Treatment of BRONJ with ozone/oxygen therapy and debridement with piezoelectric surgery.

OBJECTIVE: Bisphosphonate related osteonecrosis of the jaw (BRONJ) is progressive bone destruction in the maxillofacial region of patients under current or previous treatment with Bisphosphonates. The present case series study aimed to evaluate if ozone/oxygen therapy and debridement with piezoelectric surgery may improve the treatment of BRONJ. PATIENTS AND METHODS: The treatment modality of the patients included ozone/oxygen mixture from medical oxygen. The protocol for ozone/oxygen mixture therapy appointments was set as twice a week for 10 weeks, for a total of 20 applications for each patient. The evaluation of the lesions was based on the clinical and radiologic parameters. The primary outcome was the necrotic lesion reduction during ozone/oxygen therapy sessions and up to the end of follow up periods. The healing of the lesion was taken as a positive result. The level of significance was taken as p <0.05. RESULTS: A total of 14 patients affected by osteonecrosis were included. The mean follow-up of the patients was 14.3 months. The overall success rate after treatment was 64.2%. CONCLUSIONS: According to the results, ozone/oxygen therapy and debridement with Piezoelectric surgery for BRONJ treatment is a safe procedure with successful outcomes.

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

PURPOSE: Medication-related osteonecrosis of the jaw (MRONJ) is an infrequent but morbid and potentially serious condition associated with antiresorptive and antiangiogenic therapies. Although MRONJ can be prevented by optimizing oral health, management of established cases is supportive and remains challenging. Teriparatide, an osteoanabolic agent that improves bone healing in preclinical studies and in chronic periodontitis, represents a potential treatment option. PATIENTS AND METHODS: In a double-blind, randomized, controlled trial, 34 participants with established MRONJ, with a total of 47 distinct MRONJ lesions, were allocated to either 8 weeks of subcutaneous teriparatide (20 µg/day) or placebo injections, in addition to calcium and vitamin D supplementation and standard clinical care. Participants were observed for 12 months, with primary outcomes that included the clinical and radiologic resolution of MRONJ lesions. Secondary outcomes included osteoblastic responses as measured biochemically and radiologically and changes in quality of life. RESULTS: Teriparatide was associated with a greater rate of resolution of MRONJ lesions (odds ratio [OR], 0.15 v 0.40; P = .013), and 45.4% of lesions resolved by 52 weeks compared with 33.3% in the placebo group. Teriparatide was also associated with reduced bony defects at week 52 (OR, 8.1; P = .017). The incidence of adverse events was balanced between groups, including nausea, anorexia, and musculoskeletal pain, most of mild severity. CONCLUSION: Teriparatide improves the rate of resolution of MRONJ lesions and represents an efficacious and safe treatment for it.

Management of stage 0 medication-related osteonecrosis of the jaw with hyperbaric oxygen therapy: a case report and review of the literature.

The definition of medication-related osteonecrosis of the jaw (MRONJ) includes a stage 0 presentation where exposed bone, the hallmark of this condition, is absent. Numerous management strategies have been recommended for MRONJ including hyperbaric oxygen (HBO2) therapy. This report describes a 64-year-old woman with stage 0 MRONJ of the bilateral mandible, refractory to clindamycin and local debridement, who was subsequently managed successfully with amoxicillin/clavulanate and HBO2 therapy. The authors also explore the current literature on the pathophysiology of MRONJ and the potential role of hyperbaric oxygen in its treatment.

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.

The Effect of Polydeoxyribonucleotide Extracted from Salmon Sperm on the Restoration of Bisphosphonate-Related Osteonecrosis of the Jaw.

Bisphosphonates (BPs) used for treating skeletal diseases can induce bisphosphonate-related osteonecrosis of the jaw (BRONJ). Despite much effort, effective remedies are yet to be established. In the present study, we investigated the feasibility of polydeoxyribonucleotide (PDRN) extracted from salmon sperm for the treatment of BRONJ, in a BRONJ-induced rat model. Compared with BRONJ-induced samples, PDRN-treated samples exhibited lower necrotic bone percentages and increased numbers of blood vessels and attached osteoclast production. Moreover, local administration of PDRN at a high concentration (8 mg/kg) remarkably resolved the osteonecrosis. Findings from this study suggest that local administration of PDRN at a specific concentration may be considered clinically for the management of BRONJ.

[Focus: Drug-related osteonecrosis of the jaw]. / Les médicaments inducteurs d'ostéchimionécroses des maxillaires.

Antiresorptives and antiangiogenics are treatments that have proven effective in oncology and the treatment of osteoporosis and they are increasingly prescribed. The care of these patients requires collaboration between the prescriber and the oral health professional to establish an optimized treatment plan. Therapeutic education of the patient is essential for him to understand the issues of good oral health and the adverse effects that can be caused by these treatments. The management is essentially based on the individual benefit/risk balance resulting from the general, local and inherent of the molecule risk factors. Management of drug-related osteonecrosis of the jaw should be as early as possible.

Osteonecrosis of the Jaw and Rebound Hypercalcemia in Young People Treated With Denosumab for Giant Cell Tumor of Bone.

Context: Denosumab, an inhibitor of receptor activator of nuclear factor κ-B ligand, is an approved treatment of giant cell tumor of bone (GCTB) in adults and "skeletally mature" adolescents. Safety concerns include oversuppression of bone remodelling, with risk of osteonecrosis of the jaw (ONJ) and atypical femur fractures during treatment in adults and rebound hypercalcemia after treatment cessation in children. To date, ONJ has never been reported in children or adolescents. Objectives: To describe serious adverse effects during and following high-dose denosumab therapy in GCTB patients. Patients: Two adolescents (14 and 15 years) and a young adult (40 years) received fixed-dose denosumab for GCTB for 1.3 to 4 years (cumulative dose, 47 to 98 mg/kg), which was stopped because of development of ONJ in one adolescent and bilateral femoral cortical stress reactions in the young adult. All three patients developed rebound hypercalcemia with acute kidney injury 5.5 to 7 months after denosumab cessation. Results: The ONJ necessitated surgical debridement. Rebound hypercalcemia (serum calcium, 3.1 to 4.3 mmol/L) was unresponsive to hyperhydration alone, requiring repeated doses of calcitonin or intravenous bisphosphonate treatment. Hypercalcemia recurred in two patients within 4 weeks, with normal serum calcium profiles thereafter. All patients were naive to chemotherapy, radiotherapy, bisphosphonates, and corticosteroids and were metastases free, confirming the causative role of denosumab in these complications. Conclusion: These suppression-release effects of high-dose denosumab on bone remodeling raise questions about safety of fixed dosing and treatment duration. In young people, weight-adjusted dosing and safety monitoring during and after antiresorptive therapy is required.

Clinical Differences in Autofluorescence Between Viable and Nonvital Bone: A Case Report With Histopathologic Evaluation Performed on Medication-Related Osteonecrosis of the Jaws.

Medication-related osteonecrosis of the jaws (MRONJ) is an adverse side effect of several drug therapies, including bisphosphonates (BPs). Osteonecrosis of the jaw specifically related to BP therapy is usually referred to using the acronym BRONJ. However, no consensus has yet been reached regarding the most appropriate management of BRONJ. The greatest success rates have been recorded with surgical removal of necrotic bone. In particular, erbium:yttrium-aluminum-garnet (Er:YAG) laser-assisted surgery has shown significantly better results than conventional surgical approaches. According to a position paper reported by the American Association of Oral and Maxillofacial Surgeons in 2007, the identification of necrotic bone margins during osteonecrosis removal can be very difficult. In 2015, a review of treatment perspectives for MRONJ reported that both surgical debridement and resection cannot be standardized owing to the lack of guidance to define the necrotic margins. Recently, the use of autofluorescence (AF) of the bone as a possible suitable guide to visualize necrotic bone during surgical debridement or resection was proposed. It seems that vital bone could be highlighted by its very strong AF. In contrast, necrotic bone loses AF and, thus, appears much darker. The molecular sources of the phenomenon of AF are the specific amino acids of the collagen molecules that show AF when irradiated by ultraviolet or blue light. The use of AF as an intraoperative diagnostic tool is entirely new in the management of MRONJ, although it has been used for several years in other fields (eg, intervertebral disc surgery). The aim of the present report was to describe a case of mandibular BRONJ treated with a new surgical approach performed with an Er:YAG laser and guided by AF. The histopathologic evaluation of the removed hypofluorescent bone block and hyperfluorescent surrounding bone has also been reported in detail.

Rheumatoid Arthritis Exacerbates the Severity of Osteonecrosis of the Jaws (ONJ) in Mice. A Randomized, Prospective, Controlled Animal Study.

Rheumatoid arthritis (RA), an autoimmune inflammatory disorder, results in persistent synovitis with severe bone and cartilage destruction. Bisphosphonates (BPs) are often utilized in RA patients to reduce bone destruction and manage osteoporosis. However, BPs, especially at high doses, are associated with osteonecrosis of the jaw (ONJ). Here, utilizing previously published ONJ animal models, we are exploring interactions between RA and ONJ incidence and severity. DBA1/J mice were divided into four groups: control, zoledronic acid (ZA), collagen-induced arthritis (CIA), and CIA-ZA. Animals were pretreated with vehicle or ZA. Bovine collagen II emulsified in Freund's adjuvant was injected to induce arthritis (CIA) and the mandibular molar crowns were drilled to induce periapical disease. Vehicle or ZA treatment continued for 8 weeks. ONJ indices were measured by micro-CT (µCT) and histological examination of maxillae and mandibles. Arthritis development was assessed by visual scoring of paw swelling, and by µCT and histology of interphalangeal and knee joints. Maxillae and mandibles of control and CIA mice showed bone loss, periodontal ligament (PDL) space widening, lamina dura loss, and cortex thinning. ZA prevented these changes in both ZA and CIA-ZA groups. Epithelial to alveolar crest distance was increased in the control and CIA mice. This distance was preserved in ZA and CIA-ZA animals. Empty osteocytic lacunae and areas of osteonecrosis were present in ZA and CIA-ZA but more extensively in CIA-ZA animals, indicating more severe ONJ. CIA and CIA-ZA groups developed severe arthritis in the paws and knees. Interphalangeal and knee joints of CIA mice showed advanced bone destruction with cortical erosions and trabecular bone loss, and ZA treatment reduced these effects. Importantly, no osteonecrosis was noted adjacent to areas of articular inflammation in CIA-ZA mice. Our data suggest that ONJ burden was more pronounced in ZA treated CIA mice and that RA could be a risk factor for ONJ development. © 2016 American Society for Bone and Mineral Research.

Histopathological features of bisphosphonates related osteonecrosis of the jaw in rats with and without vitamin d supplementation.

OBJECTIVE: Aim of this study was to investigate the effect of vitamin-D3 on the osteonecrosis of bone that was induced after tooth extraction was conducted on rats that were given zoledronic acid (Z.A). MATERIAL AND METHODS: Animals were divided into four groups. Two of the experimental groups were divided into two subgroups, third study group was not divided into subgroups, and control group was divided into three subgroups. Z.A was administered twice per week over the course of 7 weeks, dexamethasone was administered twice a week during the 5th-6th-7th weeks to all groups. Dental extraction was performed by drilling around the tooth at 7th week. In study-group-1; vitamin-D was administered twice per week during the 5th-6th-7th weeks. In study-group 2; vitamin-D was administered twice per week during the 8th-9th-10th weeks. In study-group-3; vitamin-D was administered twice per week during the 15th-16th-17th weeks. The animals were sacrificed at 10th-15th-17th weeks, and histologic samples were taken. RESULTS: Postoperative-15-group had a lower osteoblast number, which was statistically significant as compared to preoperative-15 and control-15-group. Control-10-group showed significantly lower osteoclast number in comparison to preoperative-10 and postoperative-10-group. Osteoclast number was significantly higher in the osteonecrosis-17-group as compared to control-17-group. Preoperative-10-group showed significantly higher inflammation in comparison to control-10-group. Postoperative-15-group had a lower histologic osteonecrosis, which was statistically significant as compared to the control-15-group. Macroscopic osteonecrosis was significantly higher in the control-17-group in comparison to the osteonecrosis-17-group. CONCLUSIONS: We concluded that there are some proofs for the treatment of BRONJ with systemic using of vitamin-D.

[Current approaches for early detection and treatment of medication-related osteonecrosis of jaw]. / Aktuális trendek a gyógyszer indukálta állcsontnecrosis korai felismerése és kezelési stratégiája terén.

Owing to the increased life expectancy, the incidence of rheumatoid disorders and oncologic cases with bone metastasis has dramatically increased. Despite the beneficial effects of the applied antiresorptive and antiangiogenic drugs (e.g. bisphosphonates), serious side effects such as jaw osteonecrosis may also develop. The aim of the authors was to summarize present knowledge about the possibilities of prevention and treatment in medication-related osteonecrosis of the jaw. Based on literature data, currently used detection methods for medication-related osteonecrosis of the jaw (including their advantages and limitations) are summarized. In addition, novel trends of surgical and adjuvant therapeutic approaches are also reviewed. The authors conclude that possibilities of prevention and efficacy of therapeutic interventions in this disorder are still limited possibly due to an incomplete knowledge of the underlying pathomechanism. An interdisciplinary cooperation for prevention and attentive monitoring in order to decrease the incidence of iatrogenic oral and maxillofacial complications seems to be particularly important.

Early surgical laser-assisted management of bisphosphonate-related osteonecrosis of the jaws (BRONJ): a retrospective analysis of 101 treated sites with long-term follow-up.

BACKGROUND DATA: The management of bisphosphonate-related osteonecrosis of the jaws (BRONJ) is still controversial. OBJECTIVE: The purpose of this study was to compare surgical and nonsurgical approaches to the treatment of BRONJ and the possible usefulness of Nd:YAG and Er:YAG lasers. METHODS: One hundred and twenty-eight patients (33 males, 95 females; 52 with diagnosis of multiple myeloma, 53 with diagnosis of bone metastasis, and 23 with diagnosis of osteoporosis) affected by BRONJ were evaluated at the Unit of Oral Pathology and Medicine and Laser-Assisted Surgery of the University of Parma, Italy, between January 2004 and July 2009. Overall number of BRONJ sites was 151, and number of treated sites was 101. In order to assess the efficacy of different treatments, sites were subclassified as follows: Group 1 (G1): 12 sites treated with medical therapy; Group 2 (G2): 27 sites treated with medical therapy associated with low level laser therapy (LLLT); Group 3 (G3): 17 sites treated with a combination of medical and surgical therapy; Group 4 (G4): 45 sites treated with a combination of medical therapy, surgical (including laser-assisted) therapy, and LLLT. Outcome of treatment was assessed using the staging system proposed by Ruggiero et al. Transition from a higher stage to a lower one for at least 6 months was considered as clinical improvement and suggestive of a successful treatment. RESULTS: Clinical improvement was achieved in 3 out of 12 (25%) BRONJ sites in G1. Sites if G2 with an improvement were 18 out of 27 (66%). Nine out 17 BRONJ sites (53%) in G3 had a transition to a lower stage after treatment. For sites in G4, a clinical improvement was recorded in 40 out of 45 cases (89%). CONCLUSIONS: In our experience, the percentage of success obtained with a combined approach based on medical therapy, surgical (including laser-assisted) therapy, and LLLT (G4) is significantly higher than the percentage of improvement obtained in G1, G2, and G3.

Bisphosphonate-related osteonecrosis: laser-assisted surgical treatment or conventional surgery?

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.