Synthetic Hydroxyapatite Inhibits Bisphosphonate Toxicity to the Oral Mucosa In Vitro.

George Bullock,Vanessa Hearnden,Alasdair Mckechnie,Cheryl Miller

doi:10.3390/ma13092086

George Bullock, Vanessa Hearnden + Show 2 more

Open Access

https://doi.org/10.3390/ma13092086

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Journal: Materials	Publication Date: May 1, 2020
Citations: 9	License type: CC BY 4.0

Affiliation: University of Sheffield, University of Leeds

Abstract

Medication-related osteonecrosis of the jaw (MRONJ) is a side effect of bisphosphonate therapy, characterised by exposed necrotic bone. The soft tissues of the oral mucosa no longer provide a protective barrier and MRONJ patients experience pain, infections and difficulties eating. We hypothesised that hydroxyapatite (Ca5(PO4)3(OH)) could reduce bisphosphonate concentrations and protect the oral mucosa by exploiting bisphosphonate’s calcium binding affinity. The effect of zoledronic acid (ZA) and pamidronic acid (PA) on the metabolism of oral fibroblasts, oral keratinocytes and three-dimensional oral mucosa models was investigated and then repeated in the presence of hydroxyapatite granules. Without hydroxyapatite, ZA and PA significantly reduced the metabolic activity of oral cells in a dose-dependent manner. Both drugs reduced epithelial thickness and 30 µM ZA resulted in loss of the epithelium. Hydroxyapatite granules had a protective effect on oral cells, with metabolic activity retained. Oral mucosa models retained their multi-layered epithelium when treated with ZA in the presence of hydroxyapatite granules and metabolic activity was comparable to controls. These results demonstrate hydroxyapatite granules protected oral soft tissues from damage caused by bisphosphonate exposure. Porous hydroxyapatite granules are currently used for socket preservation and this data suggests their potential to prevent MRONJ in at-risk patients.

Highlights

Medication-related osteonecrosis of the jaw (MRONJ) is a disease defined by jawbone necrosis and exposure through the overlying soft tissue
The risk of developing MRONJ ranges from 1% to 10% for patients prescribed BPs for bone metastases, and 0.01% to 0.001% for those treated for osteoporosis [3]
This study has demonstrated that HA granules can bind sufficient quantities of BPs to reduce soft tissue damage, which indicates its potential as a preventative therapy for MRONJ

Summary

Introduction

Medication-related osteonecrosis of the jaw (MRONJ) is a disease defined by jawbone necrosis and exposure through the overlying soft tissue. MRONJ commonly develops in patients following wounding of the jaw and, in the majority of cases, follows a tooth extraction. The medications most commonly associated with MRONJ are bisphosphonates (BPs). Other anti-resorptives and anti-angiogenic medications have been linked to the disease [2]. Incidence is variable depending on the medication used, therapy length and other risk factors including poor oral hygiene. The risk of developing MRONJ ranges from 1% to 10% for patients prescribed BPs for bone metastases, and 0.01% to 0.001% for those treated for osteoporosis [3]. MRONJ is currently without an effective treatment [2]

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