In 2003, Marx et al. [13] identified a novel form of osteonecrosis of the jaw (ONJ) resistant to conventional therapies, specifically linked to bisphosphonates (BPs), establishing a potential association. Patients with bisphosphonate-related osteonecrosis of the jaw (BRONJ) exhibit multiple risk factors, including specific characteristics of BPs (molecule administered, route of administration, dose, duration of exposure), concurrent drug therapies (such as corticosteroids and chemotherapy), and local factors (such as dental infections, invasive dental procedures, and oral health conditions) [14] [15] [16] . Our study aims to investigate the prevalence of BRONJ in a Moroccan population and identify patient profiles associated with developing this condition.

The American Association of Oral and Maxillofacial Surgery (AAOMS) in the United States reported a prevalence of BRONJ ranging from 0.8% to 12% [17] . K. Kim et al. [18] reported a prevalence of 0.18% in South Korea. Studies by Bamias et al. [19] in Greece and Durie et al. in England [20] indicated an incidence of BRONJ ranging from 1% to 11% in patients with malignant osteopathy treated with intravenous amino BPs. In Brazil, A. Soares et al. [21] reported a prevalence of 3% among women with metastatic breast cancer undergoing BPs treatment. In Australia, Kokki et al. [22] indicated a prevalence of 1.15%. Consistent with these global findings, our study found a prevalence of BRONJ at 1.9%. However, the interpretation of any prevalence must consider the risk factors associated with the development of ONJ.

Investigating these factors thoroughly offers valuable insights for stratifying patient risks, customizing preventive approaches, and optimizing clinical decisions in BPs therapy.

The two BRONJ cases in our study involved one patient on Zoledronate and another on Pamidronate. In a similar study by K. Zervas et al., [23] most BRONJ cases were diagnosed in patients treated with Zoledronate alone, or after treatment with Pamidronate. Only one patient treated with Pamidronate developed BRONJ.

According to the literature, Pamidronate and Zoledronate are categorized as second and third-generation bisphosphonates (containing nitrogen). Second-generation BPs are 100 to 500 times more potent than non-nitrogenous BPs. Third-generation BPs, which also feature amine group methylation, are 10 to 20 times more potent than second-generation BPs. In addition to their anti-resorptive effects through direct action on osteoclasts and anti-angiogenic effects, they accumulate in bones and have a prolonged impact due to their non-metabolized nature, explaining their higher association with bone necrosis [20] . No reported cases of BRONJ are associated with non-nitrogenous BPs such as Alendronate, Residronate, and Ibandronate, which are commonly used today due to their rapid metabolism [5] .

Since oral bisphosphonates introduction approximately 20 years ago, fewer than 50 cases of osteoporotic patients developing BRONJ have been reported, highlighting the low potential for adverse effects of oral amino bisphosphonates [24] . S. Najm et al. [25] report a low risk of osteonecrosis of the jaws linked to the oral administration of BPs, particularly in osteoporosis (1 case per 20,000 patients).

Khan et al. [26] and Dupic et al. [27] reported that the risk of BRONJ increases with monthly IV injections. In our study, both cases of BRONJ involved the intravenous administration of BPs, aligning with literature suggesting that intravenous BPs are more frequently associated with BRONJ development compared to oral administration.

In our study, the number of infusions received by patients varied between one and 12. Bonacina et al., reported that patients received between 6 and 74 infusions of zoledronate, with a higher number of infusions correlating with an increased risk of developing BRONJ [19] .

In our study, the average duration of exposure to intravenous bisphosphonates was 12 months, while exposure to oral bisphosphonates averaged 28 months. According to Hoff et al., [28] the risk of BRONJ increases significantly with the duration of exposure to BPs; in patients treated with intravenous BPs, this risk appears early, with a significant increase after 18 to 24 months of treatment with zoledronate and 60 months with Pamidronate.

Furthermore, BPs have a bone half-life of around 10 years, leading to their accumulation in the skeleton with prolonged use. The risk of BRONJ occurrence is therefore proportional to the cumulative dose and increases with the duration of exposure. The American Dental Association (ADA) and the AAOMS confirm this dose- and duration-dependent increase in risk [19] .

In our study, 47 out of 104 patients received cytotoxic chemotherapy, with only one developing ONJ. This suggests a relatively low incidence of ONJ in this subgroup. Concurrently, ONJ cases associated with Avastin® (chemotherapy) and bisphosphonates were reported by the European Medicines Agency (EMA) in 2010 and the French Health Products Safety Agency (AFSSAPS). Cytotoxic chemotherapy emerged as a significant contributor to ONJ incidence [29] .

Furthermore, the two ONJ cases observed in our study were in patients undergoing long-term corticosteroid therapy. Several studies, including those by Badros et al., [30] Dimopoulos et al., [31] , and Hoff et al., [28] have highlighted the increased ONJ risk associated with corticosteroid therapy.

These findings underscore the critical need for vigilant monitoring and consideration of alternative treatment strategies in patients receiving long-term corticosteroid therapy to mitigate the risk of ONJ.

In our study, few participants maintained regular tooth-brushing habits, while most brushed irregularly or absently, but most patients were informed by their treating physician about the necessity of dental cavity management before BPs treatment, and half of the population received dental care, what can explain the low rate of ONJ occurrence. Magremanne et al. [32] state that inadequate oral hygiene constitutes a risk factor for ONJ.

According to the American Association of Oral and Maxillofacial Surgeons (AAOMS), local risk factors for ONJ include various dentoalveolar surgeries such as tooth extractions, dental implants, periapical surgeries, and periodontal procedures involving bone injury. The risk of developing ONJ escalates approximately sevenfold (from 5.3 to 21) following such procedures, with an average onset period of 6.6 months post-surgery [8] .

Dental extractions precipitated both cases of BRONJ in our study. Multiple studies indicate that invasive dental procedures contribute significantly to ONJ cases, constituting 50% to 80% of reported instances. Bamias et al. [19] reinforce this observation, reporting that 88% of ONJ patients had undergone dental extractions within 12 months before their ONJ diagnosis. SB. Woo et al., [33] , support these findings in a systematic review, emphasizing that 60% of jaw osteonecrosis cases occur following dental extractions or related surgeries.

In conclusion, our study underscores the critical role of oral hygiene practices and the potential risks associated with invasive dental procedures in ONJ development, emphasizing the importance of proactive preventive measures in clinical management.