Researchers clarify their dosing strategies in a study examining semaglutide’s effects on osteoblast ferroptosis, addressing criticisms over dosage relevance and pathway analysis, and emphasising its mechanistic focus.
Researchers behind a study on semaglutide and diabetic periodontitis have pushed back against criticism of their dosing choices and interpretation, saying the work was designed as a mechanistic experiment rather than a direct guide to clinical treatment. In a response published by Dove Press, the authors said the aim was to examine how semaglutide affects osteoblast ferroptosis under tightly controlled laboratory and animal conditions.
The team said the 10 micromolar concentration used in cell experiments was chosen after preliminary screening and produced a consistent protective effect in osteoblasts exposed to high glucose and palmitic acid. They acknowledged that the level was higher than concentrations seen in patients and above the drug’s receptor-binding range, but argued that in-vitro studies often require different exposures from those used in human medicine.
They made a similar case for the 0.5 mg/kg dose used in animal tests, saying it was based on earlier preclinical work and their own screening in the disease model. According to the authors, differences in species, metabolism, treatment schedules and disease conditions mean human-equivalent dose calculations can only go so far in judging whether a preclinical dose is appropriate.
The response also addressed concerns about signalling pathways, particularly cAMP, protein kinase A and Epac, which are known parts of GLP-1 receptor activity. The authors said those pathways may well be involved, but that their study was focused on the Wnt5a/Ror2/p38 MAPK pathway and was not meant to claim that this was the only route by which semaglutide exerts an effect.
They likewise rejected the suggestion that dimethyl sulphoxide, or DMSO, may have distorted the findings. The authors said their comparisons were made using standard vehicle controls and that, although DMSO can affect cells under some conditions, there was no clear evidence in their experiments that it changed the anti-ferroptotic results.
Overall, the researchers said the criticisms raise fair points about dose-response, translation to clinical practice and upstream signalling, but do not undermine the central findings of the paper. They concluded that the manuscript did not need revision, while conceding that future studies could use different concentrations, alternative dosing strategies and broader pathway analysis to deepen understanding.
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