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The aim of this systematic review was to establish the current status of the subject and find out what scientific evidence we have on the use of autologous plasma concentrates (APCs) and mesenchymal stem cells (MSCs) as complementary therapies at the management of Medication-related Osteonecrosis of the jaw (MRONJ). We performed a literature search of articles published between December 2019 to January 2020 in electronic databases, in accordance to PRISMA system. The variables analyzed were: the number of patients, age, sex, medical history, origin of MRONJ, imaging studies, treatment performed, and evolution of MRONJ. The articles included in the review were grouped into two groups (Group A "Therapy with APCs" and Group B "Therapy with APCs and MSCs"). Newcastle-Ottawa scale (NOS) was used to assess the quality of the articles. Fisher's exact test was used to evaluate eventual differences between groups. Of the 306 patients who were included, 297 belonged to Group A and 9 to Group B. In our sample, women predominated against men and no significant differences in age were observed. Osteoporosis was the most frequent underlying disease in both groups. The most common origin of MRONJ was oral surgery in group A. Conservative surgery was performed in all patients, but complementary treatment was applied in different ways in each group. The resolution of the pathology was achieved in 90% of cases in both groups without significant differences between them. The mean score of the reviewed studies at NOS was 4. There are currently no published scientific data that can sufficiently support the use of APCs and MSCs for the treatment of established MRONJs.

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PURPOSE: The aim of this study was to review the characteristics of 'implant presence-triggered osteonecrosis' (IPTO) in the literature and identify possible differences between IPTOs and 'implant surgery-triggered osteonecrosis' (ISTO). MATERIALS AND METHODS: Reviews using PubMed and the Cochrane Database of Systematic Reviews were performed from 2009-2018; the focus was on medication-related osteonecrosis of the jaw (MRONJ) and dental implants. In addition, the hospital records of all patients presented in our department with IPTO were retrospectively reviewed. In both studies, the following data were collected: the number of patients with ISTO or IPTO, age, gender, location, stage of MRONJ, number of implants involved in MRONJ, the elapsed time between the placement of the implants and the development of MRONJ, applied treatment and the presence of mandibular fractures and progress. RESULTS: The literature review provided 111 articles. Nine of the articles were selected for bibliographic review. The number of osteonecrosis cases was significantly higher in the IPTO group (74 cases) compared with the ISTO group (27 cases). The duration of the anti-resorptive treatment (oral and intravenous) was also longer in the IPTO group. In our centre, seven patients with IPTO were chosen; however, no patients with ISTO were selected. The significant differences between the patients in our series and the information collected in the literature for the IPTO group were the time of ingestion of alendronate, the elapsed time from the placement of the implants to the development of the MRONJ and the number of implants linked to the development of a complication. CONCLUSIONS: The use of antiresorptives causes osteonecrosis in patients with implants that are subjected to functional loading, and this occurs at a higher frequency than what is observed after implant placement surgery.

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The definition, pathobiology and risk factors of ONJ in cancer patients who receive BTAs are discussed in the recent ecancer module for osteonecrosis of the jaw (http://ecancer.org/education/module/276-osteonecrosis-of-the-jaw.php). ONJ prevention, early diagnosis and management are presented. The critical question of the performance of dental extraction, during BTA therapy, as indicated with the recent studies, is supported. The importance of the collaboration between dental and oncology professionals and the patients is highlighted and can be achieved through appropriate education. The ecancer modules are valuable tools for successful e-learning in medical oncology education, including ONJ.

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INTRODUCTION: Osteonecrosis of the jaw (ONJ) is a clinically important, potentially painful and debilitating condition, which can affect the quality of life of cancer patients. Since 2003, ONJ appeared as a Bisphosphonate(BP)-related class effect, and the term Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ) was widespread. AREAS COVERED: Under discussion in this review is the fact that ONJ cases have been reported after treatment including antiangiogenic agents and other "targeted therapy", with and without BPs. Consequently, the comprehensive term Medication-Related Osteonecrosis of the Jaw (MRONJ) has been introduced. The clinical aspects and the prognosis of ONJ associated with these new drugs are still less reported, but basing on their pharmacodynamics, they could be different from the well-known BRONJ. Accordingly, recommendations largely in use for BRONJ should be extended to these new forms, but critically applied and with respect to the individual risk assessment. EXPERT OPINION: There is a high risk of underdiagnoses for ONJ due to a lack of awareness, and too much restrictive or incomplete diagnostic criteria; at the same time, with regard to ONJ associated to the new non -antiresorptive agents, described here, we observe the strong need to improve the defining of any distinguished feature in their diagnosis, prevention and therapy.

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For patients at risk of osteonecrosis of the jaw (ONJ), information can be provided by the pharmaceutical manufacturer, pharmacist, prescribing physician, dentist, and oral and maxillofacial surgeon. Prevention strategies to reduce the incidence of osteonecrosis should be applied as soon as it is determined that a patient will be placed on antiresorptive medication. Proper screening involves a comprehensive oral examination with radiographs followed by oral hygiene instruction and necessary dental treatment; surgical techniques and adjunctive therapies that favor optimum healing of bone and soft tissue decrease the risk of ONJ. No dental procedures are absolutely contraindicated.

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Osteonecrosis of the jaws (ONJ) is a significant complication of antiresorptive medications, such as bisphosphonates and denosumab. Antiresorptive discontinuation to promote healing of ONJ lesions remains highly controversial and understudied. Here, we investigated whether antiresorptive discontinuation alters ONJ features in mice, employing the potent bisphosphonate zoledronic acid (ZA) or the receptor activator of NF-κB ligand (RANKL) inhibitor OPG-Fc, utilizing previously published ONJ animal models. Mice were treated with vehicle (veh), ZA, or OPG-Fc for 11 weeks to induce ONJ, and antiresorptives were discontinued for 6 or 10 weeks. Maxillae and mandibles were examined by µCT imaging and histologically. ONJ features in ZA and OPG-Fc groups included periosteal bone deposition, empty osteocyte lacunae, osteonecrotic areas, and bone exposure, each of which substantially resolved 10 weeks after discontinuing OPG-Fc but not ZA. Full recovery of tartrate-resistant acid phosphatase-positive (TRAP+) osteoclast numbers occurred after discontinuing OPG-Fc but not ZA. Our data provide the first experimental evidence demonstrating that discontinuation of a RANKL inhibitor, but not a bisphosphonate, reverses features of osteonecrosis in mice. It remains unclear whether antiresorptive discontinuation increases the risk of skeletal-related events in patients with bone metastases or fracture risk in osteoporosis patients, but these preclinical data may nonetheless help to inform discussions on the rationale for a "drug holiday" in managing the ONJ patient.

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BACKGROUND: Most patients with advanced prostate cancer (PCa) develop bone metastases (BM) and present with bone complications like fracture. Bone-targeted agents that prevent metastasis-induced bone complications can cause adverse events. Understanding how patients view treatment options may optimize care. This study aimed to quantify how PCa patients value a hypothetical treatment that delays BM but can cause osteonecrosis of the jaw (ONJ). The study also assessed the value patients place on avoiding metastasis-induced bone complications versus increased survival. METHODS: PCa patients from the United Kingdom (n = 201) and Sweden (n = 200) on androgen-deprivation therapy or hormone therapy for ≥ 3 years completed a 10-question discrete-choice-experiment survey examining whether patients would accept a BM-delaying treatment. Two time-tradeoff questions assessed patients' willingness to tradeoff between survival and bone complications. Percentages of patients choosing treatment were summarized by levels of treatment efficacy and ONJ risk. Odds ratios from a logit model were used to evaluate how patient and medication characteristics affected treatment choice. Proportions of patients choosing each tradeoff scenario were calculated. RESULTS: A majority of patients accepted treatment at the lowest benefit level (5-month BM delay) and highest risk level (9% ONJ risk). PCa symptoms and prior treatment affected patient preferences. Nearly 80% of patients would tradeoff at least 3 months of survival to avoid bone complications. CONCLUSIONS: PCa patients in the U.K and Sweden may value a medication that delays BM, despite the risk of ONJ. Furthermore, patients were willing to tradeoff up to 5 months of survival for prevention of bone complications.

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Osteonecrosis of the jaw (ONJ) has been recently described after intravenous administration of amino-bisphosphonates and - less frequently - in association with the use of oral bisphosphonates. Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ) may affect mandible bone (65%), maxilla bone (26%) and rarely (9%) both sites simultaneously. Although causality may never be proven, emerging experimental data have established a strong association between monthly intravenous bisphosphonate administration and ONJ. Current level of evidence does not fully support a cause and effect relationship between the use of oral BPs and ONJ. In this paper, we report a clinical case of BRONJ in a 73 years old woman affected by rheumatoid arthritis (RA) and periodontitis, after three years of treatment with alendronate 70 mg one a week, plus daily calcium and vitamin D. The patient developed a tooth abscess at the lower jaw, accompanied by increased inflammatory markers, that never returned to normal range despite antibiotic therapy, inducing deterioration of joint synovium. The worsening of joint status after the onset of ONJ was reflected by the progressive increase in the number of swollen (SJ) and tender (TJ) joints, by the deterioration of the score DAS 28 (which passed from 5.46 to 7.07), pain (with VAS increasing from 60 to 90), and by a progressively impaired quality of life, as reported using the HAQ score (from 1,25 to 2,5). The patient was switched to antifracture therapy with strontium ranelate and the osteonecrosis was successfully treated with antibiotics, surgical curettage and local ultrasounds.

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AIM: This study investigates the association between cross linked C-terminal telopetide test (CTX) and individual surgical risk of osteonecrosis in patients taking oral bisphosphonates. MATERIALS AND METHODS: 32 patients receiving bisphosphonate were treated surgically. Patients were divided into three groups according to type of drug administrated and were subjected to a treatment of oral surgery, such as simple tooth extractions and extraction of all residual teeth of the oral cavity, upon evaluation of CTX values and antibiotic prophylaxis. RESULTS: Within the sample of 32 patients, 12 patients had been treated with bisphosphonates for several years and none developed osteonecrosis of the jaw upon surgery. As for CTX, patients treated with oral bisphosphonates showed a mean value of serum Ctelopetides of 0.2869 ng/ml. The mean value of CTX did not differ significantly between patients taking oral bisphosphonates and healthy patients not treated with bisphosphonates. CONCLUSION: None of the patients subjected to preoperative antibiotic prophylaxis developed osteonecrosis of the jaw after surgery. The pharmacological and surgical protocol tested appeared valid in the prevention of osteonecrosis associated to bisphosphonates.

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Osteonecrosis of the Jaw (ONJ) is an adverse event reported especially in patients receiving cancer treatments regimen, bisphosphonates (BPs), and denosumab. We performed an open-label, prospective study in patients treated with zoledronic acid who developed ONJ lesions >2.5 cm, and had no benefit after the treatment with the standard therapy, to evaluate the efficacy and tolerability of medical ozone (O3) treatment delivered as gas insufflations on each ONJ lesions. Twenty-four patients (mean age 62.5, range 41-80; 12 female) with bone metastases due to breast (11), prostate (4)and lung (4)cancers, myeloma (2), or osteoporosis (3), previously treated with zoledronic acid and not underwent dental preventive measures and with ONJ lesions >2.5 cm, were observed and treated with topical O3 gas insufflation every third day for a minimum of 10 for each pathological area or till necrotic bone sequestrum or surgery. We used a special insufflation bell-shaped device adjusted to the specific characteristics of the patient, capable of eliminating any residue of O3 diffusion by degrading it and releasing O2 into the air. Azithromicin 500 mg/day was administered for 10 days in all patients before the first three gas insufflation although they had previously received various cycles of antibiotics. Ten patients required more than 10 O3 gas insufflations due to multiple lesions and/or purulent sovrainfections; one patient received two further O3 insufflations while waiting the day of surgery. Six of 24 patients interrupted the O3 gas therapy for oncological disease progression (five patients) and for fear of an experimental therapy (one patient). Six patients had the sequestrum and complete or partial (one patient) spontaneous expulsion of the necrotic bone followed by oral mucosa re-epithelization after a range of 4-27 of O3 gas insufflations. No patient reported adverse events. In 12 patients with the largest and deeper ONJ lesions, O3 gas therapy produced the sequestrum of the necrotic bone after 10 to 38 insufflations; surgery was necessary to remove it (11 patients). Of interest, removal was possible without the resection of healthy mandible edge because of the presence of bone sequestrum. All together the response rate was 75.0% (95% CI, 53.3-90.2%) in ITT analysis and 100% (95% CI, 81.5-100%) in the PP analysis. In all patients treated with O3 gas ± surgery, no ONJ relapse appeared (follow-up mean 18 months, range 1-3 years). Medical O3 gas insufflations is an effective and safe treatment for patients treated with BPs who developed ONJ lesions >2.5 cm. Short abstract: ONJ is an adverse event reported in patients receiving cancer treatments regimen, bisphosphonates and denosumab. We performed an open-label, prospective study in 24 patients with solid tumours, myeloma or osteoporosis due to hormonal therapy, treated with zoledronic acid without previuos preventive dental screening, who developed ONJ lesions >2.5 cm, and had no benefit after standard therapy, to evaluate the efficacy and tolerability of medical ozone (O3) treatment delivered as gas insufflations on each ONJ lesions. The patients were treated with O3 every third day for a minimum of 10 for each pathological area or till necrotic bone sequestrum or surgery. Eleven patients required more than ten O3 gas insufflations. Six of 24 patients interrupted the therapy for oncological disease progression. Six patients had the sequestrum and complete or partial (one patient) spontaneous expulsion of the necrotic bone followed by oral mucosa re-epithelization after a range of 4 to 27 of O3 gas insufflations. No patient reported adverse events. In 12 patients with the largest and deeper ONJ lesions, O3 gas therapy produced the sequestrum of the necrotic bone after 10 to 38 insufflations; surgery was necessary to remove it (11 patients). Of interest, removal was possible without the resection of healthy mandible edge because of the presence of bone sequestrum. All together the response rate was 75.0% (95% CI, 53.3-90.2%) in ITT analysis and 100% (95% CI, 81.5-100%) in the PP analysis. In all patients treated with O3 gas ± surgery, no ONJ relapse appeared (follow-up mean 18 months, range 1-3 years).