Adjuvant anastrozole versus exemestane versus letrozole, upfront or after 2 years of tamoxifen, in endocrine-sensitive breast cancer (FATA-GIM3): a randomised, phase 3 trial

Background: Uncertainty exists about the optimal schedule of adjuvant treatment of breast cancer with aromatase inhibitors and, to our knowledge, no trial has directly compared the three aromatase inhibitors anastrozole, exemestane, and letrozole. We investigated the schedule and type of aromatase inhibitors to be used as adjuvant treatment for hormone receptor-positive early breast cancer. Methods: FATA-GIM3 is a multicentre, open-label, randomised, phase 3 trial of six different treatments in postmenopausal women with hormone receptor-positive early breast cancer. Eligible patients had histologically confirmed invasive hormone receptor-positive breast cancer that had been completely remov…

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

Abstract 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 th…

Comment on Medication-Related Osteonecrosis of the Jaw: MASCC/ISOO/ASCO Clinical Practice Guideline Summary

Comments on “Diagnosis and Management of Osteonecrosis of the Jaw: A Systematic Review and International Consensus”

Simplifying the dental/periodontal management of patients with metabolic bone fragility receiving treatment with denosumab

Denosumab (DNB) is a bone-targeted medication used to preserve structural integrity and minimise the risk of fragility fractures in metastatic cancer and metabolic bone disorders. DNB targets and binds RANK Ligand, inhibiting osteoclast maturation, function, and survival. In contrast with nitrogen-containing bisphosphonates (N-BPs), DNB does not bind to hydroxyapatite and incorporate into bone; thus, bone cellular remodelling recovers rapidly after drug suspension. Denosumab has benn linked to the occurrence of osteonecrosis of the jaw (MRONJ), a uncommon but severe oral side effect with a higher prevalence in metastatic cancer patients than in patients with metabolic bone fragility. Althou…

Proceedings of the Closed Round Table and Italian Consensus on the Medication-Related Osteonecrosis of Jaws (MRONJ) at the Symposium of Italian Society of Oral Pathology and Medicine (SIPMO) Ancona, 20 October 2018 - Part III

Cigarette smoking habit does not reduce the benefit from first line trastuzumab-based treatment in advanced breast cancer patients.

Many ErbB2-positive cancers may show intrinsic resistance, and the frequent development of acquired resistance to ErbB-targeted agents represents a substantial clinical problem. The constitutive NF-κB activation in some HER-2/neu positive breast cancer may represent a potential cause of resistance to trastuzumab therapy. Preclinical data revealed that 4-(N-Methyl-N- nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), the tobacco-specific nitrosamine is able to enhance NF-κB DNA binding activity and theoretically to increase the resistance to trastuzumab. Two hundred and forty-eight women with pathologically confirmed, uni- or bidimensionally measurable, HER-2-positive metastatic breast cancer (MBC…

Osteonecrosi dei mascellari associata a bisfosfonati, denosumab e farmaci anti-angiogenetici nei pazienti oncologici e osteoporotici: diagnosi e terapia

Riassunto Obiettivi Fornire un percorso utile alla diagnosi e al trattamento dell’osteonecrosi delle ossa mascellari (solitamente definita ONJ, OsteoNecrosis of the Jaws). Materiali e metodi Gli autori del lavoro, recentemente estensori e collaboratori – su mandato della Societa Italiana di Chirurgia Maxillo-Facciale (SICMF) e della Societa Italiana di Patologia e Medicina Orale (SIPMO), delle Raccomandazioni clinico-terapeutiche sull’osteonecrosi delle ossa mascellari associata a bisfosfonati e sua prevenzione – hanno esaminato le informazioni scientifiche disponibili in merito alla ONJ associata all’assunzione sia di bisfosfonati sia di denosumab e/o anti-angiogenetici, e revisionato l’ep…

A multicenter observational study on Medication-Related Osteonecrosis of the Jaw (MRONJ) in advanced cancer and myeloma patients of a cancer network in North-Western Italy

Background Incidence of Medication-Related Osteonecrosis of the Jaw (MRONJ) related to cancer and myeloma treatments is undetermined, with scarce data varying from 2 to 7.8/million/year in limited investigated populations. A 9-years [2009-2018] regional-wide survey was conducted, deploying the North-Western Italy Cancer Network (“Rete Oncologica Piemonte e Valle d’Aosta”), to assess number and main characteristics of MRONJ cases among myeloma/cancer patients, within a population of 4.5 million inhabitants. Material and Methods MRONJ cases were collected retrospectively from January 2009 to June 2015; from July 2015 to December 2018, data were collected prospectively. Number of new MRONJ cas…

Review of: "Teriparatide Promotes Bone Healing in Medication-Related Osteonecrosis of the Jaw: A Placebo-Controlled, Randomized Trial"

Learning from experience. Proposal of a refined definition and staging system for bisphosphonate-related osteonecrosis of the jaw (BRONJ)

Dear Editor, It is the authors’ belief that the internationally accepted definition of bisphosphonate-related osteonecrosis of the jaws (BRONJ) (Ruggiero et al, 2009) has several limitations that prevent clinicians from being confident with the diagnosis of the disease. Following recognition of the non-exposed BRONJ clinical variant (Lazarovici et al, 2009), we all became aware that the presence of ‘exposed necrotic bone in the oral cavity’, as outlined in the American Association of Oral and Maxillofacial Surgery (AAOMS) case definition, is just one of the possible clinical manifestations of BRONJ and is not found in all BRONJ patients. As ‘bone exposure’ is certainly not the initial sign …

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, comp…

RE: MEDICATION-RELATED OSTEONECROSIS OF THE JAW (MRONJ)

Proceedings of the Closed Round Table and Italian Consensus on the Medication-Related Osteonecrosis of Jaws (MRONJ) at the Symposium of Italian Society of Oral Pathology and Medicine (SIPMO) Ancona, 20 October 2018 - Part I.

On 20 October 2018 a Closed Round Table brought together a wide range of stakeholders from several medical disciplines, including academic experts, dentists, oncologists, maxillo-facial surgeons, oral surgeons, radiologists, under the technical and scientific coordination of Giuseppina Campisi (for SIPMO) and Giacomo Oteri (for Italian Society of Oral Surgery- SIdCO).

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

Abstract 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 Associatio…

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, SI…

Osteonecrosis of the jaw (ONJ) risk in breast cancer patients after zoledronic acid treatment

The importance of adoption of recommendations for ONJ prevention strategy will notably grow for zoledronic acid in the next future, in view of possible further enlargement of its indications (even with different timing and schedules) in breast cancer patients without bone metastases (such as in adjuvant and neo-adjuvant settings, and in hormonotherapy-induced osteopenia

Adjuvant denosumab in early breast-cancer

We read with interest the D-CARE trial report by Robert Coleman and colleagues1 on the adjuvant administration of denosumab in patients with early-stage breast cancer. Despite the negative results, which pose concerns about high dose denosumab schedules in an adjuvant setting, this large and well- designed trial can provide useful clinical data that are usually difficult to obtain from observational studies, particularly regarding medication- related osteonecrosis of the jaw (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…

American Association of Oral and Maxillofacial Surgeons position paper: Bisphosphonate-Related Osteonecrosis of the Jaws-2009 update: the need to refine the BRONJ definition

With reference to the 2009 update of the American Association of Oral and Maxillofacial Surgeons posi- tion paper, Bisphosphonate-Related Osteonecrosis of the Jaws (BRONJ), a relevant modification to the previous classification has been made and a new stage (0) added. The latter stage has been defined as “patients with no clinical evidence of necrotic bone, but who present with nonspecific symptoms or clinical and radiographic findings . . .” and the need for various clinical and radiologic aspects in defining this condi- tion was confirmed. .

RE: Regorafenib Also Can Cause Osteonecrosis of the Jaw

Osteonecrosis of jaw (onj): impact of italian patients, and role of italian physicians, dentists, and researchers in the growing evidence of a “new” disease

Purpose: Osteonecrosis of jaw (ONJ) is an uncommon but severe complication observed mostly in patients treated with bisphosphonates (BPs) for bone metastases, myeloma, osteoporosis (so called BRONJ, Bisphosphonate-Related Osteonecrosis of Jaw), but also with other drugs (bevacizumab, sunitinib, denosumab). The number of cases observed in Italy appears high in comparison with other countries and we present a review of several aspects of ONJ in Italy and the role of Italian health professionals and researchers on increasing knowledge and adequate reporting of ONJ phenomenon; Methods: Literature review about osteonecrosis of jaw (ONJ) with selection of Italian authors and publications, on year…

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…

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

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 mandi…

Proceedings of the Closed Round Table and Italian Consensus on the Medication-Related Osteonecrosis of Jaws (MRONJ) at the Symposium of Italian Society of Oral Pathology and Medicine (SIPMO) Ancona, 20 October 2018 - Part II

On 20 October 2018 a Closed Round Table brought together a wide range of stakeholders from several medical disciplines, including academic experts, dentists, oncologists, maxillo-facial surgeons, oral surgeons, radiologists, under the technical and scientific coordination of Giuseppina Campisi (for SIPMO) and Giacomo Oteri (for Italian Society of Oral Surgery- SIdCO)

Osteonecrosis of jaw beyond antiresorptive (bone-targeted) agents: new horizons in oncology

Introduction: Osteonecrosis of the jaw (ONJ) is a clinically important, potentially painful and debilitating condition, which can affect the quality of life of cancer patients. Since 2003, ONJ appeared as a Bisphosphonate(BP)-related class effect, and the term Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ) was widespread. Areas Covered: Under discussion in this review is the fact that ONJ cases have been reported after treatment including antiangiogenic agents and other “targeted therapy”, with and without BPs. Consequently, the comprehensive term Medication-Related Osteonecrosis of the Jaw (MRONJ) has been introduced. The clinical aspects and the prognosis of ONJ associated with t…

Surgery-triggered and non surgery-triggered Bisphosphonate-related Osteonecrosis of the Jaws (BRONJ): A retrospective analysis of 567 cases in an Italian multicenter study

Invasive local procedures are often reported in clinical history of patients suffering from Bisphosphonates-Related Osteonecrosis of the Jaws (BRONJ) but over 40% of spontaneous forms have been also described in literature. We compared age, gender, underlying bone disorders, bisphosphonate therapy, clinical features and surgical outcome of 205 cases (36.2%) of BRONJ non surgery-triggered (group 1) with 362 (63.8%) cases of surgery-triggered forms (group 2). Differences between group 1 and 2 were analysed using Mann-Whitney U and χ2 tests. Statistical analysis was performed using STATA 8. Zoledronate was the most used type of bisphosphonate (63.4% versus 69.0%) and the mandible was the most …

Osteonecrosis of the Jaw in Patients With Metastatic Renal Cell Cancer Treated With Bisphosphonates and Targeted Agents: Results of an Italian Multicenter Study and Review of the Literature.

Osteonecrosis of the jaw (ONJ) associated with the use of bisphosphonates has been rarely reported in metastatic renal cell cancer (RCC) patients. Since the introduction of combined therapies consisting of nitrogen-containing bisphosphonates (NBPs) and targeted agents, an increasing number of RCC patients were reported to develop ONJ, suggesting that therapeutic angiogenesis suppression might increase the risk of ONJ in NBPs users. We performed a multicenter retrospective study and reviewed literature data to assess the occurrence and to investigate the nature of ONJ in RCC patients taking NBPs and targeted agents. Nine Italian Centers contributed to the data collection. Patients with expos…

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 typ…

Osteonecrosis of the jaws in patients assuming oral bisphosphonates for osteoporosis: A retrospective multi-hospital-based study of 87 Italian cases

Abstract Background Bisphosphonates (BPs) are currently the chief drugs for the prevention/treatment of osteoporosis; one of their adverse effects is the osteonecrosis of the jaw (BRONJ). The primary endpoints of this multi-center cross-sectional study are: i) an observation of the clinical features of BRONJ in 87 osteoporotic, non-cancer patients; and ii) an evaluation of their demographic variables and comorbidities. Methods 87 BRONJ patients in therapy for osteoporosis with BPs from 8 participating clinical Italian centers were consecutively identified and studied. After BRONJ diagnosis and staging, comorbidities and data relating to local and drug-related risk factors for BRONJ were col…

Medication related osteonecrosis of the jaw (MRONJ)

Definition and estimation of osteonecrosis of jaw (ONJ), and optimal duration of antiresorptive treatment in bone metastatic cancer patients: supplementary data from the denosumab extension study?

To the Editor, In their recent article, Stopeck et al. [1] concluded that denosumab confirms its known safety profile even after longterm exposure, or after switching to it from zoledronic acid, and that osteonecrosis of jaws (ONJ) rates increased with increasing exposure to antiresorptives, consistent with previous reports. This is based on the open label extension phase of two phase 3 studies in patients with breast and prostate cancer with bone metastases who were randomized to receive denosumab or zoledronic acid (ZA) [2, 3]. The patients were offered open-label denosumab for up to an additional 2 years after the results of the primary analysis, favorable for denosumab on several aspect…

Osteonecrosis of the jaw (ONJ) in renal cell cancer patients after treatment including zoledronic acid or denosumab.

Dear Editor, The paper by Henry et al. published by Supportive Care in Cancer comparing efficacy of denosumab versus zoledronic acid in patients with bone metastases of advanced solid tumours [1] comes to integrate the original reports of three pivotal large randomized phase 3 trials [2–4], the publication by Saad et al. about osteonecrosis of the jaw (ONJ) in those three trials [5], and the combined outcome analysis by Lipton et al. [6]. Henry et al. [1] reported outcomes of the single trial conducted on patients with solid tumours (except breast or prostate cancers, object of other two trials) [2, 3], excluding patients with multiple myeloma: This ad hoc analysis confirmed the superiority…

Osteonecrosi dei mascellari associata a bisfosfonati, denosumab e farmaci anti-angiogenetici nei pazienti oncologici e osteoporotici: prevenzione dentale e sicurezza dei trattamenti odontoiatrici

Riassunto Obiettivi Proporre protocolli di gestione odontoiatrica per il paziente che assume o che assumera farmaci (per esempio bisfosfonati, denosumab e anti-angiogenetici) correlati all’insorgenza di osteonecrosi dei mascellari (OsteoNecrosis of the Jaws, ONJ). Materiali e metodi Gli autori del lavoro, recentemente estensori e collaboratori – su mandato della Societa Italiana di Chirurgia Maxillo-Facciale (SICMF) e della Societa Italiana di Patologia e Medicina Orale (SIPMO), delle Raccomandazioni clinicoterapeutiche sull’osteonecrosi delle ossa mascellari associata a bisfosfonati e sua prevenzione – hanno esaminato le informazioni scientifiche disponibili in merito alla ONJ (associata a…

Comment on “Medication-Related Osteonecrosis of the Jaw (MRONJ)” by Elie M. Ferneini in the Section “Simply Put: JOMS Information for Patients”

We read with great interest the contribute to the section “Simply Put: JOMS Information for Patients” named “Medication-Related Osteonecrosis of the Jaw (MRONJ)” by Elie M. Ferneini.