Medication-related osteonecrosis of the jaw: a preliminary retrospective study of 130 patients with multiple myeloma

The exact mechanism of action underlying the pathogenesis of MRONJ is uncertain. MRONJ may be associated with medication-related apoptosis of osteoclasts or to the anti-angiogenic and suppressive effects that BPs have on endothelial cells [11]. The strong association of intravenous nitrogen-containing BPs with MRONJ compared to oral BPs suggests that intravenous BPs are more bioavailable, allowing increased incorporation into the bone matrix. Only 1% of oral BPs are circulated in the serum due to delayed gastrointestinal tract absorption.

The prevalence of MRONJ in patients treated with intravenous BPs ranges from 0.8 to 12% [10]. According to a cohort study, the estimated incidence of MRONJ in MM patients is 8.42%, and the highest incidence is in patients who received a combination of pamidronate and zoledronate (range 5 to 51%). Zoledronate is associated with MRONJ in 3 to 11% of MM cases, while the pamidronate-related frequency of MRONJ ranges from 0 to 18% [3]. The overall incidence of MRONJ in our study was 6.9% (9/130 MM patients). Of these nine patients, 77.7% (n = 7) received a combination of pamidronate and zoledronate.

Studies evaluating the duration of bisphosphonate therapy as a risk factor for MRONJ development in MM patients have yielded inconsistent results [6, 9]. In our patients, the median length of BP exposure was 19 months, which is similar to the results of Berenson et al. (18 months of zoledronate) [12]. However, our results are not consistent with those of Corso et al. [13] (47 months of pamidronate and zoledronate combination therapy), Zervas et al. [14] (24 months of pamidronate), and Dimopoulos et al. (53.4 months of pamidronate and zoledronate combination therapy) [15].

It is thought that the jaw is more predisposed to MRONJ compared to other bones. This may be due to healing of open bone wounds, vulnerability to bacterial infections, and that BPs are preferentially deposited in bone with higher turnover rates, such as the jaw [16, 17]. Wen et al. [18] supported the theory that BPs preferentially deposit into bones with higher rates of remodeling, such as the jaw, relative to non-oral sites. Using athymic rats, they demonstrated a significantly higher release of hydroxyapatite-bound bisphosphonate in oral bones compared to axial and appendicular sites. After injection of fluorescent pamidronate into the mice, more signal was detected and was retained for longer time periods in the mandible than in the femur [19], which demonstrates that the mandible has a high affinity for BPs. Notably, MRONJ is twice as common in the mandible as in the maxilla [10]. Marx et al. [20] reported that 68.1% of the MRONJ cases occur in the mandible and 27.7% occur in the maxilla. Similar results were found in a study by Bardos et al. [5], where 15 of 22 MM patients with MRONJ showed mandibular lesions, five showed both mandibular and maxillary lesions, and two were in the maxilla only. In our study, only one patient presented with MRONJ in the maxilla. One possible explanation for osteonecrosis secondary to BP use, especially in the mandible, may be BP’s anti-angiogenic effects, or the anatomic and physiologic features of the mandible might increase the risk of MRONJ [21, 22]. Unfortunately, the exact mechanism underlying the higher incidence of MRONJ in the mandible remains unknown.

In MRONJ, dental extraction is the biggest local risk factor [6]. The surgical damage to the jaw that occurs after extraction, especially the damage to the alveolar bone with open bone wounds, seems to be the most potent trigger for MRONJ. In extractions, jaw bone remodeling is depressed, leading to the spontaneous breakdown of the wound after the tooth is removed. Notably, the site of the pre-existing bone might not be of prime importance. Woven bone is not altered by BPs, but remodeling of woven bone into lamellar bone might be impaired, leading to MRONJ [23]. Patients receiving intravenous BPs and undergoing dentoalveolar treatment are at least seven times more likely to develop MRONJ than those who are not [5, 10]. Tooth extraction is associated with 77% of MRONJ cases in the patients with intravenously administrated BPs [6]. In our study, the most common risk factor for MRONJ was dental extraction (n = 6), followed by prosthesis irritation (n = 2), periodontal therapy (n = 1), and unknown causes (n = 1). Half of the MRONJ locations coincided with the site of the dental problem seen at the first visit.

This retrospective study has some limitations. Firstly, we did not evaluate the patients’ oral health prior to initiating bisphosphonate therapy. However, we found that periodontal disease, including calculus deposition, was the most frequent dental disease in the MM patients at the initial dental examination such as in them with MRONJ. Aside from the two patients who initially presented with MRONJ, the majority of MM patients had periodontal problems, such as calculus deposition (n = 50), periodontal lesions (n = 25), and dental caries (n = 29). These results are similar to those of MM patients with MRONJ. In MM with MRONJ, the most common dental disease was periodontal disease (n = 5), followed by calculus deposition (n = 2), periapical lesions (n = 2), mucosal irritation (n = 1), and third molar problems (n = 1). Thus, clinical examinations, including panoramic radiography, may help detect dental problems and improve oral health before and during bisphosphonate therapy.

Based on our data, prevention of MRONJ is optimal because its management is quite challenging. While some case reports have demonstrated surgical treatment with good outcomes, generally, aggressive surgery has been counterproductive, often exacerbating the bone exposure [24]. Hence, most publicized studies suggest that initial treatment (stage I, II) should be conservative, focusing on systematic antibiotic therapy, irrigation to optimize oral hygiene, and careful removal of sequesters [10, 17, 25]. However, only 23–53% of all patients achieve resolution of mucosal discontinuities [26, 27]. Bamias et al. [7] demonstrated that antibiotic therapy resulted in temporary improvement, but only one patient showed sustained improvement of their osteonecrosis after multiple courses of antibiotics. The remaining 11 MM patients with MRONJ had persistent disability, mainly experiencing recurrence with purulent discharge and pain after discontinuing their antibiotics. These results coincide well with ours. In this present study, after conservative treatment as recommended by the AAOMS, the majority of stage II patients has been improved and was reclassified as stage I, but all patients remained with unhealed exposed bone at the follow-up appointment.