Cumulative incidence and risk factors for medication-related osteonecrosis of the jaw during long-term prostate cancer management.

Bone-modifying agents (BMA) are extensively used in treating patients with prostate cancer with bone metastases. However, this increases the risk of medication-related osteonecrosis of the jaw (MRONJ). The safety of long-term BMA administration in clinical practice remains unclear. We aimed to determine the cumulative incidence and risk factors of MRONJ. One hundred and seventy-nine patients with prostate cancer with bone metastases treated with BMA at our institution since 2008 were included in this study. Twenty-seven patients (15%) had MRONJ during the follow-up period (median, 19 months; interquartile range, 9-43 months). The 2-year, 5-year, and 10-year cumulative MRONJ incidence rates were 18%, 27%, and 61%, respectively. Multivariate analysis identified denosumab use as a risk factor for MRONJ, compared with zoledronic acid use (HR 4.64, 95% CI 1.93-11.1). Additionally, BMA use at longer than one-month intervals was associated with a lower risk of MRONJ (HR 0.08, 95% CI 0.01-0.64). Furthermore, six or more bone metastases (HR 3.65, 95% CI 1.13-11.7) and diabetes mellitus (HR 5.07, 95% CI 1.68-15.2) were risk factors for stage 2 or more severe MRONJ. MRONJ should be considered during long-term BMA administration in prostate cancer patients with bone metastases.

Local E-rhBMP-2/ß-TCP Application Rescues Osteocyte Dendritic Integrity and Reduces Microstructural Damage in Alveolar Bone Post-Extraction in MRONJ-like Mouse Model.

The pathology of medication-related osteonecrosis of the jaw (MRONJ), often associated with antiresorptive therapy, is still not fully understood. Osteocyte networks are known to play a critical role in maintaining bone homeostasis and repair, but the exact condition of these networks in MRONJ is unknown. On the other hand, the local application of E-coli-derived Recombinant Human Bone Morphogenetic Protein 2/ß-Tricalcium phosphate (E-rhBMP-2/ß-TCP) has been shown to promote bone regeneration and mitigate osteonecrosis in MRONJ-like mouse models, indicating its potential therapeutic application for the treatment of MRONJ. However, the detailed effect of BMP-2 treatment on restoring bone integrity, including its osteocyte network, in an MRONJ condition remains unclear. Therefore, in the present study, by applying a scanning electron microscope (SEM) analysis and a 3D osteocyte network reconstruction workflow on the alveolar bone surrounding the tooth extraction socket of an MRONJ-like mouse model, we examined the effectiveness of BMP-2/ß-TCP therapy on the alleviation of MRONJ-related bone necrosis with a particular focus on the osteocyte network and alveolar bone microstructure (microcrack accumulation). The 3D osteocyte dendritic analysis showed a significant decrease in osteocyte dendritic parameters along with a delay in bone remodeling in the MRONJ group compared to the healthy counterpart. The SEM analysis also revealed a notable increase in the number of microcracks in the alveolar bone surface in the MRONJ group compared to the healthy group. In contrast, all of those parameters were restored in the E-rhBMP-2/ß-TCP-treated group to levels that were almost similar to those in the healthy group. In summary, our study reveals that MRONJ induces osteocyte network degradation and microcrack accumulation, while application of E-rhBMP-2/ß-TCP can restore a compromised osteocyte network and abrogate microcrack accumulation in MRONJ.

Clinical status of established MRONJ in oncology patients continuing bone-modifying agents.

The continuation of bone-modifying agents (BMAs) in patients with established medication-related osteonecrosis of the jaw (MRONJ) is a common concern among dentists and oncologists. There is little evidence supporting or refuting the continued use of BMAs or drug holidays and their impact on established MRONJ. This paper evaluates the outcome of continued BMAs use on the patient's MRONJ status. A retrospective review of 29 oncology patients undergoing active cancer care for either metastatic disease or multiple myeloma was conducted. Data on demographics, oncological status, BMA history and MRONJ status were collected. In total, 90% of patients were judged to have healed or stable MRONJ while continuing BMAs. Most patients (69%) continued the same BMA regime (three- or four-weekly) that they were on before developing MRONJ. The average number of BMAs doses received after an MRONJ diagnosis was 12 (range 1-48). Three patients (10.3%) were found to have MRONJ progression, with two patients developing new sites of necrosis. This real-world dataset suggests that the majority of MRONJ cases remain stable and will not worsen with the continuation of BMAs.

Dental Implant Failure in Post-Menopausal Women on Oral Bisphosphonates: A Systematic Review and Meta-Analysis.

A systematic review was designed to investigate the effect of treatment with oral bisphosphonate (BP) on osseointegration of dental implants and the incidence of BP-related osteonecrosis of the jaw (BRONJ) in postmenopausal women. Multiple electronic databases, including MEDLINE (PubMed), EMBASE, and SCOPUS, were searched to find all eligible articles published since 1990. All titles and abstracts retrieved by searching information sources were evaluated independently by 2 authors against the eligibility criteria. The number of cases ranged from 11 to 235, and the number of controls ranged from 14 to 343. Alendronate was used in all other studies. Risedronate was used in 6 studies, while ibandronate was used in 4 studies. The number of implants in cases ranged from 25 to 1267, while in controls, the number of implants ranged from 28 to 1450. The time between the placement of implant and the follow-up visit ranged from 4-6 months to 8 years. The results show that out of 2582 placed implants, 50 (1.94%) failed in BP-treated patients. This is while out of 4050 placed implants, 188 (4.6%) failed in the non-BP group. The results from the meta-analysis demonstrated that BP therapy is significantly associated with increased implant failure rates (RR = 1.73 [95% CI, 1.03-2.83], P = .04). Overall, the qualitative assessment of this review suggests that oral treatment with BPs in postmenopausal women does not increase the rate of dental implant failure. Thus, further studies with larger sample sizes should compare BP and non-BP groups in regard to dental implants.

The trend of dental check-up and prevalence of dental complications following the use of bone modifying agents in patients with metastatic breast and prostate cancer: analysis of data from the Korean National Health Insurance Service.

BACKGROUND: Bone-modifying agents (BMA) are key components in the management of cancer patients with bone metastasis. Despite their clinical benefits, the use of BMA is associated with dental adverse events (AEs) including medication-related osteonecrosis of the jaw (MRONJ). This study investigated the frequency of dental surveillance before BMA treatment and the prevalence of dental AEs including MRONJ, after BMA treatment in patients with bone metastasis from breast and prostate cancer using data from the national health insurance system. METHODS: Data, including age, cancer diagnosis, administered BMA, and dental AEs during cancer treatment, of patients with bone metastasis from breast and prostate cancer who received at least one infusion of BMA between 2007 and 2019 were extracted from the Korean National Health Insurance Service (KNHIS) dataset. RESULTS: Of the 15,357 patients who received BMA, 1,706 patients (11.1%) underwent dental check-ups before BMA treatment. The proportion of patients receiving dental check-up increased from 4.4% in 2007 to 16.7% in 2019. Referral to dentists for a dental check-up was more active in clinics/primary hospitals than general/tertiary hospitals, and medical doctors and urologists actively consulted to dentists than general surgeons, regardless of the patient's health insurance status. After BMA treatment, 508 patients (3.8%) developed dental AEs, including abscess (42.9%), acute periodontitis (29.7%), acute pericoronitis (14.9%), and MRONJ (12.5% of dental AEs cases, 0.5% of total BMA treated patients). CONCLUSIONS: Considering the long treatment period in patients with metastatic cancer, coordination between dentists and oncologists is necessary to ensure appropriate dental management before the initiation of BMA.

Photobiomodulation Can Prevent Medication-Related Osteonecrosis of the Jaw Formation in Tooth Extraction Site of Rat Model.

Objective: This study aims to explore the preventive potential of photobiomodulation (PBM) in bisphosphonate-related osteonecrosis of the jaw (BRONJ) using a rat model. Methods: An experimental rat model was established, exposing rats to zoledronic acid (ZA), a primary risk factor for BRONJ. An 810 nm diode laser was applied with parameters of 0.33 W/cm2 power density and 10 J/cm2 energy density for 30 sec. PBM was initiated 1 day pre-extraction and continued for 2 weeks. The impact of PBM on wound healing in both soft and hard tissues was evaluated post tooth extraction. Results: ZA exposure hindered wound healing in both soft and hard tissues after tooth extraction. PBM intervention effectively mitigated the adverse effects of ZA, promoting healing processes in both tissue types. This suggests the potential of PBM as a preventive strategy for BRONJ in patients on long-term bisphosphonate treatment. Moreover, PBM exhibited enhanced wound healing in normal rats, indicating its broader applicability beyond BRONJ cases. Conclusions: PBM shows promise in preventing and improving wound healing in BRONJ and normal cases. These findings underscore the significance of optimizing PBM parameters and suggest its potential clinical relevance as a preventive intervention for BRONJ and a promoter of wound healing.

Polysacharide of Agaricus blazei gel mitigates bone necrosis in model of the jaws related to bisphosphonate via Wnt signaling.

To investigate de effect of PAb gel on the bone tissue of rats submitted to Bisphosphonate-related osteonecrosis of the jaws (BRONJ). Initially, 54 animals were submitted to BRONJ model by Zoledronic Acid (ZA) (0.1 mg/kg 3x/wk for 9 wk, ip), followed by the 1st upper left molar extraction at the 8th wk. After tooth removal, the animals were divided into 3 groups, ZA that received placebo gel or PAb gel that received 1% PAb gel, inside the dental alveolus. The control Group (CONTROL) received 0.1 mg/kg of 0.9% saline and then placebo gel. Three weeks after tooth extraction, the animals were euthanized, and maxillae were colleted for macroscopic, radiographic, histological and Raman spectomery assays. Additionally, GSK3b, beta-catenin, and Runx2 mRNA expressions were determined. Blood samples were collected for the analysis of Bone-specific alkaline phosphatase (BALP) levels. PAb gel improved mucosal healing, increased the number of viable osteocytes, while it reduced the number of empty lacunae, as well as the amount of bone sequestration. Furthermore, PAb gel positively influenced the number and functionality of osteoblasts by stimulating Wnt signaling, thereby inducing bone remodeling. Additionally, PAb gel contributed to improved bone quality, as evidenced by an increase in bone mineral content, a decrease in bone solubility, and an enhancement in the quality of collagen, particularly type I collagen. PAb gel mitigated bone necrosis by stimulating of bone remodeling through Wnt signaling and concurrently improved bone quality. PAb gel emerges as a promising pharmacological tool for aiding in BRONJ therapy or potentially preventing the development of BRONJ.

Radiological manifestations and clinical findings of patients with oncologic and osteoporotic medication-related osteonecrosis of the jaw.

Medication-related osteonecrosis of the jaw (MRONJ) poses a challenging form of osteomyelitis in patients undergoing antiresorptive therapies in contrast to conventional osteomyelitis. This study aimed to compare the clinical and radiological features of MRONJ between patients receiving low-dose medications for osteoporosis and those receiving high-dose medications for oncologic purposes. The clinical, panoramic radiographic, and computed tomography data of 159 patients with MRONJ (osteoporotic group, n = 120; oncologic group, n = 39) who developed the condition after using antiresorptive medications for the management of osteoporosis or bone malignancy were analyzed. The osteoporotic group was older (75.8 vs. 60.4 years, p < 0.01) and had a longer duration of medication usage than the oncologic group (58.1 vs. 28.0 months, p < 0.01). Pus discharge and swelling were more common in the osteoporotic group (p < 0.05), whereas bone exposure was more frequent in the oncologic group (p < 0.01). The mandibular cortical index (MCI) in panoramic radiographs was higher in the osteoporotic group (p < 0.01). The mean sequestra size was larger in the oncologic group than in the osteoporotic group (15.3 vs. 10.6 mm, p < 0.05). The cured rate was significantly higher in the osteoporotic group (66.3% vs. 33.3%, p < 0.01). Oncologic MRONJ exhibited distinct clinical findings including rapid disease onset, fewer purulent signs, and lower cure rates than osteoporotic MRONJ. Radiological features such as sequestrum size on CT scan, and MCI values on panoramic radiographs, may aid in differentiating MRONJ in osteoporotic and oncologic patients.

Medication-related osteonecrosis of the jaw in a paediatric patient taking denosumab: a case report.

Medication-related osteonecrosis of the jaw (MRONJ) is a known complication of antiresorptive and anti-angiogenic therapies in adults. Increasingly, these drugs are being prescribed for children with a variety of conditions, such as osteogenesis imperfecta and cancers of the bone. Review of the literature, however, reveals no reported paediatric MRONJ cases to date. We present such a case in a nine-year-old female patient with a vertebral aneurysmal bone cyst, who received dental extractions subsequent to denosumab therapy.

Medical and Dental Professions' Varying Levels of Awareness Regarding Medication-related Osteonecrosis of the Jaw in Saudi Arabia? A Cross-sectional Study.

AIMS: This study aimed to assess the awareness of the risk of medication-related osteonecrosis of the jaw (MRONJ) among general dental practitioners (GDPs) and primary care physicians (PCPs), focusing on the clinical implications and coordination of treating or identifying high-risk patients. MATERIALS AND METHODS: Two Google Forms electronic questionnaires were distributed to 724 GDPs and 617 PCPs in primary care settings. One for PCPs with eight multiple choice questions and the other for GDPs with 10 multiple choice questions. A clinical case scenario and a section on open-ended comments were included in both questionnaires. The data obtained from each group were statistically analyzed and compared. RESULTS: A total of 239 GDPs and 220 PCPs participated in the study, with a response rate of 34.23%. The mean age of participants was 29.5 years and 54.35% were females (51.2% and 57.5% in the GDPs and PCPs group, respectively). Most participants had graduated from Saudi Arabia. Almost all dentists were aware of osteonecrosis of the jaw (95.1%), 68.3% of them were aware of the guidelines regarding bisphosphonate-related osteonecrosis of the jaw (BRONJ) and MRONJ, 60.5% rated their general knowledge about MRONJ as very poor to poor, and 91.8% did not know any guidelines regarding BRONJ or MRONJ. Among the participants, 75.3% did not know how MRONJ was present in the oral cavity. A total of 69.9% of participants were unaware of other factors associated with an increased risk of MRONJ. CONCLUSION: MRONJ risk awareness varies greatly between dentists who diagnose and manage patients in dental clinics and physicians who write about medicines and therapies. Counseling sessions and greater coordination between dental and medical specialists are strongly suggested while prescribing antiresorptive drugs to prevent the consequent development of MRONJ. CLINICAL SIGNIFICANCE: This study shows a significant lack of knowledge regarding MRONJ among GDPs and PCPs, which may affect the prevention and treatment of patients. Therefore, we urge GDPS and PCPs to take more information from scientific sources on this topic and more cooperation from specialties for the benefit of patients. How to cite this article: Aljohani MH, Aljohani AS, Aljohani RM, et al. Medical and Dental Professions' Varying Levels of Awareness Regarding Medication-related Osteonecrosis of the Jaw in Saudi Arabia? A Cross-sectional Study. J Contemp Dent Pract 2024;25(1):62-67.

Investigation of clindamycin concentrations in human plasma and jawbone tissue in patients with osteonecrosis of the jaw: A prospective trial.

The aim of this study was to investigate the jawbone concentration of clindamycin (CLI) in patients with an osteonecrosis of the jaw (ONJ). Patients with medication-related ONJ (MRONJ) and osteoradionecrosis (ORN) with an antibiotic treatment with CLI were included. Plasma, vital and necrotic bone samples were collected. Plasma and jawbone samples were analyzed by liquid chromatography-tandem mass spectrometry. Patients with MRONJ exhibited a mean plasma CLI concentration of 9.6 µg/mL (SD ± 3.6 µg/mL) and mean concentrations of 2.3 µg/g CLI (SD ± 1.4 µg/g) and 2.1 µg/g CLI (SD ± 2.4 µg/g) in vital and necrotic bone samples, without statistical significance (p = 0.79). In patients with ORN, mean concentration in plasma was 12.0 µg/mL (SD ± 2.6 µg/mL), in vital bone 2.1 µg/g (SD ± 1.5 µg/g), and in necrotic bone 1.7 µg/g (SD ± 1.2 µg/g). Vital and necrotic bone concentrations did not differ significantly (p = 0.88). The results demonstrate that CLI concentrations are considerably lower than in plasma, but sufficient for most bacteria present in ONJ. Within the limitations of the study, it seems that CLI is a relevant alternative to other antibiotics in the treatment of ONJ because it reaches adequate concentrations in jawbone.

[Application of double-layer soft tissue suture closure technique in the surgical treatment of patients with mandible medication-related osteonecrosis of the jaw of early and medium stages].

OBJECTIVE: To investigate the clinical application effect of double-layer soft tissue (DLST) suture closure technique in patients with mandible medication-related osteonecrosis of the jaw (MRONJ) of early and medium stages resulted in application of anti-bone-resorptive drugs. METHODS: Early to medium stage mandible MRONJ patients who underwent surgical treatment in the fourth ward of Peking University School and Hospital of Stomatology from October 2021 to September 2022 were included. Clinical information of the patients were collected, including primary disease, concomitant disease, medication regimen (drug type, duration of medication), MRONJ stage, clinical symptoms, imaging manifestations, etc. During surgery, after using marginal mandibulae resection to remove the necrotic bone, the wound was closed using DLST closure technique. Regular post-operative follow-up was performed to evaluate the therapeutic effect and complications of the DLST technique, the pain score and functional status of the patiens were evaluated. RESULTS: This study totally included 13 patients, 12 women and 1 man, aged (66.69±13.14) years. Seven patients had osteoporosis, 2 had lung cancer, 3 had breast cancer and 1 had prostate cancer among their primary diseases; 7 had no concomitant diseases, 2 had diabetes mellitus, 2 had cardiovascular disease and 1 had dry syndrome. Intravenous zoledronic acid were used in 9 patients, the average duration was (37.7±20.0) months, and other drugs, such as letrozole tablets were taken in 7 patients at the same time; Denosumab injection was used in 3 patients for an average of (10.3±11.9) months; Alendronate sodium tablets were taken in 5 patients for an average of (55.20±27.20) months, and prednisone acetate tablets or acarbose tablets were taken to varying degrees in 2 patients. The average post-operative follow-up was 11.9 months (9 to 17 months), and all the 13 patients were cured without complications, such as pus overflow and so forth. The pre-operative score of Karnofsky performance status (KPS) in the patients was 68.46±14.05, and the post-operative score was 82.31±15.36, and the difference was statistically significant (P < 0.05). The pre-operative score of visual analogue scale (VAS) in the patients was 5.77±0.73 and the post-operative score was 0.38±0.51, and the difference had statistical significance (P < 0.001). CONCLUSION: The double-layer soft tissue suture closure technique can achieve good clinical results in patients with MRONJ of the mandible using anti-bone-resorptive drugs alone, and can provide clinical treatment ideas for MRONJ patients with more complicated drug use.

Etiopathogenesis of medication-related osteonecrosis of the jaws: a review.

This study compiles the main hypotheses involved in the etiopathogenesis of medication-related osteonecrosis of the jaw (MRONJ). A narrative review of the literature was performed. The etiopathogenesis of MRONJ is multifactorial and not fully understood. The main hypothesis considers the disturbance of bone turnover caused by anti-resorptive drugs. Bisphosphonates and denosumab inhibit osteoclast activity through different action mechanisms, accumulating bone microfracture. Other hypotheses also consider oral infection and inflammation, the antiangiogenic effect and soft tissue toxicity of bisphosphonates, and the inhibition of lymphangiogenesis. Knowledge of the current theories for MRONJ is necessary to define future studies and protocols to minimize the incidence of this severe condition.

Treatment of Medication-Related Osteonecrosis of the Jaws without Segmental Resections: A Case Series.

BACKGROUND Medication-related osteonecrosis of the jaw (MRONJ) is a rare but serious reaction to anti-resorptive drugs (ARDs) in patients treated for osteoporosis and conditions related to cancer. Treatment for MRONJ consists of the use of non-operative therapies according to the evolution of the disease, which consist of the use of antimicrobial mouthwashes, systemic antibiotics, and operative therapies, such as debridement of necrotic bone, marginal or segmental resection, and bone reconstruction of the jaws in more advanced stages of the disease. CASE REPORT This is a case series of 11 female patients treated for MRONJ, with a mean age of 76.5 years. Patients with malignant diseases of the jaws or those undergoing head and neck radiotherapy were excluded. Nine patients were medicated for osteoporosis with oral bisphosphonates and denosumab, and 2 patients used zoledronate to treat metastatic breast cancer. MRONJ prevailed in the mandible, most patients were classified as stage 2, and the most frequent triggers were tooth extraction and prosthetic trauma. All patients initially underwent non-operative therapies and were operated according to MRONJ stage, but none required segmental resection. Adjuvant treatments were used in 5 patients, and mean treatment and follow-up periods were 5 and 18.3 months, respectively. There was complete resolution of disease in all patients, with only 1 relapse. CONCLUSIONS This case series suggests that it is possible to treat MRONJ with conservative therapies in the early stages of the disease and minimally invasive surgeries in more advanced stages of the disease, thus avoiding segmental jaw resections.

Physicians' awareness of medication-related osteonecrosis of the jaw in patients with osteoporosis.

A serious adverse effect of antiresorptive drugs, which are widely used to treat osteoporosis, is medication-related osteonecrosis of the jaw (MRONJ). Physicians can reduce the risk of MRONJ by educating patients and emphasizing the importance of good oral health. However, limited information is available regarding physicians' awareness and clinical practices associated with MRONJ. Hence, this study aimed to examine physicians' awareness related to MRONJ and associated clinical practices. This study was a cross-sectional study conducted from December 2022 to February 2023. An online self-administered questionnaire was sent to physicians in Thailand who prescribed antiresorptive drugs for osteoporosis. Most respondents agreed that antiresorptive drugs might cause MRONJ (92.3%), poor oral health increased the risk of MRONJ (84%), and MRONJ is an important consideration in patients with osteoporosis (85%). Of the respondents, 48.1% and 15.5% always referred patients to dentists before and during antiresorptive therapy, respectively. Approximately 60% of physicians informed patients of the MRONJ risk before prescribing antiresorptive drugs, and 30% inquired about patients' oral symptoms at the follow-up visit. Overall, 44% of physicians advised patients to receive oral health care; the most common reason for not advising this was that respondents did not consider themselves to be adequately knowledgeable to detect oral health problems. These findings indicate that while most physicians who prescribed antiresorptive drugs for osteoporosis were aware of and considered MRONJ in their practice, several took insufficient action to prevent it. This highlights the need to emphasize clinical practice guidelines and collaboration between physicians and dentists.

The role of leukocyte and platelet-rich fibrin in the prevention of medication-related osteonecrosis of the jaw, in patients requiring dental extractions: an observational study.

PURPOSE: Medication-related osteonecrosis of the jaw (MRONJ) is a significant complication which can present following a dental extraction in patients receiving anti-resorptive and anti-angiogenic medications. The purpose of this study was to investigate the possible beneficial effect of L-PRF in the prevention of MRONJ in patients receiving these medications and requiring dental extractions. METHODS: Thirty-nine patients were included and divided into two groups, depending on whether L-PRF was used after the required dental extraction or not. Subsequently, the patients were categorised into low and high-risk for developing MRONJ, as recommended by the SDCEP guidance. RESULTS: None of the patients in the L-PRF group returned with established MRONJ. Five high-risk patients in the control group presented with established MRONJ in the follow-up appointment. A significant statistical difference (p = 0.04) was observed following a comparison of the high-risk patients of the two groups. CONCLUSION: These encouraging results suggest that L-PRF may be useful in the prevention of MRONJ following a dental extraction especially in patients of the higher risk category. A protocol for the management of this type of patients is also introduced.

Spontaneous Recovery of Pathological Fracture Caused by Medication-Related Osteonecrosis of the Jaw.

Pathological fracture is one of the most serious complications in medication-related osteonecrosis of the jaw (MRONJ). This case is a report of an 87-year-old woman who had been diagnosed with pathological fracture due to MRONJ. The authors performed minimally invasive and conservative treatment, such as intraoral dressing, antibiotic therapy, and simple debridement, for patients with pathologic fractures due to MRONJ. After 1 year, the inflammatory symptoms disappeared and pathological fractures spontaneously recovered.