Sources and search strategy: A literature search was
conducted using the PubMed/Medline database,
employing the following keywords: [(monoclonal
antibodies) OR (antiresorptive drugs)] AND
[(osteonecrosis of the jaw) OR (ONJ)].
Inclusion criteria: Randomised controlled trials (RCTs) from the past 10 years describing the incidence of ONJ in patients treated with monoclonal antibodies (MAs) were included.

Exclusion criteria: In vitro studies, animal studies, and observational studies were excluded. RCTs reporting ONJ caused by drugs other than MAs were also excluded.
Selected articles: Following the initial search, a total of 3,057 results were obtained. An initial screening was conducted, excluding articles that did not meet the inclusion criteria based on title and abstract.
Subsequently, 42 articles were read in full, and ultimately, 12 articles were included in the review (Figure).

Information recorded from the articles: The names of the authors, year of publication, number, sex and age of the patients, follow-up period, type, dose and frequency of administration of the monoclonal antibody (MA) used, number of reported cases, severity, and risk factors were recorded.

In total, 13 RCTs were analysed, as the article by Stopeck et al.¹³ presented two studies. The total number of patients was 16,259, 15,027 women and 1,232 men, with a mean age of 65.22 years.

The most frequently used MA was denosumab, which was analysed in 10 studies and administered at doses ranging from 60 mg every 6 months to 120 mg monthly. The other MA, analysed in three studies, was romosozumab, administered at a dose of 210 mg monthly. The follow-up period for patients ranged from 6 to 120 months.

In five studies^{11,12,15,18,21} no cases of ONJ were
reported, whereas in the remaining seven
studies^{10,13,14,16,17,19,20} an incidence ranging from 0.028% to 8% (mean 3.87%) was observed. The severity of ONJ cases was analysed in only three studies^13,17, with 51 mild cases (stage 1–2) and 16 severe cases (stage 3) reported. Finally, the factors associated with the development of ONJ were analysed in three studies^14,17,20 in which the use of ill-fitting prostheses, extractions, invasive dental procedures, periodontal disease, and the use of
corticosteroids were described (Table 2).

ONJ is a rare pathology that considerably impairs
patients’ quality of life. In this literature review, 12 studies were included in which cases of patients
receiving monoclonal antibody therapy were
documented, with denosumab (60 mg every 6
months)^11,12,16,18 being the most frequently utilised.

The majority of cases studied were women (92.4%),
which may be explained by the high prevalence of
osteoporosis following menopause. The most commonly utilised treatments for osteoporosis are zoledronic acid, denosumab, and teriparatide, as they demonstrate high efficacy in reducing the risk of bone fractures²².

ONJ is most frequently localised in the mandible22,23; however, it may also be detected in the maxilla²⁴.
Furthermore, it may be accompanied by pain,
inflammation, erythema, suppuration, and tooth loss.
Although ONJ may occur spontaneously, in the majority of cases it results from a surgical procedure in the oral cavity²⁵.
With regard to the incidence of ONJ, a variation between 0% and 8% was observed, which may be attributable to differences in sample sizes among the studies and the follow-up period. Furthermore, when comparing the mean incidence obtained in this review (3.87%) with other drugs that may also induce ONJ, such as intravenous bisphosphonates (1.3–3.2% after 3 years of follow-up) and oral bisphosphonates (between 1–2.3% after 3 years of follow-up, the incidence of MRONJ is observed to be higher in patients taking antiresorptive agents (ARs) ^26,27. This increased incidence was already noted by Loyson et al.²⁸, who confirmed a higher risk of MRONJ in patients who switched from bisphosphonates to ARs. It is worth noting, however, that the effects of bisphosphonates on bone can last up to three years after the last dose, unlike ARs, which do not have a cumulative effect22. The risk factors for ONJ associated with monoclonal antibody therapy were described in three studies^14,17,20. The risk factors for ONJ related to the use of monoclonal antibodies that were identified are similar to those for ONJ induced by bisphosphonates: use of ill-fitting prostheses, extractions, invasive dental procedures, periodontal disease, and use of corticosteroids. Additionally, ONJ caused by bisphosphonates presents further risk factors such as the cumulative dose of bisphosphonates in the blood and tobacco use²⁹.
In this context, it is important to implement a review programme for patients treated with monoclonal antibodies, as the majority of diagnosed cases of ONJ associated with monoclonal antibody therapy are mild (stages 1–2). Seventy-six per cent of cases in which the stage is recorded are mild, thereby underscoring the particular importance of early diagnosis of ONJ³⁰.
With regard to the management of ONJ, the literature describes adjuvant treatments (antibiotics, oral rinses) for mild cases (stages 1–2). In stage 3, for those cases that do not respond to adjuvant treatment, surgical procedures (debridement, curettage, removal of sequestra, and bone resection) should be employed, ensuring complete removal of necrotic bone, smoothing of the bone margins, and meticulous wound closure³¹.
Other therapeutic alternatives are currently under investigation, such as the use of platelet concentrates, teriparatide, laser therapy, hyperbaric oxygen, and ozone applications. These therapies may be effective, although at present they exhibit a low level of evidence and a limited sample size³².

One of the limitations of the present review is the short follow-up period (< 5 years) in nine of the thirteen included studies. Furthermore, in eight of the thirteen included studies, the sample comprises exclusively women; thus, it would be of interest to determine the incidence according to gender. Finally, it would be beneficial to compare the incidence of ONJ between monoclonal antibodies and other antiresorptive agents.

The incidence of ONJ induced by monoclonal antibodies in this review is higher than that of other agents, such as oral and intravenous bisphosphonates. Furthermore, it appears that the use of ill-fitting prostheses, extractions,
periodontal disease, and corticosteroid use may promote the development of ONJ associated with the administration of monoclonal antibodies. Nevertheless, further randomised clinical trials comparing monoclonal antibodies with other antiresorptive agents are required to more precisely determine the incidence, severity, and risk
factors.