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J Am Dent Assoc, Vol 140, No 7, 864-875.
© 2009 American Dental Association
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CLINICAL PRACTICE

Bisphosphonate and Nonbisphosphonate-Associated Osteonecrosis of the Jaw

A Review



Soulafa A. Almazrooa, BDS and Sook-Bin Woo, DMD


   ABSTRACT
TOP
 ABSTRACT
SYSTEMIC MEDICATIONS
 RADIATION
 INFECTION
 DIRECT CHEMICAL TOXICITY
 TRAUMA
 IDIOPATHIC BENIGN SEQUESTRATION...
 OTHER ETIOLOGIES
 CONCLUSIONS
 REFERENCES
 
Background. The term "osteonecrosis of the jaw" (ONJ) is used almost synonymously with the term "bisphosphonate-associated ONJ." However, necrosis of the jawbones leading to exposure of bone is associated with other factors.

Types of Studies Reviewed. The authors conducted a literature search using PubMed to identify original research articles and case reports that described oral conditions and associated factors that result in sequestrum formation and bone exposure.

Results. After reviewing conditions that may lead to necrosis of the jawbones, the authors divided the causes of ONJ into the following conditions: systemic medication use; radiation; bacterial, viral and deep fungal infections; direct chemical toxicity; trauma; idiopathy; and other etiologies.

Clinical Implications. Clinicians should take a careful history when evaluating patients with ONJ because ONJ may result from one or more factors.

Key Words: Osteonecrosis of the jaw; bisphosphonates; antiangiogenic drugs; radiation; infection; trauma

Abbreviations: AAOMS: American Association of Oral and Maxillofacial Surgeons • BONJ: Bisphosphonate-associated osteonecrosis of the jaw • HBO: Hyperbaric oxygen • IMRT: Intensity-modulated radiotherapy • IV: Intravenous • NICO: Neuralgia-inducing cavitational osteonecrosis • ONJ: Osteonecrosis of the jaw • PRON: Postradiation osteonecrosis • TMJ: Temporomandibular joint

The term "osteonecrosis of the jaw" (ONJ) is used almost synonymously with the term "bisphosphonate-associated ONJ" (BONJ). However, necrosis of the jawbones is associated with other etiopathogenic factors. We conducted a literature review using PubMed to identify original research articles and case reports that described oral conditions and associated factors that result in sequestrum formation and bone exposure, including the use of bisphosphonates. In this article, we use ONJ to refer only to the clinical condition of necrosis of the jawbones and include an explanation of its putative etiopathogenesis.

The definition of ONJ we use refers to exposure of dead bone, regardless of the cause. Although conditions such as osteomyelitis may lead to necrosis of bone and sequestrum formation, the bone usually is not exposed to the oral cavity and, thus, is primarily a radiographic finding. Microscopically, the necrotic bone—regardless of its etiology—is composed of nonviable bone trabeculae that have empty lacunae often with ragged, scalloped borders (Figure 1Go). Chronic or acute inflammatory cells, abscesses or bacteria may be present.


Figure 1
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  		Figure 1. Photomicrograph from a patient with bisphosphonate-associated osteonecrosis of the jaw of necrotic bone showing ragged margins, empty lacunae and actinomycotic colonies surrounded by suppuration (hematoxylin and eosin stain, magnification x100 ).

 
Such necrosis may result from ischemia, but exacerbating or contributing factors may be understood better than the etiopathogenesis. In this article, we divided the causes of ONJ into the following categories: use of systemic medications, radiation, infection, direct chemical toxicity, trauma, idiopathy and other etiologies.


   SYSTEMIC MEDICATIONS
TOP
 ABSTRACT
 SYSTEMIC MEDICATIONS
RADIATION
 INFECTION
 DIRECT CHEMICAL TOXICITY
 TRAUMA
 IDIOPATHIC BENIGN SEQUESTRATION...
 OTHER ETIOLOGIES
 CONCLUSIONS
 REFERENCES
 
Bisphosphonates. The primary action of bisphosphonates is inhibition of osteoclastic activity. Because osteoblastic activity is coupled tightly to osteoclastic activity, the end result is suppression of bone turnover.1,2 This action makes bisphosphonates desirable to use in the management of osteoporosis (in which osteoclastic activity is increased) and cancer affecting the bone, in particular multiple myeloma and metastatic solid tumors (for example, metastatic breast, prostate and lung cancers). In the patients with multiple myeloma and metastatic solid tumors, bisphosphonates reduce skeleton-related events such as hypercalcemia, pathological fracture, spinal cord compression, bone pain, and the need for surgery or radiation.3–5

The American Association of Oral and Maxillofacial Surgeons (AAOMS) defines BONJ as exposure of portions of the jawbone in patients who have been exposed to bisphosphonates that has persisted for more than eight weeks with no history of radiation therapy to the jaws.6 The Australian and New Zealand Bone and Mineral Society, Osteoporosis Australia, Medical Oncology Group of Australia and the Australian Dental Association define BONJ as an exposed area of bone present for more than six weeks.7 The American Society of Bone and Mineral Research uses the term "suspected" for BONJ in which bone has been exposed for less than eight weeks, and at eight weeks or longer, it uses the term "confirmed."8

While it is clear that bone turnover is suppressed, why the bone becomes exposed is less well-understood. Sixty percent of patients reported onset of BONJ after undergoing dentoalveolar surgery or extractions, but 40 percent did not.9,10 Because bone remodeling is required after extractions, this supports the theory that suppression of bone turnover plays an important role in the pathogenesis of this condition. Whether lack of repair of physiological micro-damage plays a role is unresolved. The lack of or slowness in the remodeling of extraction sockets in patients with BONJ after the usual period of six months also supports the theory of suppression of bone remodeling.11,12

The most important risk factors for developing BONJ are potency of the drug and cumulative dose. Aminobisphosphonates have a much higher association with BONJ than do nonaminobisphosphosphonates, and intravenous (IV) administration increases the risk of developing BONJ as much as 4.4 times.13,14 Zoledronic acid followed by pamidronate (both are IV preparations) pose the highest risk.8–10,15,16 Patients taking bisphosphonates monthly for oncologic purposes have a prevalence rate of 3 to 7 percent of developing BONJ.15,17,18 Another factor that plays an important role is trauma, such as tooth extractions.9,10,13

Clinically, the lesions appear as exposed bone, which is painful in 60 to 69 percent of cases (Figure 2Go).9,13 AAOMS designates exposed bone with absence of pain and infection as Stage 1 BONJ.6 Pain may be associated with suppuration or infection and intraoral sinus track formation (Stage 2 BONJ). If there also is extraoral fistula, exposed necrotic bone extending beyond the region of the alveolar bone, pathological fracture, osteolysis extending to the inferior border or oroantral communication, the disease is designated Stage 3 BONJ. Other staging systems, however, also have been proposed.19 More recently, Mawardi and colleagues20 suggested that BONJ might occur even in the absence of exposed bone (Stage 0). Similarly, the AAOMS’ recent position paper included Stage 0 in its modified classification.6 Stage 0 exists when the patient has clinical nonspecific symptoms of pain, loose teeth not explained by periodontal disease, intra-oral fistula not explained by pulp necrosis and radiographic findings suggesting BONJ. The results of one study showed that 27 percent and 64 percent of patients had Stage 1 and Stage 2 BONJ, respectively.21


Figure 2
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  		Figure 2. A. Bisphosphonate-related osteonecrosis of the right mandibular torus. B. Bisphosphonate-related osteonecrosis of the left lingual mandible.

 
Microbiological studies have shown growth of Actinomycetes species and Eikenella corrodens.9,22,23 However, a diagnosis of actinomycosis should be made only if the clinical features of pain, sinus tracts and sulfur granules are noted either clinically or through histopathology.24 Radiographs have revealed no findings of BONJ in early lesions, thickening or loss of the lamina dura, mottled radiolucency or radiopacity, or persistent extraction sockets.9,13,16,22

Treatment generally is nonsurgical except for in patients whose BONJ is at Stage 3. At this stage, mobile sequestrum should be removed.6 Antimicrobial rinses such as chlorhexidine mouthrinses and systemic antibiotic therapy with careful follow-up are the mainstays of treatment at this stage, and they have led to resolution of or stable lesions in 53 percent and 37 percent of cases, respectively.21 More detailed discussions of specific dental treatment and prevention strategies have been reported elsewhere.6,25 The role of hyperbaric oxygen (HBO) therapy in treating BONJ is unclear.26–28 Dental implants have not been reported to be lost prematurely in patients who have been receiving alendronate therapy; however, the numbers of patients in these reports are fairly small and most of these patients received oral bisphosphonates for less than five years.29–33

In general, elective surgery is discouraged for patients receiving bisphosphonates; endodontic therapy and crown amputation are the preferred treatment options for nonvital teeth in such patients.6,8,25 However, when teeth are extremely mobile and associated with periodontal abscess, BONJ may be present and extraction cannot be avoided.9 Furthermore, extraction of symptomatic teeth within exposed necrotic bone should be considered, since it is unlikely that the extraction will exacerbate the established necrotic process.6,13,30,34 Informed consent must be obtained from the patient and careful follow-up performed until the surgical wound is healed.

Discontinuing bisphosphonate use before surgery is controversial because the half-life of the drug is measured in years, and its use should be discontinued only if systemic conditions permit and with the agreement of the patient’s prescribing physician.6,10,13,25,35 The effect of bisphosphonates on soft-tissue healing and vascularity is unclear, and these effects may have more rapid onset. The results of a recent in vitro study using pamidronate on cell cultures showed that there may be a compromise of soft-tissue healing.36 The value of using bone turnover markers is unclear because studies concerning this technique were not controlled adequately.23,37,38 Studies are being conducted to define risk, early lesions and prognosis of BONJ more clearly.

Systemic steroids. Long-term use of systemic steroids may lead to aseptic necrosis of the bones, especially of the femoral heads, although aseptic necrosis has not been reported in the jawbones.39,40 The femoral head exhibits radiographic changes of edema, but the bone is not exposed. In the guidelines provided by the American College of Rheumatology in 2001, bisphosphonates are recommended to prevent and treat steroid-induced osteoporosis for exposures as low as 5 milligrams of prednisone per day for three or more months.41 However, a negative association of BONJ with corticosteroid use also has been reported.42

Other agents. The results of recent studies showed that patients with metastatic cancers who were receiving the antiangiogenic drug bevacizumab may develop ONJ.43–45 The antiangiogenic drug sunitinib also has been linked with progression of ONJ.46


   RADIATION
TOP
 ABSTRACT
 SYSTEMIC MEDICATIONS
 RADIATION
INFECTION
 DIRECT CHEMICAL TOXICITY
 TRAUMA
 IDIOPATHIC BENIGN SEQUESTRATION...
 OTHER ETIOLOGIES
 CONCLUSIONS
 REFERENCES
 
ONJ caused by radiation traditionally has been referred to as "osteoradionecrosis." In the interest of standardizing terminology, we use the term "postradiation osteonecrosis" (PRON). PRON is a late complication of radiation to the head and neck structures and is associated with exposures of more than 60 grays.47 It is a chronic and progressive pathological process consisting of non-healing bone exposure that persists for three to six months.47–49 It may become evident one month to 14 years after therapy.50–52 Some studies, however, have shown that there may be recovery of bone-regenerative properties one year after radiation; therefore, dental implant placement may be safe one year after radiation.53,54

When tissue is radiated, it becomes hypovascular, hypocellular and hypoxic. The free radicals from water molecules are released and react with DNA, RNA and enzymes, causing disorganization of their nucleotide or amino acid sequences.47 Cells die, repair defects to survive with impaired function, or repair damage and function normally.47 The mandible is more susceptible to PRON (it occurs in 5 to 15 percent of cases)55 than is the maxilla because it obtains its blood supply primarily from the inferior alveolar artery. The maxilla obtains its blood supply primarily from the anterior, middle and posterior superior alveolar arteries and collateral blood vessels.56

Factors that increase risk of a patient’s developing PRON include increasing radiation dose, the tumor’s close proximity to bone, poor oral health and the type of treatment the patient undergoes.56,57 External radiotherapy has shown more detrimental effects than has brachytherapy.51,58 The risk of developing PRON is decreased if hyperfractionation techniques and intensity-modulated radiotherapy (IMRT) are used. The prevalence of PRON was 20.1 percent and 6.6 percent in conventional fractionation and hyperfractionation groups, respectively.59 In studies using IMRT, researchers found that PRON developed in up to 0.01 percent of patients.57,60 Age, sex, nutritional status, and tobacco and alcohol use may be aggravating factors.56,57

PRON starts as an asymptomatic exposure of necrotic bone that may progress to pain, abscess and fistula formation (Figure 3Go).56,61 Grading systems have been proposed that integrate the clinical findings of PRON with HBO therapy.62,63 Stage 1 consists only of exposed bone. If PRON does not respond to HBO therapy, it is considered to be at Stage 2. Stage 3 PRON includes pathological fracture, orocutaneous fistula or osteolysis to the inferior border of the mandible. Radiographs in the articles by Marx62 and Schwartz and Kagan63 show bone destruction and mottled radiolucency.


Figure 3
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  		Figure 3. Postradiation osteonecrosis of the mandibular ridge. Photo courtesy of Dr. Nathaniel Treister, Brigham and Women’s Hospital, Boston.

 
In microbiological studies, investigators found Actinomycetes species in biopsy specimens in 12 percent of cases; Actinomycetes species was associated with an increased risk of treatment failure or the need for prolonged treatment.64,65 Actinomycetes may represent opportunistic infections due to changes of microenvironment after radiation therapy. On the other hand, DNA-DNA hybridization performed on deep bony lesions showed anaerobic bacteria with a predominance of Porphyromonas gingivalis, as well as Actinomycetes species, Prevotella species and Fusobacterium nucleatum.66 This finding suggests that bacteria plays a causative role and questions an earlier theory regarding the minor role played by bacteria in the pathogenesis of PRON.47
Necrotizing ulcerative periodontitis is an unusual condition seen in immunocompromised patients, particularly those with HIV infection.

To reduce the incidence of PRON, it is customary that patients with cancer who need to undergo radiotherapy complete dental extractions before commencing radiotherapy57; extractions performed during or after radiotherapy were accompanied by HBO therapy provided before and after extractions.67,68 More recent studies, however, suggest that extractions performed before and after radiotherapy result in a similar prevalence of PRON of 24 percent and 26 percent, respectively, and that HBO does not reduce the incidence of PRON.50,69 There is a move away from the use of HBO because of cost (both time and monetary), lack of availability and complications of the therapy.69


   INFECTION
TOP
 ABSTRACT
 SYSTEMIC MEDICATIONS
 RADIATION
 INFECTION
DIRECT CHEMICAL TOXICITY
 TRAUMA
 IDIOPATHIC BENIGN SEQUESTRATION...
 OTHER ETIOLOGIES
 CONCLUSIONS
 REFERENCES
 
Bacterial infection. Noma (noma cancrum oris, gangrenous stomatitis, orofacial gangrene). Noma is an orofacial infection that usually affects immunocompromised people and malnourished children with poor oral hygiene.70,71 There were 770,000 cases worldwide in 1997.72 A more recent report estimated 25,000 cases of noma per year in the developing countries bordering the Sahara desert.73

Early clinical features of noma are pain, swelling of the buccal mucosa that mimics cellulitis, purulent discharge, a bluish black discoloration and ulceration of the overlying skin. Bone is exposed with sequestrum formation, and teeth in the affected site are lost.73,74 The disease has a rapid clinical course. Risk factors associated with noma are malnutrition, particularly vitamin A, ascorbic acid, zinc and protein deficiencies. These risk factors are associated with decreased cell-mediated immunity, impaired phagocytosis and breakdown of epithelial integrity.75 Measles, malaria, acatalasia, scarlet fever, typhoid fever, syphilis, tuberculosis, HIV infection and leukemia often are seen in association with noma.76–78 Acute necrotizing gingivitis may be an early lesion.75

In microbiological studies, investigators have identified in noma lesions the flora Prevotella melaninogenica, Corynebacterium pyogenes, Fusobacterium nucleatum, Bacteroides fragilis, Bacillus cereus, Prevotella intermedia and Fusobacterium necrophorum; some investigators believe that the last two play a key role.75,78,79 Viruses (such as Herpesviridae) also play a role by lowering the patient’s immunity, thus providing a permissive environment in which pathogenic bacteria can thrive.78,80 Other researchers believe that microthrombosis may be causative of ONJ in patients with noma, but this is a less accepted theory.78 Even though microorganisms are the cause, noma is not contagious, because experiencing malnutrition and poor living conditions predispose one to it.78

Treatment of noma is centered on systemic antibiotic agents (such as penicillin and metronidazole), debridement of nonvital tissues, improved nutrition and treatment of underlying diseases, if present.76 The introduction of antibiotic agents to treat noma reduced mortality from 80 to 90 percent to 8 to 10 percent.81 The major cause of death is dehydration, aspiration pneumonia, toxemia and complications arising from underlying diseases.82 Patients who survive usually have tooth loss,74 fibrosis and ankylosis,83 leading to functional impairment and facial disfigurement.84 Surgical reconstruction may help improve facial appearance and function.78,85 Strategies that can be used to prevent noma include good nutritional and oral hygiene practices and immunization against endemic communicable diseases. However, as long as abject poverty persists, so will noma.73

Necrotizing ulcerative periodontitis. Necrotizing ulcerative periodontitis is an unusual condition seen in immunocompromised patients, particularly those with HIV infection. It results from necrotizing ulcerative gingivitis and could progress to necrotizing stomatitis and the more serious condition noma.86,87 The underlying bone is destroyed, and the necrotic bone may become exposed (Figure 4Go).86 The pathogens are nonspecific anaerobic bacteria.88 Treatment options include local debridement, oral antibacterial rinses and systemic antibiotic agents (in particular metronidazole and penicillin).86,88


Figure 4
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  		Figure 4. Necrotic bone of the right hard palate in a patient with HIV infection and necrotizing ulcerative periodontitis.

 
Viral infection. Herpes zoster infection (also know as shingles) is an acute viral infection caused by reactivation of the varicella-zoster virus (human herpesvirus 3) that resides in the dorsal root and cranial nerve ganglia, resulting in vesicular eruptions of both the skin and mucous membrane.89 Herpes zoster commonly affects 20 percent of the population and usually is seen on the trunk of the body. The trigeminal nerve is affected in 13 percent of patients,90 and herpes zoster generally affects older patients.89

Clinical features of herpes zoster include low-grade fever and tingling, pruritus or both of the skin and mucosa, followed by the appearance of classic vesicles in the area innervated by the involved nerve.89 Complications include muscle paralysis, postherpetic neuralgia and persistent ocular and cochlear-vestibular symptoms.89 Occasionally, herpes zoster may result in ONJ either by affecting the innervations of periosteum or via the direct vasculotropic effect of the virus; both lead to alteration of the blood flow to the area and subsequently bone necrosis.91 Spontaneous exfoliation of teeth, necrosis of the jawbones or both occur three to 12 weeks after onset of symptoms (Figure 5Go).91,92 Radiographically, there is loss of alveolar bone,93,94 loss of interdental bone,91 a moth-eaten appearance95 or the presence of bony sequestrum.96,97


Figure 5
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  		Figure 5. A. Herpes zoster–induced osteonecrosis of the anterior mandibular alveolar ridge. Photo reprinted with permission of Dr. Willie Van Heerden, School of Dentistry, University of Pretoria, South Africa. All rights reserved. B. Herpes zoster–induced osteonecrosis of the right palate. Photo courtesy of Dr. J. Craig Whitt and Dr. Corey J. Auch, University of Missouri–Kansas City.

 
Besides necrotic bone fragments and inflammation, eosinophilic viral inclusion bodies may be present within the nuclei of epithelial cells, endothelial cells and fibroblasts bordering the affected vessels.98 Coinfection with cytomegalovirus,95 E. corrodens, Haemophilus aphrophilus and Actinomyces naeslundii99 also have been reported.

Herpes zoster is treated with antiviral therapy (such as valacyclovir or acyclovir) within 72 hours of the onset of symptoms.89 Herpes-associated ONJ is treated with sequestrectomy; chlorhexidine mouthrinse and 3 percent chlortetracycline ointment topically applied to the ulcerations may be useful.92

Deep fungal infection. Deep fungal infections in the oral cavity usually are caused by Aspergillus species (commonly A. fumigatus and A. flavus), and mucormycosis (also known as zygomycosis or phycomycosis) is caused by Mucor, Rhizopus and Cunninghamella species and less commonly by Absidia, Rhizomucor, Saksenaea and Apophysomyces species.100,101

Aspergillus species enters the host by means of inhalation of spores and may cause an allergic response, such as allergic fungal sinusitis, in healthy patients.102 It becomes destructive and may be fatal when it affects medically compromised patients.100,103

Species that cause mucormycosis may enter through open wounds, the mouth, nose or orbit and may involve the maxilla after tooth extraction, especially in patients with diabetes mellitus. These organisms may invade the blood vessel wall, resulting in thrombosis, vascular compromise and necrosis of soft or hard tissues.100,103–106

Clinically, both conditions begin with fever and headache followed by pain, tenderness and facial swelling of the affected side. The nose, sinuses, eyes and mouth may be affected. When the mouth is affected, yellow-black necrotic ulceration of the palate occurs. If the alveolar bone is affected, sequestrum and exposed bone may develop.100,106

Destruction of the bone and sequestrum formation may be seen radiographically. Involvement of the sinus may lead to sinus opacification and thickening of the sinus lining.105,107 Necrotic bone often is identified microscopically. Fungal organisms appear as broad, nonseptate branching hyphae, and hyphae of the fungi often are seen within thrombosed blood vessels.100,105

Treatment of deep fungal infection involves sequestrectomy, surgical debridement of necrotic tissue and use of systemic antifungal medications such as amphotericin B.103,105,108 The prognosis for immunocompromised patients is poor.


   DIRECT CHEMICAL TOXICITY
TOP
 ABSTRACT
 SYSTEMIC MEDICATIONS
 RADIATION
 INFECTION
 DIRECT CHEMICAL TOXICITY
TRAUMA
 IDIOPATHIC BENIGN SEQUESTRATION...
 OTHER ETIOLOGIES
 CONCLUSIONS
 REFERENCES
 
Agents used in dental treatment. Caustic chemicals (such as arsenic paste and formocresol) were used—and still are in use in some developing countries—for the obturation of root canals. During endodontic therapy, these agents may leak into the surrounding tissues through the apexes and accessory or lateral canals and result in ONJ.109–111

Formocresol contains formaldehyde (an effective alkylating antimicrobial agent) and cresol (a protein-coagulating phenolic compound), and it has bactericidal properties and the ability to mummify tissues.111–113 Arsenic trioxide is a water-soluble material that forms arsenious acid when it comes in contact with water, becomes extremely toxic to soft and hard tissues and is carcinogenic.110

Clinical features of chemical toxicity are exposed necrotic bone, tooth mobility and sometimes suppuration.111,114–116 Oroantral fistula formation is a rare complication from the use of arsenic trioxide.117 Treatment options include sequestrectomy, root amputation or extraction of the involved tooth.118,119

Other agents used in dental treatment. Because this review focuses on ONJ, we do not discuss necrosis of soft tissues caused by local anesthetic agents and other agents such as sodium hypochlorite and calcium hydroxide.120,121

Cocaine. According to the National Survey on Drug Use and Health, between 2002 and 2003 more than 5.9 million people aged 12 years or older used cocaine in the United States.122 While cocaine may be used safely at 2 to 3 mg per kilograms to induce anesthesia, recreational drug users may use more than 1,000 mg per day.123

Intranasal inhalation or snorting of cocaine results in local vasoconstriction. However, cocaine may be contaminated with adulterants such as talc, mannitol, lactose, amphetamines, borax and plaster of Paris.124 Such adulterants are tissue irritants and often lead to inflammation and ulceration of the nasal mucosa. In cases of chronic drug use, ischemic necrosis may lead to septum perforation as early as three weeks from first use.124,125 The anesthetic effect of cocaine in the tissue may make patients lose sensation in the affected area, which can be injured easily by trauma or thermal causes (for example, hot water or food), and patients may not be able to detect the injury when it happens because they will not be able to feel it occur.123,125 Suprainfection may occur because the immune function is suppressed and the mucosal nasociliary transport is inhibited.126,127

Regardless of the patient’s socioeconomic status and sex, cocaine-induced ONJ is seen mostly in those between 18 and 30 years (mean, 33 years).128 Common symptoms are headaches, anosmia, rhinitis, nasal speech, nasal blockage, epistaxis, crusting, fluid regurgitation, difficulty in eating, and loss of taste and smell.123,124,128 Common signs are rhinolalia (also called "rhinophonia," which is nasal quality of voice), bilateral collapse of nasal ala, saddle nose deformity and sinusitis. Perforation of the nasal septum occurs, followed by destruction of the turbinates; maxillary, nasal and paranasal sinusitis; and palatal necrosis.129 If cocaine use is suspected, urine and blood analyses for cocaine metabolites may be helpful if they are performed within 48 to 72 hours after use.124,130 A case of ONJ associated with oxycodone (Oxycontin, Purdue Pharma, Stamford, Conn.) use has been reported.131 Radiographically, bone destruction can be detected in computed tomography (CT) scans of the sinuses.123,128

Treatment includes cessation of drug use, debridement, antibiotic agents if the patient has an infection and nasal irrigation, after which obturators may be used for functional rehabilitation followed by surgical reconstruction.123,124,129 Flap failure may occur after treatment if drug use is resumed.130


   TRAUMA
TOP
 ABSTRACT
 SYSTEMIC MEDICATIONS
 RADIATION
 INFECTION
 DIRECT CHEMICAL TOXICITY
 TRAUMA
IDIOPATHIC BENIGN SEQUESTRATION...
 OTHER ETIOLOGIES
 CONCLUSIONS
 REFERENCES
 
Painful exposure of the mylohyoid ridge is an uncommon sequela seen after a difficult intubation has been performed. These exposures appear several days after intubation, manifesting as a smooth, painful area of exposed bone on the mylohyoid ridge, probably resulting from damage of the thin mucosa overlying the bone and compromise of vascularity (Figure 6Go).132 Trauma-related ONJ probably is related closely to idiopathic benign sequestration of the lingual plate of the mandible.


Figure 6
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  		Figure 6. Osteonecrosis of the right mylohyoid area secondary to traumatic intubation. Photo courtesy of Dr. Nathaniel Treister, Brigham and Women’s Hospital, Boston.

 

   IDIOPATHIC BENIGN SEQUESTRATION OF THE LINGUAL PLATE OF THE MANDIBLE
TOP
 ABSTRACT
 SYSTEMIC MEDICATIONS
 RADIATION
 INFECTION
 DIRECT CHEMICAL TOXICITY
 TRAUMA
 IDIOPATHIC BENIGN SEQUESTRATION...
OTHER ETIOLOGIES
 CONCLUSIONS
 REFERENCES
 
Idiopathic benign sequestration of the lingual plate of the mandible consists of spontaneous sequestration of the lingual mandibular bone, usually in the area of the mylohyoid ridge, in patients with no significant underlying systemic condition.133–136 In studies, patients have ranged in age from 32 to 57 years,133–136 and all cases were in the mylohyoid area or tori except for one case in the mandibular anterior area.134 All of the patients had a prominent mylohyoid ridge, mandibular exostosis, tori or a missing third molar. It has been postulated that exostosis, tori and the mylohyoid ridge have thin overlying mucosa that is more susceptible to subtle traumatic insults and ulceration even if patients do not report any history of trauma.133,135 These areas have an attenuated blood supply, which make them more vulnerable to even mild ischemia.133

Clinically, idiopathic benign sequestration of the lingual plate of the mandible appears as an exposed piece of bone that usually measures from 1 to 10 millimeters with an average dimension of 4 mm.133 Patients usually complain of pain or discomfort of one to three weeks’ duration. There are no significant radiographic findings.133 Simple removal of the sequestrum leads to complete healing within a few weeks with no recurrence.


   OTHER ETIOLOGIES
TOP
 ABSTRACT
 SYSTEMIC MEDICATIONS
 RADIATION
 INFECTION
 DIRECT CHEMICAL TOXICITY
 TRAUMA
 IDIOPATHIC BENIGN SEQUESTRATION...
 OTHER ETIOLOGIES
CONCLUSIONS
 REFERENCES
 
The following conditions may lead to necrosis of the jawbones but do not generally involve exposure of bone.

Avascular necrosis. Osteonecrosis in conjunction with vascular necrosis (which includes aseptic necrosis, ischemic necrosis, osteochondritis dissecans) may be caused by compromise of the blood supply, leading to ischemia and necrosis; in general, the bone is not exposed.137 Osteonecrosis may result from trauma such as orthognathic surgery; temporomandibular joint (TMJ) puncture; or non-traumatic causes such as hemoglobinopathies, fat embolism, alcoholism and systemic lupus erythematosus.40,138–140 There is some controversy regarding the occurrence of osteonecrosis of the TMJ due to nontraumatic causes because the TMJ is a well-vascularized joint.141

Clinically, pain is the most common symptom, with limitation of movement when the joint is affected.142 Magnetic resonance imaging is the best imaging modality for these conditions, although its results may be false-negative when lesions are small.39,137,138 CT and three-dimensional–CT scanning also may reveal bone necrosis and defects in the condyle.138,142

Treatment includes unloading the condyle to relieve condylar stress, treating underlying systemic diseases and surgical intervention as necessary.138,143

Neuralgia-inducing cavitational osteonecrosis. Neuralgia-inducing cavitational osteonecrosis (NICO) is thought to be a chronic pain syndrome that is characterized by bone necrosis and formation of intrabony cavities that are not detected radiographically.144,145 This is a controversial condition that is not well-accepted by the dental community because the symptoms often can be ascribed to some other cause.146

NICO has been seen in association with trauma, odontogenic infections, radiotherapy, corticosteroid use, tumors, alcoholism, osteoporosis, systemic lupus erythematosus, hereditary thrombophilia (protein C and S deficiency) and hereditary hypofibrinolysis.147

Bouquot and colleagues’145 theory is that interruption of blood supply leads to bone death and intramedullary alveolar cavities that change intrabony fluid dynamics and pressure, resulting in nerve damage and inappropriate pain signals.145

Osteomyelitis associated with sclerotic osseous disease and malignancies. Sclerotic bone conditions such as Paget disease of bone, osteopetrosis and cemento-osseous dysplasia may develop into osteomyelitis and necrosis of bone, particularly after the patient has undergone tooth extractions.148–150 The etiopathogenesis may be related to the relatively reduced vascularity of the bone in such conditions, leading to poor healing and subsequent infection, osteomyelitis and sequestrum formation; the sequestrum formation may become exposed.151,152

Malignancies that affect the oral mucosa, such as squamous cell carcinoma or mucosal lymphomas (including natural killer/T-cell lymphoma), may extend directly into the underlying bone and lead to osteomyelitis and necrosis of bone. These tumors, however, rarely manifest primarily as ONJ.


   CONCLUSIONS
TOP
 ABSTRACT
 SYSTEMIC MEDICATIONS
 RADIATION
 INFECTION
 DIRECT CHEMICAL TOXICITY
 TRAUMA
 IDIOPATHIC BENIGN SEQUESTRATION...
 OTHER ETIOLOGIES
 CONCLUSIONS
REFERENCES
 
In this article, we summarized some of the more common conditions that can lead to the occurrence of exposed bone in the oral cavity or ONJ. ONJ encompassed a wide range of etiologies including use of systemic medications, radiation, infection, direct chemical toxicity, trauma, idiopathy and other etiologies. Clinicians should take a careful history when evaluating patients with ONJ because ONJ may result from one or more factors.


   FOOTNOTES
 

Dr. Almazrooa is a resident, Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Division of Oral Medicine and Dentistry, Brigham and Women’s Hospital, 75 Francis St., Boston, Mass. 02115, e-mail "soulafa_almazrooa{at}hsdm.harvard.edu". Address reprint requests to Dr. Almazrooa.


Dr. Woo is an associate professor, Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, and an attending, Division of Oral Medicine and Dentistry, Brigham and Women’s Hospital, Boston.


Disclosures. Dr. Woo received $2,000 from Novartis Pharmaceutical (Basel, Switzerland) in 2006 and 2007 to conduct research on bisphosphonate-associated osteonecrosis. Dr. Almazrooa did not report any disclosures.


   REFERENCES
TOP
 ABSTRACT
 SYSTEMIC MEDICATIONS
 RADIATION
 INFECTION
 DIRECT CHEMICAL TOXICITY
 TRAUMA
 IDIOPATHIC BENIGN SEQUESTRATION...
 OTHER ETIOLOGIES
 CONCLUSIONS
 REFERENCES
 

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A. Kyrgidis and K. Vahtsevanos
OSTEONECROSIS OF THE JAW
J Am Dent Assoc, October 1, 2009; 140(10): 1216 - 1217.
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