POST-RADIATION OSTEITIS

POST-RADIATION OSTEITIS

Introduction   

Post-radiation osteitis is a serious complication of radiotherapy for cervico-maxillofacial cancers. It represents all the biological and clinical phenomena that occur in the irradiated facial bone structures and that can lead to major alterations that could put the patient’s life at risk. Osteoradionecrosis (ORN) is defined on clinical criteria and, above all, on radiological and histological criteria. 

1. Definition of ORN: 

• It is a “devitalized bone” exposed through the skin or mucosa within an irradiated territory in a patient treated for cancer with no healing after a period of 3 months and no tumor recurrence (variable according to the authors from 2 to 6 months). ORN can be spontaneous but is most often provoked.   

Clinical 

• Functional signs include pain, dysesthesia, trismus, dysgeusia, halitosis, food impaction, cutaneous fistula, mandibular fracture, or reflex otalgia. The macroscopic appearance is “necrotic bone with a wet sugar structure within an irradiated area.”
• Radiological signs are non-specific. 
• Histologically, we find necrotic bone superinfected by opportunistic bacteria and candida. 

2. GENERAL RULES AND MODE OF ACTION OF RADIOTHERAPY  

2.1. Different types of irradiation: 

2.1.1. Transcutaneous external radiotherapy or conventional external radiotherapy or teleradiotherapy: 

• It uses a radiation source placed at a distance from the irradiated tissues. It can be curative or palliative (large or metastatic tumor). 
• Cobalt (Co 60) is the most used. These are high energies. There is less absorption of the skin and better performance in depth. Lateral diffusion is low and the beams are better concentrated.
• More commonly now, using linear accelerators: Uses high energy; up to 6 MeV.
• It concerns the lesion itself, or the tumor bed in the case of primary surgery and the drainage lymph node areas. 
• These two target volumes,  tumor and lymph nodes, are irradiated with a safety margin of the order of a centimeter. The target volume = tumor with a safety margin of 1 cm. 

2.1.2. Contact therapy: 

• uses low-energy (50-200: Kilo electron Volt: KeV), low-penetrating photons emitted by an X-ray tube.
• is intended for superficial, small lesions, especially on the lips. 

2.1.3. Brachytherapy: 

• This is classically an “interstitial brachytherapy by iridium 192”, the radioactive sources are placed in the tumor to be treated. 
• The patient is hospitalized for the entire duration of the treatment, of the order of 1 day for 10 Gy during low dose rate brachytherapy. 
•  Can be performed at medium and high dose rates and the chosen dose will be delivered in several fractions of a few minutes per hour (pulsed brachytherapy) or in daily sessions, avoiding prolonged hospitalization.
• Interstitial brachytherapy can also be performed using “gold 198 grains”, an isotope with a very short half-life that is implanted permanently. It can treat superficial and vegetative lesions, whose anatomical location would make conventional brachytherapy difficult. 

2.1.4. Conformal radiotherapy  : 

• Allows better beam adaptation to the tumor volume and limitation of exposure of healthy organs. Since the irradiation volume is better defined, it is possible to increase the dose delivered within it and thus increase the effectiveness of radiotherapy. With “conventional” radiotherapy, the total doses generally administered are of the order of 65 Gy; with conformal radiotherapy, it is now possible to go beyond this without increasing toxicity. 

The advantages of conformal radiotherapy are: 

• Reduction of secondary risks because large salivary glands are partially spared by irradiation in the majority of patients.
• Reduction of mandibular bone volumes exposed to high doses.
• Reduction of exposed gingival areas.
• Reduction of doses administered to the teeth.

2.1.5. Intensity modulated radiotherapy (IMRT) combines multiple irradiation fields with multi-leaf collimators programmed according to the shape and location of the tumor. The objective is to spare as much as possible the sensitive organs near the tumor such as the spinal cord and the main salivary glands for cervical and maxillofacial tumors. It is the only technique that allows precise sculpting of the irradiation volume, making it possible to irradiate concave-shaped tumors, which is unachievable with other means, even with 3D conformal radiotherapy.

• A study of 176 patients treated with RTMI reported no ORN after a median follow-up period of 34 months (Ben David et al. 2007) 

3. Pathophysiology:

3.1. Dambrain’s “2 I” theory: ischemia and infection: 

• The three factors responsible for the appearance of ORN are irradiation beyond a critical dose, local trauma and infection.
• Histopathologically, there is the presence of bacteria, tissue changes within the osteoradionecrotic tissue, thickening of the vascular walls, a decrease in the number of osteoblasts and osteocytes, and filling of bone lacunae with inflammatory cells. 
• For Meyer-Tettirington 1970, ORN is the infection of an irradiated bone by the endobuccal flora following the formation of an entry point by trauma. Osteomyelitis induced by irradiation requires systematic antibiotic therapy in the case of dental surgery in an irradiated area. 

3.2.MARX 1983 3H theory: 

• The occurrence of ORN without prior trauma is also described. Trauma and infection are thought to be contributing factors and irradiation is responsible for hypoxic, hypocellular, hypovascular tissue.
• Hypocellularity: the direct action of irradiation is on osteocytes and bone stem cells, osteoblasts are less affected. This leads to an increase in osteoclastic resorption. Collagen synthesis is reduced and the bone marrow becomes rare and fibrotic.
• Hypovascularization: the reduction in the number of vessels leads to endarteritis lesions with stenosis, thrombosis and hyperplasia of the media.
• Hypoxia: The decrease in partial pressure of oxygen is proportional to the dose of radiotherapy and the degree of medullary fibrosis. This results in a reduction in the possibilities of healing of irradiated tissues, which would justify hyperbaric oxygen therapy in the treatment of ORN.  

3.3. Theory of irradiation-induced fibroatrophy 

• It is based on the activation and deregulation of fibroblastic activity. Irradiation would cause progressive fibrosis of tissues associated with a decrease in repair capacities. Three phases are described:

• Initial phase: pre-fibroblastic is characterized by a modification of endothelial cells and an acute inflammatory reaction.
• 2nd phase: we understand a ^predominance of abnormal fibroblastic activity with a disorganization of the extracellular matrix.
• 3rd phase  : ^we observe a remodeling of disorganized tissues (late fibroatrophy). 
• This mechanism results in the formation of fragile scar tissue which can be the site of reactivated inflammation if there is local trauma.

4. ETIOLOGIES 

4.1.Triggering factors of osteoradionecrosis: 

4.1.1. Osteoradionecrosis of mechanical or secondary origin: 

• The appearance of ORN generally follows trauma with mucosal breach and bone exposure following:

• Microtrauma from dental prosthesis, brushing, diet.
• Odontoradionecrosis and poor oral health.
• Avulsions and dental care.
• Surgical trauma (biopsy, vestibuloplasty, implantology, ridge regularization, etc.).

           4.1.2. Osteoradionecrosis of spontaneous origin: 

• According to MARX, 35 to 39% of osteoradionecroses would not be secondary to trauma, but would be spontaneous, related to high doses of rays capable of directly causing necrosis.

4.2. Contributing factors: 

• Age-sex: the average age of occurrence corresponds to the average age of occurrence of cancers (50 to 60 years). The male predominance is generally identical.
• The location of the tumor: the risk is higher when the tumor is juxta-osseous, it is multiplied by 4 when the tumor invades the bone, and by 3.5 when it is exposed.
• Radiotherapy modality: the occurrence of ORN is proportional to the dose, the risk is low below 70 Gy and increases beyond. Fractionation is also an important factor, the most used is a fractionation of 2 Gy. Hypofractionation (3 to 4 Gy) increases the risk of ORN. Hyperfractionation (1.5 Gry) has not clearly proven its superiority.
• Associated therapeutic factors: surgery plays an obvious role in weakening the bone and reducing its vascularization. The impact of chemotherapy is not clearly specified.   
• Initial dental condition: the risk is greater in patients with teeth, and is linked to the condition of these teeth, as well as the quality of oral hygiene.
• General factors aggravate circulatory factors, which will increase the risk (diabetes, atherosclerosis linked to smoking).
• Early start of radiotherapy: starting radiotherapy before the end of alveolar healing is a contributing factor. A delay of 10 to 21 days between dental extractions and radiotherapy is generally accepted.
• Lack of protection of remaining teeth : In the absence of strict oral hygiene, the remaining teeth are the site of cervical caries rapidly leading to loss of the crown. The remaining roots then constitute a triggering factor for ORN. Daily fluoride prophylaxis in the event of a significant decrease in saliva production significantly reduces the risk of caries.

5. Clinical study 

5.1. Clinical signs: two clinical pictures are to be described:

=) Early ORN or true ORN: it occurs in the weeks or months following irradiation. It is rare and most often attributable to a technical error such as an overdose, in the therapeutic protocol. It follows radioepithelitis and radiomucositis and is accompanied by painful phenomena that cannot be alleviated by the usual analgesics. Bone denudation sets in with irregular contours, with a grayish background revealing a yellowish white bone of more or less hard consistency.

=)Late ORN: it is more frequent. On average 2 years after irradiation following trauma causing mucosal breach (tooth extraction, biopsy, scaling, traumatic dental prosthesis). It evolves in two phases:

1-Bone denudation phase: 

•   Mucosal ulceration, irregular, with a specific base, revealing a bone that is very sensitive to contact, the symptoms are usually minimal. The general condition is preserved. Radiologically, no bone involvement.

2-Evolutionary phase: 

• It occurs either towards sequestration, spontaneous elimination and healing, or towards an extension of the lesions, with superinfection and appearance of a radiologically confirmed ORN. 
• At this stage, there will be very sharp, paroxysmal, radiating pain, resistant to analgesics. Infected bone denudation with necrotic bone debris. The mucosa retracts and the mucoperiosteal area peels off around the loss of substance. The trismus is tight. 
• Infection of the periosteal soft tissues, which manifests itself by a lateromaxillary swelling suggestive of peri-maxillary cellulitis with fever and pain which can lead to the formation of a mucous or cutaneous fistula, resulting in the formation of an orostoma. A fracture can form quietly, it is generally not very painful. We observe the deterioration of the general condition, due to malnutrition.

5.2. Clinical forms: 

=) Mandibular involvement: 

• Mandibular localization is predominant (97% of cases). The focus is often unilateral, generally located at the level of the horizontal branch or the angle. Bilateral forms often have an asynchronous evolution making management difficult. When one side is treated by conservative means, the other must require radical treatment.

=)Maxillary involvement: 

This location is very rare due to the very nature of the bone and its vascularization; moreover, the functional consequences are much less disabling, in particular due to the absence of orostoma and pathological fracture.

5.3. ORN classification: 

• Several classifications have been proposed, in particular Epstein which presents a classification in 3 stages:
  • Stage 1: Asymptomatic stabilized ORN.
  • Stage 2: Chronic ORN ( > 3 months) not progressive with few symptoms.
  • Stage 3: Evolving ORN. 
• And for each stage: – absence of fracture; – with fracture.
• From this Epstein classification, a clinical classification in 3 stages has been proposed:
• Stage 1: Asymptomatic or minimally symptomatic ORN with non-progressive bone denudation and/or isolated radiological sign. Absence of fracture.
• Stage 2: moderate symptoms, easy to control medically (intermittent pain, possible intermittent fistulas) radiological signs are variable, may reveal a fracture.
• Stage 3: severe symptoms requiring the use of major analgesics, with permanent fistulas or orostomas, wide intraoral bone exposure and significant radiological signs, usually with fracture and/or sequestrum. 

6. Differential diagnosis 

• The differential diagnosis is primarily with the recurrence or the evolutionary continuation of oral carcinoma. In the case of neoplastic recurrence, the appearance of denudation is slow and insidious. The appearance is more budding than ulcerative and the character is bleeding to the touch.
• In the case of ORN, the onset is sudden and provoked. The ulcerative character spreads more rapidly with the elimination of small bone sequestra.
• “The biopsy should be able to make a difference.”

7. Evolution of ORNs 

• ORNs can develop into two forms: benign or severe.

7.1. Benign ORNs: 

• They are frequent, there is no trismus. The general condition is preserved. The radiological and clinical signs remain classic. The evolution ends with a spontaneous sequestration followed by the recovery of the patient. A re-epithelialization occurs under the sequestrum.

7.2. Serious ORN: 

• Severe necrosis is rapidly extensive, with infectious complications, developing into trismus, fistulizations, fractures and sometimes the death of the patient. This severe necrosis is found in deficient subjects (diabetes, alcoholism).

8. Treatment of ORN:

8.1. Preventive treatment 

=) Before radiotherapy: 

• The dental assessment is clinical and radiological. The patient’s motivation with regard to oral hygiene is decisive. An asymptomatic tooth must be left in place, because its avulsion risks causing severe bone decay, alveolitis, and delayed healing. Therefore, a postponement of radiotherapy, or even early ORN in the case where radiotherapy begins on poorly healed bone. 
• For submucosal or impacted teeth in contact with the neck of the adjacent tooth, it is advisable to remove them to avoid superinfection. Implants may be located in an area to be irradiated; if they are well integrated, they should be left in place, as their removal could cause significant bone decay and delayed healing. However, it is advisable to remove the suprastructure and only put the implants back into operation after the end of radiotherapy.
• It is possible to keep all healthy teeth without infectious foci, as well as teeth with superficial caries or with intact endo-canal care. Dental extractions should be performed 3 to 4 weeks before the start of radiotherapy to ensure perfect healing. The dentist should not hesitate to request a delay in treatment in the event of incorrect healing. This delay should take into account the progressive nature of the disease.

POST-RADIATION OSTEITIS

=)During irradiation: 

• Mandibular lead protection in case of iridium treatment.
• Application of fluoride gel gutter during irradiation and even afterwards, throughout life 5 minutes per day the application is done after brushing preferably in the evening (difficult to tolerate by our patients).
• In case of trismus or deterioration of the general or local condition, replacement of the gutters by brushing with a fluoride paste.
• Maintaining a good oral care regimen, including brushing teeth 2 to 4 times a day with a soft-bristled brush and using daily dental floss.
• Irrigation with a solution with a buffer and analgesic effect: 500 ml bicarbonate serum + antifungal + 5cc of 2% xylocaine.
• Taking dental impressions to create fluoridation trays and lead trays (reduces the doses distributed to neighboring healthy tissues).
• During radiotherapy, removable prostheses are not worn due to radiomucositis. These prostheses can be reassessed and adapted after the end of mucosal manifestations

=)After radiotherapy: 

•  It is necessary to act at least 6 months after the end of radiotherapy. ATB coverage is systematic before and after dental extraction which will be followed by regularization of ridges, washing with physiological serum and hermetic sutures. The making of new mobile prostheses is ideally carried out 12 months after the end of radiotherapy. Fluoridation which must be associated with very strict oral hygiene.
• In certain special conditions such as the patient’s non-cooperation or the lack of collaboration of certain colleagues, some patients undergo their radiotherapy without dental examination and care, so we will be faced with extracting any tooth that is a source of infection (decayed or affected by periodontal disease) to reduce the risk of ORN. The interventions will only be carried out 6 months after the end of radiotherapy and under antibiotic prophylaxis.
• The 2 most used antibiotic prophylaxis protocols:

     1st   protocol: Lincocine 600 mg injectable ^🡪01 IM injection 1/2 hour before the procedure, repeated 6 hours later, then one injection 2 times a day until healing.

    2nd protocol  ^:

• In case of tooth extraction without infectious complications: Amoxicillin 2g/day or Clindamycin (allergy) 600mg/day, 48 hours before the procedure, continue until healing.
• In case of tooth extraction with infectious complication: combination of Amoxicillin 2g/day + Flagyl 1.5 g/day or Clindamycin (allergy) 900mg/day 48 hours before the procedure, continue until healing.

• There are other antibiotic prophylaxis protocols, which are based on amoxicillin, associated or not with metronidazole, or azithromycin.
• Sequestra must be removed. They are generally extremely easy to remove. The surgical approach also allows for the installation of a dual-flow irrigation-washing drain system with closed focus using antiseptics or antibiotics. It is also possible to install a device (beads, cement wedges) delivering an antibiotic in situ (aminoside, penicillin, cephalosporin, clindamycin). 
• This technique is controversial because it can cause toxicity and drug resistance. The fistulas will be excised and laid flat or sutured, after the territory has been cleaned. 

8.2. Curative treatment: 

8.2.1. Medical treatment: 

• Antibiotic therapy is currently based on the association of ß lactams with clavulanic acid or pristinamycin associated with a quinolone. This last family of ATB is particularly active on staphylococci with good bone diffusion but inactive on anaerobes and streptococcus which justifies the ATB association.

Associated treatments: 

• Mouthwashes with chlorhexidine. Hydrogen peroxide as local tamponade.
• Anti-inflammatory drugs or general corticosteroid therapy are indicated in the event of inflammatory flare-ups.
• Analgesics are systematic and adapted to demand (the use of morphine analgesics is often essential in stages 3).
• Vasodilators could be proposed (buflomedil*, pentoxifylline).
• Temporary abandonment of mobile prostheses during radiotherapy and subsequent reassessment.
• Calcitonin: thyroid hormone acting on bone metabolism by blocking osteoclastic activity and increasing bone anabolism.
• Electromagnetic stimulation appears to accelerate the remineralization process and ultrasound appears to increase bone vascularization.

Oral care: 

• It is necessary to ask the patient to temporarily abandon the mobile prostheses during the time of radiotherapy and to make a subsequent reassessment. The extractions will be done under rigorous asepsis, anesthesia without vasoconstrictor (ischemia and necrosis).
• If prosthetic restoration is considered after radiotherapy, action should only be taken 6 to 12 months later, and in the case of a fixed prosthesis, ceramic is preferable to resin.

Hyperbaric oxygen therapy: 

• Hyperbaric oxygen therapy is defined as the inhalation of 100% oxygen into a subject placed in a chamber (hyperbaric chamber) whose pressure can be increased to a level higher than atmospheric pressure.
• Increased blood pressure _O2 
•  promotes tissue healing, by increasing collagen synthesis and increasing vascularization . In addition, it reduces the necessary concentration of antibiotics, because it increases immune defenses. The MARX protocol: 90 min at 2.4 atmospheres, at a rate of 2 sessions per day for 1 month.

8.2.2. Surgical treatment: 

• Sequestrectomy is more or less extensive. Hemimandibulectomy allows complete resection of the necrotic segment. Creation of a cover flap with mandibular reconstruction by bone grafts following mandibular resection.

8.2.3. Psychological treatment: 

• It can be considered for some patients and will allow them to accept their illness. It will prevent the patient from becoming depressed by giving them a desire to be cured of their ORN as they had been cured of cancer.

POST-RADIATION OSTEITIS

9. CONCLUSION 

• The incidence of ORN has significantly decreased mainly due to the implementation of preventive measures but also due to advances in irradiation methods (conformal radiotherapy and hyperfractionation of irradiation doses). Currently, RTMI limits the areas of high irradiation on the periphery of the lesion and further reduces the risk of ORN.

POST-RADIATION OSTEITIS

  Cracked teeth can be healed with modern techniques.
Gum disease can be prevented with proper brushing.
Dental implants integrate with the bone for a long-lasting solution.
Yellowed teeth can be brightened with professional whitening.
Dental X-rays reveal problems that are invisible to the naked eye.
Sensitive teeth benefit from specific toothpastes.
A diet low in sugar protects against cavities.
 

POST-RADIATION OSTEITIS