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Abstract Pancreatic cancer is a highly aggressive malignancy with a poor prognosis owing to its rapid progression, high mortality rate, and alarming 5‐year survival rate of 5%. Skeletal metastases represent an understated site of metastasis in patients with pancreatic cancer, occurring in about 5%–20% of these patients. The clinical presentation of metastasis to the jaws and osteonecrosis of jaw can exhibit similarities, which may lead to an erroneous diagnosis or create a diagnostic dilemma. We present a case of a 62‐year‐old male patient diagnosed with pancreatic adenocarcinoma and a prior history of bisphosphonate administration who displayed symptoms such as jaw pain, numbness, reduced mouth opening, and an extra‐oral swelling involving a recent tooth extraction site, likely due to medication‐related osteonecrosis of the jaw (ONJ). Despite initial conservative treatment, the patient's symptoms persisted, prompting further investigation. Depending on the specific context and clinical scenario, it is crucial to employ a comprehensive approach such as clinical examination, radiographic imaging, histopathological examination and monitoring the progression of symptoms over time for accurate diagnosis and timely management. This article presents a rare case of metastatic pancreatic cancer mimicking medication related ONJ, highlighting the clinical dilemma and challenges encountered when presenting symptoms and signs are ambiguous. While the prognosis for such cases is generally poor, dentists and healthcare providers should remain vigilant regarding potential sites of metastasis in cases of pancreatic adenocarcinoma.

Osteonecrosis of the jaw (ONJ) is a rare phenomenon that usually occurs in individuals exposed to certain medications, radiation, or physical or chemical insults that ultimately result in compromised vascularity of the jaws. However, in some cases, it is difficult to pinpoint a specific risk factor that might have caused the patient to suffer this pathologic condition. Here, we are reporting a case of idiopathic maxillary necrosis for which a specific risk factor could not be established despite thorough investigations.

Abstract Background Cancer treatment-induced bone loss (CTIBL) is the most common adverse event experienced by patients affected by breast cancer (BC) patients, without bone metastases. Bone modifying agents (BMAs) therapy is prescribed for the prevention of CTIBL, but it exposes patients to the risk of MRONJ. Methods This multicentre hospital-based retrospective study included consecutive non-metastatic BC patients affected by MRONJ related to exposure to low-dose BMAs for CTIBL prevention. Patients’ data were retrospectively collected from the clinical charts of seven recruiting Italian centres. Results MRONJ lesions were found in fifteen females (mean age 67.5 years), mainly in the mandible (73.3%). The mean duration of BMAs therapy at MRONJ presentation was 34.9 months. The more frequent BMAs was denosumab (53.3%). Ten patients (66.7%) showed the following local risk factors associated to MRONJ development: periodontal disease (PD) in three cases (20%) and the remaining six (40%) have undergone PD-related tooth extractions. One patient presented an implant presence-triggered MRONJ (6.7%). In five patients (33.3%) no local risk factors were observed. Conclusions This is the first case series that investigated BC patients under BMAs for CTIBL prevention suffering from MRONJ. These patients seem to have similar probabilities of developing MRONJ as osteo-metabolic ones. Breast cancer patients under BMAs for CTIBL prevention need a regular prevention program for MRONJ, since they may develop bone metastases and be treated with higher doses of BMAs, potentially leading to a high-risk of MRONJ.

Denosumab has proved effective at low doses in increasing bone mineral density in osteoporosis patients. In contrast to high-doses antiresorptive therapy, denosumab has a transient effect on the inhibition of the bone remodeling process, suggesting that denosumab-related osteonecrosis is a self-limiting disease, with a high curative potential of surgery when performed after a proper duration of receptor activator of nuclear factor-kB ligand (RANKL) inhibitor suspension. We report the long-term clinical and radiological (Computed Tomography—CT scan) data of a patient affected by secondary osteoporosis (cancer treatment-induced bone loss—CTIBL for metastatic breast cancer) who underwent surgical treatment for stage II denosumab-related osteonecrosis of the upper maxilla 7 months after denosumab suspension. A minimally invasive approach was performed with the extraction of the first right upper molar and debridement of the surrounding alveolar bone. After surgery, the patient was followed up at three-month intervals up to 1 year, and clinical and radiological data (CT scan) were recorded at each follow-up for the early detection of signs of recurrent disease. The mucosal healing remained stable in the long term, with radiological signs of bone remodeling in the post-operative site since the 6-month follow-up. The presented case strengthens the hypothesis that denosumab induces temporary alterations of bone turnover with a predictable curative effect of minimal surgical procedures in cases of denosumab-related osteonecrosis of the jaw.

(1) Background: Medication-related osteonecrosis of the jaw (MRONJ) is a potential adverse drug reaction of antiresorptive and/or antiangiogenic treatment. MRONJ is mostly diagnosed by anamnestic data, clinical examination and radiological findings, with signs and symptoms often unspecific. On the other hand, oral squamous cell carcinoma (OSCC) is characteristic for its pleomorphic appearance (e.g., ulcer, mucous dehiscence, non-healing post-extractive socket). We report three cases where OSCC mimicked MRONJ lesions. (2) Patients: Three patients undergoing amino-bisphosphonate treatment for osteoporosis presented with areas of intraorally exposed jawbone and unspecific radiological signs compatible with MRONJ. Due to the clinical suspicious of malignant lesion, incisional biopsy for histological examination was also performed. (3) Results: Histological examination of the tissue specimen revealed the presence of OSCC. All patients underwent cancer treatment. (4) Conclusions: Several signs and symptoms of OSCC may simulate, in patients with a history of anti-resorptive, MRONJ; for these reasons, it is important to perform histologic analysis when clinicians are facing a suspicious malignant lesion.

Bisphosphonates (BPs) are successfully used to cure a number of diseases characterized by a metabolic reduction in bone density, such as Osteoporosis, or a neoplastic destruction of bone tissue, such as multiple myeloma and bone metastases. These drugs exert their therapeutic effect by causing a systemic osteoclast depletion that, in turn, is responsible for reduced bone resorption. Unfortunately, in addition to their beneficial activity, BPs can also determine a frightening side effect known as osteonecrosis of the jaw (ONJ). It is generally believed that the inability of osteoclasts to dispose of inflamed/necrotic bone represents the main physiopathological aspect of ONJ. In principle, a therapeutic strategy able to elicit a local re-activation of osteoclast production could counteract ONJ and promote the healing of its lesions. Using an experimental model of Vitamin D3-dependent osteoclastogenesis, we have previously demonstrated that Magnesium is a powerful inducer of osteoclast differentiation. Here we show that, surprisingly, this effect is greatly enhanced by the presence of Zoledronate, chosen for our study because it is the most effective and dangerous of the BPs. This finding allows us to hypothesize that Magnesium might play an important role in the topical therapy of ONJ.

(1) Background: Medication-related osteonecrosis of the jaws (MRONJ) is an adverse drug reaction characterized by progressive bone disruption and necrosis in the mandibular and/or maxillary bones. It occurs in individuals who have received antiresorptive drugs without prior radiotherapy. Since its first reported cases in the USA in 2003, extensive literature has emerged worldwide, leading to significant advancements in understanding MRONJ’s pathogenesis and management. (2) Results: This article aims to compare the current national recommendations provided by the Italian Society of Maxillofacial Surgery (SICMF)/Italian Society of Oral Pathology and Medicine (SIPMO) and the American Association of Oral and Maxillofacial Surgeons (AAOMS). (3) Conclusions: Historically, the AAOMS advocated for a more conservative approach compared to the Italian guidelines. However, in their 2022 update, the AAOMS adopted a different perspective based on reported evidence, highlighting the advantages of early surgical treatment. Despite resolving some initial controversies, differences still exist between the two sets of recommendations, particularly regarding diagnosis and staging.

Medication-Related Osteonecrosis of the Jaw (MRONJ) was first reported in 2003. Despite the progress in the understanding of this oral complication in cancer patients for the past 18 years, there is still discussion about the best way to define MRONJ, prevent the complication, how to diagnose, and the options of treatment available. The initial reports associated MRONJ to bisphosphonates and denosumab, medications that work as bone-modifying agents. Later, other agents such as the antiangiogenics, have also been reported to cause the oral complication, either alone or in combination with antiresorptives. Initially, these medications were prescribed to patients with osteoporosis and cancers patients with bone metastasis. Today, because of the effect of the medications in the bone remodeling system, patients with several other diseases such as giant cell tumors, rheumatoid arthritis, Paget's disease of bone, fibrous dysplasia, osteogenesis imperfecta, are managed with these medications, significantly increasing the population of individuals at risk for developing MRONJ. This mini review focused on the cancer patient. It updates the dental clinician on the recent scientific literature about MRONJ and provides information on how to diagnose and manage patients being treated with these medications, suggests protocols to prevent the development of MRONJ, and present ways to manage those patients who develop the oral complication.

(1) Background: Multiple myeloma is a rare cancer that primarily affects the bone marrow. Osteoclasts are responsible for increased bone resorption and, therefore, bone destruction. Bisphosphonates are a class of drugs that can slow down bone resorption by reducing the number and action of osteoclasts. Intravenous injections of bisphosphonates (generally Zoledronic Acid) are administered to patients affected by Multiple Myeloma, but BRONJ is described as a serious side effect. This 5-year retrospective study aims to evaluate the efficacy of appropriate dental treatment protocols prior to initiating bisphosphonate therapy to prevent the development of BRONJ. (2) Methods: A total of 99 patients with symptomatic multiple myeloma were involved in this study (41–90 years, mean age 65 years, standard deviation 5 years). The data relating to the visits were tracked using a specific server and consulting the clinical reports. The AAOMS (American Association of Oral and Maxillofacial Surgeons) position was applied for both diagnosis and treatment. A total of 79 patients were examined before the administration of bisphosphonates (group A) and 20 after (group B). (3) Results: The entire sample required dental treatment: 23.2% underwent restorative therapy, 8% endodontic treatments, 44.4% tooth extractions. Periodontal disease was present in 41.4% of the patients. No osteonecrosis was observed in the first group, whereas BRONJ was found in five patients of the second one (25%) and two patients (10%) showed osteosclerotic areas under investigation [OR 0.026 (CI 0.0027 to 0.2454)]. (4) Conclusions: In the literature, there are no precise data about the prevalence of BRONJ. Despite the limitation of the present study, we point out that dental treatment before the treatment with intravenous bisphosphonates can help in reducing the incidence of BRONJ and good dental status is necessary for BRONJ prevention.

Dental extraction has often been described as the main trigger event of osteonecrosis of the jaws (ONJ). This longitudinal hospital-based study aimed to evaluate the outcome at 2 years of a standardized medical-surgical protocol for dental extraction, combined with platelet rich-plasma (PRP) application, compared with conventional protocol not combined with PRP or any other autologous platelet concentrate in cancer (ONC) and osteometabolic (OST) patients, at risk of bisphosphonate (BP)-related ONJ. Twenty patients were consecutively recruited: six received BPs for cancer skeletal-related events (34.17 ± 19.97 months), while fourteen received BPs for metabolic bone disease (74.5 ± 34.73 months). These patients underwent a standardized protocol for dental extraction, combined with autologous PRP application in the post-extraction socket. A total of 63 dental extractions were performed (24 and 39 in ONC and OST groups, respectively). As controls, historical cases, derived from the literature and including 171 ONC and 734 OST patients, were considered. The outcome of the surgical treatment was successful in all patients treated with PRP: two years after extraction, no patient had clinical or radiological signs of ONJ. When this datum was compared with historical controls, no statistically significant differences were found (p > 0.1). The combination of a standardized medical-surgical protocol with PRP application may contribute to limit the occurrence of BP-related ONJ, in both ONC and OST patients. Additional prospective studies with a larger patient sample are necessary to confirm this datum.

The recent randomized trial, published by Raje et al., on Lancet Oncology is potentially practice changing. It proposes that denosumab is a valid alternative to zoledronic acid in the treatment of myeloma patients. However, several points need further data and more details, such as information on incidence, diagnosis, and follow-up of osteonecrosis of the jaw (ONJ) cases, observed among treated patients. Adopted definition to adjudicate ONJ cases, type of registration of potential ONJ cases, length of observation are possible causes of potential underestimation of ONJ incidence in their study. Future updated evaluations with longer follow-up, and including actuarial estimation, are required for final judgment on ONJ risk in myeloma patients receiving denosumab, and comparison with ONJ risk by zoledronic acid.

While the optimal treatment concept of medication-related osteonecrosis of the jaws (MRONJ) is still in debate, several adjunct therapies have been introduced. Among these adjunctive measures, recombinant human parathyroid hormone (rhPTH, teriparatide) seems to be the most promising treatment modality. Several studies have presented the beneficial effect of short-term teriparatide; they have shown an improved level of bone markers and radiographic evidence of bone healing. Although clinical validation by a controlled trial with prospective design would be essential, short-term teripratide therapy would be a good treatment option for MRONJ patients with impaired bone remodeling.

Medication-induced Osteonecrosis of the Jaw (MRONJ) has been reported not only after use of antiresorptive agents (bisphosphonates and denosumab), but also in cancer patients receiving antiangiogenic agents, alone or combined with antiresorptive drugs. We report two cases of MRONJ observed in colorectal cancer patients after bevacizumab therapy only. MRONJ was diagnosed, respectively, two and seven months after a tooth extraction; both the patients had received two courses of bevacizumab infusions (for a total of 29 and 10 administrations, respectively). We discuss if tooth extraction during or after antiangiogenic therapy could be a potential trigger of MRONJ, but also if an underlying bone disease not evident before oral surgery might be a possible cause. A careful drug history has to be registered by dental specialists in cancer patients before oral surgery and adequate imaging might be obtained to avoid a delayed diagnosis.