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Bone. 2019 Mar 26;123:115-128. doi: 10.1016/j.bone.2019.03.027. [Epub ahead of print]

Rescue bisphosphonate treatment of alveolar bone improves extraction socket healing and reduces osteonecrosis in zoledronate-treated mice.

Author information

1
Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Los Angeles, CA 90095, USA; Regenerative Bioengineering and Repair Laboratory, Division of Plastic and Reconstructive Surgery, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
2
Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Los Angeles, CA 90095, USA; Department of Periodontology, Asahi University School of Dentistry, Gifu 501-0296, Japan.
3
Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Los Angeles, CA 90095, USA; BioVinc, LLC, Pasadena, CA 91107, USA. Electronic address: shuting.sun@biovinc.com.
4
Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Los Angeles, CA 90095, USA; Department of Oral Rehabilitation, Section of Implantology, Fukuoka Dental College, Fukuoka 814-0175, Japan.
5
Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Los Angeles, CA 90095, USA; Department of Dental Implant Centre, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing 10050, China.
6
Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Los Angeles, CA 90095, USA; Department of Oral Implantology, Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Stomatological Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing 400015, China.
7
Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Los Angeles, CA 90095, USA; Department of Oral and Maxillofacial Implantology, Tokyo Dental College, Tokyo 101-0061, Japan.
8
Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Los Angeles, CA 90095, USA; Division of Molecular and Regenerative Prosthodontics, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan.
9
Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Los Angeles, CA 90095, USA.
10
BioVinc, LLC, Pasadena, CA 91107, USA.
11
Department of Chemistry, Dana and David Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA 90089, USA. Electronic address: mckenna@usc.edu.
12
Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Box 951668 CHS B3-087, Los Angeles, CA 90095, USA. Electronic address: inishimura@dentistry.ucla.edu.

Abstract

Bisphosphonate (BP)-related osteonecrosis of the jaw, previously known as BRONJ, now referred to more broadly as medication-related osteonecrosis of the jaw (MRONJ), is a morbid condition that represents a significant risk for oncology patients who have received high dose intravenous (IV) infusion of a potent nitrogen containing BP (N-BP) drug. At present, no clinical procedure is available to prevent or effectively treat MRONJ. Although the pathophysiological basis is not yet fully understood, legacy adsorbed N-BP in jawbone has been proposed to be associated with BRONJ by one or more mechanisms. We hypothesized that removal of the pre-adsorbed N-BP drug common to these pathological mechanisms from alveolar bone could be an effective preventative/therapeutic strategy. This study demonstrates that fluorescently labeled BP pre-adsorbed on the surface of murine maxillo-cranial bone in vivo can be displaced by subsequent application of other BPs. We previously described rodent BRONJ models involving the combination of N-BP treatment such as zoledronate (ZOL) and dental initiating factors such as tooth extraction. We further refined our mouse model by using gel food during the first 7 days of the tooth extraction wound healing period, which decreased confounding food pellet impaction problems in the open boney socket. This refined mouse model does not manifest BRONJ-like severe jawbone exposure, but development of osteonecrosis around the extraction socket and chronic gingival inflammation are clearly exhibited. In this study, we examined the effect of benign BP displacement of legacy N-BP on tooth extraction wound healing in the in vivo model. Systemic IV administration of a low potency BP (lpBP: defined as inactive at 100 μM in a standard protein anti-prenylation assay) did not significantly attenuate jawbone osteonecrosis. We then developed an intra-oral formulation of lpBP, which when injected into the gingiva adjacent to the tooth prior to extraction, dramatically reduced the osteocyte necrosis area. Furthermore, the tooth extraction wound healing pattern was normalized, as evidenced by timely closure of oral soft tissue without epithelial hyperplasia, significantly reduced gingival inflammation and increased new bone filling in the extraction socket. Our results are consistent with the hypothesis that local application of a rescue BP prior to dental surgery can decrease the amount of a legacy N-BP drug in proximate jawbone surfaces below the threshold that promotes osteocyte necrosis. This observation should provide a conceptual basis for a novel strategy to improve socket healing in patients treated with BPs while preserving therapeutic benefit from anti-resorptive N-BP drug in vertebral and appendicular bones.

KEYWORDS:

BRONJ; Bisphosphonates; Drug displacement; MRONJ; Osteonecrosis of the jaw; Prophylaxis

PMID:
30926440
DOI:
10.1016/j.bone.2019.03.027

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