Competitive Equilibrium-based Displacement of Bisphosphonates as Novel Therapeutic Approach for BRONJ

Ebetino, Frank; Nishimura, Ichiro

Abstract

Osteonecrosis of the jaw (ONJ) is a rare but severe oral complication, which is characterized by symptoms consisting painful bone exposure or fistulation that do not resolve over several months to years. It was initially described in patient treated with nitrogen-containing bisphosphonates (BPs), and was also found later in some patients taking other antiresorptive or antiangiogenic medications. In some cases, ablation surgery of necrotic oral and maxillofacial bones has been required, significantly affecting patients' life quality. Clinical reports have indicated that dental procedures markedly increase the risk of developing ONJ, thus causing uncertainty and apprehension among dental healthcare professionals and patients in recent years. Drug holiday has been recommended by American Association of Oral and Maxillofacial Surgeons (AAOMS) as a possible preventive measure for the patients. However, the FDA determined that there was no substantial data available to guide decisions regarding the initiation or duration of a drug holiday, which may partially be due to BPs' prolonged half-life in the skeletal system. In addition, because BPs have been marketed for nearly 15 years, a large number of patients have been treated with BPs and those patients who had received BPs but discontinued the therapy may retain the legacy BPs in their skeletal system for an extended period. Therefore, it may be essential to actively remove adsorbed BP from jawbone prior to dentoalveolar procedures in order to achieve more effective prevention. C.E. McKenna (University of Southern California, USC) and I. Nishimura (University of California Los Angeles, UCLA) recently demonstrated using fluorescently labeled BPs that one BP can displace another from hydroxyapatite modeling bone mineral. This suggests that a previously adsorbed pharmacologically active BP in bone could be displaced by a newly administered pharmacologically inactive BP. In this application, we propose this competitive equilibrium-based displacement of BPs as a novel preventive modality of bisphosphonate-related ONJ (BRONJ). We will test the hypothesis that a pre-adsorbed functional BP such as risedronate may be effectively displaced by a non-functional BP administered by intraoral injection to the jaw. As such, application of a non-functional BP to the site of dentoalveolar procedures such as tooth extraction should displace the functional BP locally and thus significantly reduce or abate the risk of developing BRONJ while preserving the benefit of skeletally adsorbed drug. In this Phase I STTR project, we will perform a proof- of-concept study in a mouse model and establish the drug distribution profile with local intraoral injection. Our program combines complementary strengths in ONJ mechanism (Nishimura, UCLA) with BP drug chemistry and biology (F.H. Ebetino, BioVinc LLC, C.E. McKenna, USC).

Public Health Relevance

The proposed research addresses a health need that particularly challenges cancer patients requiring dental procedures, namely to prevent and treat bisphosphonate-related osteonecrosis of the jaw (BRONJ). In a partnership involving BioVinc LLC and the School of Dentistry at the University of California Los Angeles, the proposed STTR Phase I project will utilize fluorescent bisphosphonate imaging probes to demonstrate proof- of-concept for an innovative 'competitive equilibrium'-based local displacement of jaw bone-adsorbed BP drug by an inactive BP. The outcome will be the prerequisite data/model for Phase II preclinical development.