Another hypothesis is angiogenesis inhibition Angiogenesis

Another hypothesis is angiogenesis inhibition. Angiogenesis is a process that involves the growth, migration and differentiation of endothelial haloperidol haldol mg to form new blood vessels. Angiogenesis favorably influences tumor growth and also influences tumor invasion of vessels, resulting in tumor metastasis. Angiogenesis requires binding of signaling molecules such as vascular endothelial growth factor (VEGF) to receptors on endothelial cells. This signaling promotes new blood vessel growth. Osteonecrosis is classically considered an interruption in vascular supply or avascular necrosis, and thus it is not surprising that inhibition of angiogenesis is a leading hypothesis in ONJ pathophysiology [5,6]. Pazopanib (Votrient) and everolimus (Afinitor) were used as antiangiogenic agents for renal cell carcinoma. Pazopanib is a tyrosine kinase inhibitor(TKI) that inhibits tumor growth and angiogenesis and is an approved treatment for renal cell carcinoma and sarcoma of soft tissue. The mechanism of action is a multikinase inhibitor, with c-KIT, FGFR, PDGFR and VEGFR being amongst the inhibited enzymes. TKIs available for use in clinical practice which are similar to sunitinib include axitinib, pazopanib and cabozantinib [7]. There was a single case report [8] about a 51 year old female patient with medullary thyroid cancer treated with cabozantinib (dose not specified). Two months after tooth extraction, the patient presented with MRONJ, presumably caused by cabozantinib since the patient had no previous history of BP treatment. Case reports describing MRONJ with the use of pazopanib are currently lacking [7]. The present case is a MRONJ because of inhibition of angiogenesis by pazopanib. Everolimus is a sirolimus derivative that acts as an inhibitor of mammalian target of rapamycin (mTOR). It is currently used as an immunosuppressant to prevent rejection of organ transplants and treatment of renal cell cancer and other tumors. Everolimus is also approved for other indications such as hormone positive breast cancer, pancreatic neuroendocrine tumors, and prevention of solid organ rejection [7]. Because mTOR signaling is regulated by the VEGF pathway, it is also reasonable or plausible to expect some reported cases of ONJ with the use of these agents [7]. Currently, there are two published cases of ONJ with everolimus. In the case report by Giancola and colleagues [9], an association between everolimus and ONJ incidence is hard to infer in light of the fact that the 64 year old patient had been on zoledronate for the past 2 years for bone metastasis from renal cell carcinoma prior to the addition of everolimus at a daily dose of 10 mg. Although the patient presented with ONJ 6 months after the introduction of everolimus, it is most likely that zoledronate was the culprit. Yet, the possibility that the addition of everolimus exacerbated the condition should not be ruled out or precluded. In the second report by Kim and colleagues [10], everolimus might have been the trigger for ONJ since at least 6 years had elapsed since the last administered dose IV zoledronate making it highly unlikely that this adverse event might have been exacerbated by the concomitant use of a BP. The present case was not treated with BP. The patient was treated by administration of pazopanib and everolimus and MRONJ may have developed as a result. Critical mechanisms of development of MRONJ include local factors as well as the action of medications. Surgical treatment is a local factor. Dentoalveolar surgery is considered a critical risk factor of the development of MRONJ. Several studies on MRONJ have reported that tooth extraction is a common predisposing event ranging from 52 to 61% of patients reporting tooth extraction as the precipitating event [11,12]. Tooth extraction is also a critical risk factor for the development of MRONJ. In the present case, there was no history of surgery or tooth extraction. The unique portion of this case was that MRONJ developed in both mandibular posterior areas without any history of surgery. There were implants in both MRONJ sites. Implant treatments were completed 6 years prior. There were no symptoms at implant sites until recently.