Medication-related osteonecrosis of the jaw : occurence, risk factors, pathogenesis & treatment

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Medication-related osteonecrosis of the jaw : occurence, risk factors, pathogenesis & treatment


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Publication Doctoral Thesis
Doctoral Thesis, comprehensive summary
Title Medication-related osteonecrosis of the jaw : occurence, risk factors, pathogenesis & treatment
Author Hallmer, Fredrik
Date 2019
English abstract
The antiresorptive drugs bisphosphonates and denosumab are widely used to preserve bone strength by inhibiting osteoclast mediated bone resorption. High dose intravenous bisphosphonates and high dose denosumab are mainly used to treat skeletal related events in patients with metastatic bone disease such as metastatic breast cancer and metastatic prostate cancer or in patients with multiple myeloma. In patients with osteoporosis, oral bisphosphonates are mostly used. Medication-related osteonecrosis of the jaw (MRONJ) is a serious side effect associated both with bisphosphonates and denosumab treatment. The first report on MRONJ was published in 2003. At first, the condition was believed to be a new disease, but it was later proved to be the same disease, which existed more than 100 years ago in match factory workers, and phosphate miners, in whom the disease was recognized as phossy jaw. The overall aim of this thesis was to study the occurrence, risk factors, pathogenesis and treatment of MRONJ. Study I describes prevalence, trigger factors and treatment outcomes of MRONJ retrospectively between the years 2003-2010 in Region Skåne. During this time, 55 patients had been diagnosed with MRONJ. Of these patients, 31 patients with a malignant disease were treated with high dose intravenous bisphosphonates and 24 patients with osteoporosis were treated with oral bisphosphonates. The prevalence of MRONJ was estimated to be 0.024% for patient on oral bisphosphonates and 2.8% for patients on high dose intravenous bisphosphonates. Tooth extraction was the most common trigger factor. After treatment of MRONJ, healing occurred more frequently in patients with osteoporosis treated with oral bisphosphonates than in patients with a malignant disease treated with high dose intravenous bisphosphonates. Study II investigated the association between microflora and MRONJ by using 16S rRNA pyrosequencing technique for the detection of bacteria in necrotic bone lesions. Included were 18 consecutive patients with MRONJ, ten with osteoporosis and eight with metastatic disease. Bone biopsies were retrieved with two separate 3 mm sterile trepan burrs from the centre of the necrotic bone and from visible healthy bone. The necrotic bone lesions contained mainly anaerobic bacteria, representative for periodontal microflora, suggesting that a periodontal infection in combination with antiresorptive treatment could initiate the osteonecrosis. Study III is a prospective cohort study where the prevalence and initiating factors of MRONJ and the outcome of surgical therapy were analysed. All new cases of MRONJ between 2012 and 2015 in Region Skåne were included. Fifty-five patients with MRONJ were identified. The prevalence of MRONJ for patients on oral bisphosphonates was 0.043%, on high dose intravenous bisphosphonates 1.03% and on high dose denosumab 3.64%. Periodontal disease preceded development of MRONJ in 41 patients. Fifty patients were treated surgically and followed up for at least 2 months. Lesions progressed to remission or healing in 80.0% of patients treated with sequestrectomy and in 92.5% of patients treated with block resection. In study IV, the aim was to prospectively determine the incidence and define risk factors for MRONJ in patients with metastatic breast cancer treated with zoledronic acid and/or denosumab. Breast cancer patients diagnosed between 2012 and 2015 in the region of Skåne with one or several bone metastases and treated with zoledronic acid or denosumab were included. Systemic risk factors (age, zoledronic acid or denosumab use, treatment time, chemo-therapy or corticosteroid use, diabetes and smoking habits) were recorded. Sixteen patients of 242 (6.6%) developed MRONJ during the 77 months study period (from 1st of January 2012 to 31st of May 2018). The incidence of MRONJ in patients treated with high dose zoledronic acid was 4.1%, and for patients with high dose denosumab 13.6%. The risk of developing MRONJ in patients on denosumab was significantly higher compared to patients treated with zoledronic acid. Corticosteroid use was associated with a significant decreased risk of MRONJ and diabetes was associated with a significantly increased risk of MRONJ. Chemotherapy or smoking was not associated with a significant increased risk of MRONJ. In conclusion, the incidence of MRONJ is more than three times higher in breast cancer patients treated with denosumab compared to breast cancer patients treated with zoledronic acid. The prevalence in patients with osteoporosis on oral bisphosphonates is low, < 0.05%. Corticosteroid use decreases the risk of developing MRONJ whilst diabetes increases the risk. The most common local risk factor is a periodontal disease. Periodontal bacteria play a central role in the pathogenesis and development of MRONJ. The treatment outcome of MRONJ demonstrates healing in most patients treated surgically.
DOI (link to publisher's fulltext.)
Publisher Malmö university
Series/Issue Doctoral dissertation in odontology;
ISBN 9789171049834
Language eng (iso)
Subject Medicine
Research Subject Categories::ODONTOLOGY
Included papers
  1. I. Osteonecrosis of the jaw in patients treated with oral and intravenous bisphosphonates: experience in Sweden. Hallmer F, Bjørnland T, Nicklasson A, Becktor JP, Andersson G. Oral Surg Oral Med Oral Pathol Oral Radiol. 2014 Aug;118(2):202-8.

  2. II. Bacterial diversity in medication-related osteonecrosis of the jaw. Hallmer F, Bjørnland T, Andersson G, Becktor JP, Kristoffersen AK, Enersen M. Oral Surg Oral Med Oral Pathol Oral Radiol. 2017 Apr;123(4):436-444.

  3. III. Prevalence, initiating factor, and treatment outcome of medication-related osteonecrosis of the jaw-a 4-year prospective study. Hallmer F, Andersson G, Götrick B, Warfvinge G, Anderud J, Bjørnland T. Oral Surg Oral Med Oral Pathol Oral Radiol. 2018 Dec;126(6):477-485.

  4. IV. Incidence of and risk factors for medication-related osteonecrosis in women with breast cancer with bone metastasis: a cohort study. Hallmer F, Bjarnadottir O, Malmström P, Götrick B, Andersson G. Manuscript.

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