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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.

A 12‐year‐old, neutered female, domestic medium hair cat was evaluated for a nonhealing, oral mucosal ulceration. The cat had a history of idiopathic hypercalcemia that had been treated with a bisphosphonate for 41 months. Oral examination identified exposed maxillary bone adjacent to a previous extraction site. Histopathology of the exposed bone and associated mucosa was most consistent with medication‐related osteonecrosis of the jaw. Treatment involved both medical and surgical interventions. Oral mucosal healing occurred after 6 months of treatment.

Background Bisphosphonate-related osteonecrosis of the jaw (BRONJ) adverse drug reactions (ADRs) have been increasing since 2002. Following information about causes, incidence and risk factors collected from the scientific community, the Italian Ministry of Health submitted Ministerial Recommendation no. 10. Purpose To assess the effects of the submitted recommendation: by measuring ADRs due to BRONJ included in the Italian pharmacovigilance database (RNFV) from 2006 to 2012; by examining what the local health structures and hospitals (the ones with the highest numbers of ADRs) did in order to put into practice what the Ministry published. Materials and methods We searched the RNFV database looking for all ADRs that happened between 01/01/2006 and 31/12/2012 for every active principle and included in the RNFV till 31/05/2013. We selected the following preferred terms: osteonecrosis of the jaws, osteonecrosis, osteomyelitis. ADRs were analysed by: year of onset, active principle, therapeutic indications, seriousness, health structures and reporter type. We phoned the local pharmacovigilance manager (RLFV) to collect information on how the Ministerial recommendation has been put into practice. Results We found 683 reports and they came from 94 health structures (33% from the RLFV). In 98% (671) of the reports the suspect drug is at least one bisphosphonate (BP) (zoledronic acid in 74.5%) and 67.5% of the reports come from 10, mainly academic, health structures. Four of these have produced an internal procedure and 2 started an education plan. Since 2009 we can observe a gradual decrease in the following parameters: number of reports and number of reports coming from health structures; reports coming from dentists; the percentage of ADRs in the oncological area versus all the other diseases in which BPs are used (86.2% in 2006 and 72.9% in 2012); percentage of BRONJ associated with BP-related ADRs (103 out of 157, equal to 65.6% in 2006, and 61 out of 182 equal to 33.5% in 2012). The consumption of zoledronic acid has not decreased in the time interval analysed. 40% of the ADRs happened between 2006 and 2009 had been included in the database after the recommendation’s submission. Conclusions The well-known problem of under-reporting is clearly apparent. The increased notoriety of this ADR, also due to the Ministerial Recommendation, draws attention to all BPs. The Ministerial Recommendation has succeeded in reducing BRONJ cases due to increased preventative measures. It has stimulated the recovery of ADRs that had happened in previous years and has given a good stimulus to good practice in pharmacovigilance, an important jigsaw piece that has proved efficient in the management of clinical risk for the safer use of drugs. No conflict of interest.

SummaryGiven the widespread practice of recommending drug holidays, we reviewed the impact of medication discontinuation of two common anti-osteoporosis therapies (bisphosphonates and denosumab). Trial evidence suggests the risk of new clinical fractures, and vertebral fracture increases when osteoporosis treatment with bisphosphonates or denosumab is stopped.IntroductionThe aim of this paper was to review the available literature to assess what evidence exists to inform clinical decision-making with regard to drug holidays following treatment with bisphosphonates (BiP) or denosumab.MethodsSystematic review.ResultsDiffering pharmacokinetics lead to varying outcomes on stopping therapy. Prospective and retrospective analyses report that the risk of new clinical fractures was 20–40% higher in subjects who stopped BiP treatment, and vertebral fracture risk was approximately doubled. Rapid bone loss has been well described following denosumab discontinuation with an incidence of multiple vertebral fractures around 5%. Studies have not identified risk factors for fracture after stopping treatment other than those that provide an indication for treatment (e.g. prior fracture and low BMD). Studies that considered long-term continuation did not identify increased fracture risk, and reported only very low rates of adverse skeletal events such as atypical femoral fracture.ConclusionsThe view that patients on long-term treatment with bisphosphonates or denosumab should always be offered a drug holiday is not supported by the existing evidence. Different pharmacokinetic properties for different therapies require different strategies to manage drug intermission. In contrast, long-term treatment with anti-resorptives is not associated with increased risk of fragility fractures and skeletal adverse events remain rare.

SummaryTooth extraction in patients receiving bisphosphonates is thought to be a risk factor for osteonecrosis of the jaw (ONJ); however, ONJ did not develop, even when tooth extraction was performed with continued oral bisphosphonate therapy. A drug holiday from bisphosphonates before tooth extraction may not be necessary.IntroductionIt is controversial whether bisphosphonate withdrawal is necessary prior to invasive procedures such as tooth extraction in order to prevent bisphosphonate-related osteonecrosis of the jaw (BRONJ). This study aimed to evaluate the clinical safety of continuing oral bisphosphonate therapy in patients undergoing tooth extraction.MethodsWe prospectively enrolled 132 patients (20 men, 112 women) who were receiving oral bisphosphonates for the prevention or treatment of osteoporosis and required tooth extraction. All patients were managed using an identical protocol, which included preoperative antibiotic prophylaxis and did not necessarily require complete wound closure. The patients were classified into groups according to the duration of bisphosphonate administration: < 2 years (n = 51), 2–5 years (n = 41), 5–10 years (n = 28), and > 10 years (n = 12). The groups were compared regarding the time taken for the extraction socket to heal, and the occurrence of BRONJ. Follow-up duration was at least 3 months.ResultsA total of 274 teeth were removed. Long-term oral bisphosphonate therapy for > 5 years significantly delayed the healing of the extraction socket in comparison with administration for < 5 years; however, BRONJ did not develop in any group. There was no prolongation of wound healing due to systemic risk factors such as glucocorticoid administration and diabetes mellitus. There were no adverse skeletal events such as bone fracture.ConclusionsPatients who underwent tooth extraction with continued oral bisphosphonate therapy showed delayed healing of the extraction socket as the cumulative administration period prolonged, but BRONJ did not develop.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is one of the side effects of bisphosphonate (BP) administration. Despite some preventive measures having been suggested, a definitive and effective treatment strategy for BRONJ remains to be established. Recent evidence has indicated that BPs dramatically impair the function of orofacial bone marrow stromal cells (BMSCs), which may contribute to the development of osteonecrosis. Thus, we hypothesized that recovery-impaired function of BMSCs at lesion sites could be beneficial in treating BRONJ. N6-methyladenosine (m6A) modification is the most common epigenetic modification and has been demonstrated to play a vital role in the modulation of BMSCs’ function. We detected the role of m6A modification in regulating the function of orofacial BMSCs under BP stimulation, and found that BPs led to a reduction in the global m6A methylation level, SAM level, and METTL3 expression in BMSCs during the osteogenic differentiation period. Meanwhile, betaine, a methyl group donor, effectively reversed the BP-decreased global m6A methylation level and SAM level in BMSCs, as well as rescuing the differentiation ability of impaired BMSCs. In the last part, we built a BRONJ rat model and supplemented rats with betaine via drinking water. The results showed that betaine successfully attenuated bone lesions and promoted wound healing in BP-injected rats, thereby providing new insight into future clinical treatment for BRONJ.

Background Medication-related osteonecrosis of the jaw (MRONJ) is an infrequent, but potentially serious, adverse event that can occur after exposure to bone-modifying agents (BMAs; e.g., bisphosphonates, denosumab, and antiangiogenic therapies). BMAs are typically used at higher doses to prevent skeletal-related events in cancer patients and at lower doses for osteoporosis/bone loss. MRONJ can cause significant pain, reduce quality of life, and can be difficult to treat, requiring a multiprofessional approach to care. Methods We reviewed the literature and guidelines to summarize a practical guide on MRONJ for nurses and other allied healthcare professionals. Results While there is a risk of MRONJ with BMAs, this should be considered in relation to the benefits of treatment. Nurses and other allied healthcare professionals can play a key role alongside physicians and dentists in assessing MRONJ risk, identifying MRONJ, counseling the patient on the benefit–risk of BMA treatment, preventing MRONJ, and managing the care pathway of these patients. Assessing patients for MRONJ risk factors before starting BMA treatment can guide preventative measures to reduce the risk of MRONJ. Nurses can play a pivotal role in facilitating multiprofessional management of MRONJ by communicating with patients to ensure compliance with preventative measures, and with patients’ physicians and dentists to ensure early detection and referral for prompt treatment of MRONJ. Conclusions This review summarizes current evidence on MRONJ and provides practical guidance for nurses, from before BMA treatment is started through to approaches that can be taken to prevent and manage MRONJ in patients receiving BMAs.