Medication-related osteonecrosis of the jaw: evolving research for multimodality medical management.

PURPOSE: Medication-related osteonecrosis of the jaw (MRONJ) is a debilitating side effect of antiresorptive and antiangiogenic agents that can lead to progressive bone destruction in the maxillofacial region. Dental surgery, including tooth extractions, commonly trigger the onset of MRONJ. While guidelines suggest avoiding extraction when possible, complete avoidance is not always feasible, as necrosis can develop from dental and periodontal disease without dental procedures. The goal of this article is to provide an update review of current preventive and therapeutic approaches for MRONJ. METHODS: A comprehensive electronic search was conducted on PubMed/MEDLINE, Embase, and Scopus databases. All English articles encompassing randomized controlled trials, systematic reviews, observational studies, and case studies were reviewed. The current medical treatments and adjuvant therapies for managing MRONJ patients were critically assessed and summarized. RESULTS: Pentoxifylline and alpha tocopherol (PENT-E), teriparatide, photobiomodulation (PBM), photodynamic therapy (PDT), and the use of growth factors have shown to enhance healing in MRONJ patients. Implementing these methods alone or in conjunction with surgical treatment has been linked to reduced discomfort and improved wound healing and increased new bone formation. DISCUSSION: While several adjuvant treatment modalities exhibit promising results in facilitating the healing process, current clinical practice guidelines predominantly recommend antibiotic therapy as a non-surgical approach, primarily addressing secondary infections in necrotic areas. However, this mainly addresses the potential infectious complication of MRONJ. Medical approaches including PENT-E, teriparatide, PBM, and PDT can result in successful management and should be considered prior to taking a surgical approach. Combined medical management for both preventing and managing MRONJ holds potential for achieving optimal clinical outcomes and avoiding surgical intervention, requiring further validation through larger studies and controlled trials.

Adjuvant therapies in the management of medication-related osteonecrosis of the jaws: Systematic review.

BACKGROUND: We investigated the efficacy of hyperbaric oxygen (HBO), low-intensity laser (LIL), and platelet-rich plasma (PRP) in the management of medication-related osteonecrosis of the jaws (MRONJ). METHODS: A literature search was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Two examiners independently assessed eligibility and risk of bias and extracted data. RESULTS: There was improvement in 75.6% of the 41 patients submitted to HBO, with positive effects on pain relief and decreased size and number of lesions at a faster rate, with better effects when the drug was discontinued. For LIL, 158 (64.2%) of the 246 patients/sites improved the symptoms and 98 (39.8%) healed completely. Fourteen (17.3%) of the 81 patients treated with PRP significantly improved the symptoms and 65 (80.2%) completely healed. CONCLUSIONS: These therapies served as safe and effective adjuvant modalities for MRONJ treatment. The lack of randomized clinical trials evidences the need for more high-quality investigations on the subject.

Osteoradionecrosis of the jaws: case series treated with adjuvant low-level laser therapy and antimicrobial photodynamic therapy.

BACKGROUND: Osteoradionecrosis of the jaw (ORNJ) is the most severe and complex sequel of head and neck radiotherapy (RT) because of the bone involved, it may cause pain, paresthesia, foul odor, fistulae with suppuration, need for extra oral communication and pathological fracture. We treated twenty lesions of ORNJ using low-level laser therapy (LLLT) and antimicrobial photodynamic therapy (aPDT). The objective of this study was to stimulate the affected area to homeostasis and to promote the healing of the oral mucosa. METHODS: We performed aPDT on the exposed bone, while LLLT was performed around the bone exposure (red spectrum) and on the affected jaw (infrared spectrum). Monitoring and clinical intervention occurred weekly or biweekly for 2 years. RESULTS: 100% of the sample presented clinical improvement, and 80% presented complete covering of the bone exposure by intact oral mucosa. CONCLUSION: LLLT and aPDT showed positive results as an adjuvant therapy to treat ORNJ.

Interventions for managing medication-related osteonecrosis of the jaw.

BACKGROUND: Medication-related osteonecrosis of the jaw (MRONJ) is a severe adverse reaction experienced by some individuals to certain medicines commonly used in the treatment of cancer and osteoporosis (e.g. bisphosphonates, denosumab and antiangiogenic agents) and involves the progressive destruction of bone in the mandible or maxilla. Depending on the drug, its dosage, and the duration of exposure, the occurrence of this adverse drug reaction may be rare (e.g. following the oral administration of bisphosphonate or denosumab treatments for osteoporosis, or antiangiogenic agent-targeted cancer treatment) or common (e.g. following intravenous bisphosphonate for cancer treatment). MRONJ is associated with significant morbidity, adversely affects quality of life (QoL), and is challenging to treat. OBJECTIVES: To assess the effects of interventions versus no treatment, placebo, or an active control for the prophylaxis of MRONJ in people exposed to antiresorptive or antiangiogenic drugs.To assess the effects of non-surgical or surgical interventions (either singly or in combination) versus no treatment, placebo, or an active control for the treatment of people with manifest MRONJ. SEARCH METHODS: Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 23 November 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2016, Issue 10), MEDLINE Ovid (1946 to 23 November 2016), and Embase Ovid (23 May 2016 to 23 November 2016). The US National Institutes of Health Trials Registry (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials. No restrictions were placed on language or publication status when searching the electronic databases; however, the search of Embase was restricted to the last six months due to the Cochrane Embase Project to identify all clinical trials and add them to CENTRAL. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing one modality of intervention with another for the prevention or treatment of MRONJ. For 'prophylaxis of MRONJ', the primary outcome of interest was the incidence of MRONJ; secondary outcomes were QoL, time-to-event, and rate of complications and side effects of the intervention. For 'treatment of established MRONJ', the primary outcome of interest was healing of MRONJ; secondary outcomes were QoL, recurrence, and rate of complications and side effects of the intervention. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the search results, extracted the data, and assessed the risk of bias in the included studies. For dichotomous outcomes, we reported the risk ratio (RR) (or rate ratio) and 95% confidence intervals (CI). MAIN RESULTS: We included five RCTs (1218 participants) in the review. Three trials focused on the prophylaxis of MRONJ. Two trials investigated options for the treatment of established MRONJ. The RCTs included only participants treated with bisphosphonates and, thus, did not cover the entire spectrum of medications associated with MRONJ. Prophylaxis of MRONJOne trial compared standard care with regular dental examinations in three-month intervals and preventive treatments (including antibiotics before dental extractions and the use of techniques for wound closure that avoid exposure and contamination of bone) in men with metastatic prostate cancer treated with zoledronic acid. The intervention seemed to lower the risk of MRONJ: RR 0.10; 95% CI 0.02 to 0.39 (253 participants; low-quality evidence). Secondary outcomes were not evaluated.As dentoalveolar surgery is considered a common predisposing event for developing MRONJ, one trial investigated the effect of plasma rich in growth factors (PRGF) for preventing MRONJ in people with cancer undergoing dental extractions. There was insufficient evidence to support or refute a benefit of PRGF on MRONJ incidence when compared with standard treatment (RR 0.08, 95% CI 0.00 to 1.51; 176 participants; very low-quality evidence). Secondary outcomes were not reported. In another trial comparing wound closure by primary intention with wound closure by secondary intention after dental extractions in people treated with oral bisphosphonates (700 participants), no cases of intraoperative complications or postoperative MRONJ were observed. QoL was not investigated. Treatment of MRONJOne trial analysed hyperbaric oxygen (HBO) treatment used in addition to standard care (antiseptic rinses, antibiotics, and surgery) compared with standard care alone. HBO in addition to standard care did not significantly improve healing from MRONJ compared with standard care alone (at last follow-up: RR 1.56; 95% CI 0.77 to 3.18; 46 participants included in the analysis; very low-quality evidence). QoL data were presented qualitatively as intragroup comparisons; hence, an effect estimate of treatment on QoL was not possible. Other secondary outcomes were not reported.The other RCT found no significant difference between autofluorescence- and tetracycline fluorescence-guided sequestrectomy for the surgical treatment of MRONJ at any timepoint (at one-year follow-up: RR 1.05; 95% CI 0.86 to 1.30; 34 participants included in the analysis; very low-quality evidence). Secondary outcomes were not reported. AUTHORS' CONCLUSIONS: Prophylaxis of MRONJOne open-label RCT provided some evidence that dental examinations in three-month intervals and preventive treatments may be more effective than standard care for reducing the incidence of MRONJ in individuals taking intravenous bisphosphonates for advanced cancer. We assessed the certainty of the evidence to be low.There is insufficient evidence to either claim or refute a benefit of either of the interventions tested for prophylaxis of MRONJ (i.e. PRGF inserted into the postextraction alveolus during dental extractions, and wound closure by primary or secondary intention after dental extractions). Treatment of MRONJAvailable evidence is insufficient to either claim or refute a benefit for hyperbaric oxygen therapy as an adjunct to conventional therapy. There is also insufficient evidence to draw conclusions about autofluorescence-guided versus tetracycline fluorescence-guided bone surgery.

Identifying and acting on potentially inappropriate care? Inadequacy of current hospital coding for this task.

INTRODUCTION: Recent Australian attempts to facilitate disinvestment in healthcare, by identifying instances of 'inappropriate' care from large Government datasets, are subject to significant methodological flaws. Amongst other criticisms has been the fact that the Government datasets utilized for this purpose correlate poorly with datasets collected by relevant professional bodies. Government data derive from official hospital coding, collected retrospectively by clerical personnel, whilst professional body data derive from unit-specific databases, collected contemporaneously with care by clinical personnel. AIM: Assessment of accuracy of official hospital coding data for hyperbaric services in a tertiary referral hospital. METHODS: All official hyperbaric-relevant coding data submitted to the relevant Australian Government agencies by the Royal Hobart Hospital, Tasmania, Australia for financial year 2010-2011 were reviewed and compared against actual hyperbaric unit activity as determined by reference to original source documents. RESULTS: Hospital coding data contained one or more errors in diagnoses and/or procedures in 70% of patients treated with hyperbaric oxygen that year. Multiple discrete error types were identified, including (but not limited to): missing patients; missing treatments; 'additional' treatments; 'additional' patients; incorrect procedure codes and incorrect diagnostic codes. Incidental observations of errors in surgical, anaesthetic and intensive care coding within this cohort suggest that the problems are not restricted to the specialty of hyperbaric medicine alone. Publications from other centres indicate that these problems are not unique to this institution or State. CONCLUSIONS: Current Government datasets are irretrievably compromised and not fit for purpose. Attempting to inform the healthcare policy debate by reference to these datasets is inappropriate. Urgent clinical engagement with hospital coding departments is warranted.

Treatment of periodontal intrabony defects using autologous periodontal ligament stem cells: a randomized clinical trial.

BACKGROUND: Periodontitis, which progressively destroys tooth-supporting structures, is one of the most widespread infectious diseases and the leading cause of tooth loss in adults. Evidence from preclinical trials and small-scale pilot clinical studies indicates that stem cells derived from periodontal ligament tissues are a promising therapy for the regeneration of lost/damaged periodontal tissue. This study assessed the safety and feasibility of using autologous periodontal ligament stem cells (PDLSCs) as an adjuvant to grafting materials in guided tissue regeneration (GTR) to treat periodontal intrabony defects. Our data provide primary clinical evidence for the efficacy of cell transplantation in regenerative dentistry. METHODS: We conducted a single-center, randomized trial that used autologous PDLSCs in combination with bovine-derived bone mineral materials to treat periodontal intrabony defects. Enrolled patients were randomly assigned to either the Cell group (treatment with GTR and PDLSC sheets in combination with Bio-oss(®)) or the Control group (treatment with GTR and Bio-oss(®) without stem cells). During a 12-month follow-up study, we evaluated the frequency and extent of adverse events. For the assessment of treatment efficacy, the primary outcome was based on the magnitude of alveolar bone regeneration following the surgical procedure. RESULTS: A total of 30 periodontitis patients aged 18 to 65 years (48 testing teeth with periodontal intrabony defects) who satisfied our inclusion and exclusion criteria were enrolled in the study and randomly assigned to the Cell group or the Control group. A total of 21 teeth were treated in the Control group and 20 teeth were treated in the Cell group. All patients received surgery and a clinical evaluation. No clinical safety problems that could be attributed to the investigational PDLSCs were identified. Each group showed a significant increase in the alveolar bone height (decrease in the bone-defect depth) over time (p < 0.001). However, no statistically significant differences were detected between the Cell group and the Control group (p > 0.05). CONCLUSIONS: This study demonstrates that using autologous PDLSCs to treat periodontal intrabony defects is safe and does not produce significant adverse effects. The efficacy of cell-based periodontal therapy requires further validation by multicenter, randomized controlled studies with an increased sample size. TRIAL REGISTRATION: NCT01357785 Date registered: 18 May 2011.

The management of osteoradionecrosis of the jaws--a review.

PURPOSE: To review the conservative and surgical management options of osteoradionecrosis, in particular, highlighting the recent the use of anti-radiation fibrosis drugs (pentoxifylline, tocopherol and clodronate). MATERIAL AND METHODS: We performed a literature review. The management options were divided into two groups, conservative and surgical management. RESULTS: Over the years several treatment options have been proposed including; conservative management (antibiotics, analgesics, oral hygiene), ultrasound therapy, hyperbaric oxygen therapy, surgical resection with reconstruction and more recently the use of anti-radiation fibrosis drugs (pentoxifylline, tocopherol and clodronate). Early or low grade ORN can be managed conservatively using a combination of treatment options. In advanced or refractory cases of ORN (pathological fracture, orocutaneous fistula) surgical treatment, at present, remains the only treatment option available. A new understanding of the pathophysiology of ORN (radiation induced fibroatrophic process) has lead to the development of new therapeutic management regimes. CONCLUSION: In advanced or refractory cases of ORN surgical treatment, including microvascular reconstructive techniques for bone and soft tissue, remains the only option available.

[The effectiveness of the application of mineral water from the Klyuchi health resort in the programs of combined spa-based rehabilitation of the patients presenting with acquired jaw defects].

The results of the present study give evidence of the well-apparent sanation effect of balneotherapy with the use of therapeutic mineral water (MW) extracted at the Klyuchi health resort. Irrigation of the oral cavity with this mineral water was shown to reduce the number of the strains of opportunistic microorganisms and their virulence potential. It is concluded that the proposed method may be recommended for the treatment and prevention of dysbiosis in the oral cavity of the patients presenting with acquired jaw defects.

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.

Hyperbaric oxygen therapy in the management of radiation-induced injury in the head and neck region: a review of the literature.

PURPOSE: Radiotherapy is generally used in the treatment of malignant tumors in the head and neck region. It causes a hypoxic, hypocellular, and hypovascular environment that leads to injury to surrounding normal tissue, both acute and chronic, ranging from xerostomia to osteoradionecrosis. These side effects are debilitating and greatly influence quality of life in these patients. Hyperbaric oxygen (HBO) therapy is clinically used to prevent or treat these side effects by enhancing oxygen pressure and thereby regeneration. Although this therapy is widely applied, its mechanism of action is still poorly understood, and controversy exists in the literature about its clinical use. This review therefore aims to analyze the existing experimental and clinical research on this topic. MATERIALS AND METHODS: A systematic search was performed in PubMed for experimental and clinical studies conducted regarding the use of HBO therapy in previously irradiated tissue, in the period from January 1990 to June 2009. RESULTS: Experimental research is scarce, and clinical studies are especially lacking in terms of randomized controlled studies. Although discussions on the subject are ongoing, most studies suggest a beneficial role for HBO in previously irradiated tissue. CONCLUSION: Further research, both experimental and clinical, is necessary to unravel the working mechanism of HBO therapy and validate its clinical use.

Resolution of oral bisphosphonate and steroid-related osteonecrosis of the jaw--a serial case analysis.

PURPOSE: To offer recommendations of risk factors, prevention, and treatment of oral bisphosphonate and steroid-related osteonecrosis of the jaw (BSRONJ) in Taiwan. MATERIALS AND METHODS: Twelve patients were clinicopathologically proved to have bisphosphonate-related osteonecrosis of the jaw (BRONJ). All of the patients were taking oral bisphosphonates and were concurrently administered long-term steroids. Of the 12 patients, 3 patients were assigned to the first stage of BRONJ; 5 patients were assigned to the second stage, and 4 patients were assigned to the third stage. The patients' symptoms, localization of necrosis, presence of a fistula, and association with possible triggering factors for onset of the lesion were recorded. RESULTS: The radiologic investigations revealed osteolytic areas and scintigraphy demonstrated increased bone metabolism. Microbiologic analysis showed pathogenic actinomycosis organisms in a majority of patients (91.6%). Antibiotic therapy, minor debridement surgery, and combined hyperbaric oxygen therapy were useful in obtaining short-term symptomatic relief. CONCLUSIONS: Comorbidities of steroid use along with bisphosphonates may cause osteonecrosis of the jaw to occur sooner, be more severe, and respond more slowly to a drug discontinuation. The clinical disease of BSRONJ is more severe and more unpredictable to treat than BRONJ. From the data gained from other published studies of BRONJ and our clinical experience with the series of cases of BSRONJ, we offer recommendations of risk factors, prevention, and treatment of BSRONJ in southern Taiwan.

Osteoradionecrosis of the jaws--a current overview--Part 2: dental management and therapeutic options for treatment.

PURPOSE: The aim of this paper is to explore the current theories about pretreatment assessment and dental management of patients receiving head and neck radiotherapy, and the therapeutic options to treat osteoradionecrosis of the jaws, based on the literature review. DISCUSSION: Osteoradionecrosis is one of the most serious oral complications of head and neck cancer treatment. Osteoradionecrosis is a severe delayed radiation-induced injury, characterized by bone tissue necrosis and failure to heal. Osteoradionecrosis either stabilizes or gradually worsens and is notoriously difficult to manage. Because most cases occur in patients who were dentulous in the mandible at tumor onset, proper dental management is the single most important factor in prevention. CONCLUSIONS: Complete dental clearance before treatment is no longer necessary. Controversy exists regarding the management of osteoradionecrosis of the maxillofacial skeleton because of the variability of this condition. The treatment of osteoradionecrosis has included local wound care, antibiotic therapy, surgical procedures, and the administration of hyperbaric oxygenation. Recently, new methods of treatment were introduced, according to the new theory about its pathophysiology.

Resolution of cavitational osteonecrosis through NeuroModulation Technique, a novel form of intention-based therapy: a clinical case study.

OBJECTIVES: This study evaluated the possibility of using NeuroModulation Technique (NMT), a form of intention-based medicine, to induce osteogenesis and healing of cavitational osteonecrosis, a common progressive form of ischemic disease of the alveolar arch. DESIGN: Eleven (11) adult patients were enrolled based on the presence of lesions in the jawbone. Ten (10) subjects underwent NMT therapy for up to 10 months, while 1 subject received no treatment. OUTCOME MEASURES: A sensitive analysis of bone density in the alveolar processes of maxilla and mandible was performed before and after therapy using the U.S. Food and Drug Administration-approved Cavitat system of through-transmission ultrasonography and computer imaging. RESULTS: All subjects presented between one and six cavitational lesions at the first scan, most of which (92%) were associated with sites of previous tooth extraction. NMT-treated patients demonstrated significant improvement in bone density in 27 of the 34 lesions analyzed (79%). The median number of lesions per patient was 4 pretreatment and 0 post-treatment (p < 0.01). One NMT-treated patient, 1 surgically treated patient, and the control subject were also imaged at later time points, showing a durable healing of the lesions through NMT comparable to that of surgery, as opposed to disease persistence in the untreated control. CONCLUSIONS: NMT therapy provides a safe and potentially effective treatment for jawbone osteonecrosis. Preclinical placebo-controlled trials are encouraged to investigate in depth the potential of NMT for treating inflammatory and degenerative pathologies.