Abstract
Medication-related osteonecrosis of the jaws (MRONJ) is a rare complication of bisphosphonates, or antiresorptive or antiangiogenic medication. Treatment is difficult as the bone has a poor capacity for healing, and further progression after surgery can occur. Quality of life (QoL) in patients with MRONJ has not been well documented. The aim of this study therefore was to identify and analyse data on QoL in this group of patients. Eight studies that were identified through a systematic search of the literature were qualitatively analysed. Overall, data on QoL are lacking and are complicated by concurrent disease such as cancer. Patients generally have a poor QoL because of MRONJ, and multiple oral-specific complaints including pain and problems with speech. Development of a questionnaire specific to patients with MRONJ would help improve the specificity of the data collected. Prospective questionnaires before and after intervention, including information on stage and comorbidities, would guide future treatment strategies.
Introduction
Medication-related osteonecrosis of the jaws (MRONJ) is a rare complication of treatment with bisphosphonates, or antiresorptive or antiangiogenic medication. First identified in 2003, the name has evolved from “bisphosphonate-related” to “antiresorptive-related”, and finally to MRONJ as further drugs such as steroids and biologicals have been implicated in its pathogenesis. MRONJ is characterised by osteonecrosis in bone with poor turnover, often with an initiating event such as a dental extraction.
Bisphosphonates and other antiresorptive medications are typically prescribed for metabolic bone disease such as osteoporosis, or for the prevention of skeletal-related events or hypercalcaemia in advanced malignancy. The risk of MRONJ is approximately 0.1% in patients treated for osteoporosis and 1% in those treated for cancer, although the rate is highly variable depending on the duration of exposure and the study population. Women are affected more often than men, and most patients are over the age of 60. A recent prospective study in the United Kingdom provided an estimated incidence of 8.2-12.8 cases/million/year, which is expected to rise with an ageing population and continuing use of bisphosphonate-related drugs.
The American Association of Oral and Maxillofacial Surgeons (AAOMS) have defined MRONJ ( Table 1 ) and produced the staging system used most often in clinical practice ( Table 2 ).
| 1 | Current or previous treatment with antiresorptive or antiangiogenic agents |
| 2 | Exposed bone or bone that can be probed through an intraoral or extraoral fistula(s) in the maxillofacial region that has persisted for more than 8 weeks |
| 3 | No history of radiation therapy to the jaws or obvious metastatic disease to the jaws |
| Stage | Description |
|---|---|
| At risk | No apparent necrotic bone in patients who have been treated with either oral or IV bisphosphonates |
| 0 | No clinical evidence of necrotic bone, but non-specific clinical findings, radiographic changes, and symptoms |
| 1 | Exposed and necrotic bone or fistulas that probe to bone in patients who are asymptomatic and have no evidence of infection |
| 2 | Exposed and necrotic bone, or fistulas that probe to bone, associated with infection as evidenced by pain and erythema in the region of the exposed bone with or without purulent drainage |
| 3 | Exposed and necrotic bone or a fistula that probes to bone in patients with pain, infection, and one or more of the following: exposed and necrotic bone extending beyond the region of alveolar bone(that is: inferior border and ramus in the mandible, maxillary sinus and zygoma in the maxilla) resulting in pathological fracture, extraoral fistula, oroantral/oronasal communication, or osteolysis extending to the inferior border of the mandible of sinus floor |
Treatment is difficult as the bone has a poor capacity for healing, and further progression after surgery can occur. Current recommendations are mainly supportive, including analgesia, antibacterial mouthwashes, and oral antibiotics for established infections. Debridement can be considered in cases with clear sequestra or loose necrotic bone, and resection is reserved for extensive disease. Adjuvant treatments including hyperbaric oxygen therapy and platelet-rich plasma have been proposed, but evidence is conflicting.
Quality of life (QoL) for patients with MRONJ has not, to our knowledge, been well documented. The aim of this study was to undertake a systematic analysis of the data on QoL in this group with a view to developing recommendations that will enable future comparisons to be made, particularly regarding treatment outcomes.
Material and methods
The PRISMA method was used to identify and review the relevant studies. EMBASE and PubMed were reviewed in December 2018 using the following search terms: BRONJ, ARONJ, MRONJ, bisphosphonate-associated osteonecrosis, bisphosphonate-related osteonecrosis, antiresorptive-related osteonecrosis, antiresorptive-associated osteonecrosis, medication-related osteonecrosis, medication-associated osteonecrosis, QoL, and quality of life. All original research articles that evaluated QoL in patients with MRONJ, regardless of language or date of publication, were included.
Reference lists were reviewed for further papers. Fig. 1 shows the selection process. Eight papers were included in the study.
For each paper the number of patients, QoL questionnaire used, and study design were reviewed. A formal meta-analysis could not be done due to the heterogeneity of the data, subjects, and methods. A qualitative approach was therefore used to tabulate and descriptively examine the studies.
Results
Details of the eight papers are tabulated in Table 3 . Two focused on the QoL of patients with MRONJ with no intervention, and six used QoL as an outcome measure as part of a trial. A variety of questionnaires were used including the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-HN35, Oral Health Impact 14 (OHIP 14), Duke Health Profile, University of Washington (UW) QoL, and Short Form Survey 12 (SF 12). The EORTC QLQ-C30 and QLQ-HN35 were used most often, appearing in three of the papers. None of the papers directly compared data from different questionnaires. Kyrgidis et al validated the use of EORTC QLQ-C30 and QLQ-HN35 in patients with MRONJ by comparing results in patients with head and neck cancer, and breast cancer alone. Only the the EORTC QLQ-HN35, OHIP 14, and UWQoL are questionnaires specific to oral health.
| First author, year, and reference | Design | Questionnaire | No. of patients | MRONJ stage |
|---|---|---|---|---|
| Miksad 2011 | Retrospective telephone interview of patients with MRONJ who had been treated with bisphosphonates for cancer. Patients questioned on QoL before and after being diagnosed with MRONJ | OHIP 14 Health on a visual analogue scale (VAS), Time to trade off (TTO) and EQ-5D |
34 | Results separated by stage |
| Freiberger 2012 | Prospective, unblended, randomised controlled trial primarily looking at the role of hyperbaric oxygen in MRONJ. Patients’ QoL recorded at the start of trial and after 6 months | Duke Health Profile | 49 | Unavailable |
| Kyrgidis 2012 | Prospective observational controlled study. Compared QoL in patients with 1: metastatic breast cancer and MRONJ, 2: metastatic breast cancer, and 3: oral cancer | EORTC QLQ-C30 and QLQ-HN35 | 66 (21 of which had MRONJ) |
Unavailable |
| Rathbone 2013 | Randomised controlled trial on zolendrenate in breast cancer. Oral QoL recorded as a secondary outcome | OHIP 14 | 486 (of which 1 patient with confirmed MRONJ) | Unavailable |
| Sadiq 2014 | Case series of 3 patients with MRONJ treated with resective surgery. QoL a secondary outcome | UWQoL Results discussed qualitatively |
3 | Unavailable |
| Capocci 2017 | Cross-sectional study of patients with MRONJ | SF12. | 30 | Stage given |
| Oteri 2018 | Observational study of patients given conservative with or without surgical treatment for MRONJ. QoL recorded before and after treatment | EORTC QLQ-C30 and QLQ-HN35 | 100 | Stage not correlated with data. |
| Oteri 2018 | Observational study of osteoporotic patients with MRONJ treated with resective surgery. QoL measured before and after operation | EORTC QLQ-C30 and QLQ-HN35 | 41 | Unavailable |
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