Treatment of bone metastases from solid tumors with bone-modifying agents: a web survey of Italian oncologists investigating patterns of practice drug prescription and prevention of side effects.

PURPOSE: Optimal use of bone-modifying agents (BMAs) in patients with bone metastases from solid tumors is uncertain in some aspects: the drug choice; the planned treatment duration and long-term therapy; the prevention and management of possible side effects, including renal toxicity, hypocalcaemia, and medication-related osteonecrosis of the jaw (MRONJ). METHODS: Italian oncologists were invited to fulfil a 24-question web survey about prescription of BMAs for bone metastases of breast cancer, prostate cancer, and other solid tumors. Prevention and management of side effects were also investigated. RESULTS: Answers of 191 oncologists were collected. BMAs are usually prescribed at the time of diagnosis of bone metastases by 87.0% (breast cancer) and 76.1% (solid tumors except breast and prostate cancers) of oncologists; the decision is more articulated for prostate cancer (endocrine-sensitive versus castration-resistant). The creatinine level (32.3%), the availability of patient venous access (15.8%), and the type of primary neoplasm (13.6%) are the most reported factors involved in choice between bisphosphonates and denosumab. Zoledronic acid every 3 months was considered as a valid alternative to monthly administration by 94% of Italian oncologists. Oncologists reported a good confidence with measures aimed to prevent MRONJ, whereas uncertainness about prevention and management of hypocalcemia was registered. CONCLUSION: Italian oncologists showed a high attitude in prescribing bisphosphonates or denosumab at the time of diagnosis of bone metastases, with a large application of preventive measures of side effects. Further studies are needed to investigate some controversial aspects, such as optimal drug treatment duration and long-term drug schedules.

Italian position paper (SIPMO-SICMF) on medication-related osteonecrosis of the jaw (MRONJ).

OBJECTIVE: This paper aims to describe the 2023 update position paper on MRONJ developed by the Italian Societies of Oral Pathology and Medicine (SIPMO) and of Maxillofacial Surgery (SICMF). METHODS: This is the second update following the 2013 and 2020 Italian position papers by the Expert panel, which is a representation of the two scientific societies (SIPMO and SICMF). The paper is based on an extensive analysis of the available literature from January 2003 to February 2020, and the subsequent review of literature conducted between March 2020 and December 2022 to include all new relevant published papers to confirm or modify the previous set of recommendations. RESULTS: This position paper highlights the main issues of MRONJ on risk estimates, disease definition, diagnostic pathway, individual risk assessment, and the fundamental role of imaging in the diagnosis, classification, and management of MRONJ. CONCLUSION: The Expert Panel confirmed the MRONJ definition, the diagnostic work-up, the clinical-radiological staging system and the prophylactic drug holiday, as recognized by SIPMO-SICMF; while, it presented novel indications regarding the categories at risk of MRONJ, the prevention strategies, and the treatment strategies associated with the therapeutic drug holiday.

Immune Dysfunction in Medication-Related Osteonecrosis of the Jaw.

The pathogenesis of medication-related osteonecrosis of the jaw (MRONJ) is multifactorial and there is a substantial consensus on the role of antiresorptive drugs (ARDs), including bisphosphonates (BPs) and denosumab (Dmab), as one of the main determinants. The time exposure, cumulative dose and administration intensity of these drugs are critical parameters to be considered in the treatment of patients, as cancer patients show the highest incidence of MRONJ. BPs and Dmab have distinct mechanisms of action on bone, but they also exert different effects on immune subsets which interact with bone cells, thus contributing to the onset of MRONJ. Here, we summarized the main effects of ARDs on the different immune cell subsets, which consequently affect bone cells, particularly osteoclasts and osteoblasts. Data from animal models and MRONJ patients showed a deep interference of ARDs in modulating immune cells, even though a large part of the literature concerns the effects of BPs and there is a lack of data on Dmab, demonstrating the need to further studies.

MRONJ in breast cancer patients under bone modifying agents for cancer treatment-induced bone loss (CTIBL): a multi-hospital-based case series.

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.

One changing and challenging scenario: the treatment of cancer patients with bone metastases by bisphosphonates and denosumab, the cost-benefit evaluation of different options, and the risk of medication-related osteonecrosis of the jaw (MRONJ).

Antiresorptive drugs (bisphosphonates and denosumab) have become the cornerstone of medical supportive treatment of bone metastases in solid cancer patients. In the beginning, the choice of available antiresorptive agents was limited to bisphosphonates and the treatment options restricted principally to monthly pamidronate and monthly zoledronic acid. Introduction of new antiresorptive therapies (monthly denosumab) and schedules (zoledronic acid every 3 months, upfront or after initial period of monthly infusion) in the last decade increased the range of available options, thus challenging treatment decision making. Direct and indirect costs of very different treatment options are difficult to interpret in a global cost-benefit analysis. In addition, awareness of the increased risk of medication-related osteonecrosis of the jaw (MRONJ) in bone metastatic cancer patients receiving long-term antiresorptive medications is likely to influence therapy choice in the real-life scenario. We discuss the possible threat of MRONJ risk underestimation and the need for long-term risk stratification of patients based on actuarial data, the role of bisphosphonates and denosumab in that scenario, and the emerging role of surgical therapy to successfully cure MRONJ, in the light of the improved quality of life and survival of patients with bone metastases from solid cancers.

The preventive care of medication-related osteonecrosis of the jaw (MRONJ): a position paper by Italian experts for dental hygienists.

PURPOSE: The prevention and early diagnosis of medication-related osteonecrosis of the jaw (MRONJ) is fundamental to reducing the incidence and progression of MRONJ. Many in the field believe that dental hygienists should play an integral role in primary and secondary MRONJ prevention. However, to date, very few publications in the literature have proposed standardised MRONJ protocols, which are dedicated to dental hygienists. The aim of this study was to provide guidance to the health care providers managing MRONJ. METHODS: The expert opinion in this study was developed by dental hygienists from the main Italian technical-scientific associations (Italian Dental Hygienists Association, AIDI and National Union of Dental Hygienists, UNID) and authors of the latest Italian recommendations regarding MRONJ from the field of dentistry and maxillofacial surgery. RESULTS: The oral care protocol outlined in this position paper is focused on the role of dental hygienist in patients at risk or affected by MRONJ, and it regards 3 main issues: primary prevention, secondary prevention and supporting the treatment of MRONJ. Each issue contains easy-to-apply indications and procedures, as described by the authors, regarding the role of the dental hygienist. CONCLUSION: Referring to the main issues under consideration (primary prevention, secondary prevention and the treatment of MRONJ), a clinical examination of periodontal tissue is critical in preventing MRONJ. It is the opinion of the authors of this study that the application of a periodontal screening score is fundamental in defining personalised strategies for patients at risk of MRONJ. By means of these basic procedures, a protocol for assisting the health care provider and the presentation of a practical approach for patients at risk or affected by MRONJ are described in this study.

Epidemiology, clinical manifestations, risk reduction and treatment strategies of jaw osteonecrosis in cancer patients exposed to antiresorptive agents.

 Osteonecrosis of the jaws (ONJ) is an adverse side event of bisphosphonates and denosumab, antiresorptive agents that effectively reduce the incidence of skeletal-related events in patients with metastatic bone cancer and multiple myeloma. Available data suggest that 0-27.5% of individuals exposed to antiresorptive agents can develop ONJ. There is increasing evidence that avoidance of surgical trauma and infection to the jawbones can minimize the risk of ONJ, but there are still a significant number of individuals who develop ONJ in the absence of these risk factors. Bone necrosis is almost irreversible and there is no definitive cure for ONJ with the exclusion, in certain cases, of surgical resection. However, most ONJ individuals are affected by advanced incurable cancer and are often managed with minimally invasive nonsurgical interventions in order to control jawbone infections and painful symptoms. This article summarizes current knowledge of ONJ epidemiology, manifestations, risk-reduction and therapeutic strategies. Further research is needed in order to determine individual predisposition to ONJ and clarify the effectiveness of available treatments.

A pragmatic window of opportunity to minimise the risk of MRONJ development in individuals with osteoporosis on Denosumab therapy: a hypothesis.

Denosumab is associated with the development of medication-related osteonecrosis of the jaw (MRONJ), an uncommon but severe oral side effect with a higher prevalence in metastatic cancer patients than in patients with metabolic bone fragility. Although several oral triggers can initiate MRONJ, invasive oral treatments and tooth extraction still remain the most common precipitating event. In general, tooth extraction and oral surgery should be avoided in patients at increased risk of MRONJ, while extraction of non-restorable teeth should be performed based on specific risk reduction protocols to eliminate dental/periodontal infections, still protecting from MRONJ onset. Based on the different pharmacological activity of denosumab and nitrogen-containing bisphosphonates, it is likely that the MRONJ risk profile of patients with osteoporosis could somewhat vary. We hypothesize the chance to maximize the pharmacokinetic of denosumab 60 mg (Prolia®) and identify a time interval in which invasive oral treatments can ideally take place without restrictions in patients with metabolic bone fragility, We propose that dental surgery (e.g. tooth extraction) may be safely performed without additional intra or peri-operative procedures in osteoporosis patients using denosumab provided that careful case selection, adequate communication among specialists, planning of a delayed dosing window (1-month deferral) and rigorous postoperative follow-up are granted.

Is Medication-Related Osteonecrosis of the Jaws (MRONJ) Associated to Cyclin-Dependent Kinase (CDK) 4/6 Inhibitors? A Word of Cautiousness. Comment on Marcianò et al. Medication-Related Osteonecrosis of the Jaws and CDK4/6 Inhibitors: A Recent Association. Int. J. Environ. Res. Public Health 2020, 17, 9509.

Marcianò et al. launched an alert in this journal about a possible association between medication-related osteonecrosis of the jaws (MRONJ) and cyclin-dependent kinase (CDK) 4/6 inhibitors in breast cancer patients [...].

The Treatment of Medication-Related Osteonecrosis of the Jaw (MRONJ): A Systematic Review with a Pooled Analysis of Only Surgery versus Combined Protocols.

Medication-related osteonecrosis of the jaw (MRONJ) is a serious adverse reaction of antiresorptive and antiangiogenic agents, and it is also a potentially painful and debilitating condition. To date, no specific studies have prospectively evaluated the efficacy of its treatment and no robust standard of care has been established. Therefore, a systematic review (2007-2020) with a pooled analysis was performed in order to compare MRONJ surgical techniques (conservative or aggressive) versus combined surgical procedures (surgery plus a non-invasive procedure), where 1137 patients were included in the pooled analysis. A statistically significant difference in the 6-month improvement rate, comparing combined conservative surgery versus only aggressive (91% versus 72%, p = 0.05), was observed. No significant difference regarding any group with respect to the 6-month total resolution rate (82% versus 72%) was demonstrated. Of note, conservative surgery combined with various, adjuvant, non-invasive procedures (ozone, LLLT or blood component + Nd:YAG) was found to achieve partial or full healing in all stages, with improved results and the amelioration of many variables. In conclusion, specific adjuvant treatments associated with minimally conservative surgery can be considered effective and safe in the treatment of MRONJ, although well-controlled studies are a requisite in arriving at definitive statements.

Medication-Related Osteonecrosis of Jaws (MRONJ) Prevention and Diagnosis: Italian Consensus Update 2020.

The Medication-Related Osteonecrosis of Jaws (MRONJ) diagnosis process and its prevention play a role of great and rising importance, not only on the Quality of Life (QoL) of patients, but also on the decision-making process by the majority of dentists and oral surgeons involved in MRONJ prevention (primary and secondary). The present paper reports the update of the conclusions from the Consensus Conference-held at the Symposium of the Italian Society of Oral Pathology and Medicine (SIPMO) (20 October 2018, Ancona, Italy)-after the newest recommendations (2020) on MRONJ were published by two scientific societies (Italian Societies of Maxillofacial Surgery and Oral Pathology and Medicine, SICMF and SIPMO), written on the inputs of the experts of the Italian Allied Committee on ONJ (IAC-ONJ). The conference focused on the topic of MRONJ, and in particular on the common practices at risk of inappropriateness in MRONJ diagnosis and therapy, as well as on MRONJ prevention and the dental management of patients at risk of MRONJ. It is a matter of cancer and osteometabolic patients that are at risk since being exposed to several drugs with antiresorptive (i.e., bisphosphonates and denosumab) or, more recently, antiangiogenic activities. At the same time, the Conference traced for dentists and oral surgeons some easy applicable indications and procedures to reduce MRONJ onset risk and to diagnose it early. Continuous updating on these issues, so important for the patient community, is recommended.

The Dental Management of Patients at Risk of Medication-Related Osteonecrosis of the Jaw: New Paradigm of Primary Prevention.

Medication-related osteonecrosis of the jaw (MRONJ) is a serious adverse reaction of antiresorptive and antiangiogenic agents; it is a potentially painful and debilitating condition that can considerably affect the quality of life of patients. Furthermore, even if its epidemiology and pathogenesis have still not been fully clarified, several risk factors related to MRONJ have been recognized in prevention protocols. Three main risk factors are as follows: (i) the type of ONJ-related medications: antiresorptive (e.g., Bisphosphonates, Denosumab) and antiangiogenic drugs (e.g., Bevacizumab, Sunitinib); (ii) the category of patient at MRONJ risk: cancer versus non-cancer patient; (iii) the typologies and timing of dental treatments (e.g., before, during, or after the drug administration). The aim of this paper is to describe the new paradigm by the Italian Society of Oral Pathology and Medicine (SIPMO) on preventive dental management in patients at risk of MRONJ, prior to and during/after the administration of the aforementioned ONJ-related drugs. In reducing the risk of MRONJ, dentists and oral hygienists are key figures in applying a correct protocol of primary prevention for pre-treatment and in-treatment patients. However, the necessity of a multidisciplinary standardized approach, with a sustained dialogue among specialists involved, should be always adopted in order to improve the efficacy of preventive strategies and to ameliorate the patient's quality of life.

Osteonecrosis of the Jaw in Myeloma Patients Receiving Denosumab or Zoledronic Acid. A Commentary of the Pivotal Trial by Raje et al. Published on Lancet Oncology.

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.