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Medication-related osteonecrosis of the jaw
Other namesBON of the jaw, bisphosphonate-related osteonecrosis of the jaw (BRONJ), bisphosphonate-induced osteonecrosis of the jaw (BIONJ)
SpecialtyRheumatology, oral and maxillofacial surgery Edit this on Wikidata

Bisphosphonate-associated osteonecrosis of the jaw (BON, BONJ) is death of the jawbone in a person with a history of bisphosphonate use who undergoes subsequent dental surgery. It may lead to surgical complication in the form of impaired wound healing following oral and maxillofacial surgery, periodontal surgery, or endodontic therapy.[1]

An association between history of bisphosphonate use and osteonecrosis of the jaw after later surgery was detected for several years and its cause is still not entirely clear. BON has been nicknamed "bis-phossy jaw"[2] based on its similarity with phossy jaw. There is no known prevention for bisphosphonate-associated osteonecrosis of the jaw.[3] Avoiding the use of bisphosphonates is not a viable preventive strategy on a general-population basis because the medications are beneficial in the treatment and prevention of osteoporosis (including prevention of bony fractures) and treatment of bone cancers.

Definition

Osteonecrosis, or localized death of bone tissue, of the jaws is a rare potential complication in cancer patients receiving treatments including radiation, chemotherapy, or in patients with tumors or infectious embolic events. In 2003,[4][5] reports surfaced of the increased risk of osteonecrosis in patients receiving these therapies concomitant with intravenous bisphosphonate.[6] Matrix metalloproteinase 2 may be a candidate gene for bisphosphonate-associated osteonecrosis of the jaws, since it is the only gene known to be associated with both bone abnormalities and atrial fibrillation, another side effect of bisphosphonates.[7]

In response to the growing base of literature on this association, the United States Food and Drug Administration issued a broad drug class warning of this complication for all bisphosphonates in 2005.[8]

Signs and symptoms

Lesions and areas of necrotic bone may remain asymptomatic for weeks, months, or even years,[9] and most commonly become symptomatic with inflammation of surrounding tissues.[10] Clinical signs and symptoms associated with but not limited to BONJ include the following:

Pathogenesis

Although the methods of action are not yet completely understood, it is hypothesized that bisphosphonate-associated osteonecrosis of the jaw is related to a defect in jaw bone healing and remodelling. The inhibition of osteoclast differentiation and function, precipitated by bisphosphonate therapy, leads to decreased bone resorption and remodelling.[15][16] Evidence also suggests bisphosphonates induce apoptosis of osteoclasts, resulting in resorption of bones.[17] Another suggested factor is the inhibition of angiogenesis due to bisphosphonates but its effect remains uncertain.[18][19][20] Several studies have proposed that bisphosphonates cause excessive reduction of bone turnover, resulting in a higher risk of bone necrosis when repair is needed.[21][22][23]

Light micrograph of an osteoclast displaying typical distinguishing characteristics: a large cell with multiple nuclei and a "foamy" cytosol.

Because bisphosphonates are preferentially deposited in bone with high turnover rates, it is possible that the levels of bisphosphonate within the jaw are selectively elevated. To date, there have been no reported cases of bisphosphonate-associated complications within bones outside the craniofacial skeleton.[8]

Diagnosis

A diagnosis of bisphosphonate-associated osteonecrosis of the jaw relies on three criteria:[3]

  1. the patient possesses an area of exposed bone in the jaw persisting for more than 8 weeks,
  2. the patient must present with no history of radiation therapy to the head and neck
  3. the patient must be taking or have taken bisphosphonate medication.

According to the updated 2009 BRONJ Position Paper published by the American Association of Oral and Maxillofacial Surgeons, both the potency of and the length of exposure to bisphosphonates are linked to the risk of developing bisphosphonate-associated osteonecrosis of the jaw.[24]

Cause

Cases of BRONJ have also been associated with the use of the following two intravenous and three oral bisphosphonates, respectively: Zometa (zoledronic acid) and Aredia (pamidronate) & Fosamax (alendronate), Actonel (risedronate), and Boniva (ibandronate).[25]

Risk

The overwhelming majority of BRONJ diagnoses, however, were associated with intravenous administration of bisphosphonates (94%). Only the remaining 6% of cases arose in patients taking bisphosphonates orally.[3]

Although the total United States prescriptions for oral bisphosphonates exceeded 30 million in 2006, less than 10% of BON cases were associated with patients taking oral bisphosphonate drugs.[26] Studies have estimated that BRONJ occurs in roughly 20% of patients taking intravenous zoledronic acid for cancer therapy and in between 0-0.04% of patients taking orally administered bisphosphonates.[27]

Owing to prolonged embedding of bisphosphonate drugs in the bone tissues, the risk for BRONJ is high even after stopping the administration of the medication for several years.[28]

Prevention

Dentoalveolar surgery is a risk factor for development of BRONJ. Prevention including the maintenance of good oral hygiene, comprehensive dental examination and dental treatment including extraction of teeth of poor prognosis and dentoalveolar surgery should completed prior to commencing any medication which is likely to cause osteonecrosis (ONJ). Patients with removable prostheses should be examined for areas of mucosal irritation. Procedures which are likely to cause direct osseous trauma, e.g. tooth extraction, dental implants, complex restoration, deep root planning, should be avoided in preference of other dental treatments. Some[who?] have advocated “drug holiday’s”, but this remains controversial.[citation needed]

Management

Bisphosphonate-related osteonecrosis of the jaw (BRONJ), now referred to as Medication-related osteonecrosis of the jaw (MRONJ) is an adverse reaction which can occur as a result of medicines used to treat cancer and osteoporosis. Some medications which induce these effects are Bisphosphonates, Denosumab and Antiangiogenic agents. They involve the destruction of bone in a progressive manner, particularly associated with the mandible or maxilla. The overall effects depend on which drug is being used, the dose and the duration of taking this drug. MRONJ is associated with significant severe disease, negative affects on the quality of life and remains to be increasingly challenging to treat. [29] It is of high debate whether the various management techniques used for MRONJ are effective or not but due to the severity of the disease it is continually understood action must be taken.[30] The management of patients taking the drugs of concern undergo initial management and continuing management. Before either of these are considered the patient must be as dentally fit as possible.

Initial Management

This involves patients who are about to start, or very recently have started, taking the drugs of concern. There is a small portion of observational studies which promote the idea of preventative dental treatment to decrease oral complications in patients taking these drugs. These preventative measures may require a change in the patients’ oral hygiene technique and lifestyle factors such as smoking and alcohol consumption. There is also a benefit in prescribing high fluoridated toothpaste if the patient is of high caries risk. Before prescribing of any kind or when noticing a patient is on the treatment already, it is encouraged to tell the patient of the risk of developing MRONJ, although this risk is small. This is followed by personalised advice given to the patient, involving: a healthy diet, excellent oral hygiene, stop smoking, limited alcohol consumption and regular dental appointments. If a patient has a complex medical history and is of particular high risk it is advised before any treatment to commence, communication with a specialist with regards to the clinical assessment and treatment plan. It is also advised for individuals who take bisphosphonates to never allow the tablet to dissolve in the mouth as this causes damage to the oral mucosa. The patient must follow the instructions given with the tablets.


Continuing Management

This involves patients who have a regime which actively incorporates the drugs of concern and also for the patients whom undergone initial management. In terms of dental treatment all must be done as normal, accompanied by personalised advice to the patient. If there is a need for an extraction or any procedure which implicates bone a discussion with the patient about the risks and benefits must occur. Due to bacterial resistance and possible side effects of antibiotic therapy, they are only prescribed if there is a necessity for them. There is minimal evidence to say the use of prophylactic antibiotics will reduce MRONJ.[31]

Medical Management of MRONJ is most commonly performed for patients who have less severe cases or those whom have contraindicating health conditions. The antimicrobials therapies commonly used are topical, oral and intravenous.

Topical Antimicrobials

A commonly used medicament, chlorhexidine gluconate 0.12% is bacteriostatic and bacteriocidal making an effective agent against MRONJ. Advantages of this topical gel is the low cost, ease of use, availability and patient acceptance. The disadvantages of this are the low compliance, patient acceptance, dental staining and risk of opportunistic bacterial resistance.

Oral Antimicrobials

The use of these are based on the clinical evaluation of the condition and if pathogenic bacteria presence is indicated. This is generally a 2 week course for a patient with a persistent presentation of the disease or a 4-6 week course for more severe cases. Penicillin is the first line of choice, although if this is contraindicated commonly used antimicrobials are: clindamycin, fluoroquinolones and/or metronidazole.

Intravenous Antimicrobials

This means of therapy may be of benefit with patients who possess specific pathogenic organisms which resist oral therapies. Although this method has perceived greater penetration of tissue there is little evidence of being a substantial greater efficacy when compared to other methods of management.[32]

Advanced Methods of Management Although there are many methods of managing MRONJ there is no definitive treatment as of yet. Recently there has been regenerative concepts using stem cells from a variety of sources combined with growth factors, in order to treat MRONJ. This gives a promising future for management but is not yet a routine procedure.[33]


Treatment

Treatment usually involves antimicrobial mouth washes and oral antibiotics to help the immune system fight the attendant infection, and it also often involves local resection of the necrotic bone lesion. Many patients with BRONJ have successful outcomes after treatment, meaning that the local osteonecrosis is stopped, the infection is cleared, and the mucosa heals and once again covers the bone.

The treatment the person receives depends on the severity of osteonecrosis of the jaw.

Conservative

Indicated in patients who have evidence of exposed bone but no evidence of infection. It may not necessarily eliminate all the lesions, but it may provide patients with a long term relief. This approach involves a combination of antiseptic mouthwashes and analgesics and the use of teriparatide.[34] However, note that the teriparatide treatment should not be used in cancer patients, or patients with a history of skeletal radiation or active bone metastases. Splints may be used to protect sites of exposed necrotic bone.

Non-surgical

Indicated for patients with exposed bone with symptoms of infection. This treatment modality may also be utilised for patients with other co-morbidities which precludes invasive surgical methods. This approach requires antimicrobial mouthwashes, systemic antibiotics and antifungal medication and analgesics.[35]

Surgery

Surgical intervention is indicated in patients with symptomatic exposed bone with fistula formation and one or more of the following: exposed and necrotic bone extending beyond the alveolar bone resulting in pathological fracture; extra-oral fistula; oral antral communication or osteolysis extending from the inferior border of the mandible or the sinus floor. Surgical management involves necrotic bone resection, removal of loose sequestra of necrotic bone and reconstructive surgery. The objective of surgical management is to eliminate areas of exposed bone to prevent the risk of further inflammation and infection. The amount of surgical debridement required remains controversial.

Other

See also

References

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  2. ^ Abu-Id, Mario; et al. (2008). "'Bis-phossy jaws' – High and low risk factors for bisphosphonate-induced osteonecrosis of the jaw". Journal of Cranio-Maxillofacial Surgery. 36 (2): 95–103. doi:10.1016/j.jcms.2007.06.008. {{cite journal}}: Explicit use of et al. in: |last2= (help)
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External links

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