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PurposeBisphosphonates reduce bone metastases in postmenopausal women with early-stage breast cancer but carry the risk of bisphosphonate-related osteonecrosis of the jaw (BRONJ). We describe risk factors for BRONJ and compare BRONJ provoked by infection or trauma with spontaneous lesions, which carry a better prognosis.MethodsSWOG 0307 randomized women with stage I–III breast cancer to receive zoledronic acid (ZA), clodronate (CL), or ibandronate (IB) for 3 years, implemented BRONJ prevention guidelines, and collected information about dental health and development of BRONJ. All statistical tests were two-sided.ResultsOf 6018 women, 48 developed BRONJ. Infection was present in 21 (43.8%). Median time to BRONJ was 2.1 years for ZA, 2.0 years for IB, and 3.4 years for clodronate (p = 0.04). BRONJ was associated with bisphosphonate type (28/2231 (1.26%) for ZA, 8/2235 (0.36%) for CL, 12/1552 (0.77%) for IB), dental calculus (OR 2.03), gingivitis (OR 2.11), moderate/severe periodontal disease (OR 2.87), and periodontitis > 4 mm (OR 2.20) (p < 0.05). Of 57 lesions, BRONJ occurred spontaneously in 20 (35.1%) and was provoked by dental extraction in 20 (35.1%), periodontal disease in 14 (24.6%), denture trauma in 6 (10.5%), and dental surgery in 2 (3.5%). Spontaneous BRONJ occurred more frequently at the mylohyoid ridge. There were no differences in dental disease, infection, or bisphosphonate type between spontaneous and provoked BRONJ.ConclusionZA and worse dental health were associated with increased incidence of BRONJ, with a trend toward additive risk when combined. BRONJ incidence was lower than in similar studies, with prevention strategies likely linked to this.Clinical trial numberNCT00127205Registration dateJuly 2005

Bisphosphonates (BSPs) are used for the treatment of multiple myeloma, metastatic breast and lung cancer, Paget's disease, osteoporosis, hypercalcemia due to malignancy, and many other skeletal diseases. BSPs reduce osteoclastic functions, which result in bone resorption. Bisphosphonates-related osteonecrosis of jaws (BRONJ) is a newly developed term that is used to describe the significant complication in patients receiving bisphosphonates. BSPs are known to exhibit an anti-angiogenetic effect that initiates tissue necrosis of the hard tissue. There is currently no consensus on the correct approach to this issue. The aim of this retrospective study is to compare the effects of laser surgery with biostimulation to conventional surgery in the treatment of BSP-induced avascular bone necrosis on 20 patients who have been treated in our clinic. BRONJ was evaluated in patients with lung, prostate, and breast cancer under intravenous BSP treatment. Twenty patients in this study developed mandibular or maxillary avascular necrosis after a minor tooth extraction surgery or spontaneously. Bone turnover rates were evaluated by serum terminal C-telopeptide levels (CTX) using the electrochemiluminescence immunoassay technique and patients were treated with laser or conventional surgical treatments and medical therapy. Ten patients were treated with laser surgery and biostimulation. An Er:YAG laser (Fotona Fidelis Plus II® Combine laser equipment, Slovenia) very long pulse (VLP) mode (200 mJ, 20 Hz) using a fiber tip 1.3 mm in diameter and 12 mm in length was used to remove the necrotic and granulation tissues from the area of avascular necrosis. Biostimulation was applied postoperatively using an Nd:YAG laser. Low-level laser therapy (LLLT) was applied to the tissues for 1 min from 4 cm distance using an Nd:YAG laser (Fotona-Slovenia) with a R24 950-µm fiber handpiece long-pulse (LP) mode, 0.25-W, 10 Hz power/cm 2 from the mentioned distance the spot size was 0.4 cm 2 , and power output was 2.5 J. Energy density from the mentioned distance was calculated to be 6.25 J/cm 2 . The other ten patients were treated with conventional surgery. Treatment outcomes were noted as either complete healing or incomplete healing. There were no statistically significant differences between laser surgery and conventional surgery ( p  > 0.05). CTX values also did not affect the prognosis of the patients. Treatment outcomes were significantly better in patients with stage II osteonecrosis than in patients with stage I osteonecrosis. Our findings suggest that dental evaluation of the patients prior to medication is an important factor in the prevention of BRONJ. Laser surgery is a beneficial alternative in the treatment of patients with this situation. Further randomized studies with larger patient numbers may also improve our understanding of treatment protocols for this situation.

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.