treatment. 1,6 Concerning the methodological setup chosen by Xu et al, 15 it is deeply troubling that the authors did not use OPG-Fc or a specific animal knock-in model expressing chimeric human RANKL, as suggested by previous studies, but instead treated rats with denosumab. Indeed, the lack of effectiveness of denosumab was reflected by gene expression analyses performed by the authors: Treatment with a RANKL inhibitor suggested a significant downregulation of RANKL between the intervention group and the nontreated control group.…”

The role of vitamin D on rotator cuff tear with osteoporosis

“…Rotator cuff repair surgery in patients with osteoporosis is now receiving increasing attention, and anti-osteoporosis treatment has shown significant results in improving rotator cuff repair surgery (38). There is a clear association between osteoporosis and rotator cuff injury in clinical studies.…”