Denosumab alleviates intervertebral disc degeneration adjacent to lumbar fusion by inhibiting endplate osteochondral remodeling and vertebral osteoporosis in ovariectomized rats

Sun, Qi; Tian, Faming; Liu, Fang; Fang, Jia-Kang; Hu, Yunpeng; Lian, Qiangqiang; Zhou, Zhuang; Zhang, Liu

doi:10.1186/s13075-021-02525-8

Cited by 17 publications

(11 citation statements)

References 41 publications

(48 reference statements)

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“…Also, tartrate-resistant acid phosphatase staining showed a significantly decreased number of active osteoclasts after denosumab treatment. 8 The in vivo response to denosumab application was assessed by these available data, which is consistent with the results of our pilot study. After considering all the factors above, we decided to use denosumab in our animal study.…”

supporting

confidence: 86%

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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: Response

Xu¹,

Ye²,

Chen³

et al. 2022

Am J Sports Med

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supporting

confidence: 86%

“…Moreover, denosumab treatment inhibited the expression of RANKL. 3 Sun et al 8 found that denosumab significantly increased vertebral biomechanical properties and bone mineral density. Also, tartrate-resistant acid phosphatase staining showed a significantly decreased number of active osteoclasts after denosumab treatment.…”

mentioning

confidence: 99%

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: Response

Xu¹,

Ye²,

Chen³

et al. 2022

Am J Sports Med

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“…The evidence from recent studies demonstrating the in vivo response of denosumab in rats is another factor that motivates us to use it. 2,9,12 The letter provided us with a lot of inspiration for future research and a better analysis of existing studies. According to Prof. Kostenuik's findings, the huRANKL knock-in mice, which have a human RANKL fragment encoded by the fifth exon of the RANKL gene, dramatically responded to denosumab.…”

Section: Authors' Responsementioning

confidence: 99%

“…The evidence from recent studies demonstrating the in vivo response of denosumab in rats is another factor that motivates us to use it. 2,9,12…”

mentioning

confidence: 99%

“…It is critical to identify the extra possible binding site in rats and where it is situated, given that denosumab’s in vivo response in rats was discovered in our as well as other studies. 2,9,12 Recent developments in protein engineering technology have produced a variety of bispecific antibody forms, each of which is capable of acting as a single agent to target several antigens with different binding epitopes 13 —for instance, catumaxomab, blinatumomab, or faricimab. As an artificially synthesized antibody with high affinity to the RANKL, denosumab is indicated for the treatment of osteoporosis and prevention of the complications of bone metastases.…”

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confidence: 99%

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Denosumab Use in Rats: Response

Xu¹,

Ye²,

Chen³

et al. 2023

Am J Sports Med

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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.

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Zoledronate Reduces Height Loss Independently of Vertebral Fracture Occurrence in a Randomized Trial in Osteopenic Older Women

Reid

Bastin

Horne

et al. 2020

Journal of Bone and Mineral Research

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Vertebral fractures are associated with height loss, reduced quality of life, and increased mortality and are an important endpoint for osteoporosis trials. However, height loss is associated with quality of life and mortality independent of associations with fracture. We have used data from a recent 6‐year trial of zoledronate in 2000 osteopenic women aged >65 years to assess the impact of the semiquantitative and quantitative components of the definition of vertebral fracture on the outcome of that trial, to determine what factors impacted on height loss and to test whether height loss can be used as a surrogate for vertebral fracture incidence. In the trial protocol, an incident vertebral fracture was defined as a change in Genant grade plus both a 20% and 4 mm decrease in a vertebral height. The addition of the quantitative criteria reduced the number of fractures detected but did not change the size of the anti‐fracture effect (odds ratios of 0.49 versus 0.45) nor the width of the confidence intervals for the odds ratios. Multivariate analysis of baseline predictors of height change showed that age accelerated height loss (p < 0.0001) and zoledronate reduced it (p = 0.0001). Incident vertebral fracture increased height loss (p = 0.0005) but accounted for only 0.7% of the variance in height change, so fracture could not be reliably inferred from height loss. In women without incident vertebral fractures, height loss was still reduced by zoledronate (height change: zoledronate, −1.23; placebo −1.51 mm/yr, p < 0.0001). This likely indicates that zoledronate prevents a subtle but widespread loss of vertebral body heights not detected by vertebral morphometry. Because height loss is associated with quality of life and mortality independent of associations with fracture, it is possible that zoledronate impacts on these endpoints via its effects on vertebral body integrity. © 2022 American Society for Bone and Mineral Research (ASBMR).

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Denosumab alleviates intervertebral disc degeneration adjacent to lumbar fusion by inhibiting endplate osteochondral remodeling and vertebral osteoporosis in ovariectomized rats

Cited by 17 publications

References 41 publications

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: Response

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: Response

Denosumab Use in Rats: Response

Zoledronate Reduces Height Loss Independently of Vertebral Fracture Occurrence in a Randomized Trial in Osteopenic Older Women

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