Is the conservative non-surgical management of medication-related osteonecrosis of the jaw an appropriate treatment option for early stages? A long-term single-center cohort study

Purpose

No consensus has been reached regarding the best treatment option for early-stage lesions in medication-related osteonecrosis of the jaw (MRONJ). The purpose of the present study was to evaluate the long-time outcomes of conservative non-surgical management in stage I patients with underlying malignant disease.

药物性颌骨坏死的研究进展

药物性颌骨坏死（MRONJ）是使用双膦酸盐类药物（BPs）或其他生物靶向药物而产生的一种严重不良反应,临床上以颌骨骨面裸露、流脓、面部肿胀等为特征,手术治疗或保守治疗均不能达到理想的效果。近年来,除了已经普遍使用的BPs外,国内外报道了许多可以导致颌骨坏死的新型药物,包括抑制骨吸收药物狄诺塞麦,抗血管生成药物贝伐单抗,以及其他生物靶向药物舒尼替尼、西罗莫司等。本文就这些导致颌骨坏死的新药研究进展作一综述。     

Bisphosphonate-related osteonecrosis of the jaws: a case series of 25 patients affected by osteoporosis

Bisphosphonates (BPs) are used to treat metabolic bone diseases, such as osteoporosis. In this study the occurrence of bisphosphonates-related osteonecrosis of the jaws (BRONJ) is reported in 25 patients who received BP therapy for osteoporosis with different drug schedules. From June 2005 to May 2009, 25 patients affected by BRONJ were observed. A history of oral surgery was reported for 18 patients (72%). Of the 22 patients treated by the authors, 20 (91%) recorded healing improvement with a mean follow-up of 16.6 months, with particular regard for those treated with oral surgery and laser applications (10/22, 45%) who were all characterised by complete mucosal healing over time. The risk of developing BRONJ in patients treated with BP for osteoporosis is lower than in cancer patients, but is not negligible. It is advisable for the prescribing physician to recommend a dental check-up prior to treatment, at least for patients who have not been to the dentist in the last 12 months. An early surgical and possible laser-assisted approach for patients who develop BRONJ is recommended.     

Relevance of surgical management of patients affected by bisphosphonate-associated osteonecrosis of the jaws. A prospective clinical and radiological study

Objectives

Actually, consensus management of osteonecrosis of the jaws (ONJ) related to nitrogen-containing bisphosphonates (NBPs) is mostly a conservative approach. It does not always control the symptoms and the progression of the disease. The aim of this study was to evaluate the clinical and radiological outcomes of three therapeutic management strategies of established ONJ.

Materials and methods

Three treatment strategies, i.e., conservative approach, minimal invasive surgery, and extensive surgery were evaluated in 39 ONJ patients treated with NBPs for malignant diseases or osteoporosis. The patients were closely monitored, and the outcome (extension, improvement, or healing) of mucosa and bone was clinically and radiographically evaluated on a long-term period (27.05?±?2.96 months).

Results

Primary pathology (osteoporosis or malignancies) and clinical severity of ONJ (mild, moderate, severe) were decisive factors. Osteoporotic patients showed more frequently complete mucosa or bone healing (p?=?0.0128 and p?=?0.00021, respectively) than malignant patients. Mucosa closure and bone improvement occurred more in mild ONJ patients than in severe ONJ (p?=?0.0053 and p?=?0.0319, respectively). Treatment strategy appeared to be a crucial factor for mucosa but not for bone healing. The rate of complete mucosa healing increased after an extensive surgical procedure (p?=?0.0096).

Conclusions

A surgical management of patients with ONJ positively influenced the clinical outcome by enhancing mucosa healing.

Clinical relevance

These results deserve further investigations involving a larger cohort. However, they strongly suggest that the guidelines of management of patients with ONJ related to NBPs have to be reconsidered.     

Influence of induced infection in medication-related osteonecrosis of the jaw development after tooth extraction: A study in rats

Purpose

The mechanisms underlying the pathophysiology of medication-related osteonecrosis of the jaw (MRONJ) development have not yet been fully elucidated. MRONJ is described as a multi-factorial process in which bacterial infection seems to play an important role. The purpose of the present study was to investigate the influence of a primary installed infectious disease in the development of MRONJ after dental extraction.

Effective ancillary role and long-term course of daily or weekly teriparatide treatment on refractory medication-related osteonecrosis of the jaw: a clinical case series

Medication-related osteonecrosis of the jaw (MRONJ) is a potentially severe adverse side effect of antiresorptive agents. However, withdrawal of such agents in patients with osteoporosis may increase the risk of fracture. The treatment of MRONJ is challenging, and standard treatment guidelines have yet to be established. In this study, the aim was to find out whether adjuvant daily or weekly teriparatide (TPTD) injections were beneficial for exposed bony MRONJ lesions compared with standard conservative management. We also studied the complications and the patients’ response to TPTD therapy. We enrolled 27 patients (January 2012 - December 2016) with chronic and refractory MRONJ. There were four men and 23 women (85% female). Nine patients who did not select TPTD therapy for several reasons formed the non-TPTD group; the remaining 18 were randomly assigned to the daily (n=9) or weekly (n=9) groups. All patients in both groups continued standard conservative therapy in addition to their daily or weekly subcutaneous injection of TPTD (20 μg or 56.5 μg, respectively). We evaluated the complications of TPTD and its benefits. Three patients in the daily group did not complete the study, resulting in six patients in the daily group, nine in the weekly group, and nine in the non-TPTD group in the final analysis. The exposed bone was completely covered with normal mucosa in all patients in the TPTD groups, and the healing period was shorter than that in the non-TPTD group. No patient had complications of atypical fractures of the femoral head. Daily and weekly TPTD treatment resulted in a shortened treatment period compared with standard conservative therapy, with no increase in the rate of complications or worsening of osteoporosis.     

Medication‐related osteonecrosis of the jaw: Surgical or non‐surgical treatment?

Medication‐related osteonecrosis of the jaw (MRONJ) is a severe side effect of antiresorptive (bisphosphonates and denosumab) and anti‐angiogenic therapy used in the management of oncologic and, less frequently, osteoporotic patients. While there is good international agreement on the diagnostic and staging criteria of MRONJ and the cessation of antiresorptive/anti‐angiogenic treatments, the gold standard of treatment is still controversial, in particular between non‐surgical and surgical approaches. The former usually includes antiseptic mouth rinse, cyclic antibiotic therapy, low‐level laser therapy and periodic dental checks; the latter consists of surgical necrotic bone removal. The purpose of this retrospective study was to describe the therapeutic approaches and outcomes of 131 lesions from 106 MRONJ patients treated at the Policlinic of Bari. Non‐surgical treatments were chosen for 24 lesions that occurred in 21 patients who, due to comorbidities and/or the impossibility of stopping oncologic therapies, could not undergo surgical treatment. As to the outcome, all the surgically treated lesions (107) showed complete healing, with the exception of 13.5% of the lesions, all of which were stage III, which did not completely heal but showed reduction to stage I. The 24 non‐surgically treated lesions never completely healed and, rather, generally remained stable. Only two cases exhibited a reduction in staging. Based on our observations, MRONJ occurring both in neoplastic and non‐neoplastic patients benefits more from a surgical treatment approach, whenever deemed possible, as non‐surgical treatments do not seem to allow complete healing of the lesions.     

Case series of medication-related osteonecrosis of the jaw (MRONJ) patients prescribed a drug holiday

The role of a drug holiday in the management of medication-related osteonecrosis of the jaw (MRONJ) remains controversial. Current UK guidance does not recommend this practice given the lack of conclusive evidence, and potential risk of skeletal-related events or cancer metastasis. This paper aims to describe a series of fifty patients with confirmed MRONJ who were prescribed a drug holiday as part of their management. Data were collected on exposures including: anti-resorptive and/or anti-angiogenic drug history, duration of drug, method of administration, concurrent therapy, MRONJ stage, management of MRONJ and duration of drug holiday. The primary outcome was complete healing as documented in the clinical notes. Multivariate Cox regression analysis was performed to evaluate the association between exposures and primary MRONJ outcome. Models were adjusted for age, sex, and index of multiple deprivation. Survival analysis was performed using a log-rank test, censoring any patients with no primary outcome recorded (p < 0.05). A total of 44% of patients stopped their medication for >36 months. Over half of all MRONJ cases presented in the posterior mandible and dental extraction was the most common precipitating factor (76%). Almost three-quarters (72%) of patients achieved complete healing. MRONJ recurrence (new site) was reported at 30%, mainly in those with incomplete healing of the initial area. There was a lack of evidence for an association between all recorded exposures and the primary MRONJ outcome using multivariate Cox regression. Similarly, we did not demonstrate evidence for an association between the duration of the drug holiday and MRONJ outcome. Our results support published guidelines, which do not recommend the discontinuation of bone modifying drugs for the prevention of MRONJ, or as part of treatment for established MRONJ.     

Double-layer closure techniques after bone surgery of medication-related osteonecrosis of the jaw – A single center cohort study

Introduction

Mucosal wound closure plays a key role after surgery of manifested medication-related osteonecrosis of the jaw (MRONJ). Additional soft tissue layers promise better vascularization and mechanical stability. The objectives of this study were to examine success rates of double-layer closure techniques in MRONJ patients, namely the mylohyoideus muscle flap (MMF) for the lower jaw and the pedicled buccal fat flap (BFF) for the upper jaw.

Surgical treatment of stage 2 medication-related osteonecrosis of the jaw compared to osteomyelitis

Objective: To compare the characteristics and outcomes of patients who underwent surgical treatment for stage 2 medication-related osteonecrosis of the jaw (MRONJ) versus osteomyelitis.

Methods: This retrospective study compared the following variables in 73 patients with stage 2 MRONJ versus 89 patients with osteomyelitis: impaired wound healing after surgery, sex, age, the presence of actinomycosis, location of the jaw lesion, and involvement of the inferior alveolar nerve (IAN).

Results: There were significant differences between the groups in age, sex, rates of impaired wound healing, actinomycosis, and the location (anterior/posterior) of the lesion. Impaired wound healing after surgical treatment in the stage 2 MRONJ group was associated with patient age. All patients with impaired wound healing after the initial surgery recovered fully after reoperation.

Conclusions: These findings for surgical treatment of stage 2 MRONJ may help clinicians plan surgical treatment of MRONJ.     

Distress thermometer for preoperative screening of patients with oral squamous cell carcinoma

In this study, we evaluate the association between distress, various demographic and medical variables, and the prevalence of psychosocial distress in preoperative patients with oral squamous cell carcinoma. A total of 100 consecutive patients were recruited into the study and asked to complete the Distress Thermometer (DT) form with the Problem List questionnaire prior to surgical intervention; the average distress score was 5.7 ± 2.7. The distress score was neither correlated with age (r = ?0.025; p = 0.804) nor with tumor size (r = 0.028; p = 0.785). General worries, anxiety, sadness, depression, pain, exhaustion, sleeping disorders, or problems with nutrition resulted in significantly higher distress scores compared to patients without these complaints. Individuals with a DT score of 5 or higher (p = 0.006) were advised to seek out psychological support. There is a strong correlation between a high DT score and emotional disorders, as well as physical problems.     

Treatment of medication-related osteonecrosis of the jaws (MRONJ) with ultrasonic piezoelectric bone surgery. A case series of 20 treated sites

Purpose

There is no consensus on how to successfully treat medication-related osteonecrosis of the jaws (MRONJ). We report here on the application of piezoelectric bone surgery to treat MRONJ in combination with antibiotherapy and on its possible benefit.

Materiel and methods

A cohort of 18 consecutive patients has been treated for MRONJ; they involved 20 sites, 15 in the mandible, and five in the maxilla. Surgical removal of the necrotic areas and debridement was performed with a powerful piezoelectric surgery device (max 90 W) in combination with antibiotherapy.

Results

All patients healed and obtained a complete soft tissue closure within 1 month. No recurrence of the symptoms was observed during the present follow-up (10–54 months).

Conclusion

We hypothesize that healing of all treated sites might have resulted from the synergic effect of bone ablation, biofilm alteration, and antibiotic administration. Biofilm alteration might have permitted a better access of antibiotics to the involved germs. These encouraging results warrant further studies on the use of ultrasonic surgery to treat MRONJ patients in order to confirm or refute the hypothesized effect.

     

Osteonecrosis of the jaw in patients transitioning from bisphosphonates to denosumab treatment for osteoporosis

Antiresorptive-related osteonecrosis of the jaw (ARONJ) is a rare but severe side effect of antiresorptive treatment with bisphosphonates or RANKL-antibody denosumab in patients with malignant diseases or osteoporosis. Whilst osteonecrosis of the jaw (ONJ) related to the administration of bisphosphonates (BPs) has been investigated for more than 1 decade now, only few data are available on denosumab-related ONJ, especially in patients with osteoporosis. From 2008 to 2016, 52 osteoporosis patients were treated with ARONJ in the Department of Oral and Maxillofacial Surgery, University Medical Center Freiburg, Germany. In all patients, a surgical regimen consisting of complete removal of necrotic bone, primary wound closure and perioperative i.v. antibiotic therapy was applied. Of the 52 patients, 38 developed ARONJ after BP monotherapy; in 11 patients, antiresorptive therapy had been transitioned from BPs to denosumab and 3 patients had received denosumab monotherapy. From July 2013, when the first patient with ONJ and transitioning therapy from BPs to denosumab presented to our department, to October 2016, we found recurrences in 17.6% of the patients with BP monotherapy and in 45.5% of the patients with transitioning therapy from BPs to denosumab. Transitioning antiresorptive therapy from BPs to denosumab may be an additional risk factor for developing ARONJ. In these patients, treatment of ARONJ-lesions seems to provoke more complications. An additional dental screening before transitioning should be initiated. Further studies are needed to evaluate if a first-line treatment with denosumab decreases the incidence of ARONJ in patients with osteoporosis and simplifies its treatment.     

Osteonecrosis of the jaw in patients treated with denosumab: A multicenter case series

Purpose

Osteonecrosis of the jaw has been recently reported in patients receiving denosumab for the treatment of metastatic bone disease and osteoporosis. It is essential to investigate this disease as a new osteonecrosis entity in order to recognize its optimal management strategies.

Radiographic patterns of multiple myeloma in the jawbones of patients treated with intravenous bisphosphonates

Background

The purpose of this study was to evaluate whether intravenous (IV) bisphosphonate (BP) therapy can change the radiographic patterns of multiple myeloma (MM) in the jawbones.

Bisphosphonate use and the risk of adverse jaw outcomes: a medical claims study of 714,217 people

BACKGROUND: While osteonecrosis of the jaw (ONJ) has been associated with the prolonged use of bisphosphonates (BPs), there is limited information about the risk of ONJ among users of oral BPs or about the magnitude of the risk among users of intravenous (IV) BPs. METHODS: The authors studied medical claims data from 714,217 people with osteoporosis or cancer to identify diagnostic codes or procedure codes for three outcomes: inflammatory conditions of the jaws, including osteonecrosis; major jaw surgery necessitated by necrotic or inflammatory indications; and jaw surgeries necessitated by a malignant process. The authors calculated stratified odds ratios and 95 percent confidence intervals. RESULTS: The results indicate that oral administration of BPs decreases the risk of adverse bone outcomes. In contrast, IV administration strongly and significantly increases the risk (P < .05) of adverse jaw outcomes or surgery. Across both osteoporosis and cancer, patients receiving IV BPs had a fourfold increased risk of having inflammatory jaw conditions and a greater than sixfold increased risk of having undergone major surgical resection in the jaw. CONCLUSIONS: Mode of bisphosphonate use results in different risk profiles for adverse jaw outcomes. While the authors documented an increased risk of inflammatory conditions and surgical procedures of the jaw for users of IV BPs, they did not find these observed increases for users of oral BPs. CLINICAL IMPLICATIONS: Physicians and dentists must be aware of the higher frequency of adverse jaw effects in patients receiving IV BPs, especially osteonecrosis of the jaw. While the authors' results have internal consistency, more clinical studies are needed to replicate and clarify the observed associations over long follow-up periods.     

Osteonecrosis and spontaneous exfoliation of dental implants associated with oral bisphosphonate therapy: a case report

Bisphosphonates (BPs) have long been used for the treatment of osteoporosis and diseases like bone malignancies, active Paget's disease of bone, severe osteogenesis imperfecta and fibrous dysplasia among others. They bond highly to the bone surface and inhibit bone resorption. As BPs have a long half-life in bone because of their irreversible binding to bone, patients retain their risk profile even after drug cessation. This property also explains the complications wherein the cessation of bone resorption leads to halt in bone turnover. Usually with alendronate the risk of bisphosphonate-related osteonecrosis of jaw (BRONJ) wears off after 12 months. Reporting of the development of BRONJ is commonly associated with the intravenous BPs. Invasive surgical procedure associated with the placement of implants has been shown to be a major reason for the occurrence or initiation of BRONJ in susceptible patients. The prognosis of implants placed in the jaws of patients under or past BP medication is still uncertain. The present case report describes a patient on long-term oral BP therapy with spontaneous exfoliation of implant supported bone due to osteonecrosis.     

Pulpal Disease Arising from Medication-related Osteonecrosis of the Jaw: A Case Report

Although bisphosphonates are widely used to treat conditions such as osteoporosis, they may cause osteonecrosis of the jaw. We treated a patient with no history of tooth extraction or other surgical treatment who developed medication-related osteonecrosis of the jaw (MRONJ) with secondary pulpal disease. A 79-year-old woman presented with purulent discharge from the gum at the incisor region. She had been using bisphosphonates for 9 years. Tooth #6 had undertaken root canal treatment at a general practice. All teeth other than tooth #6 reacted to electric pulp testing. Computed tomographic imaging revealed signs suggestive of necrotic bone, and MRONJ was diagnosed. Teeth #7 and #8, which had initially exhibited vital reactions, also subsequently ceased to react to thermal and electric pulp testing. Root canal treatment was performed on teeth #6–8, and their condition was monitored. Computed tomographic imaging at 9 months after the first presentation revealed that the bone defect had greatly enlarged with separation of the necrotic bone; therefore, excision of the necrotic bone and curettage were performed in the department of oral and maxillofacial surgery. The loss of pulp reaction in teeth that had exhibited a vital reaction at the first presentation was considered to indicate that teeth #6–8 had developed dental pulp pathosis as a result of MRONJ.     

Ten years of observations and demographics of hemimandibular hyperplasia and elongation

Introduction

The full epidemiology and etiology of hemimandibular hyperplasia (HH) has not yet been clarified. In most cases it starts before puberty and results in various forms of dento-alveolar and skeletal discrepancies. This study is the first attempt at evaluating and describing some of the authors' key experiences, clinical philosophical approach, and gathered demographic data on hemimandibular hyperplasia and hemimandibular elongation (HE) among the Polish population.