ReviewOsteonecrosis of the jaws in patients treated with intravenous bisphosphonates (BRONJ): A concise update
Introduction
Osteonecrosis of the jaws (ONJ) or bisphosphonate-related osteonecrosis of the jaws (BRONJ) was first reported by Marx (2003).1 This severe complication occurs most frequently in patients on intravenous bisphosphonates treatment for malignant diseases such as multiple myeloma or metastatic malignant disease, mainly breast cancer. Bisphosphonates prevent, reduce and delay cancer-related skeletal complications.2
Many authors however, consider that the benefits of bisphosphonate treatment in malignant disease generally outweigh any risks.3 Some cases of BRONJ have also been reported in patients on oral bisphosphonates treatment for osteoporosis.[4], [5] but millions of patients are on oral bisphosphonates treatment for osteoporosis, and the risk of ONJ is very low indeed6 overall incidence ranging from 1/10,000-1/100,000 treatments,7 and these oral drugs are helpful in preventing hip fractures in older women in particular.
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Pathogenesis
Bisphosphonates inhibit the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, block osteoclast protein prenylation, and thus block osteoclast-mediated bone resorption.8 This predisposes to BRONJ. There is an inhibition of osteoclast development from monocytes, increased osteoclast apoptosis and prevention of osteoclast development and recruitment from bone marrow precursors.9 Other possible mechanisms include an anti-angiogenic effect and a suppressive effect on endothelial
Incidence
BRONJ is far more frequently induced by intravenous bisphosphonates than by oral bisphosphonates. Hoff et al.13 found that 16 out of 1338 patients with breast cancer (1.2%) and 13 of 548 with myeloma (2.4%) on intravenous bisphosphonate treatment developed BRONJ. Wang et al.14 reported a slightly greater incidence both in myeloma (3.8%), in breast cancer (2.5%) and prostate cancer (2.9%) but Mavrokokki et al.15 reported a lower overall incidence. Recently Stumpe et al.16 found a global
Risk factors
Several studies have focussed on the risk factors for developing BRONJ. Treatment with high potency (nitrogenated) intravenous bisphosphonates such as zoledronic acid and pamidronate, and dental extractions, are important risk factors.[17], [18] The duration of bisphosphonate treatment, the number of infusions and the total infusion hours may also be risk factors for BRONJ.[16], [19]
Other suspected risk factors, which have largely been excluded, include concomitant therapy with corticosteroids,
Prognostication
Marx et al.5 described collagen C-terminal telopeptide (CTX) test as a useful serological marker for the risk of BRONJ, but this has not been supported by other authors.[24], [25] and we found no statistically significant relationship between the serum CTX and the number of exposed bone necrotic areas and the size of BRONJ.26
New clinical forms of presentation
The main clinical signs and symptoms are pain, areas of exposed and necrotic bone with tooth mobility, mucosal swelling, erythema, and ulceration, abscesses and fistulas.12 Ruggiero et al.27 described three stages in BRONJ patients (Figure 1, Figure 2, Figure 3, Figure 4, Figure 5, Figure 6), but some authors have suggested the need to include in this classification early stages where patients without bone exposed may be presented.28 However, Junquera and Gallego29 presented two cases of BRONJ
Diagnostic methods for assessing the extent of lesions
Computed tomography (CT) scan is helpful to assess the size and the extent of bone necrosis30 but magnetic resonance imaging (MRI) is also an effective tool31 though findings are not specific.30
Management
Management of BRONJ remains controversial. The consensus is to manage patients with BRONJ conservatively[7], [32] when at least 23–53% of patients achieve resolution of mucosal discontinuities (Table 1).[13], [33] However, some patients need surgery. Wutzl et al.34 conducting the first prospective study showed that minimal resection of necrotic bone and local soft closure resulted in success in 58.5%. Other authors have reported that surgery can improve the patient’s symptoms and may resolve
Prevention
The importance of preventive measures is thus highlighted.[12], 39, 40 One prospective study found that the risk of BRONJ decreased after the implementation of preventive dental procedures41 and this was supported by another that showed a reduction in BRONJ incidence from 3.2% to 1.3% after a preventive programme.42 Finally, the risk of BRONJ diminishes when the frequency of administration of bisphosphonates is reduced, so a reduced drug schedule may be a useful tool to prevent this severe
Conflict of interest statement
None declared.
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