Effect of the phosphodiesterase inhibitors on bisphosphonate-induced osteonecrosis in mice: Comparing the inhibition of phosphodiesterases 4 and 5

Yunus Baş ¹ OLGUN TOPAL ^1* Gökhan Sadi ² Esra Aslan ¹ Halit Buğra Koca ¹ Mehmet Bilgehan Pektaş ¹

• ¹ Afyonkarahisar Health Sciences University, Afyonkarahisar, Türkiye
• ² Karamanoğlu Mehmetbey University, Karaman, Türkiye

Osteonecrosis in the jaw bone develops due to bisphosphonate use for a certain period.Although the exact mechanism is not known, variables such as tooth extraction and inflammation are considered risk factors. Therefore, suppression of inflammation is of great importance in treatment.This study aimed to compare the effects of rolipram and sildenafil, which are phosphodiesterase 4 and phosphodiesterase 5 inhibitors, respectively, on zoledronic acid-induced bisphosphonate-related osteonecrosis in mice.After applying zoledronic acid to Balb-c female mice for 8 weeks, the upper left central teeth of the animals were extracted. The mice were divided into three groups: control, rolipramtreated, and sildenafil-treated. mRNA expression of parameters that play a role in inflammation and bone development in the anterior maxilla bone samples of mice were measured and compared with plasma inflammatory capacity. Changes in bone tissue were evaluated by histological and immunostaining methods.Results: Proinflammatory factors in plasma decreased with rolipram and sildenafil treatment, whereas their mRNA expression in bone tissue increased significantly. The expression of osteocalcin mRNA in maxillary bone decreased significantly with treatments, and unlike rolipram, sildenafil significantly increased the levels of osteopontin and receptor activator of nuclear factor kappa-Β. Vascular endothelial growth factor A levels significantly increased at both mRNA and protein levels in the rolipram and sildenafil groups. Accordingly, it was determined that blood supply and number of osteocytes increased in the treatment groups compared with the control group, and the number of empty lacunae decreased.In the treatment of osteonecrosis, phosphodiesterase 5 inhibition will provide more effective results than inhibition of phosphodiesterase 4. Further studies are needed to both elucidate the molecular mechanisms and determine the basis of treatment.