Bisphosphonate-associated osteonecrosis of the jaw

Bisphosphonate-associated osteonecrosis of the jaw (often abbreviated as BON, BONJ, or BON of the jaw), also called bisphosphonate-related osteonecrosis of the jaw (BRONJ) (pronounced /brɒndʒ/) or bisphosphonate-induced osteonecrosis of the jaw (BIONJ), is osteonecrosis of the jaw 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]

A correlation between history of bisphosphonate use and osteonecrosis of the jaw after later surgery was detected in the oral medicine fields for several years before the exact nature of the relationship (etiology, pathogenesis) could begin to be understood, and it is still not entirely clear, although it 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 prevention on a general-population basis because the drugs have more benefit throughout the population (preventing osteoporotic fractures and treating bone cancers) than harm (BRONJ).

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:

• Jaw pain and neuropathy^[11]
• Loose teeth ^[12]
• Mucosal swelling ^[12]
• Erythema
• Suppuration ^[12]
• Soft tissue ulceration ^[12] persisting for more than 8 weeks^[13]
• Trismus ^[12]
• Non-healing extraction sockets ^[12]
• Paraesthesia or numbness in the jaw ^[14]
• Bad breath
• Exposed necrotic jaw bone ^[10]

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]

Bisphosphonates: intravenous vs. oral

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]

Treatment and outcomes

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.

Management Strategies:

The treatment that patient receive depends on the severity of osteonecrosis of the jaws.

1) Prevention

Dentoalveolar surgery is a significant 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 osteoradionecrosis (ORN). 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 have advocated “drug holiday’s” but this remains controversial.

2) Education

Patients should be educated regarding the warning signs and symptoms of ORN and the importance of maintaining good oral health throughout the treatment period.

3) 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.^[29] 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 sued to protect sites of exposed necrotic bone.

4) Non-surgical management

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.^[30]

5) Surgical

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.

6) Adjuvent strategies

· Hyperbaric Oxygen Therapy

· Pentoxifylline and tocopherol (Vitamin E)

· Ozone Therapy

· Low Level Laser Therapy

· Treatment with Growth Factor (Platelet Rich Plasma or Bone Morphogenetic protein)

· Parathyroid Hormone and teriparatide

· Fluorescence-guided debridement

· Ultrasonic therapy^[31][32]

See also

• Osteonecrosis of the jaw, see section on Bisphosphonates
• Phossy jaw
• C-terminal telopeptide, commonly known as CTX, a serum biomarker for bone turnover rate and a tool used to evaluate patient risk for complications due to BRONJ

References

External links

• http://www.ada.org/sections/professionalResources/pdfs/topics_ARONJ_report.pdf