Osteoradionecrosis


Osteoradionecrosis is a serious complication of radiation therapy in cancer treatment where radiated bone becomes necrotic and exposed. ORN occurs most commonly in the mouth during the treatment of head and neck cancer, and can arise over 5 years after radiation. Common signs and symptoms include pain, difficulty chewing, trismus, mouth-to-skin fistulas and non-healing ulcers.
The pathophysiology of ORN is fairly complex and involves drastic changes to bone tissue as a result of DNA damage and cell death caused by radiation treatment. Radiation therapy targeting tumor cells can affect normal cells as well, which can result in the death of bone tissue. Advances in radiation therapy have decreased the incidence of ORN, estimated at around 2%. Certain risk factors including the size and location of tumor, history of smoking or diabetes, and presence of dental disease can affect the chances of developing ORN.
Osteoradionecrosis is difficult to prevent and treat. Current prevention strategies are aimed at avoiding excess doses of radiation as well as maintaining excellent dental hygiene. Treatments are variable depending on the provider and disease severity, and can range from medical treatment with antibiotics to hyperbaric oxygen therapy to surgical debridement or reconstruction. showing osteoradionecrosis in the cervical vertebrae following radiotherapy for laryngeal cancer.

Clinical findings

There are not many specific clinical signs of ORN. It may be first seen as an area of exposed bone which is not healing, or the non-specific signs may become evident prior to this. Symptoms vary depending on the degree of ORN that has occurred. Early indicators may be numbness or paresthesias within the mouth or jaw. Other signs and symptoms include:
If symptoms are evident, these should be reported to the patient's doctor or healthcare team as soon as possible.

Epidemiology and etiology

Epidemiology

The epidemiology of osteoradionecrosis has proven difficult to estimate, with previous studies reporting incidence of disease between 4.74-37.5%. More recent reports have estimated the incidence to 2%, which is likely attributable to improvements in radiation therapy.

Pathophysiology

destroys cancer primarily by causing DNA damage that promotes cell death. Tumor cells within a cancer are especially susceptible to damage by radiation as they frequently develop mutations in the DNA repair mechanisms that allow normal, healthy cells to recover from radiation damage. However, excessive radiation doses can cause even normal cells to be overwhelmed by DNA damage and lead to local tissue changes and necrosis. Scientists have been conducting investigations into the exact mechanisms of these changes to help create treatments since osteoradionecrosis was first described by Regaud in 1922. Several competing theories have emerged over the years with resultant changes to accepted treatments. Initially, it was believed that ORN arose from a combination of radiation, trauma and infection. According to this belief, radiation damage to the bone caused the bone to weaken, making it susceptible to microfractures caused by trauma and allowing bacteria to invade. This theory placed ORN on a spectrum of disease with osteomyelitis, so it was primarily treated with antibiotics. In 1983, Robert E. Marx, a prominent oral and maxillofacial surgeon, refuted the notion that trauma and infection were requirements in the development of ORN. Marx proposed that ORN was the result of cumulative tissue damage caused by radiation, creating disturbances in cell metabolism and homeostasis that resulted in cell death and hypocellular tissues. In addition, radiation causes injury to the endothelial cells of local vasculature, creating a hypovascular environment which leads to decreased oxygen delivery resulting in hypoxic tissues. The decrease of vasculature helps explain why the mandible is more commonly affected than maxilla, as the mandible is served primarily by the inferior alveolar artery, whereas the maxilla is served by various arteries and has a more robust blood supply. In sum, Marx believed that ORN was essentially hypocellular-hypovascular-hypoxic tissues behaved much like chronic non-healing wounds. Initial reports by Marx and others showing that treatment with hyperbaric oxygen prevented ORN helped support this theory. However, later studies began to raise doubts about the effectiveness of HBO therapy and question whether Marx's theory was comprehensive enough to guide treatment.
Current understanding is guided primarily by the work of Delanian and Lefaix, who proposed the radiation-induced fibroatrophic prefibrotic, 2) constitutive organized and 3) late fibroatrophic phases. During the prefibrotic phase, injury to endothelial cells secondary to radiation causes destruction of local vasculature, and recruitment of inflammatory cells and fibroblasts via pro-inflammatory cytokines like TNF-α, FGF-β and TGF-β1. In addition, osteoblasts within the bone are damaged and destroyed, leading to decreased production of normal bone tissue. In the constitutive organized phase, fibroblasts persist and are converted to myofibroblasts by these same cytokines, that begin to fibrous extracellular matrix within the affected bone. Consequently, the increased production of ECM by myofibroblasts coupled with decreased production of osteoid by osteoblasts results in weakened bony tissue. Finally, during the late fibroatrophic phase, the affected bone becomes hypocellular as myofibroblasts begin to die and leave behind weak, fibrotic tissue. Ultimately, these tissues are fragile and susceptible to damage by trauma or infection with little ability to repair or defend themselves due to the lack of vasculature caused during the pre-fibrotic phase. Given this understanding of the pathophysiology of ORN, current treatments are targeted at decreasing inflammatory cytokines and reducing free radical damage to DNA.

Risk factors

Risk factors for osteoradionecrosis include:
The staging system can be useful as a baseline reference for management after a definitive diagnosis of ORN has been established.
StagePresentationDurationPlain radiographsSigns & Symptoms
0Exposed mandibular bone< 1 monthNo significant changeNo Pain
No Sinus/ fistulas
IA
Exposed mandibular bone≥ 1 monthNo significant changeNo Pain
No Sinus/ fistulas
IB
Exposed mandibular bone≥ 1 monthNo significant changePain
Sinus/ fistulas
IIA
Exposed mandibular bone≥ 1 monthSignificant change
Lower border of mandible is not involved		No Pain
No Sinus/ fistulas
IIB
Exposed mandibular bone≥ 1 monthSignificant change
Lower border of mandible is not involved		Pain
Sinus/ fistulas
IIIExposed mandibular bone≥ 1 monthSignificant change
Lower border of mandible is involved		Irrespective other signs of symptoms

Prevention and management

There is currently no universally accepted prevention and management of ORN and in many cases depends on how severe the condition presents. Currently, there are many preventive approaches for ORN proposed, but yet to be justified by high quality evidence. This leads to uncertainty for clinicians and patients on deciding the best treatment that can be provided.
There are a number of classifications of ORN stages present with different basis of staging and most updated one being the Notani classification. The Notani classification of stages is based on the radiographic and clinical findings, with studies describing low grade ORN being treated conservatively and advanced ORN including pathological fractures, and oro-cutaneous fistula treated surgically.

Prevention

Prior to radiotherapy

Dental assessment
It is recommended to have a multi-disciplinary approach to care and dental assessment before the patient undergoes radiotherapy. It has been reported, that analysis of patients who have a strict preventative regime paired with IMRT resulted in no cases of ORN.
Dental extractions
As dental extractions are a major risk factor in ORN development, it was recommended to extract all teeth prior to radiotherapy. However, this is now discouraged as a treatment of choice and has many disadvantages. According to one study, the frequency of ORN pre-radiotherapy extractions and post-radiotherapy extractions are almost the same. Extractions of teeth of poor prognosis, usually less than five years is recommended and planning should take into account the likely future problems with oral care, for example if severe trismus develops and if dentures were to be prescribed, denture trauma may cause ORN. The patient’s wishes must also be taken into account.
If teeth are required to be extracted, they should ideally be completed as soon as possible to maximise healing prior to radiotherapy. One study recommended a minimum of 14–21 days prior to radiotherapy. However, commencement of radiotherapy should not be delayed as there is little difference in frequency of ORN in pre- and post-radiotherapy extractions and it is recommended that trauma should be kept to a minimum during extractions.
Preventative regime
It is important to ensure that tooth brushing technique and habit is kept to a high standard. Patients undergoing head and neck radiotherapy may experience a sore mouth, therefore a soft bristle toothbrush may be preferred. Chlorhexidine mouthwash can also be used in conjunction with tooth brushing, and if too sore on the mucosa, can be diluted with equal amounts of water.
A fluoride regime is also encouraged with either high fluoride toothpaste, wearing splints with fluoride gel applied for 10 minutes/day or alcohol free fluoride mouthwashes. The patient’s oral condition needs to be taken into consideration and tailored accordingly as trismus may be present which would not allow the back of the mouth to be accessed by fluoride splints or trays. Some may also experience difficulty tolerating toothpastes and mouthwashes for a while due to altered taste and mucosal ulceration.
It is also very important that the patient maintains a high level of motivation in taking care of their oral hygiene, and attending dental appointments where a dental practitioner will be able to monitor them during and after radiotherapy. Oral preparations prescribed to aid sore or dry mouth should be fully understood by patients to avoid any preparations which can cause damage to the teeth. Any saliva substitutes given should be pH neutral.

Post-radiotherapy

Patients will still be susceptible to radiation caries and periodontal disease, more so if they present with dry mouth or access difficulty when tooth brushing. Any restorative or periodontal procedures should be commenced if indicated and endodontic treatments should take priority over extractions, although if there is a difficulty in mouth opening, endodontic treatments can be difficult or impossible. Where a tooth is deemed unrestorable, decoronation can be done. Although dentures should be avoided if a shortened dental arch is manageable, if a denture is required or being used, they should be checked routinely and any adjustment to pressure areas should be made to avoid ORN secondary to denture trauma.
Extractions post-radiotherapy
A practical recommendation  is provided in some case where it is necessary to extract teeth from the jaw after radiotherapy. An assessment of the risk of ORN should be done based on the dose of radiation, the site and how easy is the extraction. Any information on risk and early signs of ORN should be given to the patient. The recommendations are listed below, however, there are some controversies on the ideal antibiotic regime and the use of hyperbaric oxygen therapy.
Summary of recommendations:
Majority of studies on ORN have recommended the use of prophylactic antibiotic where extractions are needed post-radiotherapy, although there is no universally agreed choice, timing and course duration of antibiotic regime.
In one study, it was discovered that cases after 1986, the incidence of ORN after extractions post-radiotherapy was 3.6% in antibiotic prescribed cases and 2.6-3.4% in cases where there is no report on the prescription of antibiotics, showing no difference in reducing the risk of ORN and possibly reconsidering antibiotic regime in preventing ORN.
Hyperbaric oxygen therapy
Results since 1986 have shown of far lower rates of ORN incidence, even without HBO and even a slightly higher rate for HBO patients. Prophylactic use of HBO has been recommended in some studies with a Cochrane review suggesting evidence for some reduction in ORN. However, the use of HBO prophylaxis is not agreed by others due to the insufficient evidence. Majority of British maxillofacial surgeons who participated in a survey recommended prophylactic HBO but protocols are varied.

Management

Conservative

Research to treat ORN at a molecular level has increased with progress in the field of medicine. The pharmacological methods to treat ORN listed below were developed to treat the etiologic factors.