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.

Osteonecrosis of the jaw and antiresorptive agents in benign and malignant diseases: a critical review organized by ECTS

Context Antiresorptive therapy significantly reduces fracture risk in patients with benign bone disease and skeletal-related events (SREs) in patients with bone metastases. Osteonecrosis of the jaw (ONJ) is a rare, but severe condition, manifested as necrotic bone lesion(-s) of the jaws. ONJ has been linked to the use of potent antiresorptive agents, termed as Medication Related ONJ (MRONJ). Methods A working group of the European Calcified Tissue Society (ECTS) and two experts performed an updated detailed review of existing literature on MRONJ incidence, characteristics, and treatment applied in bone diseases with variable severity of skeletal insult, ranging from osteoporosis to prevention of cancer treatment-induced bone loss and SREs in cancer patients with bone metastases. We aimed to identify the differences in various aspects of MRONJ among these distinct patient categories and provide recommendations on how to mitigate the risk and optimally manage MRONJ in each one of them. Results The risk for MRONJ is much higher in patients with advanced malignancies compared to those with benign bone diseases, because of the higher doses and more frequent administration of antiresorptive agents in individuals with compromised general health, along with co-administration of other medications that predispose to MRONJ. The overall risk for MRONJ is considerably lower than the benefits in all categories of patients. Conclusions The risk for MRONJ largely depends on the underlying bone disease and the relevant antiresorptive regimen applied. Physicians and dentists should keep in mind that the benefits of antiresorptive therapy far outweigh the risk for MRONJ development.

Impact of Antiresorptive Agents on Maxillary Bones: a Narrative Literature Review

Antiresorptive drugs operate in the bone metabolism modulation and are widely used in the treatment of bone metastases and bone losses related to hormonal deficiency. Although this therapy shows satisfactory results, there are adverse effects associated with its use, such as osteonecrosis of the jaws. Medication-related osteonecrosis of the jaws (MRONJ) is, therefore, a serious and challenging condition with important implications in dentistry. The aim was to conduct a narrative literature review on anti-resorptive drugs and their latest repercussions on the maxillary bones. The review was carried out through a bibliographic search using Decs/Mesh descriptors of interest, in Portuguese and English, in the PubMed, Virtual Health Library (VHL) and Scielo databases. After applying the inclusion and exclusion criteria, a total of 33 studies were selected for analysis. It can be noticed that therapy with anti-resorptive agents is complex, especially in dental practice, since MRONJ is a complication that is difficult to manage. Regarding the therapeutic options, these are divided into conservative, surgical or adjuvant therapy, however, there are no protocols in the literature, and there is no consistency regarding the indication of the suspension of the drug administration - "Drug Holiday". Thus, it is important that the multidisciplinary team seeks strategies that minimize complications and promote control over the use of these drugs. In addition, there is a need for investigations that contribute with guidelines for the management and control of adverse effects resulting from therapy with antiresorptive drugs. Keywords: Bone Density Conservation Agents. Diphosphonates. Denosumab. Bisphosphonate-Associated Osteonecrosis of the Jaw. ResumoAs drogas antirreabsortivas atuam na modulação do metabolismo ósseo e são indicadas para o tratamento de metástases ósseas e perdas ósseas relacionadas à deficiência hormonal. Ainda que esta terapia apresente resultados satisfatórios, observam-se efeitos adversos associados ao seu uso, como a osteonecrose dos maxilares. A osteonecrose dos maxilares associada ao uso de medicamentos (OMAM) é, portanto, uma condição séria e desafiadora com implicações importantes na Odontologia. O objetivo foi realizar uma revisão narrativa de literatura sobre as drogas antirreabsortivas e suas respectivas repercussões nos ossos maxilares. A revisão foi realizada através de busca bibliográfica utilizando descritores Decs/Mesh de interesse, em português e inglês, nas bases de dados PubMed, Biblioteca Virtual de Saúde (BVS) e Scielo. Após aplicação dos critérios de inclusão e exclusão, um total de 33 trabalhos foram selecionados para análise. Pode-se constatar que a terapia com agentes antirreabsortivos é complexa, sobretudo na prática odontológica, visto que a OMAM é uma complicação de difícil manejo. Em relação às condutas terapêuticas para esta condição, divide-se em terapia conservadora, cirúrgica ou adjuvante, todavia, não existem protocolos validados na literatura, bem como não há consistência quanto à indicação do intervalo de suspensão da administração da droga - “Drug Holiday”. Desse modo, é importante que a equipe multidisciplinar busque estratégias que minimizem as complicações e promovam o controle no uso dessas drogas. Além disso, nota-se a necessidade de realizar investigações que contribuam com diretrizes para o manejo e controle dos efeitos adversos decorrentes da terapia com medicamentos antirreabsortivos. Palavras-chave: Conservadores da Densidade Óssea. Bisfosfonatos. Denosumabe. Osteonecrose Associada a Bisfosfonatos.

Effects of Preoperative Drug Holiday On Sequester Separation and Treatment Outcome in Cancer Patients With Medication-Related Osteonecrosis of The Jaw

We aimed to investigate whether antiresorptive agent drug holidays contributed to the formation of sequester separation and treatment outcome in medication-related osteonecrosis of the jaw (MRONJ) patients whose primary disease was malignancy. A total of 105 MRONJ patients with malignant tumors as the primary disease who underwent surgery at Nagasaki University Hospital and Kansai Medical University Hospital from January 2009 to December 2020 were included. We recorded patient age, sex, primary disease (solid cancer, non-solid cancer), MRONJ stage, type and administration period of antiresorptive agents, presence of diabetes, corticosteroid use, drug holiday period, white blood cell count, serum, albumin, serum creatinine, outcomes, and computed tomography findings. We examined the relationship between a drug holiday and sequester separation and outcome. Drug holiday of more than 90 days (P=0.629) was not a significant factor for sequester separation in the univariate analysis. In the multivariate analysis, steroid use (P=0.009) and serum albumin (P=0.003) were extracted as factors affecting prognosis; withdrawal for more than 90 days (P=0.98) was not a significant factor. MRONJ patients with cancer as the primary disease should be operated early without drug holidays if their general condition is relatively good, clinical symptoms are strong, and quality of life is improved.

What is the impact of drug therapy with antiresorptive agents on the success of dental implants? a literature review

Objective: To review the current literature and provide the latest information on anti-resorptive agent-induced osteonecrosis of the jaw (ARONJ), including our basic and clinical research findings, as well as discuss the risks of developing osteonecrosis in patients undergoing dental implant surgery in use of anti-resorptive drugs (ARDs). Methods: A literature review was performed using articles published in indexed journals based on Pubmed, Web of Science, Embase and Scopus databases. Results: Our results show that the placement of dental implants in patients treated with ARDs should be carefully evaluated, these patients are not free from complications and, therefore, the risk assessment should be done individually, as one of the most serious complications, although rare, is the ARONJ. Conclusion: Thus, all patients treated with this type of drug should be informed about the risk of implant loss or the possibility of osteonecrosis, being necessary to inform about the increased risk also patients who already have osteointegrated implants and will start therapy with bisphosphonates (BPT). And, in addition, establishing a relationship and collaboration between doctor, dentist and patient is essential for the good prognosis of these cases.

Osseointegration of Dental Implants and Osteoporosis

Osteoporosis is a disease characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and susceptibility to fractures. Osteoporosis also results in loss of bone mineral density throughout the body, including the maxilla and mandible. Successful osseointegration of dental implants is attributed to their ability to integrate well with bone. The influence of bone quality on dental implant osseointegration has been discussed in several studies, and higher rates of dental implant failure have been reported in patients with low bone quality and an inadequate bone volume. Osteoporosis represents a risk factor for osseointegration, and this relationship may be derived from the association of the disease with a deficiency in bone formation. This condition would compromise the healing capacity and the apposition of bone at the implant interface. Currently, there is no clear consensus regarding dental implant treatment in osteoporotic individuals. Studies have revealed contradictory reports regarding the success and failure of dental implants in patients with osteoporosis. Antiresorptive agents have been widely used to treat osteoporosis. Dental implant placement in patients on bisphosphonate therapy may trigger osteonecrosis of the bone. Hence, it is important to analyze factors that have to be taken into consideration prior to implant therapy in patients with osteoporosis and those undergoing treatment. This chapter outlines dental implant osseointegration under osteoporotic conditions. The possible effect of bisphosphonate therapy on dental implant survival will also be discussed based on the current literature.

Menopausal osteoporosis in the practice of a gynecologist

Osteoporosis represents a great healthcare challenge due to an increased risk of fragility fractures that significantly decreases quality of life, shortens life expectancy, and looms as an onerous burden on both the social environment of patients and society as a whole. Osteoporotic fractures can’t be prevented without early diagnosis of low bone mineral density in people at risk. Unfortunately, the population at risk of osteoporosis is not covered by the periodic health examination program in real practice, and involving doctors of different specialties in the prevention and treatment of this disease is one of the options for addressing the challenge. As the risk of osteoporosis is associated with age and estrogen deficiency in women, the gynecologist can and should assume responsibility for the formation of risk groups, monitoring and timely recommendations on preventive and therapeutic actions. The gynecologist’s possibilities should not be reduced solely to recommendations for correcting lifestyle and prescribing menopausal hormone therapy. Antiresorptive agents of the first-line osteoporosis therapy may also be included in the gynecologist’s drug arsenal. Among them are the most commonly used bisphosphonates that are characterized by a good efficacy and safety profile during the long-term use. However, oral administration of bisphosphonates is associated with low compliance due to adverse reactions and the need for strict observance of the rules for their administration. In contrast, intravenous administration of bisphosphonates improves compliance and allows to ensure the optimal treatment outcome. Ibandronate intended for intravenous bolus administration once every three weeks for 5 years is one of the possibilities of using parenteral bisphosphonate therapy in the practice of gynecology.

Use of antimicrobial photodynamic therapy in the treatment of medication-related osteonecrosis of the jaw

Medication-related osteonecrosis of the jaw (MRONJ) is a debilitating complication associated with antiresorptive agents, in which treatment can be quite challenging. This study aimed to report two cases of cancer patients with MRONJ treated in a complementary manner by antimicrobial photodynamic therapy (aPDT). Both patients were male, 84 and 82 years old, respectively, and had a diagnosis of prostate adenocarcinoma and bone metastasis, treated with intravenous injections of bisphosphonates. The dental history for both was toothache, followed by extraction of dental elements that culminated with the appearance of necrotic bone in the mandibular region, which was confirmed with imaging exams and histopathological reports. The treatment protocol for both cases consisted of performing the aPDT once a week, associated with the use of 10 volumes hydrogen peroxide and 0.12% chlorhexidine digluconate for continuous use after oral brushing and amoxicillin with clavulanate three times a day for 7 days. The patient in case 1 performed 27 sessions, responded well to treatment, however, due to complications of the underlying neoplasm, he died without complete resolution of the osteonecrosis. In case 2, 32 sessions were carried out, with a good evolution of the symptoms. The patient is being followed up for 14 months, with no need for surgical intervention to date. Based on the reported cases and the literature survey, it can be concluded that aPDT can be an effective alternative in cases of MRONJ. The patients in the study in question showed success and control of the clinical picture.