Zoledronate and pamidronate depress neutrophil functions and survival in mice
Bibliographic record
Abstract
BACKGROUND AND PURPOSE: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) has been identified as a severe complication of patients previously treated with i.v. bisphosphonates. It has been noted that necrotic bone from BRONJ sites display signs of bacterial infection suggesting that an immune defect may play a role in the pathophysiology of BRONJ. Here, we have examined the effect of two potent bisphosphonates, zoledronate and pamidronate, on neutrophil function, differentiation and survival. EXPERIMENTAL APPROACH: The effect of bisphosphonates on chemotaxis, NADPH oxidase activity and neutrophil survival were assessed in vitro using bone marrow-derived primary neutrophils or in vitro differentiated haematopoetic progenitors from mice. The same parameters and the number of circulating neutrophils were quantified in neutrophils isolated from mice treated in vivo with zoledronate. In vivo recruitment of neutrophils was assessed by sodium periodate-induced peritonitis. KEY RESULTS: Zoledronate and pamidronate inhibited in vitro neutrophil chemotaxis and NADPH oxidase activity in a dose-dependent manner. In vivo recruitment of neutrophils was also suppressed. Zoledronate did not affect in vitro differentiation of neutrophils but shortened their life span in a granulocyte-colony stimulating factor-dependent manner. fMLP-induced activation of RhoA activity was decreased by zoledronate treatment. CONCLUSIONS AND IMPLICATIONS: Our results show that bisphosphonate exposure leads to impaired neutrophil chemotaxis, neutrophil NADPH oxidase activity and reduced circulating neutrophil counts. This work suggests that bisphosphonates have the potential to depress the innate immune system for a prolonged time, possibly contributing to the pathogenesis of BRONJ.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".