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

ABSTRACT Sinceseveral nitrogen containing bisphosphonateNBPdrugs have been approved for the treatment of Pagetandapos s diseasemetastatic disease of the boneand osteoporosisThe later indication has led to the prescription of these drugs to millions of patients in the lastyearsPatients who have bone metastasis receive very large doses of these drugsin some cases receiving the amount in one month that osteoporosis patients receive in a yearThe NBPs are effective and safe drugs which have reduced morbidity and mortality for a large number of patients with osteoporosis and bone metastatic diseaseA side effect now notoriously associated with NBP use is BRONJbisphosphonate associated osteonecrosis of the jawWhile the overall risk of developing this side effect is smallit is associated with significant morbiditySome have advocated for drug holidays prior to dental worka risk factor for the development of BRONJhoweverthis is not an option for the patients with cancer and bone metastases who are at high risk for fractureIn our Phase I studywe developed a novel strategy for preventing or treating BRONJ based on the removal of anti resorptive NBPs by local application of a secondary fluorescent bisphosphonateFL BPthat does not have effects on bone metabolismIn our Phase II study we will build on the feasibility demonstrated in Phase I using three specific aims with the goal of generating data to demonstrate clinical utility and safety of this conceptAimSynthesize the novel indocyanine greenICGbased near infraredNIRFL BP conjugatesICG BPsbased on the antiresorptive inactive para pyridyl ethanebisphosphonatep PyrEBPAimTest the effectiveness of the ICG BP from Aimin a murine model to prevent ONJ via local deliveryand AimDevelop a method for compound analysis in plasma and other tissues and carryout initial PK and toxicology studiesThe product ultimately developed in this project will be delivered locally to the oral cavity without significant systemic effects and will have a near infrared fluorescent moiety that allows visualization of the loading of this new drug and therefore the displacement of the active NBPthus serving as an indicator for safely initiating a dental procedureIf successfulthis product would find great use to help remove the fear of this debilitating side effect of NBP use for these patient populations PROJECT NARRATIVE Osteonecrosis of the jawONJis a debilitating side effect of the use of drugssuch as nitrogen containing bisphosphonatesNBPsthat reduce bone loss for diseases such as osteoporosis and bone metastasis from cancerONJ is very rare but causes significant morbidity and no treatment is currently availableHere we outline a preventative strategy for this complication of bisphosphonate therapy which would be of significant value to the public health