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.

Background: Anterolateral structure augmentation (ALSA) has been applied to prevent residual rotatory instability and lower clinical failure rates after anterior cruciate ligament (ACL) reconstruction (ACLR); however, the effect of combined ALSA on the maturity of ACL grafts remains unknown. Purpose: To evaluate the graft maturity and patient–reported outcomes in patients who underwent double–bundle ACLR with or without ALSA. Study Design: Cohort study; Level of evidence, 3. Methods: A total of 92 patients who underwent double–bundle ACLR between January 2016 and July 2019 were included in the present study—44 patients with isolated ACLR (ACLR group) and 48 patients with combined ACLR and ALSA (ALSA group). Demographic characteristics, intraoperative findings, and patient–reported outcomes were prospectively collected. On postoperative magnetic resonance imaging at the 2–year follow–up, the signal–to–noise quotient (SNQ) values were separately calculated for 6 sections of the ACL graft, including the femoral intratunnel graft (FTG), intra–articular graft (IAG), and tibial intratunnel graft (TTG) of the anteromedial bundle (AMB) and the posterolateral bundle (PLB). Superior graft maturity was usually indicated by lower SNQ values. Results: The rates of return to preinjury sports were 47.9% and 27.3% in the ALSA and ACLR groups, respectively (difference, 20.6% [95% CI, 1.3%-40%]; P = .042). The AMB demonstrated significantly lower SNQ values in the ALSA group than in the ACLR group (FTG, 7.04 ± 3.65 vs 9.44 ± 4.51 [ P = .006]; IAG, 6.62 ± 4.19 vs 8.77 ± 5.92 [ P = .046]; TTG, 6.93 ± 3.82 vs 8.75 ± 4.55 [ P = .040]). The SNQ values were significantly lower in the ALSA group for 2 of the 3 sections of the PLB (IAG, 7.73 ± 4.61 vs 9.88 ± 5.61 [ P = .047]; TTG, 5.88 ± 3.10 vs 8.57 ± 4.32 [ P = .001]). Partial lateral meniscectomy was correlated with higher SNQ values of the TTG in the AMB (β = 0.27; P = .009) and the PLB (β = 0.25; P = .008), with both groups pooled. Higher body mass index, smaller ACL graft–Blumensaat line angles, larger AMB graft diameters, and lower postoperative Tegner scores were also associated with inferior maturity in specific regions of the ACL graft. Conclusion: A combination of ACLR and ALSA is a desirable option to improve the maturity of ACL grafts for patients who are young or expected to return to pivoting sports. Meanwhile, further investigations with higher levels of evidence and longer periods of follow–up are warranted.

I feel obligated to bring to your attention a potential problem with an article that was recently published in The American Journal of Sports Medicine. The article describes the effects of abaloparatide versus denosumab in a rat rotator cuff repair model. 6 The potential problem with the article is that denosumab does not recognize rat RANKL, yet the article describes numerous differences between the denosumab group and vehicle controls, which the authors interpreted as pharmacodynamic effects. But such differences do not seem biologically plausible and might at best reflect the play of chance.It was first revealed in 2009 that denosumab lacks pharmacodynamic effects in normal rats and mice owing to important interspecies divergence in amino acid sequences within RANKL. 3 Specifically, denosumab bioactivity relies on the D-L-A-T-E sequence encoded within the fifth exon of human RANKL, whereas the corresponding sequence in mice is S-V-P-T-D. An article by Kostenuik et al 3 included data showing that denosumab does not bind to murine RANKL in vitro, nor does it have any antiresorptive effects in mice; the lack of denosumab activity in rats was cited as ''data not shown.'' However, an article published in 2000 reported 5 stated that the corresponding amino acid sequence in rat RANKL is S-V-P-A-D, indicating total divergence of the denosumab binding epitope between humans and rats. Based on the syngeneic rat study design described by Xu et al, 6 it appears that there were no human cells in their model; hence, there should be no meaningful effects of denosumab.In justifying the use of denosumab in their rat study, Xu et al 6 cited two previous rodent studies. However, neither of those references used denosumab. 1,2 Instead, both studies relied on recombinant OPG-Fc as a suitable RANKL inhibitor because it recognizes RANKL in multiple species, including humans, rats, mice, pigs, and rabbits. Moreover, one of those articles (Hadaya et al) 2 stated that ''denosumab does not bind to mouse or rat RANKL.'' Xu et al 6 also failed to cite an important article showing that OPG-Fc improved tendon-bone healing in a rabbit ACL model. 4 Readers may refer to those results for a more definitive description of how RANKL inhibition affects tendon-bone healing.