整理by Dr.陳怡睿
Bisphosphonates prevent, reduce and delay cancer-related skeletal complications.
Bisphosphonate-related osteonecrosis of the jaws (BRONJ) was first reported by Marx (2003). 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.
Many authors, however, consider that the benefits of bisphosphonate treatment in malignant disease generally outweigh any risks. Some cases of BRONJ have also been reported in patients on oral bisphosphonates treatment for osteoporosis but millions of patients are on oral bisphosphonates treatment for osteoporosis, and these oral drugs are helpful in preventing hip fractures in older women in particular.
BRONJ appears as a non‐healing exposed bone in the maxillofacial region and may affect patients undergoing intravenous cancer‐related bisphosphonate therapy or more rarely, patients treated with oral or IV bisphosphonates for osteoporosis.
The 2009 Position Paper retains the case definition of BRONJ:
1. The patient is or has been treated with a bisphosphonate.
2. Exposed bone has been present in the maxillofacial region for more than eight weeks; and
3. There is no history of radiation therapy to the jaws.
Specifically, the 2009 BRONJ Position Paper observes that the risk of developing BRONJ is linked to:
1. The potency the bisphosphonate used in therapy; and
2. The length of exposure to bisphosphonates.
Other factors that may increase the risk of developing BRONJ include:
1. A history of inflammatory dental disease, such as periodontal disease and dental abscesses;
2. Increased age;
3. Other systemic factors or conditions, such as renal dialysis, low hemoglobin, obesity and diabetes; and
4. In some cases, there may be a genetic predisposition to developing BRONJ.
The 2009 BRONJ Position Paper offers some strategies for preventing BRONJ in cancer patients treated with IV bisphosphonates.
1. Prior to initiation of cancer‐related IV bisphosphonate treatment, patients should have a thorough dental examination and complete the necessary procedures to achieve optimal periodontal health.
2. Given the long‐term biologic activity of IV bisphosphonates noted in the literature, the 2009 Position Paper suggests that alternative dosing regimens that reduce bisphosphonate exposure may be effective in decreasing the risk for BRONJ.
Pathogenesis
Bisphosphonates
1. inhibit the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase,
2. block osteoclast protein prenylation, and thus
3. block osteoclast-mediated bone resorption. This predisposes to BRONJ.
Ruggiero and Drew described the elective involvement of the jaws compared to other bone sites and may be due to the healing of an open bone wound and that bisphosphonates are preferentially deposited in bones with high turnover rates as the jaws.
Incidence
BRONJ is far more frequently induced by intravenous bisphosphonates than by oral bisphosphonates. Hoff et al. found that 1.2% patients with breast cancer and 2.4% with myeloma on intravenous bisphosphonate treatment developed BRONJ. Wang et al. reported a slightly greater incidence both in myeloma (3.8%), in breast cancer (2.5%) and prostate cancer (2.9%). Recently Stumpe et al. found a global incidence of 0.94%.
Risk factors
Several studies have focussed on the risk factors for developing BRONJ. Treatment with high potency intravenous bisphosphonates such as zoledronic acid and pamidronate, and dental extractions, are important risk factors. The duration of bisphosphonate treatment, the number of infusions and the total infusion hours may also be risk factors for BRONJ.
Oral health appears not to be a risk factor for BRONJ. Obesity and smoking were recently associated with BRONJ. Delayed-onset BRONJ associated with zoledronic acid has also been described.
Genetic factors also influence the risk for BRONJ (single nucleotide polymorphism rs1934951 of the drug-metabolising enzyme cytochrome P450 CYP2C8).
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.
Diagnostic methods for assessing the extent of lesions
Computed Tomography (CT) scan vs. Magnetic Resonance Imaging (MRI)
Management
BRONJ is painful and difficult to treat. Management of BRONJ remains controversial. The consensus is to manage patients with BRONJ conservatively when at least 23–53% of patients achieve resolution of mucosal discontinuities. However, some patients need surgery. Hyperbaric oxygen (HBO) has been suggested and recommended by some authors as a complementary therapy.
Prevention
One prospective study found that the risk of BRONJ decreased after the implementation of preventive dental procedures and this was supported by another that showed a reduction in BRONJ incidence from 3.2% to 1.3% after a preventive programme.
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 adverse effect.
