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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 32  |  Issue : 1  |  Page : 50-54

Medication-related osteonecrosis of the jaw: A review about etiology, risk factors, pathophysiology, and treatment


Department of Oral Medicine and Radiology, Government College of Dentistry, Indore, Madhya Pradesh, India

Date of Submission21-Dec-2019
Date of Decision13-Mar-2020
Date of Acceptance19-Mar-2020
Date of Web Publication17-Apr-2020

Correspondence Address:
Dr. Sheetal Singar
Shangrila 6, Shri Krishna Nagar, Airport Road in Front of BSF Campus, Indore, Madhya Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jiaomr.jiaomr_206_19

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   Abstract 


Medication-related osteonecrosis of the jaw (MRONJ) is a serious adverse effect of antiresorptive and antiangiogenic medication. MRONJ is considered when a patient has exposed bone in the jaw for more than 8 weeks and has a history of antiresorptive and antiangiogenic medication with a negative history of radiotherapy. Antiresorptive and antiangiogenic medication do not independently cause necrosis of bone. Various systemic and local risk factors like dentoalveolar trauma and extraction play an important role in the development of MRONJ. MRONJ can be prevented by proper dental evaluation and by performing the required treatment before commencing antiresorptive and antiangiogenic medication.

Keywords: Antiangiogenic drugs, antiresorptive drugs, MRONJ, osteonecrosis


How to cite this article:
Singar S, Parihar AP, Reddy P, Maurya A, Bamaniya V. Medication-related osteonecrosis of the jaw: A review about etiology, risk factors, pathophysiology, and treatment. J Indian Acad Oral Med Radiol 2020;32:50-4

How to cite this URL:
Singar S, Parihar AP, Reddy P, Maurya A, Bamaniya V. Medication-related osteonecrosis of the jaw: A review about etiology, risk factors, pathophysiology, and treatment. J Indian Acad Oral Med Radiol [serial online] 2020 [cited 2020 Jun 4];32:50-4. Available from: http://www.jiaomr.in/text.asp?2020/32/1/50/282618




   Introduction Top


Osteonecrosis also is known as avascular necrosis of bone, as the name suggests it is a degenerative condition of bone which is caused by the reduced blood supply. This occurs due to direct tissue toxicity which may result from chemotherapy, radiotherapy, thermal injury, or smoking.[1] In the eighteenth century, there was a term phossy jaw described for osteonecrosis of the jaw (ONJ) among workers exposed to phosphorus vapors. With the emergence of bisphosphonates (BPs), the prevalence of ONJ was noticed among BPs users, which is termed as bisphosphonate-related osteonecrosis of the jaw (BRONJ).[2] BRONJ was again renamed to medication-related osteonecrosis of the jaw (MRONJ) by the special committee formed by the American Association of Oral and Maxillofacial Surgeons (AAOMS). They published a position paper in 2014, as the incidence of ONJ also increasing with other antiresorptive and antiangiogenic medication. According to them, patients who are under treatment with antiresorptive or antiangiogenic agents, and have exposed bone or fistula that can be probed to the bone in the maxillofacial region for more than 8 weeks with a negative history of radiation therapy to the jaws are considered to have MRONJ.[3] Both groups of drugs are mostly used in the management of cancer and its complications. The other contributing systemic and local risk factors are diabetes, anemia, dentoalveolar surgical procedures, extraction, implant placement, periodontal surgery, and infectious dental diseases.[4],[5],[6],[7]

MRONJ is a very serious condition, with less known pathophysiology. However, many proposed hypotheses with respect to pathogenesis are available in the literature.[3],[8] MRONJ can be preventable, with many evident studies showing that any invasive procedure required in dento-maxillomandibular region should be performed 2–3 weeks preceding antiresorptive and antiangiogenic medication.[3],[9],[10],[11],[12],[13] The management of MRONJ can be nonsurgical and surgical. With the adjuvant therapy like laser-assisted debridement, platelet-rich plasma (PRP)/platelet-derived growth factor (PDGF) give good results. Some literature also has shown stage-related management of MRONJ.[3],[14]


   Etiology and Risk Factor Top


Antiresorptive therapy is used for the management of osteoporosis, multiple myeloma, and hypercalcemia-related metastatic malignancy.[4],[9],[15],[16],[17] This group of drugs [Table 1] includes BPs and RANK ligand inhibitors (denosumab).[18] The commonly used BPs are zoledronic acid and pamidronate. The risk of developing MRONJ in BP users depends on the type of BPs, duration of treatment, and route of administration along with the presence of other systemic and local conditions.[19] Studies have also reported that the risk of developing MRONJ is higher in cases with intravenous administration of BPs.[20],[21] Also, patients with cancer have a higher risk of MRONJ in comparison with patients with osteoporosis[7]
Table 1: Drugs associated with medication-related osteonecrosis of the jaw

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The receptor activator of nuclear factor-kappa ligand (RANKL) inhibitor denosumab is very effective in minimizing bone loss associated with breast and prostate cancers, menopause, osteoporosis, and giant cell tumor.[22] Denosumab in fewer doses contributes to MRONJ.[22],[23] A retrospective study (denosumab and zoledronic acid) has also shown a significant relationship between dosage and duration of therapy with the development of MRONJ.[4]

Angiogenesis is a process that involves growth, migration, and differentiation of endothelial cells to form new blood vessels.[3] Antiangiogenic drugs [Table 1] are used in the management of malignancies involving ovary, metastatic renal cell cancer, breast cancer, colorectal cancer, non-small cell lung cancer (NSCLC), and glioblastoma multiforme.[24] The antiangiogenic medication administered with antiresorptive medication has a significant association between duration of exposure and the development of MRONJ.[25],[26] Case reports have also suggested an association between ONJ and isolated use of sorafenib (tyrosine kinase inhibitor used as antiangiogenic) and infliximab (chimeric human-murine IgG1 monoclonal antibody).[27],[28] Newly added drugs that may be associated with MRONJ are steroid and methotrexate [not included in [Table 1]. The long-term use of systemic administration of steroids increases the risk of osteonecrosis or avascular necrosis. The most common sites are the femur, tibia, humerus, calcaneus, or scaphoid. Corticoids do not appear to cause ONJ alone if patients concomitantly administered BPs or denosumab could have an increased risk of developing ONJ. Methotrexate is a cytotoxic medication that is indicated in the treatment of a number of solid tumors, hematological malignancies, and rheumatoid arthritis. But the occurrence of ONJ not available with isolated use of methotrexate.[29]

Besides these medications, the literature suggests the role of other systemic and local risk factors in the development of MRONJ like diabetes and anemia[4],[5],[7],[30] However, the process behind the development of MRONJ in DM patient is yet to be determined.[5] There are many pieces of literature reporting positive correlation between MRONJ and tooth extraction and dentoalveolar infections.[30],[31],[32],[33]


   Pathogenesis Top


Although the first MRONJ case was reported more than 16 years earlier, the pathophysiology of the disease has not known yet. Various proposed hypotheses related to pathophysiology are available in the literature. These hypotheses attempt to explain the exclusive occurrence of MRONJ to the jaws.[3] Bone remodeling inhibition is considered as one of the pathogenesis for MRONJ development. Bone remodeling is a highly complex process by which old bone is replaced by new bone. This process includes three phases: bone resorption; transition; and bone formation, which is achieved by the coordinated actions of osteoblasts, osteocytes, osteoclasts, and bone-lining cells. Bone resorption is carried out by osteoclast. RANKL plays a very crucial role in osteoclast formation, it is secreted by osteoblast, osteocyte, and bone stromal cells. It induces osteoclast formation by binding to a RANK receptor on osteoclast precursor.[34]

BPs and other antiresorptive such as denosumab, inhibit osteoclast function, differentiation, and increase apoptosis of osteoclast all leading to decreased bone remodeling.[3] BPs have a strong affinity for hydroxyapatite. It gets accumulated into the bone matrix and is retained there for a longer time. This deposited BP gets incorporated into osteoclasts through transcytosis during the resorption process leading to impaired function of osteoclasts.[18]

RANKL is produced by osteoblasts and mesenchymal cells and is one of the most important cytokines regulating the differentiation, function, and survival of osteoclasts. Thus, by inhibiting RANKL, denosumab inhibits the differentiation of osteoclast leads to decreasing resorption of bone.[18] Osteoclast differentiation and function play vital roles in bone healing and remodeling at all skeletal sites but osteonecrosis only occurs in the alveolar bone of the jaw. The alveolar bone may demonstrate an increased remodeling rate as compared to other bones of the skeleton[3],[8] but still its not a proven.fact.

Inflammation or infection is another pathogenesis to be considered as an important component of ONJ. In most of the literature available, tooth extraction was followed by ONJ. These teeth commonly had the preexisting periodontal or periapical disease and pus discharge.[3],[4],[6],[30],[33] Jaw bone covered by a thin layer of mucosa, and also the presence of >800 species of bacteria make jaw bone more susceptible to osteonecrosis as compare to other bones. Inflammation/infection often occurs after the extraction of teeth with advanced dental disease or around teeth with periodontal or periapical infection.[8]

The bone becomes necrotic without adequate blood supply. Antiangiogenic therapies are now widely utilized to inhibit tumor invasion and metastases, targeting vascular signaling molecules.[8],[24] Osteonecrosis is classically considered as an interruption in vascular supply or avascular necrosis, and therefore, it is not surprising that inhibition of angiogenesis is a leading hypothesis in ONJ pathophysiology.[3]

Other proposed hypothesis is soft-tissue toxicity and innate or acquired immunity dysfunction. BPs bind to hydroxyapatite in bone, during the resorption process it gets incorporated in osteoclast.[18] Soft-tissue toxicity has been also reported with BP but not associated with denosumab.[3],[8] A continued debate exists about the effect of altered immunity on ONJ development. Tumor pathogenesis is often associated with an impaired immune function.[8]

All pathogenesis suggests that the underlying mechanism of developing MRONJ is probably multifactorial. Many patients taking antiresorptive medications for the treatment of different diseases but the very less patient suffered from ONJ. It suggests that some genetic factors are also involved in the development of ONJ. A meta-analysis was done by Gua et al. on pharmacogenetics of MRONJ, according to them CYP2C8 rs1934951 (in multiple myeloma patients) and vascular endothelial growth factor (VEGF) rs3025039 is associated with the development of MRONJ in patients treated with BPs. And no significant difference observed in MRONJ and Non- MRONJ group for PRARG rs1152003 (peroxisome proliferator-activated receptor-gamma). CYP2C8 is a drug-metabolizing enzyme that presents on chromosome 10q24, it is not involved in the metabolism of BP, but it may affect the differentiation of osteoblasts by mediating cholesterol synthesis by the HMG-CoA pathway. PPARG is located on chromosome 3, band 3p25, and is involved in regulating glucose utilization and adipocyte differentiation, inhibiting inflammatory signaling, and mediating bone homeostasis. VEGF regulates the angiogenesis and thus contributing important role osteogenesis.[35]


   Treatment Top


Many treatment modalities available in various literature include conservative management, surgical treatment and adjuvant to surgical treatment like laser assisted debridement, PRP/PDGF.[9],[36],[37],[38],[39],[40] Some pieces of literature also show the stage related management of MRONJ.[3],[14] The conservative/nonsurgical management of ONJ includes the antimicrobial mouth rinses (0.2% chlorhexidine digluconate), local cleaning of exposed bone and fistula, pain control, the systemic antibiotic and nutritional support.[9],[41],[42] Broad-spectrum antibiotics (amoxicillin/clavulanic acid, ampicillin/sulbactam, metronidazole, or clindamycin) are the first-line drugs to be used in combination although the use of other antibiotics (such as erythromycin, ciprofloxacin, and doxycycline) has also been documented in the literature. 10 days to a 3-week course with oral antibiotic therapy has been suggested, but there is little research available that indicates the most efficient drug and course duration.[41] Oral pentoxifylline and α tocopherol (Vita. E) in combination with antimicrobial therapy improves healing by improving blood supply and its antioxidant properties respectively. Other options adjunct to nonsurgical treatment are hyperbaric oxygen (HBO) therapy, topical ozone therapy (OT), and low-intensity laser therapy to improve healing.[43],[44] Low-intensity laser therapy has shown to be effective management as it reduces pain, improves healing, facilitates nerve regeneration, and stimulates re-epithelization providing antimicrobial properties.[44] The most commonly used laser is argon, carbon dioxide, and helium.[43] The main aim of a conservative treatment to provide symptomatic relief and improving the stage of MRONJ.[41],[42] Improvement in the necrotic bone cannot be expected through conservative therapy alone unless the necrotic bone is removed.[45] A case report shows conservative management of ONJ with discontinuation antiresorptive medication, but the nonsurgical management took a long duration, and in the meantime, patient ONJ worsen and also the probability of metastasis increases, after spontaneous shedding of sequestrum the complete healing occurred.[36]

Surgical treatment includes the conservative debridement of necrotic bone and complete resection of necrotic bone along with surrounding healthy bone. It has been offered mainly to patients with advanced disease not responding to medical treatment.[41],[44] Additional measures such as the use of PRP, platelet-rich fibrin (L-PRF), laser, and drug holiday are also promising adjuvant therapies.[37],[38],[39],[46] The outcome of surgical treatment is better than nonsurgical treatment.[42]


   Conclusion Top


MRONJ is a rare and serious side effect of the antiresorptive and antiangiogenic medication but potentially avoidable conditions. Although etiology is still controversial, it is understood that the dental professional plays a very important role in preventing MRONJ. The prevalence of MRONJ can be reduced if the patient receives prophylactic dental treatment before commencing antiresorptive and antiangiogenic drugs. Also, most importantly, it is the dental professional who evaluates the patients at risk by taking a proper medical history, clinical examination to identify and manage MRONJ.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

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