# Effect of phosphodiesterase inhibitors on medication-related osteonecrosis of the jaw in mice: a comparison of phosphodiesterase-4 and phosphodiesterase-5 inhibition

## TL;DR

This study compares two drugs in a mouse model to prevent medication-related jaw bone death, finding one more effective than the other.

## Contribution

The study provides the first comparison of PDE4 and PDE5 inhibitors in a mouse model of medication-related osteonecrosis of the jaw.

## Key findings

- Both drugs reduced pro-inflammatory cytokines and increased bone repair signaling.
- Sildenafil showed more consistent improvements in blood vessel and osteocyte counts compared to rolipram.
- Sildenafil reduced empty bone cell spaces more effectively than the vehicle control.

## Abstract

Medication-related osteonecrosis of the jaw lacks proven pharmacological prevention. We compared a phosphodiesterase-4 inhibitor rolipram and a phosphodiesterase-5 inhibitor sildenafil in a zoledronic acid– and dexamethasone–based mouse model with maxillary incisor extraction.

Aged female mice were assigned to control, rolipram, or sildenafil after osteonecrosis induction and tooth extraction. Outcomes included histology of the extraction socket, immunostaining for vascular endothelial growth factor A (H-score), plasma cytokines, and bone-tissue gene expression measured by real-time quantitative polymerase chain reaction.

Circulating pro-inflammatory cytokines were lower with both inhibitors, whereas selected transcripts in bone were relatively higher, a pattern consistent with early, localized repair signaling during socket healing. Vascular endothelial growth factor A increased at transcript and protein levels. Both treatments were associated with higher blood-vessel and osteocyte counts; sildenafil additionally showed a clearer reduction in empty lacunae versus vehicle. Across inflammatory and angiogenic readouts, sildenafil produced more consistent improvements than rolipram.

In this mouse model of medication-related osteonecrosis of the jaw, phosphodiesterase-5 inhibition outperformed phosphodiesterase-4 inhibition across histological and molecular outcomes. These findings suggest potential benefit and support further preclinical validation and hypothesis-generating clinical research.