Osteonecrosis development by tooth extraction in zoledronate treated mice is inhibited by active vitamin D analogues, anti-inflammatory agents or antibiotics

Abstract

Invasive dental treatment such as tooth extraction following treatment with strong anti-bone resorptive agents, including bisphosphonates and denosumab, reportedly promotes osteonecrosis of the jaw (ONJ) at the extraction site, but strategies to prevent ONJ remain unclear. Here we show that in mice, administration of either active vitamin D analogues, antibiotics or anti-inflammatory agents can prevent ONJ development induced by tooth extraction during treatment with the bisphosphonate zoledronate. Specifically, tooth extraction during treatment with zoledronate induced osteonecrosis in mice, but administration of either 1,25(OH)2D3 or ED71, both active vitamin D analogues, significantly antagonized osteonecrosis development, even under continuous zoledronate treatment. 1,25(OH)2D3 or ED71 administration also significantly inhibited osteocyte apoptosis induced by tooth extraction and bisphosphonate treatment. Administration of either active vitamin D analogue significantly inhibited elevation of serum inflammatory cytokine levels in mice in response to injection of lipopolysaccharide, an infection mimetic. Furthermore, administration of either anti-inflammatory or antibiotic reagents significantly blocked ONJ development following tooth extraction and zoledronate treatment. These findings suggest that administration of active vitamin D, anti-inflammatory agents or antibiotics could prevent ONJ development induced by tooth extraction in patients treated with zoledronate.

Correlations between Immune Response and Etiopathogenic Factors of Medication-Related Osteonecrosis of the Jaw in Cancer Patients Treated with Zoledronic Acid

“…Therefore, a correct interaction between immune cells and bone cells is essential to prevent both bone and immune changes [ 78 ]. An animal model study reported that the administration of anti-inflammatory drugs or antibiotics significantly blocked zoledronic acid-induced osteonecrosis after tooth extraction [ 79 ], suggesting that this type of treatment should be considered in the prevention of MRONJ. Thus, the therapeutic approach using anti-inflammatory drugs or antibiotics shows the potential to block the development of BP-induced osteonecrosis after tooth extraction [ 79 ].…”

“…An animal model study reported that the administration of anti-inflammatory drugs or antibiotics significantly blocked zoledronic acid-induced osteonecrosis after tooth extraction [ 79 ], suggesting that this type of treatment should be considered in the prevention of MRONJ. Thus, the therapeutic approach using anti-inflammatory drugs or antibiotics shows the potential to block the development of BP-induced osteonecrosis after tooth extraction [ 79 ]. These findings indicate the need to explore this type of treatment for the prevention and management of MRONJ [ 80 ].…”

Immune Dysfunction in Medication-Related Osteonecrosis of the Jaw

“…These data confirm other previously published data, showing that the serum level of inflammatory cytokines was increased in MRONJ patients and that the administration of anti-inflammatory cytokines, such as antitumor necrosis factor-α (TNFα) and anti-interleukin 6 (IL-6), were effective in preventing a cytokine storm induced by N-BPs [33]. Recently, it has been reported in a murine model that the administration of either anti-inflammatory or antibiotic drugs significantly blocked Zol-induced osteonecrosis following tooth extraction [34], suggesting that this type of treatment should be considered to prevent MRONJ onset.…”

Pathophysiology of Medication‐Related Osteonecrosis of the Jaw—A Minireview

“…(80) Osteocytic death during MRONJ likely involves multiple mechanisms, including apoptosis and cell necrosis, and is observed at early stages of disease setting. (97)(98)(99) Dying osteocytes release cellular signals that enhance the degree and severity of periodontal tissue inflammation. The presence of necrotic bone that cannot be removed further inhibits healing of periodontal tissues.…”