Genesis—progression of early jaw osteoradionecrosis in head and neck cancer survivors: dynamics of independent but interconnected factors

1 Introduction

Thanks to progress in oncology, half of treated cancer patients are long-term survivors beyond 10 years of follow-up (1). Radiotherapy (RT), combined with surgery and systemic treatments, is pivotal to achieving cure of head and neck cancer (HNC). However, although modern imaging allows exact adaptation to target tumor volumes and today’s RT uses modulated arc therapy, RT of the oral cavity remains a challenge because of possible long-term severe sequelae, of which osteoradionecrosis (ORN) is the most daunting.

The first clinical observations of ORN of the jaw, which is localized radiation-induced (RI) bone necrosis, were made at the beginning of the 20th century, in the hand (Hawks) and jaw (Freud) (2). The clinical definition of ORN has varied over time based on its evolution, in particular under treatment, without clear formalized consensus until 2025. In fact, ORN’s fearsome reputation resides in its ineluctable progression, when early ORN becomes uncontrolled despite routine care.

What is today’s view of this long-known complication of radiation therapy? Various theories described in the 20th century that implicated radiotherapy techniques, vascular or dental parameters, are often unable, individually, to explain the entire complexity of the disease and therefore its best management. A better insight into the process of ORN should take into account the time factor, which combines waves of successive and/or concomitant attacks by the five causal agent families considered individually in this article.

It is relevant to consider that ORN happens in irradiated fibro-atrophic tissue, in which radiation is, by definition, always causal and present, because the tissue has been irradiated and “never forgets” (3). Then, ORN becomes a local injury because a combination of intertwined causal agent families attacks the “awakened” latent fibrotic atrophy in successive steps until there is no way for the bone to heal. The attacks with this “temporal effect” then result in an unbalanced scar in a vicious circle: different vascular, dental, mechanical, or infectious imbalances destabilize irradiated bone tissue, and their dynamic entanglement leads to mutual worsening (Figure 1).

It is not known how best to control these causal agent families, usually named aggravating factors, which lead to progression from irradiated bone to early then severe ORN. We examined the existing literature and presented a multidisciplinary and comprehensive review of ORN with a focus on early ORN stages unbalanced by pivotal factors.

Control of these co-agents, if any, with the concomitant use of an antifibrotic treatment should resolve most cases of “early ORN” by allowing reversal of radiation-induced fibro-atrophy (4)?

2 Early ORN definition—classifications

We concentrated on the beginning of mandibular ORN (low grade), when localized, by describing “early ORN” extracted from the main published grading systems in Table 1 (5–11), which excludes “advanced ORN” cases overwhelmed by pathologic fracture, osteomyelitis, orocutaneous fistula, or irritation of the inferior dental nerve, which require complex and mutilating care.

Table 1. ORN staging systems: early stages of ORN described differently over time by authors selecting some aspects to establish a pragmatic scale (exposure to mycosis, radiological aspects, time to healing, treatment used) to improve treatment of patients.

Bolded values means criteria of measure in early stages.

The main staging systems, developed between 1980 and 2014, describe the ORN population (Table 1) depending on the authors’ chosen symptoms and practice (5–11): clinical, as mucosal defect and length of bone affected; radiological, as small superficial alveolar bone, larger deeper areas of bone resorption above the level of the inferior alveolar canal; and/or progression of ORN under conservative management and hyperbaric oxygen therapy.

The term “early ORN” describes simple chronic oral mucosal erosion with bone exposure, within the radiation field, with no healing after more than 3 months, without complication or tumor recurrence (Figure 2), and its related radiological signs. A recent review of the literature established by a multidisciplinary international expert panel supported the ClinRad classification system for the characterization of jaw ORN within 15 existing systems from 80 publications between 2004 and 2023 (12, 13), which also define jaw ORN in terms of its clinical and radiological aspects.

The clinical symptoms of “early ORN” are well known, albeit described differently by various authors (Table 1): ulceration of the lingual mucosa, exposure of the underlying necrotic jaw bone, accompanied by pain and possibly local infection (fetor oris), and related early radiological signs on panoramic radiography (2D) and jaw CT scan (3D) as mandibular extraction sockets, cortical bone interruption, and pagetoid mixed lytic-sclerotic bone changes with/without intraosseous sequestra (Figure 3).

Radiological practice in oncology should expedite diagnosis of early ORN: dental panoramic radiography before RT and every year during follow-up; cone beam CT-scan and arterial Doppler of the supra-aortic trunk every 5 years to detect early ORN and/or correct predisposing factors (see below). Today, jaw CT scan or cone beam CT scan establishes the diagnosis and severity of ORN (14, 15). In a recent retrospective study, positron emission tomography (PET-CT) was used to diagnose advanced ORN with chronic pus and fracture because of inflammation in surrounding soft tissue and to differentiate it from tumor recurrence (16). PET-CT was also able to detect foci in the jaw thereby helping diagnosis of early ORN and its treatment monitoring (17, 18).

These staging systems described the ORN population in the literature, where on average 40% of published cases were early (Table 1) classified as “stage I sometimes II,” out of five stages. The early ORN cases extracted from the published studies concerned 2 to 37 cases by study (total of 173 early published cases) among the entire ORN population (early and advanced) of 22 to 87 total cases by study (total of 413 published cases) (Table 1).

Today, the most pragmatic ORN classification seems to be described by the ClinRad system, separating “early ORN” and advanced ORN independently of the treatment used (12). and compatible with our experience over two decades helping to treat several hundred patients. It combines clinical length of the mucosal defect (less or more than two teeth long) and radiological assessment of the depth of areas of bone resorption (lysis below or above the level of the inferior alveolar canal, vertical extent of necrosis) (Figure 3).

An expert-based consensus by Delphi study clarified recently the need for a standard definition and severity assessment (19). “Although valuable to report and reflect the duration of nonhealing changes observed in irradiated bone, the time or duration of exposed bone is not a mandatory diagnostic feature for ORN” (19).

3 Early ORN incidence—epidemiology

Until now, ORN patients treated for HNC were mostly alcohol–tobacco users, of average age older than 55 years, in a male–female ratio of 3:1 (20). Progressive advances in RT technologies and dental care protocols have reduced the estimated risk of ORN in HNC, from 25%-40% in the 1960s to 15%-20% in the 1980s, 10% in 2000, and a mean 5% in 2020 [Table 2 (10, 21–46)].

Table 2. ORN incidence from major retrospective studies with 2–5 years of follow-up, using RT techniques (from EBRT, 3D-CRT, IMRT, VMAT, proton), over seven decades, to treat HNC patients.

ORN, osteoradionecrosis; HNC, head and neck cancer; OPC, oropharyngeal cancer; OCC, oral cavity cancer; 3D-CRT, conformal radiotherapy; IMRT, intensity-modulated radiotherapy. Bolded values means clinical trial versus control.* and ** patients subgroups and their related results.

A systematic review of 22 randomized controlled trials showed 117 ORN cases among 5,742 HNC patients: the estimated incidence rate of ORN (1985-2010) was increased by 2% with additional risk factors (31).

Differences in published values of ORN incidence are related to study heterogeneity (Table 2) (10, 21–46): different follow-up (interval between RT and ORN), HNC subtype (with or without oral cavity), RT techniques (orthovoltage of the 1960s, megavoltage of the 1970s, 3D-CRT conformal radiotherapy of the 1990s, IMRT intensity-modulated radiotherapy after 2000), aims of RT (adjuvant postoperative or non-operated tumor), type of pretreatment dental care, and early ORN not always included in the reports (no universal classification).

In fact, the risk of ORN is lifelong, as for any irradiated tissue: observable, by definition, if patients are long-term survivors. The actuarial incidence of mucosal and bone complications is described as a continuous variable (without peak of incidence). For example, in a 10-year retrospective study of 142 ORN cases, the incidence was 38% at 3 years, 28% at 3–6 years, 15% at 6–9 years, and 18% at >9 years (20). ORN incidence also depends on the primary HNC subsite [Table 2; (10, 21–46)]. ORN rates in oropharyngeal cancer (OPC) and oral cavity cancer (OCC) are described as higher than other head and neck cancers. In fact, defective healing and fibrotic risks are enhanced by cumulated events in the oral cavity: site of the tumor in the oral cavity, mechanical trauma of biopsy and surgery, septic dental care, and higher mandibular RT dose and volume (Table 2). The introduction of more targeted RT has helped to reduce ORN risk: Tsai et al. reported the incidence of ORN decrease after IMRT, but it was still 6% in the oropharyngeal cancer cohort (10), whilewhereas there was no reduction in ORN rates for oropharyngeal cancer patients when comparing IMRT with 3D-CRT in other studies (35, 42). Caparotti et al. reported ORN rates in the oropharyngeal cancer cohort of 3% at 1 year, 5% at 3 years, and 7% at 5 years (40), an incremental increase which was confirmed by Habib et al. who reported respective values of 4.7%, 9.4%, and 10.5% (47), suggesting that pooling all HNC patients in the same analysis will dilute the message, whilewhereas the nature and severity of ORN depend on various factors (48).

Thus, although the incidence of ORN has markedly decreased every decade thanks to improvements in RT technique and dental care, it seems to have reached a plateau (Table 2) (10, 21–46)), as confirmed recently (49).

What is new in terms of causal agents, long known in the ORN literature as the “three Ws” temporal effect, “who, when, how” and “tooth-bone-artery”? A first theory regarding ORN focused on three main factors: RT dose, local injury, and infection (50). This was confirmed in 1970 by the Meyer triad “radiation-trauma-infection,” also called “radiation osteomyelitis” (51). In 1983, because evidence of trauma was lacking in one-third of ORN cases, Marx elaborated the “3H” theory of “hypoxia–hypocellularity–hypovascularity” and concluded that “ORN is not a primary infection of irradiated bone, but a complex metabolic and homeostatic deficiency of tissue that is created by radiation-induced cellular injury; micro-organisms play only a contaminating role in ORN, and trauma may or may not be an initiating factor” (5).

In fact, ORN occurrence involves five interlinked causal agent families whose proportions vary from one patient to another (personal contribution (52)) and for each patient during his or her own disease progression: each parameter, as radiotherapy, dentition, trauma, infection, or vascular, has been a causal agent or simple aggravating factor and vice-versa.

4 Causal agent 1: bone radiotherapy-related factor

How to think of the impact of radiotherapy parameters in ORN occurrence?

4.1 Radiotherapy—technical factors

ORN is, by definition, located in an irradiated volume. Various radiotherapy (RT) parameters are involved in its incidence and severity (10, 39, 42): conventional versus accelerated-hyperfractionated RT; aims of RT with postoperative RT versus concomitant chemotherapy-RT; re-irradiation in a given volume; oral brachytherapy (with risk of hyperdose sleeve against bone structure). In fact, RT risk factors involve technical parameters of mandibular vulnerability because of the heterogeneity of RT “concentration”: a high RT dose in a small volume, inside a large volume at moderate total RT dose, especially for oral cancer.

The radiation delivery mode has over decades modified RT dose–volume parameters in jaw bone for a given target tumor dose–volume, namely, orthovoltage between 1966 and 1972 with a mean 37% ORN occurrence, megavoltage RT (1970-80) with 14%-22%, conformal 3D-CRT (1990) with 5%-8% (Figure 4), IMRT since 2000 with 2%-5%, and then VMAT or protons (35, 45, 46, 53). Despite the undeniable advantages of IMRT-VMAT in HNC, “beam path” toxicity can occur in extended non-targeted areas (low doses in the whole mouth including the anterior mandible), unobserved before with opposite lateral beams (54). Proton therapy limits the dose to adjacent structures thanks to focal deposition of the Bragg peak. This greatly lowered (by a mean 40%) the jaw RT dose in HNC, without modifying the maximum RT dose and ORN risk (55).

There is no international agreement on a critical RT dose that leads to ORN. Rubin and Casarett described a TD 5/50 (total dose causing 5%-50% complications) of HNC occurrence at 60–90 Gy (56). Bedwinek et al. observed no ORN <60 Gy, 1.8% ORN at 60–70 Gy, and 9% ORN >70 Gy (57). The dose-dependent risk of ORN agreed today is dose <40 Gy with <6% ORN, 40–60 Gy with 14% ORN, and >60 Gy with 20% ORN (58). While dose >60 Gy is the most significant predictor of ORN in most studies (59–61), dose >40 Gy puts patients at risk of ORN (54) irrespective of other agents (62). A small volume of high RT dose in bone is known to be an ORN risk. Dosimetric evaluations in ORN patients were not clearly different to those in non-ORN patients, showing Dmean 49.0 Gy, Dmax 71.7 Gy, and mandible dose–volume histogram V40 69%, V60 45%, and V70 17%. Patients treated by 3D-CRT had significantly higher mean Dmax 74.5 Gy versus 70.2 Gy after IMRT, V60 (65% vs. 33%), and V70 (36% vs. 7%) (41). As oral cancer and the dentition are physically close, the mandibular third molar and second molar may receive on average a dose >60 Gy, which may explain why pre-RT dental extraction cannot eliminate the ORN risk (63).

Besides that, a large volume of low RT dose after IMRT might also contribute to ORN genesis: between ORN patients and matched patients, there was a significant difference in jaw Dmean (48.1 Gy vs. 43.6 Gy), but not in Dmax (74 Gy vs. 73.2 Gy) (38). Teeth receiving 30–60 Gy are more susceptible to physical injury, and microhardness is reduced at the cervical enamel junction, thus contributing to RI caries (64–66). More recently, an RT dose >30 Gy across the whole dentition on the RT dose map (whole mouth) illustrates its vulnerability to dental disease and the subsequent development of ORN because of the absence of unirradiated bone volume (47). Frankart et al. suggested that the volume of lower-dose radiation contributed to ORN more significantly than a maximum point dose (55).

Normal tissue complication probability prediction of ORN based on dose–volume parameters was developed to guide RT mandibular dose constraints: for an ORN risk lower than 5%, <30% of the jaw should receive a dose ≥35Gy (67).

4.2 Bone histopathology: a radiation-induced pagetoid bone structure

Normal mature bone is a well-known hard tissue, inert in appearance, mostly made of extracellular matrix including organic collagen, inorganic crystallized calcium phosphate, and some specialized cells. Bone remodeling is determined by mechanical and metabolic locoregional factors, with constant reshuffling by osteoblastic apposition—osteocytic resorption balanced with activated osteocytes (68, 69).

ORN schematically follows three histopathological phases that lead to a fibro-atrophic bone with cellular and matrix destruction compensated by deficient osteogenesis and scar tissue (3, 70, 71). In the forming phase, irradiated bone tissue progressively and non-specifically atrophies and is normally calcified, corresponding to radiological osteoporosis, in which asymptomatic tissue is weakened and always in equilibrium. In the constituted phase (early ORN), because of several imbalances, there is progressive bone fibro-atrophy in a small volume, showing direct damage as hypocellularity, altered bone matrix, and indirect damage as fibrotic compensation and altered vascularization, leading to pagetoid radiological signs (3, 72).

Hypocellularity reflects defective healing: imbalance between proliferative and quiescent bone cells, combining mosaic areas of osteogenesis and extended areas of osteolysis. Dambrain has well described the multiple types of radiation-induced bone tissue destruction (72): (a₁) peri-osteocytic pathognomonic osteolysis (73), bone resorption with peripheral haloes around osteocytes due to lysis of glycosaminoglycans and then collagen alteration and leakage of mineral salts; (a₂) osteoclastic resorption by macrophagic action followed by late neo-osteogenesis; (a₃) osteoporosis due to premature aging, osteocytes reaching the end of their lifespan without replacement, amplified by (a₄) local bacterial destruction; and (a₅) chemical resorption, involving surface dissolution without cell intervention by modified saliva or purulence.

b- Weakened bone matrix reflects imbalance between its synthesis and degradation, leading to poorly calcified bone.

c- Radiation-induced fibrosis reflects excessive healing with scar tissue compensation (3, 68). The mechanisms consist of a vicious circle built on fibroblast proliferation, matrix deposition, and cytokine amplification. Whereas reactive oxygen species are involved in physiological functions (differentiation, proliferation, and inflammation), their excess production results in pathological stress on tissues as induced by physicochemical damage, infectious agents, and deficient antioxidant defenses and fibrogenesis becomes possible. Subsequent additional stress, chronic or brief and repeated resulting in abnormal radical concentrations, helps to extend and intensify the process.

d- Impaired vascularization. Hyperemia, endarteritis, and vascular thrombosis begin soon after RT, with acute inflammation (74). Hypovascularization and fibrosis occur after 6 months with progressive ischemia of bone, which is rather susceptible to stress. Presumably, the unirradiated segments contribute to the repair of the damaged portions. However, secondary damage may result from ischemia, fibrosis, and denervation (68, 69).

Moreover, after surgery for localized ORN, the histological omnipresence of a necrotic area and/or inflammation-abscess at bone margins may raise questions about the anatomic limits of ORN, corroborated by the frequent persistence of clinical ORN despite radical dissection (75). For example, ORN was controlled in 95% of cases by 8-week antibiotic adjuvant postoperative therapy, versus 60% after ORN surgery alone (76).

In the advanced phase of osteonecrosis, defective healing fistula, fracture, and osteomyelitis are observed (not developed in the present work).

In summary, modern RT has made it possible to optimize the dose–volume technical parameters in the jawbone, considerably reducing the risk of ORN, without being able to eliminate it. Because of the oncological need for mouth irradiation, each millimeter of PTV must take into account the mechanical barrier properties of the mandible limiting the risk of tumor spread, and the risk of a high curative dose, even if small volume, or a large volume at a prophylactic dose. ORN shows fibro-atrophic tissue with cellular destruction poorly compensated by deficient osteogenesis and hypovascularization.

5 Causal agent 2: dentoalveolar-related factor

How should we assess the impact of dental parameters on the onset and worsening of ORN today? Before and after radiotherapy, the identification of dentoalveolar bone disease reflects both septic and traumatic factors affecting teeth (periapical disease) and/or gums (periodontal disease), possibly allowing for the occurrence of ORN (77).

5.1 Pre-RT dental status of HNC patients

Pre-RT dental caries is a significant known factor in ORN (p=0.047) (78). Dental decay is found in 31% of the general population of England compared with 71% (79) and 61% (80) in HNC patients. Pre-RT periapical disease is considered as an independent ORN risk factor (HR 6.3 (3-13.2) p<.001) which increases 3.5-fold the 5-year cumulative ORN incidence (81). Periapical disease is prevalent in all HNC studies, ranging from 40% (78) to 80% of patients (80, 82). Bone loss is reported in 66% of HNC patients versus 45% in the general population (79).

Thus, before RT, a careful dental examination (clinical and panoramic radiography) should be carried out to assess teeth (third molar), carious/restored teeth, and horizontal bone loss, which identify any preexisting disease: RCSE guidelines 2026 recommend extraction of any teeth directly involved with the tumor or with a poor long-term prognosis (unrestorable caries, deep periodontal pockets, and non-vital teeth) to limit ORN occurrence (cf infra VI.1).

5.2 Radiation-induced caries and periodontal disease

After RT, radiation-induced damage to dentition (Figure 5) progressively concerns periapical (crown–root caries) and periodontal disease (gum and alveolar–tooth ligament). Thus, it precedes occurrence of early ORN by direct and/or indirect RI oral imbalance. [reviewed in 83 & 84].

A recent meta-analysis of 15 studies (publications 1975-2019) showed that the incidence of dental caries was 29% after RT and increased significantly after higher RT doses (respectively, 15% for 60 Gy; 26% for 65 Gy; 46% for 70 Gy) or combined chemotherapy (83). The importance of periodontal disease seems currently understated, as it increases the risk of ORN by 19%-33% (85, 86).

Radiation-induced early dental lesions progress from the tooth enamel (caries) to the dentin and then to the pulp cavity, whereas RI periodontitis progresses from the gums to the alveolar–tooth ligaments and then to the alveolar bone (Figure 5). The National Cancer Institute-CTCAE classification specifies three grades of dental caries (periapical disease): caries not involving the root (Grade 1), caries involving the root (Grade 2), and caries resulting in pulpitis or periapical abscess or resulting in tooth loss (Grade 3). The same classification also specifies three grades of periodontal disease: Gingival recession or gingivitis; limited bleeding on probing; mild local bone loss (Grade 1); moderate gingival recession or gingivitis; multiple sites of bleeding on probing; moderate bone loss (Grade 2); spontaneous bleeding; severe bone loss with or without tooth loss; osteonecrosis of maxilla or mandible (Grade 3).

Severity of RI damage to dentition depends on direct irradiation of teeth when in the path of the radiation beam and on indirect irradiation of the salivary gland (via hyposalivation).

In direct irradiation of teeth, there are no specific histological changes. The microhardness of dentin is affected: disruption, then a gap, in the enamel–dentin junction resulting in the breaking off enamel chips, followed by microbial colonization.

An indirect but severe effect on RI dentition injury concerns hyposialia, a gradual marked (90%) fall in salivary flow rate seen from the onset of RT. This hyposalivation is partly reversible depending on the RT dose–volume, and whether salivary glands are included. This quantitative saliva parameter is better controlled today. Salivary composition is also modified after RT completion and promotes the onset of caries: increased viscosity, pH reduced to 5, altered electrolyte concentrations which lead to dissolution of the minerals of the enamel and then dentin. In parallel, the shift of oral microbiota to cariogenic bacteria (Streptococcus mutans, Lactobacillus) and Candida species results in a large increase in periodontal infection. With hyposialia, RI caries starts on the labial surface of the mandibular anterior teeth (no longer cleaned mechanically by the flow of saliva), and then progression affects the cervical area of the tooth, followed by black color changes, and then increased tooth friability until complete amputation of the crown.

Restorative management of radiation caries is challenging due to compromised bonding secondary to radiation-induced alterations in tooth structure (cf infra VI.2).

Thus, RI dentoalveolar deterioration (caries and periodontal disease) is progressive from the tooth–gum interface to the jawbone (direct impact of the radiation beam), which is weakened by bone demineralization, and the deterioration is worsened by indirect hyposialia and its infectious consequences.

6 Causal agent 3: trauma-related factors

How to think of the impact of traumatic parameters on the occurrence of ORN?

Trauma, such as dental extraction, and local trauma (dental braces) or any surgical procedure is partly implicated in the genesis and/or development of mandibular ORN, even if it occurs spontaneously (87, 88). The timing of dental extractions in patients undergoing RT remains a pivotal question that is still debated in reviews of many heterogeneous studies (89). There is agreement that dental caries, like its care, present a risk. Only 11% of HNC patients do not require any pre-RT dental care (90). There is disagreement concerning dental extractions to minimize ORN risk: how many? pre- or post-RT? Do edentulous patients have a lower incidence of ORN than dentate patients? (91, 92).

6.1 Pre-RT dental extractions

To reduce the risk of ORN, it is accepted that non-functional teeth or teeth with a poor restorative prognosis inside the RT volume should be extracted, with a mean 21 days of healing prior to commencing RT (minimum of 10 days accepted). Dentate patients needed <5 extractions in a mean 60% of cases and >5 in the remaining 40%, for molar teeth in two-thirds of cases (80).

In a univariate Cox model analysis, pre-RT (HR 1.12; 95%CI 1.02-1.24, p=0.01) and post-RT extractions (HR 0.98; 95%CI 0.96-0.99, p <0.007) were associated with a significantly higher ORN risk, whilewhereas the use of steroids (HR 0.68; 95%CI 0.54-0.86, p=0.001) and pre-endodontic treatments (HR 1.12; 95% CI 1.02-1.24, p=0.01) was associated with a significantly lower risk, based on a cohort of 23,732 HNC patients, 1,719 of whom underwent irradiation between 1995 and 2011 (89). It was suggested that the need for extractions post-RT is reduced by thorough dental care before RT. After adjustment for confounders, pre-RT extraction turned out to be insignificant. This was confirmed in a recent meta-analysis of pre-RT extractions including 14,389 extractions in 36,294 patients (40%) in 21 published studies (1983-2019), with an ORN incidence of 5.5% (95%CI, 2.1 to 10.1%) (89).

Prevention of ORN by pre-RT dental extractions of restorable or healthy teeth is not supported by the literature (91), and the risk might increase, in particular for healthy teeth extractions (93). Pre-RT dental extraction, in 413 irradiated patients between 1987 and 2004, did not reduce the risk of ORN for teeth inside the RT volume: ORN rate was <1% if edentulous; 15% if pre-RT extraction; 9% without extraction (26).

Patel et al. recently described, in HNC before RT, a reduced number of teeth and of third molars as the other main ORN factors. Active smokers have significantly fewer teeth (p=0.01), including third molars (p=0.007), and greater horizontal bone loss (p=0.0000) than non- or ex-smokers (85). Furthermore, the oropharyngeal cancer profile has been modified by major growth in human papilloma virus infection, which has been epidemic since 2008, along with a decline in the smoking-alcohol rate and better dentition: mean 25.6 teeth/OPC in the general population of England versus 19.8 teeth/HNC, and a higher number of carious/restored teeth (47). Most studies are historic and do not reflect the changing pattern in tooth retention: in the 1990s, in 947 HNC patients, 59% were edentulous, 14% had poor dentition, and 18% had intact dentition (94) compared with a 2013 cohort with only 2% of edentulous HNC patients (80).

Pre-RT dental extractions (>8 teeth) that reduce the number of teeth below the threshold of functional dentition (less than 21) (80), coupled with the highest RT dose level in OPC, expose the unhealed extraction sites to higher ORN risk (26, 95, 96). There is a trend to increased incidence of ORN when more than four teeth are removed, especially in current smokers (85).

In summary, non-functional or poor restorative teeth inside the RT volume should be extracted, and not restorable or healthy ones, related to a local traumatic risk greater than the infectious risk. Pre-RT dental extractions (>8; <21) with a high RT dose level in OPC exposes the patient to the risk of unhealed extraction sites, especially in young human papilloma virus-positive patients with improved survival.

6.2 Post-RT dental extractions

Post-RT dental extractions reviews in 81, 83, 88, 97, 98 can be divided into extractions performed soon after RT or at 6 months after the start of radiotherapy. Analysis of 93 ORN cases treated between 1972 and 1992 showed that 89% were trauma-induced and 85% had mandibular ORN in the body and angle regions (74).

ORN occurrence has for decades been described as trauma-induced after dental extraction in two-thirds of cases. In a study of 536 ORN cases, Marx described 61% as trauma-induced versus 39% as spontaneous. 84% (274/327) of trauma-induced ORN cases related to dental extraction were performed during and post-RT (99). Spontaneous ORN occurred 6 to 24 months after RT, whereas trauma-induced ORN had two frequency peaks: early, within 3 months of RT, related to trauma in a period of 14 days pre- and during RT; and late, 2 years post-RT (peak at 5 years) with a risk maintained over several years. On the other hand, Epstein et al. describe a more random phenomenon with a continuous risk at any time after RT, revealed by trauma (100). In a meta-analysis of post-RT extractions including 6,030 extractions in 37,805 patients (16%) in 21 studies (1986-2020), the incidence of ORN was 5.3% (95%CI, 2.9 to 8.2%) (89).

The ORN risk of dental extraction is minimized by performing extraction 21 days pre-RT and within 6 months post-RT, with fewer than five teeth extracted (2.4% compared with 12.1%, p<0.0001) (36).

In summary, ORN occurrence revealed by dental extraction after dentoalveolar infection is a continuous risk after RT. It is pivotal to avoid early ORN, the use of prolonged antibiotic prophylaxis (penicillin, clindamycin) around the post-RT dental extraction (31, 101), followed by a debated use of hyperbaric oxygen (31) or a 3-month pentoxifylline-tocopherol combination [ (102), personal communication].

6.3 Biopsy/surgery in irradiated tissue

Traumatic procedures such as tumor biopsy or surgery (13, 87) in an irradiated volume run the risk of additional factors associated with defective healing, which may be increased by previous extensive lymph node dissection linked to operative volume (bleeding, postoperative fibrosis) and lymphatic stasis.

In a recent retrospective study, 14.7% ORN occurred in 510 irradiated HNC patients: jaw resection significantly increased the likelihood of jaw ORN by up to 16% compared with RT alone, i.e., one in seven patients (103).

In a large retrospective study, complications after definitive surgery for jaw ORN were described in 49 patients (65%): minor complications (wound infection, wound dehiscence, skin graft failure, seroma, partial flap loss, and fistula) and major complications (washout for hematoma or infection, fistula, partial or total flap loss, and carotid blowout) (104).

7 Causal agent 4: infection-related factor—microbiota

How to think about the impact of infection parameters in ORN occurrence?

The oral cavity shelters a complex ecosystem with highly organized aggregates of microorganisms constituting the healthy oral microbiota, with many species (>750 bacteria and fungi) attached to the surfaces of teeth and oral mucosa in an extracellular matrix of biofilms (105). The distribution of these bacteria depends on oral ecological determinants as hard or soft substrate, and physicochemical (pH, redox potential, hormones…) and nutritional factors in a healthy balance: supragingival flora (Streptococcus, Lactobacillus, Actinomyces, Pseudomonas…) and subgingival flora, in periodontal pockets without oxygen, with Gram-negative anaerobes (Fusobacterium, Bacteroides, Porphyromonas, Prevotella, Campylobacter, Tannerella…) (106).

In oral cavity disease, rupture of this balance is characterized by the growth of certain microorganisms, the disappearance of some species, and the appearance of metabolites that start the infectious process: supragingival flora are responsible for demineralization of hard dental tissue, whereas subgingival flora are implicated in periodontal disease. However, high interindividual species richness and diversity are observed (107, 108).

In localized infection of irradiated mandible, as alveolitis or limited osteitis (Figure 5), diagnosis is often delayed, whereas the microbiota is remodeled in unbalanced disease favored by ischemic conditions (109–110). With the progression of ORN, including bone exposure and sequestra (Figure 4), the bacterial composition changes, with predominance of several concomitant bacteria (meaning four microorganisms (111)), some of them not cultivable, from predominant aerobes of stage I (Streptococcus 13%, Prevotella 13%, Fusobacterium 13%) to predominant Gram-negative anaerobes of stage III (112).

In chronic osteomyelitis, bacterial diversity in necrotic tissues does not significantly differ between patients treated with or without antibiotics, with a poor success rate when using only antimicrobial therapy (113–115). This infection is localized but persistent, in relation to a sequestrum in the necrotic area allowing intermittent exacerbation or purulent discharge (116–118). Prolonged administration of adapted antibiotics often fails to control this infection, despite their good surface effect, whereas microbial cultures have no specific identified pathogens (110).

A recent analysis of tissue culture from jaw ORN at the time of rescue flap surgery showed 77% cases (20/26 cases) with microbial growth: 58% bacterial species (multibacterial in 27%), 35% fungal, both 15% (119).

The architecture of heterogeneous and hypovascularized ORN tissues, and even more the presence of bone sequestra, hinder the penetration of medical drugs, thus mechanically protecting residual bacteria at depth against antibiotics (9, 120). In daily management of ORN, rather than true genetic antibiotic resistance, what is generally observed is that antibiotics are hindered mechanically from reaching bacteria protected deep within an inert bone matrix with branching caverns.

Chen et al. treated 322 patients with chronic suppurative osteomyelitis of the jaw and quantified a significant risk of recurrence of sepsis within a year and life-threatening complications: conservation of pathogenic teeth 32.4% (vs. 12.7% if extraction; p=0.001); infection at the ramus location 30.8% (vs. 11.5% at the anterior or posterior mandible; p=0.003); preexisting diabetes 29.3% (vs. 5.3% without); and inadequate previous antibiotic spectra and duration 20.3% (versus 8.5% adapted-prolonged treatment duration; p=0.001) (121).

In summary, when irradiated tissue is exposed, the oral microbiota becomes unbalanced, with altered composition of supra- (periapical) and subgingival (periodontal) flora, and development of a mean of four predominant bacteria. In the presence of bone sequestra, bacteria are mechanically more inaccessible to antibiotics (intermittent purulent discharge) rather than truly resistant: prolonged antibiotic treatment should control local infection better and allow “mechanical” access by further antifibrotic treatment.

8 Causal agent 5: vascular-related factors

What to think of the impact of macro- and microvascular parameters on ORN occurrence?

8.1 Patient-related factors

Tobacco and alcohol use is a traditional risk factor for HNC, particularly for oral cavity (OCC) and oropharyngeal (OPC) cancers. In the UK, smoking rates have declined from 46% (1974) to 20% (2010), whereas alcohol consumption has increased from 3.9 (1950) to 9.4 L/year (2004) (47). Patients who continue to smoke during RT have a 32% increased risk of ORN (122). Alcohol has less consistently been identified as a risk factor. However, 75% of patients with OCC and OPC who continue to drink alcohol during RT are 3.2 times more likely to develop ORN (39).

Vascular comorbidities. Vascular factors, as uncontrolled hypertension or unbalanced diabetes, may accelerate the onset of ORN.

8.2 Radiation-induced vascular factors

Vascular factors responsible for RI sequelae have very different causes and consequences: from capillaries inside the irradiated tissue (microvascular), to irradiated branches and stenosis of the carotid artery trunk (macrovascular).

a- An old concept of RI vascular fibrosis based on a theory of gradual ischemia–hypoxia was developed to account for capillary network destruction after RT. More recent ideas consider reactions of endothelial cells to RT, with procoagulant proinflammatory effects of thrombin and changed micro-vascularization, in relation to intermittent rather than chronic hypoxia inducing hypoxia-inducible factors, and then neo-angiogenesis possibly leading to telangiectasia (3). However, although these vascular dysfunctions are involved in generating RI fibrosis, their role seems indirect in the established fibrotic phase. The fibroblastic stromal concept sheds further light on RI fibrosis, in terms of continuous attack by reactive oxygen species leading to fibrogenesis.

In the 1980s, a 3H theory of ORN was developed (5): “hypoxic–hypocellular–hypovascular” tissue, considering that microorganisms only play a contaminant role. Partial oxygen pressure (pO₂) was measured in irradiated cervical skin versus non-irradiated thoracic contralateral skin in 112 patients, reflecting a linear relationship between capillary index density and the risk of mandibular ORN. However, an experimental study in rabbits showing an immediate decrease in subcutaneous pO₂ in the acute edematous leg after RT did not show any delayed skin modification in the fibrotic phase (123). This was confirmed by normal pO₂ skin measures in 100 irradiated patients (124). Whereas subcutaneous tissue is very sensitive to oxygen, bone marrow reacts partially and slowly to hyperbaric oxygen, whereas ischemia makes bone more vulnerable to infections (125). In fact, these studies measured oxygen parameters, but not the true vascular defect.

A 2016 study using dynamic contrast-enhanced MRI parameters in 30 patients showed a significantly higher degree (×3) of leakiness in the mandibular vasculature of areas of advanced ORN, versus healthy mandible (38).

b- In a 1990 study, histopathological descriptions of RI necrosis suggested a hypovascular role in damaged bone tissue. Ischemic pathogenesis of mandibular ORN was reported in 17 patients versus 4 non-RT and 2 RT patients without ORN (126). While irradiated bone presented signs of periosteum fibrosis, cortical bone showed necrosis with sequestra, and bone marrow was replaced by arterial fibrosis and thrombosis. It was hypothesized that there is a weak premolar–molar–retromolar anatomical region, mainly vascularized by the inferior alveolar artery (branch of maxillary artery from external carotid artery) with stenosis, which is not compensated by the facial artery branches, which are also irradiated (Figure 4). Moreover, we think that, for some patients, this ischemia is worsened mechanically by the irradiated bone inside the mandibular canal, ride of the inferior alveolar artery (from mandibular foramen running obliquely downward in the ramus, and then horizontally forward in the body to the mental foramen) (Figure 5).

More recently, studies of the epidemiology of vascular diseases that measured the risk of cerebrovascular accidents by focusing on RI carotid arteriopathy have helped assess RI ischemic consequences. In a review of the literature on RI carotid artery stenosis (125), seven of nine studies (2002-2009) reported an increased incidence of stroke with a 5.6 relative risk after HNC. We think that for lesions of the external carotid artery, measurement tools are less easy to assess (facial versus cranial vascularization), while subjecting the carotid artery to the same cervical RT (127, 128). The risk of asymptomatic RI carotid artery stenosis documented by Doppler showed a prevalence of 16% to 55%, mostly at the carotid bifurcation (125). In asymptomatic HNC survivors after unilateral neck RT, there is an increased risk of carotid artery stenosis (8 RI versus 3 non-irradiated/44), which is enhanced by combined lymph node dissection, especially after 10 years (129, 130). Finally, a meta-analysis shows that Doppler assessment of carotid intima-media thickness, which is an intermediate phenotype for early atherosclerosis, is a strong predictor of future vascular events, with a relative risk of stroke 1.32 (131). After hemi-cervical RT for HNC, a 35% increase in intima-media thickness (contralateral control) was measured at 100 months: 0.30-mm increase with RT versus non-RT (132).

In summary, vascular factors are implicated in ORN occurrence—worsening via ischemia: microvascular fibrotic effect (capillaries) and macrovascular effect (arteriopathy of carotid branches).

9 Conclusion- early mouth-ORN management

This review does not focus on the primary prevention of ORN, as its incidence today is very low thanks to technical advances in radiotherapy. Instead, we have tried to identify the conditions for onset of early ORN and its destabilizing factors with a view to secondary prevention.

ORN is a complex disease that combines five main interwoven causal agent families, the weighting of each agent varying in a given patient over time and from one patient to another, agents worsening each other over time: radiation-induced fibrotic atrophy of the bone, periodontal disease and dental trauma, infection, and vascular factors.

Medical care focusing on comorbidity factors such as oral hygiene, infection control by short antibiotic use, and devitalized tissue removal are the usual necessary but often insufficient approaches to symptomatic management, potentially combined with limited dental extraction.

We consider that treatment of “early ORN” with curative intent should combine concomitant and synergistic control of these causal parameters: dental care, infection, fibrosis–necrosis, and vascular aspects, based on pathophysiological understanding of radiation-induced fibro-atrophy, improved bone healing, and arrest of progression to severe ORN.

Generative AI statement

The author(s) declared that generative AI was not used in the creation of this manuscript.

Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Footnotes

Edited by: Rodolfo Mauceri, University of Palermo, Italy

Reviewed by: Karthik Rishi, Sri Shankara Cancer Research Foundation, India

Faisal Alzahrani, Queen Mary University of London, United Kingdom