Medication-related osteonecrosis of the jaw

According to the updated 2014 AAOMS position paper (modified from 2009), in order to distinguish MRONJ, the working definition claims patients may be considered to have MRONJ if all the following characteristics are present: :1. Current or previous treatment with antiresorptive or antiangiogenic agents. :2. Exposed bone or bone that can be probed through an intraoral or extraoral fistula in the maxillofacial region that has persisted for longer than 8 weeks. :3. No history of radiation therapy to the jaws or obvious metastatic disease to the jaws. Osteonecrosis, or localized death of bone tissue, of the jaws, is a rare potential complication in cancer patients receiving treatments including radiation, chemotherapy, or in patients with tumors or infectious embolic events. In 2003, reports surfaced of the increased risk of osteonecrosis in patients receiving these therapies concomitant with intravenous bisphosphonate. Matrix metalloproteinase-2 may be a candidate gene for bisphosphonate-associated osteonecrosis of the jaws, since it is the only gene known to be associated with both bone abnormalities and atrial fibrillation, another side effect of bisphosphonates. In response to the growing base of literature on this association, the United States Food and Drug Administration issued a broad drug class warning of this complication for all bisphosphonates in 2005. ==Signs and symptoms==

Classically, MRONJ will cause an ulcer or areas of necrotic bone for weeks, months, or even years following a tooth extraction. While the exposed, dead bone does not cause symptoms these areas often have mild pain from the inflammation of the surrounding tissues. Clinical signs and symptoms associated with, but not limited to MRONJ, include: • Jaw pain and neuropathy • Loose teeth • Mucosal swelling • Trismus • Bad breath • Exposed necrotic jaw bone ==Cause==

Cases of MRONJ have also been associated with the use of the following two intravenous and three oral bisphosphonates, respectively: zoledronic acid and pamidronate and alendronate, risedronate, and ibandronate. Despite the fact that it remains vague as to what the actual cause is, scientists and doctors believe that there is a correlation between the necrosis of the jaw and time of exposure to bisphosphonates. Causes are also thought to be related to bone injury in patients using bisphosphonates as stated by Remy H Blanchaert in an article about the matter. Risk factors . These drugs are also used for rare conditions like Paget's disease, osteogenesis imperfecta and fibrous dysplasia. The two main types of anti-resorptive drugs are bisphosphonate and denosumab. These drugs help to decrease the risk of bone fracture and bone pain. Because the mandible has poorer blood circulation, it is more affected by the effects of these drugs. • Bisphosphonate • Bisphosphonates are either administered orally or intravenously. They reduce bone resorption. • Mechanism of action: Bisphosphonate binds to the mineral component of the bone and inhibits enzymes (i.e. farnesyl-pyrophosphate synthase) responsible for bone formation, osteoclast recruitment and osteoclast function. • Denosumab • Denosumab is a monoclonal antibody which is administrated subcutaneously. It inhibits osteoclast differentiation and activation, reduces bone resorption, improves bone density and lessens skeletal-related events associated with metastasis. They prevent the tumour from growing. For example, bevacizumab/aflibercept is a monoclonal antibody that specifically binds to vascular endothelial growth factor (VEGF), preventing VEGF from binding to receptors on the surface of normal endothelial cells. Sunitinib is a different example of an anti-angiogenic drug; it inhibits cellular signalling by targeting multiple receptor tyrosine kinases. It reduces the blood supply to the tumour by inhibiting new blood vessel formation in the tumor. The tumour may stop growing or even shrink. ==Pathogenesis==

Although the methods of action are not yet completely understood, it is hypothesized that medication-associated osteonecrosis of the jaw is related to a defect in jaw bone healing and remodelling. The inhibition of osteoclast differentiation and function, precipitated by drug therapy, leads to decreased bone resorption and remodelling. Evidence also suggests bisphosphonates induce apoptosis of osteoclasts. Another suggested factor is inhibition of angiogenesis due to bisphosphonates; this effect remains uncertain. Several studies have proposed that bisphosphonates cause excessive reduction of bone turnover, resulting in a higher risk of bone necrosis when repair is needed. It is also thought that bisphosphonates bind to osteoclasts and interfere with the remodeling mechanism in bone. To be more specific, the drug interferes with the cholesterol biosynthesis pathway through the inhibition of farnesyl diphosphate synthase. Over time, the cytoskeleton of the osteoclasts loses its function and the essential border needed for bone resorption does not form. Like aminobisphosphonates, bisphosphonates have shown to have antiangiogenic properties. Therefore, effects include an overall decrease in bone recycling/turnover as well as an increased inhibition of the absorptive bone abilities. of an osteoclast displaying typical distinguishing characteristics: a large cell with multiple nuclei and a "foamy" cytosol. One theory is that because bisphosphonates are preferentially deposited in bone with high turnover, it is possible that the levels of bisphosphonate within the jaw are selectively elevated. To date, there have been no reported cases of bisphosphonate-associated complications within bones outside the craniofacial skeleton. ==Diagnosis==

A diagnosis of bisphosphonate-associated osteonecrosis of the jaw relies on three criteria: In the 2014 AAOMS update on MRONJ, a staging and treatment strategies table was created: ==Prevention==

Tooth extraction is the major risk factor for development of MRONJ. Prevention including the maintenance of good oral hygiene, comprehensive dental examination and dental treatment including extraction of teeth of poor prognosis and dentoalveolar surgery should completed prior to commencing any medication which is likely to cause osteonecrosis (ONJ). Patients with removable prostheses should be examined for areas of mucosal irritation. Procedures which are likely to cause direct osseous trauma, e.g. tooth extraction, dental implants, complex restoration, deep root planning, should be avoided in preference of other dental treatments. There are limited data to support or refute the benefits of a drug holiday for osteoporotic patients receiving antiresorptive therapy. However, a theoretical benefit may still apply for those patients with extended exposure histories (>4 yr), and current recommendations are for a 2 month holiday for those at risk. Patients may be advised to limit alcohol consumption, stop smoking, and practice good dental hygiene. It is also advised for individuals who take bisphosphonates to never allow the tablet to dissolve in the mouth as this causes damage to the oral mucosa. ==Management==

Treatment usually involves antimicrobial mouth washes and oral antibiotics to help the immune system fight the attendant infection, and it also often involves local surgery(resection) to get rid of the dead bone (necrotic bone lesion). Many patients with MRONJ have successful outcomes after treatment, meaning that the local osteonecrosis is stopped, the infection is cleared, and the mucosa heals and once again covers the bone. The treatment the person receives depends on the severity of osteonecrosis of the jaw. Conservative Indicated in patients who have evidence of exposed bone but no evidence of infection. It may not necessarily eliminate all the lesions, but it may provide patients with long term relief. This approach involves a combination of antiseptic mouthwashes and analgesics and the use of teriparatide. Splints may be used to protect sites of exposed necrotic bone. Non-surgical Indicated for people with exposed bone with symptoms of infection. This treatment modality may also be utilised for patients with other co-morbidities which precludes invasive surgical methods. This approach requires antimicrobial mouthwashes, systemic antibiotics and antifungal medication and analgesics. Surgery Surgical intervention is indicated in patients with symptomatic exposed bone with fistula formation and one or more of the following: exposed and necrotic bone extending beyond the alveolar bone resulting in pathological fracture; extra-oral fistula; oral antral communication or osteolysis extending from the inferior border of the mandible or the sinus floor. Surgical management involves necrotic bone resection, removal of loose sequestra of necrotic bone and reconstructive surgery. The objective of surgical management is to eliminate areas of exposed bone to prevent the risk of further inflammation and infection. The amount of surgical debridement required remains controversial. Other • Ultrasonic therapy Antibiotics Antibiotics are used to treat cases involving infections. Penicillin is the first line of choice, although if this is contraindicated commonly used antimicrobials are: clindamycin, fluoroquinolones and/or metronidazole. Intravenous antibiotics may be used if the infection resists oral treatment. However, there is little evidence of intravenous antibiotics being more efficacious than other methods of treatment. == Epidemiology ==

The likelihood of this condition developing varies widely from less than 1/10,000 to 1/100, as many other factors need to be considered, such as the type, dose and frequency of intake of drug, how long it has been taken for, and why it has been taken. In patients taking drugs for cancer, the likelihood of MRONJ development varies from 0 - 12%. This again, varies with the type of cancer, although prostate cancer and multiple myeloma are reported to be at a higher risk. In patients taking oral drugs for osteoporosis, the likelihood of MRONJ development varies from 0 - 0.2%. == See also ==