Recently, it has been reported that the number of patients with medication-related osteonecrosis of the jaws (MRONJs) is increasing . The most debated side-effects of antiresorptive medication is MRONJ [2,3], including bisphosphonate-related osteonecrosis of the jaw (BRONJ)  and denosumab-related osteonecrosis of the jaw [5,6]. The American Association of Oral and Maxillofacial Surgeons (AAOMS) change the term MRONJ at 2014 in effort of increasing number of osteonecrosis cases with other antiresorptive (e.g., denosumab) and antiangiogenic therapies which the diagnostic criteria for MRONJ are based on clinical, radiographic features and pharmacological history . In 2021, The Korean Association of Oral and Maxillofacial Surgeons (KAOMS) and the Korean Society for Bone and Mineral Research (KSBMR) had proposed the localized guideline customized for the local Korean situation on MRONJ . In 2022, the AAOMS revisions in treatment strategies highlighted current research status . Especially since the position paper was published in 2022 AAOMS after 8 years, the new position paper is required to compare the 2014 AAOMS position paper with the 2021 KAOMS and KSBMR paper to investigate the latest trend of MRONJ.
A patient with lesions on the maxillofacial region can be diagnosed with MRONJ if the following criteria are satisfied: (1) Current or past use of antiresorptive or antiangiogenic agents; (2) Exposure of the jaw bone or intraoral or extraoral fistula persisting for more than 8 weeks; (3) No history of head and neck radiation therapy . The disease worsens oral hygiene, increasing morbidity, inducing an adverse effect on quality of life, and interrupts ideal dental treatment [7,9]. It is important to establish the precise mechanisms and treatment strategies of MRONJ. Available clinical information about when to perform dental treatments in osteoporosis patients and other agents important to prevent developing MRONJ  are to be discovered. Although MRONJ is induced by the various drugs, taking antiresorptive medications as a treatment for osteoporosis induces the high incidence of MRONJ in particular. Hence, this paper focuses on the effect of antiresorptive drugs prescribed in osteoporosis. This paper reviews the definitions of MRONJ, and antiresorptive medications, clinical manifestation and staging, risk factors, treatment strategies, and prevention methods of MRONJ.
Generally, some medical conditions cause abnormal osteoclast activity [10,11]. Antiresorptive medications are currently considered the treatment in patients with osteoclastic bone disease to decrease bone turnover as these medications improve bone density and bone quality . Antiresorptive medications are commonly prescribed for the benefits of stopping the progression of osteoporosis [10-12]. The prior antiresorptive drugs are bisphosphonate and denosumab, which have the most dominant effect in MRONJ.
Bisphosphonate is a dominantly effected to developing MRONJ, it is most famous antiresorptive medication taking either orally or intravenously. It targets osteoclasts and interrupts their function . Since its powerful effect in inhibiting osteoclastic activity by increasing bone density and reducing the remodeling process, the quality of life in most patients is given to the decreased risk of osteoporotic fractures . However, MRONJ results from taking antiresorptive medications with the occurrence of a significant downside risk [2,13]. Bisphosphonate can be use either nitrogen-containing bisphosphonates (alendronate, ibandronate, risedronate, and zoledronate) (Table 1) [2,14] or non-nitrogen-containing bisphosphonates (etidronate, tiludronate, and clodronate) . The effect of medication appears within six hours. Since its powerful affinity to the bone, a long half-life of medication may last at least 10 years [13,15]. Bisphosphonate administration can be done orally and intravenously. Oral administration uptake shows only 1% absorbance into the gastrointestinal tract and intravenous (IV) shows an absorption rate of over 50% . The prevalence of BRONJ in osteoporosis patients with the administration of bisphosphonates is known to range from 0% to 0.04%, and some papers show a prevalence of less than 0.001% [17,18]. The prevalence of BRONJ with the administration of bisphosphonates for more than 2 years is known to range from 0.05% to 0.21% and seems to be related to the duration of the bone exposure .
Denosumab is newly released antiresorptive medication and administered by subcutaneous (SQ) injection. Denosumab plays a role as osteoprotegerin produced by osteoblasts which are induced in an anti-RANKL antibody . It decreased bone resorption in disrupting osteoclast creation, differentiation, and existence . Since the RANKL-inhibitors cannot be attached to the bone, unlike bisphosphonate, denosumab has a short half-life. As a result, the effects of denosumab in the bone do not last longer than that of bisphosphonate and generally decrease within six months of the last treatment .
Romosozumab is a new monoclonal antibody drug administered through SQ, that is used in osteoporotic women for prevention of fracture. Binding and inhibiting sclerostin via the Wnt pathway results in decreased bone resorption and increased bone formation. When exposed to romosozumab, the risk for development of MRONJ ranges from 0.03% to 0.05% . Patients with romosozumab administration should be continuously monitored to assess a risk factor for MRONJ.
An optimal and exquisite staging system founded on clinical features and radiographic findings is used for the diagnosis of MRONJ, which clinicians can provide suitable treatment strategies to patients with MRONJ . The MRONJ staging system adopted by AAOMS was developed by Ruggiero et al. in 2006, then subsequently updated by the AAOMS in 2014 and 2022 (Table 2) [2,8,22,23]. The 50% of stage 0 of patients developed MRONJ, and the other 50% would not develop to clinically obvious MRONJ, thus the stage 0 has been under discussion . In 2022, AAOMS defined the symptoms, clinical findings and radiographic findings of stage 0 of MRONJ .
Symptoms: (1) Odontalgia not explained by an odontogenic cause; (2) Dull, aching bone pain in the jaw, which may radiate to the temporomandibular joint region; (3) Sinus pain, which may be associated with inflammation and thickening of the maxillary sinus wall; (4) Altered neurosensory function. Clinical findings: (1) Loosening of teeth not explained by chronic periodontal disease; (2) Intra oral or extra oral swelling. Radiographic findings: (1) Alveolar bone loss or resorption not attributable to chronic periodontal disease; (2) Changes to trabecular pattern sclerotic bone and no new bone in extraction sockets; (3) Regions of osteosclerosis involving the alveolar bone and/or the surrounding basilar bone; (4) Thickening/obscuring of periodontal ligament (thickening of the lamina dura, sclerosis and decreased size of the periodontal ligament space) . Radiographic parameters in estimated MRONJ were sclerosis, lytic changes, periosteal reaction and sequestration . Typical characteristics of the radiography of MRONJ are in Fig. 1 and a radiographic of a patient with MRONJ symptoms is shown in Fig. 2.
There are a lot of the risk factors that contributed to developing MRONJ. The risk factors can be classified in three themes: the type of medication, systemic risk factor, and a local risk factor (Table 3) . The use of bisphosphonate, denosumab, and romosozumab are considered serious risk factors for development of MRONJ [1,24]. The risk of medication highly depends on the dosage, route, and intake duration after administration . The risk of development of MRONJ is increases as the dose-time increasing .
Systemic risk factors for developing MRONJ involve cardiovascular disease (hyperlipidemia, angina, and hypertension), vitamin D deficiency, corticosteroid use, diabetes, osteomalacia, hypocalcemia, hypoparathyroidism, anemia, osteoporosis, renal dialysis, sarcoidosis, rheumatoid arthritis, Paget’s disease of bone, Sjögren’s syndrome, erythropoietin therapy, alcoholism, tobacco use, age, and obesity [2,26,27].
The most often reported risk factor for MRONJ is tooth extraction as the causative factor (52%-61%) [1,26,28]. The most known risk factor in developing MRONJ is existing periodontal infection of the patients with antiresorptive medication administration . The acidity was increased by the infection, leading to suppression of the healing mechanism and resulting in osteonecrosis . In this result, the bone of the jaw is susceptible from various infections compared to other sites of bones in the body . Furthermore, when comparing bone necrosis sites affected by antiresorptive drugs, osteonecrosis occurs more in the mandible about 73% than in the maxilla about 22.5% . Despite the biological mechanisms not exactly known, MRONJ arises more commonly in the mandible than maxilla. The mandible is susceptible to necrosis and infections due to the only single blood supply it has . Moreover, acute dental infection, endodontic treatment, implant management (implant placement, bone augmentation, and peri-implantitis), periodontal disease, periodontal surgery, trauma occurred by unfitted dentures, anatomical factors (exostoses, torus, knife-edge ridge, and mylohyoid ridge), and other oral conditions (xerostomia, poor oral hygiene, and excessive bite force) have also been stated [2,26,27].
Treatment strategies are controversial because the scientific evidence for the pathogenesis of MRONJ is limited, and current treatment strategies are based on clinical symptoms rather than definitive criteria. Treatment strategies for MRONJ were established for each stage in the position paper between AAOMS in 2014  and 2022 , and KAOMS and KSBMR in 2021  (Table 4). The goal of treatment can be achieved to avoid infection, pain control, and the management of bone resorption and necrosis [24,26].
A patient with some symptoms without exposed bone should be carefully diagnosed as Stage 0, because it has been reported that about 50% of patients in Stage 0 have progressed to a higher stage (stage 1, 2, or 3) . The patients with Stage 0 are recommended to symptomatic treatment (e.g., infection and pain control) and non-operative treatment. A close observation could allow early detection of the advance to an upper stage [2,27,29].
Non-operative therapy is recommended along with patient education, patients monitoring per 3 to 4 months, the rinsing with antimicrobial, and improving oral hygiene. Immediate operation is not required at stage 0 and 1, although minor surgical treatments such as removal of necrotic bone or sequestrectomy are recommended to remove the necrotic bone and reduce soft tissue trauma [2,29-31]. Non-operative treatment is provided for patients with at-risk stage or asymptomatic in early stages. This treatment could be executed to patients who cannot receive surgical therapy, though non-operative treatment only provides temporary relief of symptoms in about 70% of cases of early stage MRONJ patients . It includes chlorhexidine mouthwash, antibiotic therapy, keeping good oral hygiene, and periodic clinical follow-up and it can minimally improve the state or stabilize the oral condition. The adjunctive treatments like low-intensity laser therapy, hyperbaric oxygen, and ozone therapy were reported in some studies with a higher success result through a combination therapy [33,34]. Among the adjunctive treatments, recombinant human parathyroid hormone (rhPTH, teriparatide) would be a promising therapeutic modality, while short-term teriparatide medication would be a good choice to impaired bone remodeling for MRONJ patients . The administration of teriparatide improves the activity of osteoclasts and increases the number of osteoclasts which lesser osteocytes that are unable to survive and greater turnover of bone, then decreasing the chance of bone necrosis .
The stage 2 and 3 of MRONJ are tough to be distinguished clearly, then treatment strategies for stages 2 and 3 of MRONJ are not clear. Although there is insufficient clinical evidence that antibiotics are preferable to stage 2 of MRONJ, antimicrobial mouth rinsing and use of antibiotics for systemic antimicrobial control are recommended for patients with stage 2 [2,21,31]. A bacterial membrane is formed above exposed necrotic bone reported to interrupt the effect of antimicrobial treatment. Therefore, removal or debridement of the osteonecrosis area should be considered . Follow-ups per 8 weeks and education to patients are also fulfilled focused on the guideline of MRONJ . A surgical approach to exposed necrotic bone may be carried out, when conservative treatment results in dissatisfaction. Necrotic bone exposure state requires surgical approach with conservative or adjunctive treatment . The surgical treatment is achieved through sequestrectomy of necrotic bone with antibiotic medication and antiseptic mouth rinsing, combined with adjunctive treatments like leukocyte-platelet rich fibrin and ozone therapy . However, when conservative debridement method has failed and progressed to the advanced stage of MRONJ, segmental resection to the elimination of all necrotic bone and only leaving healthy bone is applied to osteonecrosis bone for obtaining pure, healthy bone [33,34,38].
In 2022, the position paper of AAOMS presented a treatment approach through algorithms to streamline the process of the evaluation and to improve management strategies for patients with MRONJ . The strategies are based on a current review on non-operative treatment and operative treatment. It is acceptable for all stages based on judgment to surgical treatment and patient risk factors . It was recommended that decisions on non-operative or operative treatment should be done under consideration of the specific situation of a patient and tailored to individual needs according to the size and location of the MRONJ. Radiographic imaging is important in evaluation of MRONJ lesions. Especially, cone beam computerized tomography image identifies forming or fully formed sequestrum and it helps to potentially minimize the surgical procedure [25,39]. Sometimes, segmental resection or marginal resection of the mandible and partial maxillectomy are effective operative methods [40,41], and this approach can be applied to patients with all stages of MRONJ, including Stage 1 lesion existing above the inferior alveolar nerve or inferior to the maxillary sinus floor . MRONJ is a complex disease that should be performed operative treatment at the right time [41,43]. The management and treatment protocol for MRONJ is demanding and remains a controversial issue [13,15,28].
Prevention is essential in reducing the risk of MRONJ [10,11,32]. As a preventive measure, a thorough patient screening can significantly lower the risk of MRONJ outbreak . To recognize an individual at risk stage and prevent dental infection are the dentist’s responsibility. It should be carried out through regular check-ups to maintain good oral hygiene . Moreover, patients taking antiresorptive therapy should be examined clinically and radiographically in effort not to create any acute infections and to prevent possible symptoms [2,24].
A drug-holiday is a temporary terminated drug administration, having a drug-holiday prior to surgical treatment remains a controversial subject to minimize the risk of osteonecrosis . Patients with a history or current antiresorptive drug use through an orally for less than four years have a low risk of development of MRONJ and requires no alteration in the planned procedure (e.g., surgical extraction or any other surgical treatments) . However, the physician should be deciding drug holidays or possible dose alteration medication and patients should be announced about the risk of development of MRONJ. Patients with orally bisphosphonate administration more than four years or less than four years with combination use of corticosteroids and an antiangiogenic medication will be given a guideline as follows: the physician would suggest the withdrawal of bisphosphonate medication for at least two months before surgical treatment if the systemic condition of the patient allows a drug holiday, and it could last until the osseous and mucosal recovery .
One of the most serious risk factors is tooth extraction that develops MRONJ [2,31]. Recently, clinicians recommended starting dental treatment without discontinuation of bisphosphonate medications , although they previously recommended that endodontic treatment should be chosen rather than extraction of tooth in patients who receive bisphosphonates to IV . Tooth extraction is done on patients with taking bisphosphonate, then the remaining sharp edges near tooth extraction area must be smoothened and extraction socket closure with mucoperiosteal flaps would be performed. Also, antibacterial medication should be administered after tooth extraction . But there is limited correlation between users of denosumab and tooth extraction. Some clinical papers recommended without a drug holiday for invasive dental treatment including tooth extraction [21,29].
Implant placement, peri-implantitis, taking bisphosphonates after placement of dental implant, and removal of dental implants have been announced to trigger MRONJ in patients with osteoporosis [29,44]. The degrees of risk for development of MRONJ on implant treatment have not been exactly elucidated. The removal of dental implant would be the risk factors for development of MRONJ, then, patients taking bisphosphonates for osteoporosis with peri-implantitis should not easily consider implant removal . Strict management programs like short-term intervals of follow-up, oral examinations of teeth and implants, taking radiographs to evaluate the implant, and cleaning of peri-implant are recommended.
Antiresorptive medications for treated osteoporosis have been strongly associated with MRONJ. An effective and appropriate management for MRONJ should be defined. Careful treatment planning with periodic and frequent follow-ups are recommended for preventing of MRONJ. In addition, minimally invasive surgical procedures are preferred, and evaluating the individual risk in each patient is very important.
No potential conflict of interest relevant to this article was reported.