Review
Osteoradionecrosis of the jaws: current understanding of its pathophysiology and treatment

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Abstract

During the past 80 years a number of theories about the pathogenesis of osteoradionecrosis (ORN) have been proposed, with consequent implications for its treatment. Until recently tissue hypoxia and its consequences were accepted as the primary cause, and this led to the use of hyperbaric oxygen (HBO) for both treatment and prevention of complications of radiotherapy in the head and neck. The benefit of HBO has not been validated. A new theory for the pathogenesis of ORN has proposed that damage to bone is caused by radiation-induced fibrosis. Cells in bone are damaged as a result of acute inflammation, free radicals, and the chronic activation of fibroblasts by a series of growth factors. New treatments have therefore been devised that include pentoxifylline, a vasodilator that also inhibits fibrosis, and tocopherol (vitamin E) to reduce damage caused by free radicals. Impressive results in terms of reversing the process of ONR have been reported using these agents. It has been suggested that this theory and these agents could be the basis of future treatment and prevention of ORN.

Introduction

In 1922, Regaud published what was arguably the first report about osteoradionecrosis (ORN) of the jaws after radiotherapy.1 During the past 80 years, this condition has persisted as a consequence of radiotherapy for head and neck cancer in an appreciable minority of patients. Since then several theories have been propounded to explain its cause including the release of histamine, the theory of radiation, trauma, and infection2 and, until recently, the most widely accepted theory of hypoxia, hypovascularity, and hypocellularity.3 There is a general consensus, however, about the clinical presentations of ORN, which are pain, drainage, and fistulation of the mucosa or skin that is related to exposed bone in an area that has been irradiated. Once ORN is recognised, it is irreversible and extremely difficult to treat. We explore recommendations and current theories about its aetiology, pathogenesis, and treatment.

Section snippets

Terminology and definition

Various terms and definitions of ORN are given in Table 1, Table 2. Perhaps the most widely used definition of ORN that affects the jaws is based on clinical presentation and observation: irradiated bone becomes devitalised and exposed through the overlying skin or mucosa without healing for 3 months, without recurrence of tumour.4

Although widely used, this definition is far from perfect, and can be criticised for two reasons; the duration of the bone's exposure to radiation, and the definition

Theories of the pathophysiology of osteoradionecrosis: a critical appraisal

Watson and Scarborough reported three crucial factors in the development of ORN based purely on clinical observations; exposure to radiotherapy above a critical dose; local injury; and infection.28 Early experimental models of the pathophysiology of ORN showed evidence of bacteria in tissues affected by ORN, and documented microscopic tissue changes, namely thickening of arterial and arteriolar walls, loss of osteocytes and osteoblasts, and the filling of bony cavities with inflammatory cells.29

Contemporary understanding of the pathophysiology of osteoradionecrosis: radiation-induced fibroatrophic theory

Radiation-induced fibrosis is a new theory that accounts for the damage to normal tissues, including bone, after radiotherapy.47 It was introduced in 2004 when recent advances in cellular and molecular biology explained the progression of microscopically observed ORN.

The histopathological phases of the development of ORN closely reflect those seen in chronic healing of traumatic wounds.48 Three distinct phases are seen: the initial prefibrotic phase in which changes in endothelial cells

New protocols for prevention and treatment of osteoradionecrosis

Based on current understanding of the pathophysiology of ORN, new protocols could be developed for its prevention and treatment. Previously, patients who required multiple dental extractions or extensive surgical extractions, or both, might have been given HBO before and after operation. Instead, all patients having dental extractions could be given eight weeks of pentoxifylline 400 mg twice daily with tocopherol 1000 IU, starting a week before the procedure. If ORN developed then they could be

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