Osteoradionecrosis

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Osteoradionecrosis (ORN) is a serious complication associated with the use of radiotherapy in the management of mouth cancer which can result in infection and possibly pathological jaw fractures.[1] It is defined as exposed radiated bone that fails to heal without any evidence of persisting tumour.[2] Reported prevalence varies from 0.4% to 56%.[3] Modern radiotherapy has changed significantly and more modest occurrences have been reported recently, 4.3% over 10 years [3] and 8% over 30 years.[4] A significant change in radiotherapy has been the development of Intensity-modulated radiation therapy (IMRT). The development of proton beam radiation therapy may also help.

Bone is relatively radio-resistant compared to other tissues due its blood supply and limited reparative ability and poses a problem when irradiated. ORN is more common in the posterior mandible due to a reduced blood supply. Additional risk factors include: poor dental health, tobacco and alcohol use,[3] operative surgery involving mucosa and bone in the site of the radiotherapy and high dose radiation.[5] ORN can occur spontaneously, due to periodontal and apical disease and possibly after trauma induced by dentures, or after surgery or tooth extraction. A balance of tumour eradication and normal tissue preservation must be reached to achieve cure without further debilitating the patient.[6]

MRI showing osteoradionecrosis in the cervical vertebrae following radiotherapy for laryngeal cancer.

Clinical findings[edit]

There are not many specific clinical signs of ORN.[7] 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. An early indicator may be paraesthesia or numbness of the lip or other area of the mouth such as;

If symptoms are evident, these should be reported to the patient's doctor or healthcare team as soon as possible.[8]

Pathophysiology[edit]

In 1926, Erwing described the changes in bone that associated with radiotherapy as radiation osteitis. The precise pathogenic mechanisms are not fully understood but in 1983, a theory was proposed by Marx, suggesting that osteoradionecrosis is cumulative tissue damage induced by ionising radiation[9] from radiotherapy rather than trauma or bacterial infection of soft tissue or bone. Marx described ORN as disturbance in complex metabolism and tissue homeostasis that result in local tissue hypoxia, hypocellular and hypovascular tissue.[10] This would eventually lead to breakdown of infected tissue and chronic non-healing wounds due to avascular necrosis.[9] There are also various of studies and clinical cases to support the Marx’s theory.[11]

The mandible is more commonly affected than maxilla due to the lesser vascularity. Irradiation to the overlying soft tissue, periosteum and bone would possibly undergo hyperaemia and endarteritis. Osteoradionecrosis of the mandible is mainly due to radiation-induced obstruction of the inferior alveolar artery and ultimately lead to ischaemic of tissue. The damaged periosteum and hypovascularity decrease the chance of revascularisation of tissue by the branches of facial artery. The buccal cortex of the premolar, molar, and retromolar of the mandible are the most commonly affected areas.[12]

Cells such as fibroblasts, osteoblasts, and undifferentiated osteocompetent cells in irradiated area are most likely damaged as a result of free radicals and inflammation.[13] A series of growth factors chronically activate the fibroblast. Some studies showed proliferation and function of fibroblast are affected but high dose of radiation. The affected fibroblast has lower production and secretion of collagen to the surrounding tissue and there is a significant drop of cell number in response to radiation exposure. This is also known as fibroatrophic. High and/ or fractioned radiation doses would cause radiation induced fibrosis (RIF). There are different factors that may increase the severity and presentation of RIF such as age, obesity, high blood pressure, diabetes, surgery in irradiated area, chemotherapy, and concomitant radiotherapy.[14]

Staging[edit]

The staging system can be useful as a baseline reference for management after a definitive diagnosis of ORN has been established.[15]

Stage Presentation Duration Plain radiographs Signs & Symptoms
0 Exposed mandibular bone < 1 month No significant change No Pain

No Sinus/ fistulas

IA

(Asymptomatic)

Exposed mandibular bone ≥ 1 month No significant change No Pain

No Sinus/ fistulas

IB

(Symptomatic)

Exposed mandibular bone ≥ 1 month No significant change Pain

Sinus/ fistulas

IIA

(Asymptomatic)

Exposed mandibular bone ≥ 1 month Significant change

Lower border of mandible is not involved

No Pain

No Sinus/ fistulas

IIB

(Symptomatic)

Exposed mandibular bone ≥ 1 month Significant change

Lower border of mandible is not involved

Pain

Sinus/ fistulas

III Exposed mandibular bone ≥ 1 month Significant change

Lower border of mandible is involved

Irrespective other signs of symptoms

Aetiology[edit]

ORN is one of the most serious complications arising from head and neck radiation therapy[16]

Ionising radiation was thought to cause tissue injury due to local inflammatory process. Delanian and Lefaix (2004) suggested that ionising radiation might create a local inflammatory process resulting in tissue injury, death of osteoblasts and inhibiting repopulation of cellular components of bone.[17] This creates fibrotic bone with a less vascularised and viable cells.[18] Injured tissue has an increased risk for developing ORN and the slightest chemical or physical trauma could trigger a late inflammatory response leading to tissue necrosis.[13]

Radiation dose[edit]

  • External beam radiation of greater than 50 gray significantly increases risk for developing ORN
  • Duration of radiation dose: Radiotherapy injures tissues at a cellular level before progressing on to damage at a humoral level. Total radiation dose given over a shorter period of time will cause more damage as it prevents any remaining vital non-tumour cells in the area from recovering. Similarly, different sequences of fractionated delivery or radiation were proven to minimise risks associated with radiotherapy[19][20]
  • Mode of delivery, location and volume of irradiated tissues
    • Techniques such as brachytherapy delivery radiation to a small area of tissue, limiting radiation damage to peripheral tissues. This reduces risk of complication in comparison to external bean irradiation which involves radiating an entire block of tissue
    • Areas such as the mandible which are less vascularised are more susceptible to ORN
    • It is important to plan the optimal delivery strategy to avoid unnecessary radiation to surrounding healthy tissues. Therefore, minimising risk of ORN

Jaw damage[edit]

Damage or trauma to jaw after radiotherapy.[21]

  • Surgical procedures involving the jaw post radiation therapy increases the risk of ORN. Already irradiated tissues have impaired vascularisation. If surgical procedures are subsequently carried out, tissue vascularisation is further hindered, predisposing that area to ORN. Examples of surgical procedures are; Loss of periosteal blood supply due to a marginal mandibular resection, unstable fixation of the mandibular split osteotomy leading to mal-union or non-union and inadequate tissue coverage of the bone after resection of a tumour.
  • Dental Implants are a risk factor for developing ORN. Irradiated tissues are subjected to cellular and tissue damage. This creates an unfavourable host condition for implant placement, therefore implants are contraindicated in areas which have had radiation therapy.[6][10]
  • Inadequate oral hygiene: Intraoral tissues are damaged by irradiation, which causes mucositis and xerostomia. These conditions, in combination with poor dental care
  • Denture Irritation - Poorly fitting tissue-borne prosthesis may result in odontogenic and periodontal infections, increasing risk of osteonecrosis
  • Tooth extraction inflicts trauma to the jaw. As vascularisation of the socket post-extraction is impaired, this increases the susceptibility of that area to ORN[21]

Medications[edit]

Antiresorptive and antiangiogenic agents used in antitumor therapy and for treating in various diseases.[22] These drugs cause a decrease in bone remodelling capability. An imbalance between osteoblastic activity of bone deposition and osteoclastic activity of bone resorption may increase the risk of pathology occurring. This can result in Medication related Osteonecrosis of the jaws (MRONJ)

Examples of antiresorptive medications include:

Bisphosphonates
These are a class of drugs that prevent the resorption of bone. The compound inorganic pyrophosphate found in bisphosphonates regulates calcification and inhibits bone resorption. Bisphosphonates bind to the mineral surface of bones and eventually embed in bone. This results in accumulation in the bone matrix, only to be released slowly. Therefore patients can experience pharmacological effects for up to a few years after discontinuing these drugs.
Inhibitor RANK-L
RANK-L is a protein that activates osteoclasts. Inhibiting this protein prevents osteoclastic activity, therefore increasing bone density and decreases the risk of bone fracture. Inhibitor RANK-L, for example Denosumab, is usually used to treat bone disorders such as osteoporosis.[23]

Examples of antiangiogenic agents include:

Bevacizumab
This is a monoclonal antibody that inhibits vascular endothelial growth factor (VEGF) which inhibits tumour growth.[24] However, this could weaken microvessels resulting in impaired bone tissue repair in response physiological trauma, including MRONJ.[17]

Spontaneously[edit]

Thorn et al. (2000) reported 23 cases (29%) of spontaneous ORN, mostly asymptomatic, with only a slight dehiscence of the oral mucosa. Thus, the authors emphasized the importance of identifying early-stage ORN and listed other risk factors such as: trauma by prosthesis, surgery and extraction, 3%, 14% and 55% of cases, respectively.[5]

Prevention and management[edit]

There is currently no universally accepted prevention and management of ORN and in many cases depends on how severe the condition presents.[25] Currently, there are many preventative approach for ORN proposed, but yet to be justified by high quality evidence.[26] This leads to uncertainty for clinicians and patients on deciding the best treatment that can be provided.[25][26]

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.[25]

Prevention[edit]

Prior to Radiotherapy[edit]

Dental Assessment[edit]

It is recommended to have a multi-disciplinary approach to care and dental assessment before the patient undergoes radiotherapy.[27] It has been reported,[28] that analysis of patients who have a strict preventative regime paired with IMRT resulted in no cases of ORN.

Dental extractions[edit]

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.[29] According to one study, the frequency of ORN pre-radiotherapy extractions and post-radiotherapy extractions are almost the same.[30] 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.[26][29] The patient’s wishes must also be taken into account.[29]

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.[27] However, commencement of radiotherapy should not be delayed as there is little difference in frequency of ORN in pre- and post-radiotherapy extractions[30] and it is recommended that trauma should be kept to a minimum during extractions.[27]

Preventative regime[edit]

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.[29]

A fluoride regime is also encouraged with either high fluoride toothpaste (Duraphat 5000), wearing splints with fluoride gel applied for 10 minutes/day or alcohol free fluoride mouthwashes.[27] 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.[29]

Post-Radiotherapy[edit]

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,[26][29]

Extractions post-radiotherapy[edit]

A practical recommendation  is provided in some case where it is necessary to extract teeth from the jaw after radiotherapy.[31] 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 (HBO).[29]

Summary of recommendations:[31]

  • 0.2% chlorhexidine mouthrinse given before extraction
  • Oral antibiotics(3g) given 1 hour prior to extraction ( if allergic 600 mg clindamycin)
  • Amoxicillin 250 mg 3 times/day or metronidazole 200 mg 3 times/day for 3–5 days post-operatively.
  • Extractions should be completed with as little trauma as possible, and on simple extractions of mobile teeth
  • Primary closure for firm teeth, by a minimal periosteal flap and alveolectomy
  • An experienced operator
  • Possibly pre-operative hyperbaric oxygen for mandibular molars in areas of high radiation
  • Review 5 days post-extraction and weekly review after  until healing is complete.
Antibiotics[edit]

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.[32]

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.[33]

Hyperbaric oxygen Therapy[edit]

Results since 1986 have shown of far lower rates of ORN incidence, even without HBO (3.1-3.5%) and even a slightly higher rate for HBO patients (4.0%).[33] Prophylactic use of HBO has been recommended in some studies [34][31] with a Cochrane review suggesting evidence for some reduction in ORN.[35] However, the use of HBO prophylaxis is not agreed by others due to the insufficient evidence.[36] Majority of British maxillofacial surgeons who participated in a survey recommended prophylactic HBO but protocols are varied.[37]

Management[edit]

Conservative Management[edit]

  • Antiseptic mouthwashes: Mouthrinses such as 0.02% aqueous chlorhexidine and saline can be used in acute ORN together with analgesics and anti-inflammatory drugs.[25]
  • Antibiotics: In order to eliminate infection in the region, tetracyclines can be prescribed due to their selective uptake by bone.[25] Penicillin antibiotics can also be used because of their superficial contamination with oral bacteria.[38]
  • Ultrasound therapy: First introduced as a treatment modality in 1992,[7] it involves the application of high-frequency sound waves to induce angiogenesis and improve blood circulation to muscles.[39][40] Harris demonstrated that 48% of cases showed healing when 15 minutes of ultrasound therapy was applied daily on the skin affected by ORN, while combined with debridement.[7]
  • Hyperbaric oxygen therapy (HBO): First described in 1973, HBO was intended to be an adjunctive treatment method in ORN.[41] The theoretical basis behind this treatment was the fact that it causes an increase in tissue oxygen tension and an improvement in collagen synthesis, angiogenesis and epithelialization.[42] However, its use as the only method in the management of ORN is controversial. There is little evidence to show any clinical benefit, and that it may not have therapeutical significance over a placebo.[25]

Surgical management[edit]

  • Multidisciplinary approach (HBO + Surgery): Studies have shown support of combining HBO therapy and a surgical approach to treat ORN.[43] This is in order to improve local blood circulation, with resection of necrotic bone and reconstruction with a free flap.[25]  However, some studies still state lack of benefit HBO therapy brings.[44] It does not revive dead bone, therefore microvascular reconstruction without the use of HBO therapy is still a successful method of treating ORN.[45]
  • Surgery: The procedures involved in the surgical management of ORN are as listed: Removal of small sequestra, sequestrectomy, alveolectomy with primary closure, closure of orocutaneous fistula and large resections. Surgical management is usually required in cases of advanced disease,[8] or if conservative measures fail to work.[25] Methods used to reconstruct anatomical structures involve plates, autogenous bone grafts, regional flaps and free tissue transfer.[8] Vascularised bone flaps are known to be the most effective mode of reconstruction.[8]  

Therapeutic approach[edit]

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.

  • Pentoxifylline is methylxanthine derivative that drives vascular dilation and increased erythrocyte flexibility, resulting in enhanced blood flow.[46] It also contains anti-tumour necrosis factor α activity, and reduces the cytokine cascade that facilitates the process of ORN.[47] However, pentoxifylline is not meant for the long-term treatment of ORN.
  • Tocopherols can occur in various forms. Its alpha form, also known as vitamin E, has antioxidant properties which results in the inhibition of platelet aggregation.[48] Alpha-tocopherol is also able to scavenge reactive oxygen species involved in the ORN disease process, by inducing cell membrane peroxidation.[13]
  • Clodronate is a non-nitrogenous bisphosphonate used in the treatment of numerous diseases, such as hyperparathyroidism, osteoporosis, and multiple myeloma.[25] Clodronate functions by inhibiting bone resorption, due to the reduction in the activity and quantity of osteoclasts.[49] Clodronate also acts directly on osteoblasts, which increases bone formation and reduces the growth of fibroblasts.[50]

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