Osteonecrosis of the jaw has emerged as a serious side effect of long-term bisphosphonate therapy and other anti-osteoclast medications. Bisphosphonates have the unique attribute of matrix localization, in addition to their direct anti-osteoclast action, rendering the matrix itself toxic for osteoclasts for years after the treatment has been stopped. Most cases of bisphosphonate-related osteonecrosis of the jaw (BRONJ) occurred following an invasive dental trauma. Our central hypothesis is that the local deposition of bisphosphonates in the bone matrix is important for the induction of BRONJ, and that local chelation will prevent osteonecrosis. Recently, anabolic teriparatide has shown promising results in treating established cases of BRONJ. However, it does not reduce the local bisphosphonates in bone, which can be the main target for prevention. A critical barrier to development in the field is the lack of an effective prevention strategy of BRONJ after dental trauma, and our goal is to develop such a safe and reliable strategy. Our objectives and expected outcomes are to (1) optimize the local chelation of zoledronate after dental extraction; and (2) demonstrate that local chelation of zoledronate at the time of trauma will prevent osteonecrosis in our BRONJ model. The impact of the proposed studies includes (1) proving that the local deposition of bisphosphonates is an important factor for the induction of BRONJ, and (2) establishing a novel strategy for its prevention.
Aim 1 : Optimizing the precision of local chelation of zoledronate (ZA). We have proven that bisphosphonates can be removed from alveolar bone by local, as well as systemic, chelation. We will optimize the local chelation of longstanding ZA from alveolar bone. We will treat rats with 14C-labeled ZA or saline for 12 weeks, followed by bilateral extraction of the 1st mandibular molars. The extraction sockets will be infused with chelating agent (EDTA or citric acid), immediately after the surgical procedure. Using liquid scintillation, we will quantify the decrease in 14C-ZA content in the alveolar bone after each chelating agent, with and without iontophoresis. We hypothesize that local chelation will remove longstanding 14C-ZA from alveolar bone; and that iontophoresis will improve the results.
Aim 2 : Test the hypothesis that local chelation of zoledronate (ZA) from the extraction site will rescue the socket healing and prevent BRONJ. We have established a rat model where 100% of ZA- treated animals develop severe osteonecrosis of the jaw after dental extraction, with no additional comorbidities. We will treat rats with either ZA or saline, followed by dental extraction of the left-side 1st and 2nd mandibular molars. In half the control and treated animals, the defect will be infused with a chelating agent (EDTA or citric acid) immediately after extraction. The effect of local chelation on the incidence and severity of BRONJ will be compared to those of anabolic teriparatide treatment and drug holiday. We anticipate that targeted chelation of ZA from the bone matrix will rescue the socket healing and prevent osteonecrosis. Teriparatide treatment will augment the effect of local chelation, accelerating the healing process.
Bone death occurs in the jaw area has been associated with drugs that inhibit the cells that break down bone (osteoclasts). However, bisphosphonates have the added feature of being deposited in the bone itself, where they remain for many years. We suggest that this local deposition is a major factor in the induction of this complication that mostly takes place after dental trauma. We will prove our hypothesis by removing the locally deposited bisphosphonates after we perform dental extraction and expect this removal to be sufficient to prevent bone death.
| Elsayed, Ranya; Abraham, Pheba; Awad, Mohamed E et al. (2018) Removal of matrix-bound zoledronate prevents post-extraction osteonecrosis of the jaw by rescuing osteoclast function. Bone 110:141-149 |
| Howie, R Nicole; Borke, James L; Kurago, Zoya et al. (2015) A Model for Osteonecrosis of the Jaw with Zoledronate Treatment following Repeated Major Trauma. PLoS One 10:e0132520 |
| Howie, R Nicole; Bhattacharyya, Maryka; Salama, Mohamed E et al. (2015) Removal of pamidronate from bone in rats using systemic and local chelation. Arch Oral Biol 60:1699-707 |
