Bisphosphonates and osteonecrosis of the jaw

Recently, the United States Food and Drug Administration drew attention to the problem of osteonecrosis (also described as avascular or aseptic necrosis) of the mandible and/or maxilla, occurring in association with intravenously administered bisphosphonates used to control hypercalcaemia in metastatic bone disease.1 In addition, two case series were published recently summarising 99 case reports of osteonecrosis of the jaw associated with bisphosphonates.2,3 Combined with smaller case series, they bring the total reported to 129 cases.4-8 Not all bisphosphonates have been implicated. Most commonly associated with the problem were zoledronic acid and pamidronate, possibly because these are the only intravenous bisphosphonates in widespread use, and because zoledronic acid has been approved for regular use in metastatic disease. However, seven reports implicated oral alendronate or risedronate used to treat osteoporosis.4,6

Osteonecrosis of the jaw closely resembles the occupational disorder “fossy jaw”, which occurred in workers in match factories using white phosphorus in manufacturing.9 The condition was distressingly painful, refractory to treatment and disfiguring to the extent that some sufferers committed suicide.

Bisphosphonates are not metabolised and have a strong binding affinity with osteoclasts. They can persist in bone for months and sometimes years after the drug has been discontinued. Accordingly, withdrawal of bisphosphonate therapy does not appear to hasten recovery of the osteonecrosis. Other treatments, including mouth rinses, systemic antibiotics, hyperbaric oxygen and surgical debridement have been tried, but so far none has proven consistently effective.

The mechanism underlying the reaction is unknown, but it has been postulated that bisphosphonates inhibit new vessel formation, thereby impairing healing. Although dental extractions and other oral surgery have been identified as precipitants in many cases, there is evidence suggesting that alveolar bone can be involved before, and independently of, such procedures. Indeed, the clinical presentation may closely simulate dental abscesses, “toothaches”, denture sore spots, and osteomyelitis.

Documented risk factors include a diagnosis of cancer, concomitant therapies (eg, chemotherapy, radiotherapy and corticosteroids) and comorbid conditions (eg, anaemia, coagulopathies, infection, and pre-existing oral disease).10 Concomitant chemotherapy and corticosteroid treatment, in particular, may result in immunosuppression and thereby predispose to ongoing local sepsis after minor trauma.

Because this condition and its complications result in significant chronic pain, dysfunction and disfigurement which are difficult to treat, the focus should be on prevention. It is important that all health professionals, especially dentists, oncologists and oral surgeons, be aware of the possibility that patients being considered for dental extractions or other oral surgery are undergoing intravenous bisphosphonate therapy. Also, it is important for patients to be informed of the risk of this complication of bisphosphonate therapy, so that they have the opportunity to assess the need for dental treatment before starting therapy.11 It is not known at this stage whether discontinuing bisphosphonates before major dental procedures can help prevent the problem, but, given the persistence of bisphosphonates in bone, it is unlikely. Prescribers should also be aware that osteonecrosis of the jaw can occur in association with oral bisphosphonate therapy for osteoporosis.