Medication-related osteonecrosis of the jaw: definition and best practice for prevention, diagnosis, and treatment

Abstract

Skeletal complications caused by osteoporosis or bone metastases are associated with considerable pain, increased mortality, and reduced quality of life. Furthermore, such events place a burden on health care resources. Agents that prevent bone resorption, such as bisphosphonates or denosumab, can reduce the risk of skeletal-related events and are widely used in patients with osteoporosis or bone metastases of cancer. Medication-related osteonecrosis of the jaw (MRONJ) is a rare, but potentially serious, adverse event associated with high cumulative doses of bisphosphonates or denosumab. However, MRONJ can be treated, and the likelihood of the development of this condition can be reduced through prophylactic dental care and the maintenance of good oral hygiene. Dentists, as part of a multiprofessional team, have a critical role in preventing MRONJ. This review describes the incidence and pathophysiology of MRONJ and provides guidance for dental practitioners with regard to the screening, prophylactic treatment, diagnosis, and management of patients with this condition. (Oral Surg Oral Med Oral Pathol Oral Radiol 2019;127:117À135) Medication-related osteonecrosis of the jaw (MRONJ) is an uncommon condition that can occur after exposure to agents used to prevent bone complications, such as bisphosphonates or denosumab, or treatment with other agents, such as angiogenesis inhibitors. 1 In the majority of cases, MRONJ manifests as exposed bone in the maxillofacial region (Figure 1), although non-exposed MRONJ has also been recognized (Figure 2). 2-5 Bisphosphonates and denosumab are predominantly used to reduce the risk of skeletal complications in patients with bone loss, resulting from long-term cancer treatment or osteoporosis, and in patients with malignant bone disease. 6-8 Bisphosphonates are small molecules that dock in hydroxyapatite-binding sites on bone surfaces. When osteoclasts begin to resorb bisphosphonate-impregnated bone, the liberated bisphosphonates bind to farnesyl pyrophosphate synthase inside the osteoclasts, ultimately leading to apoptosis. 8-10 Denosumab is a fully human monoclonal antibody, which has a different mode of action from that of bisphosphonates. It targets and binds to the receptor activator of nuclear factor k-B (RANK) ligand (RANKL); in doing so it prevents the activation of RANK on the surface of osteoclasts and osteoclast precursors. Inhibition of the RANKLÀRANK interaction impedes osteoclast formation, function, and survival, thereby decreasing bone resorption. 11 MRONJ is more prevalent among patients receiving high cumulative doses of bisphosphonates or denosumab than in patients who receive lower doses. 12,13 The first cases Statement of Clinical Relevance Medication-related osteonecrosis of the jaw is a rare, but potentially serious, complication of treatment with bisphosphonates and denosumab. It is important for dentists to be aware of ways to identify and treat patients at risk of this condition.

Workshop of European task force on medication‐related osteonecrosis of the jaw—Current challenges

“…Recent studies have reported the presence of histologically proven alveolar necrotic bone associated with dental/periodontal infection at the time of the extraction of teeth (Nicolatou-Galitis et al, 2015;Nicolatou-Galitis, Schiødt, et al, 2019). Similarly, animal studies have reported that MRONJ can develop to areas of periodontal infection in the absence of dental extraction surgery (Nowicki et al, 2019; (Patel et al, 2018;Rugani et al, 2014).…”

“…The Group suggested that dental infection might currently be a more common and relevant risk factor for MRONJ compared to extraction and that a notable proportion of MRONJ cases believed to have been triggered by dental extraction in fact represent cases of non‐exposed MRONJ that had already developed because of dental/periodontal infection before the actual extraction took place. Recent studies have reported the presence of histologically proven alveolar necrotic bone associated with dental/periodontal infection at the time of the extraction of teeth (Nicolatou‐Galitis et al, ; Nicolatou‐Galitis, Schiødt, et al, ). Similarly, animal studies have reported that MRONJ can develop to areas of periodontal infection in the absence of dental extraction surgery (Nowicki et al, ; Otto et al, ).…”

Alveolar bone histological necrosis observed prior to extractions in patients, who received bone‐targeting agents

“…Medication‐related osteonecrosis of the jaw (MRONJ) is a potentially serious complication related to bone‐targeting agents (BTAs), such as bisphosphonates and denosumab, which, in the cancer setting, are used to prevent cancer‐related bone complications (Nicolatou‐Galitis, Schiodt, et al, ; Otto, Pautke, Van den Wyngaert, Niepel, & Schiodt, ; Ruggiero et al, ). Exposed and non‐exposed type of MRONJ have been documented (Fedele et al, , ; Schiodt, Reibel, Oturai, & kofod, ).…”

Avaliação da diferenciação osteoblástica de células-tronco mesenquimais de ratos tratados cronicamente com bifosfonatos

“…Considerando que a MRONJ, patologia óssea multifatorial de difícil tratamento (FASSIO et al, 2017), pode ser desencadeada por tratamentos odontológicos envolvendo tecido ósseo, como doença periodontal, lesões periapicais, instalação de implantes, cirurgia oral, e extrações (ALIJOHANI et al,2017;FASSIO et al, 2017;NICOLATOU-GALITIS et al, 2019), sendo a última responsável por mais de 50% dos desencadeamentos da enfermidade, pode-se considerar também a ocorrência espontânea (RUGGIERO, 2014; KUROSHIMA; SASAKI; SAWASE; 2019), o propósito deste estudo consistiu em analisar a capacidade de diferenciação osteoblástica de células-tronco mesenquimais (CTMs) de ratos que foram tratados cronicamente com alendronato de sódio ou ácido zoledrônico.…”

“…A osteonecrose dos maxilares causada pelo uso de medicamentos ["medicine drug related osteonecrosis of the jaw (MRONJ)"], tais como os antirreabsortivos, caracteriza-se pela presença de exposição óssea ou osso que pode ser examinado por meio uma fístula intra ou extraoral na região dos maxilares, persistente por mais de 8 semanas, durante ou após tratamento com BPs, sem histórico de radioterapia na região maxilofacial (RUGGIERO, 2014). Esse efeito adverso de difícil resolução tem mecanismos desconhecidos, causa destruição severa nos maxilares (MIGLIORATI, 2006) e sua gravidade varia de acordo com a via de administração, a dose, a frequência e o tempo de uso do medicamento (BASSO, 2013;FERREIRA JÚNIOR; CARDOSO; BARBOZA, 2007; ALIJOHANI et al, 2017;FASSIO et al, 2017).Considerando que a MRONJ, patologia óssea multifatorial de difícil tratamento (FASSIO et al, 2017), pode ser desencadeada por tratamentos odontológicos envolvendo tecido ósseo, como doença periodontal, lesões periapicais, instalação de implantes, cirurgia oral, e extrações (ALIJOHANI et al,2017;FASSIO et al, 2017;NICOLATOU-GALITIS et al, 2019), sendo a última responsável por mais de 50% dos desencadeamentos da enfermidade, pode-se considerar também a ocorrência espontânea (RUGGIERO, 2014; KUROSHIMA; SASAKI; SAWASE; 2019), o propósito deste estudo consistiu em analisar a capacidade de diferenciação osteoblástica de células-tronco mesenquimais (CTMs) de ratos que foram tratados cronicamente com alendronato de sódio ou ácido zoledrônico.…”