Macrophage Involvement in Medication-Related Osteonecrosis of the Jaw (MRONJ): A Comprehensive, Short Review

Antiresorptive agents such as bisphosphonates (BP) and denosumab are commonly prescribed for the management of primary bone malignancy, bone metastasis, osteoporosis, Paget disease, or other bone disorders. Medication-related osteonecrosis of the Jaws (MRONJ) is a rare but significant complication of antiresorptive medications. Duration, dose, and antiresorptive potency as well as concomitant diseases, additional medications, and local factors affect MRONJ incidence and severity. MRONJ pathophysiology is still poorly understood. Nevertheless, decreased bone resorption due to osteoclastic inhibition along with trauma, infection/inflammation, or blood supply inhibition are considered synergistic factors for disease development. In addition, previous data research examined the effects of antiresorptive medication on immune system components and introduced potential alterations on immune response as novel elements in MRONJ pathogenesis. Considering that macrophages are the first cells in the nonspecific immune response, it is not surprising that these multifaceted players attracted increased attention in MRONJ research recently. This current review attempted to elucidate the effects of antiresorptive medications on several aspects of macrophage activity in relation to the complex inflammatory microenvironment of MRONJ. Collectively, unravelling the mode of action and extent of macrophages’ potential contribution in MRONJ occurrence will provide novel insight in disease pathogenesis and potentially identify intrinsic therapeutic targets.

Differentially Expressed Genes Reveal the Biomarkers and Molecular Mechanism of Osteonecrosis

Osteonecrosis is one of the most refractory orthopedic diseases, which seriously threatens the health of old patients. High-throughput sequencing (HTS) and microarray analysis have confirmed as an effective way for investigating the pathological mechanism of disease. In this study, GSE7716, GSE74089, and GSE123568 were obtained from Gene Expression Omnibus (GEO) database and used to identify differentially expressed genes (DEGs) by R language. Subsequently, the DEGs were analyzed with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. Moreover, the protein-protein interaction (PPI) network of DEGs was analyzed by STRING database and Cytoscape. The results showed that 318 downregulated genes and 58 upregulated genes were observed in GSE7116; 690 downregulated genes and 1148 upregulated genes were screened from 34183 genes in GSE74089. The DEGs involved in progression of osteonecrosis involved inflammation, immunological rejection, and bacterial infection-related pathways. The GO enrichment showed that osteonecrosis was related with extracellular matrix, external encapsulating structure organization, skeletal system development, immune response activity, cell apoptosis, mononuclear cell differentiation, and serine/threonine kinase activity. Moreover, PPI network showed that the progression of osteonecrosis of the femoral head was related with CCND1, CDH1, ESR1, SPP1, LOX, JUN, ITGA, ABL1, and VEGF, and osteonecrosis of the jaw is related with ACTB, CXCR4, PTPRC, IL1B, CXCL8, TNF, JUN, PTGS2, FOS, and RHOA. In conclusion, this study identified the hub factors and pathways which might play important roles in progression of osteonecrosis and could be used as potential biomarkers for diagnosis and treatment of osteonecrosis.

Osteonecrosis development by tooth extraction in zoledronate treated mice is inhibited by active vitamin D analogues, anti-inflammatory agents or antibiotics

Invasive dental treatment such as tooth extraction following treatment with strong anti-bone resorptive agents, including bisphosphonates and denosumab, reportedly promotes osteonecrosis of the jaw (ONJ) at the extraction site, but strategies to prevent ONJ remain unclear. Here we show that in mice, administration of either active vitamin D analogues, antibiotics or anti-inflammatory agents can prevent ONJ development induced by tooth extraction during treatment with the bisphosphonate zoledronate. Specifically, tooth extraction during treatment with zoledronate induced osteonecrosis in mice, but administration of either 1,25(OH)2D3 or ED71, both active vitamin D analogues, significantly antagonized osteonecrosis development, even under continuous zoledronate treatment. 1,25(OH)2D3 or ED71 administration also significantly inhibited osteocyte apoptosis induced by tooth extraction and bisphosphonate treatment. Administration of either active vitamin D analogue significantly inhibited elevation of serum inflammatory cytokine levels in mice in response to injection of lipopolysaccharide, an infection mimetic. Furthermore, administration of either anti-inflammatory or antibiotic reagents significantly blocked ONJ development following tooth extraction and zoledronate treatment. These findings suggest that administration of active vitamin D, anti-inflammatory agents or antibiotics could prevent ONJ development induced by tooth extraction in patients treated with zoledronate.

Dental Awareness and Barriers in Reducing the Risk of Medication-related Osteonecrosis of the Jaw (MRONJ) Among Non-head and Neck Cancer Patients

Objectives. The objectives of this study are to assess the dental awareness in reducing the risk of Medication-Related Osteonecrosis of the Jaw (MRONJ) among non-head and neck cancer patients and their barriers of attending pre-medication dental evaluation (PMDE). Methodology: This study was conducted in the Department of Oncology of the University of Malaya Medical Centre. Non-head and neck cancer patients who are currently or will be undergoing anti-resorptive and/or anti-angiogenic therapy were interviewed using a questionnaire that consist of questions on patient’s awareness, attitude, and barriers of receiving PMDE. Ethics approval was obtained. Results. In total, 17 patients were interviewed. Only 6 patients were informed by the medical doctors about the risk of MRONJ. Nine patients were advised by the medical doctors to have the PMDE prior to the therapy, and most of them in this group follow the instruction and already had their PMDE done prior to the therapy. The other 8 patients, who did not attend a PMDE, thought it was not important because their medical doctors neither inform them about MRONJ, nor refer them for PMDE. Conclusion. Patients’ awareness of MRONJ risks and preventive strategies are poor. The main barrier for PMDE is the lack of referral and information on MRONJ from the medical doctors. Patients’ attitudes were positive towards PMDE if they were referred by the medical doctors.

Denosumab-Induced Medication-Related Osteonecrosis of the Jaw (DRONJ): A 5-Year Retrospective Cohort Study

Denosumab (Dmab) has been suggested as a first-line therapy for osteoporotic patients. However, a standardized protocol for the prevention of Dmab induced medication-related osteonecrosis of the jaw (MRONJ) has not yet been established. Thus, we investigated the factors that can affect Dmab induced MRONJ (DRONJ) to elucidate the relationship between invasive dental treatment and Dmab administration in patients who underwent Dmab and invasive dental treatment (especially tooth extraction) between October 2016 and March 2020. Four of the 98 patients developed MRONJ before and after tooth extraction. Two out of 4 patients developed MRONJ regardless of invasive treatment after Dmab administration and proceeded with extraction, and one patient developed DRONJ after Dmab administration and extraction. The other patient underwent a tooth extraction without osteoporosis treatment, and spontaneous DRONJ developed after Dmab administration. All MRONJ/DRONJ cases reported in this study show that MRONJ/DRONJ can develop as chronic inflammation without invasive dental treatment, therefore, implementing preventive dental treatment before initiating Dmab treatment is necessary to reduce the likelihood of DRONJ.