Since the 1960, bisphosphonates (BPs) are commonly used to treat patients with certain resorptive bone diseases such as osteoporosis, Paget’s disease, and hypercalcemia associated with certain malignancies such as multiple myeloma and bone metastasis from the breast or prostate who are at a significantly higher risk of developing osteonecrosis of the jaw (ONJ) for several reasons 1–3. In 2007, the Advisory Task Force on bisphosphonates-related osteonecrosis of the jaw (BRONJ) 4 categorized various risk factors of BRONJ such as drug-related, local, demographic, or systemic factors. The NSW Health Guidelines 5 and a recent position paper by AAOMS 2 further added two new sets of factors, namely genetic and preventive. Therefore, up to 2009, the risk factors for BRONJ were grouped as drug-related, local, demographic or systemic, genetic, and preventive.
Bisphosphonate-related osteonecrosis of the jaw
Papapetrou 6, reviewed the adverse effects of BPs and reported side effects such as upper gastrointestinal tract adverse events, renal toxicity, ocular adverse events, acute-phase responses, hypocalcemia, secondary hyperparathyroidism, musculoskeletal pain, arterial fibrillation, atypical fractures of the femoral diaphysis, and ONJ, etc 6. In 2002, the Food and Drug Administration reviewed some reports on ONJ in cancer patients who had received intravenous (i.v.) BP therapy 6. After 1 year, Marx reported a series on 36 patients with ONJ who were treated with pamidronate or zoledronic acid. Later on, this hypothesis was also supported by many authors who highlighted a strong correlation between intraoral bone necrosis and BP treatment, especially after avulsion or other dentoalveolar procedures.
The exact etiopathogenesis and diagnosis of BRONJ was not clear until recently. However, numerous hypotheses in the literature aim at promoting and interlinking the development of BRONJ. Factors that may influence the development of BRONJ include the potency of BPs, the biology of the jaw bone, the antiangiogenic property of BPs, and soft-tissue toxicity; all these factors are compounded by the presence of an infection, use of other concomitant drugs and presence of pre-existing pathologies and a compromised immune response. The diagnosis of BRONJ is mainly based on four characteristics, namely having undergone current or previous treatment with a BP, presence of an exposed or necrotic bone in the maxillofacial region that has persisted for more than 8 weeks, having no history of radiation therapy to the jaws, and having no evidence of cancer at the site. Lesions in patients who have not fulfilled the above four characteristics should be excluded from the diagnosis of BRONJ 2,3,5,7,8.
BRONJ is initially asymptomatic for many weeks or months and may only be recognized clinically by the presence of an exposed bone in the oral cavity. The typical signs and symptoms include pain, soft-tissue swelling, paresthesia, suppuration, soft-tissue ulceration, loosening of the teeth, and drainage that is similar to that observed in osteoradionecrosis 3,9. The radiographic findings of BRONJ are overlapping to those of osteomyelitis, osteoradionecrosis, and metastatic bone lesions; however, the most common radiographic finding in ONJ is osseous sclerosis. Osseous sclerosis can vary from subtle thickening of the lamina dura and alveolar crest to attenuated osteopetrosis-like sclerosis. Other findings such as osteolysis, soft-tissue swelling, periosteal new bone formation, periapical lucencies, oroantral fistulas, and sequestra are likely to correspond with the presence of an infection 10,11.
Microbial cultures may help in identification of the pathogens causing secondary infections (actinomyces and other pathogens), which is important for the selection of appropriate antibiotics. Microscopic evaluation of hard tissues may help reveal necrotic bone spicules with bacterial colonization and interspersed acute and chronic inflammatory cells, whereas a soft-tissue evaluation may help reveal a proliferating stratified squamous epithelium with arcading rete pegs and neutrophilic exocytosis and adjacent fibrous connective tissue revealing the presence of patches of plasma cells, interspersed neutrophils, and surgical hemorrhage that are similar to those observed in osteomyelitis 12,13.
Recently, Vincenzi et al. 14 reported decreased levels of circulating vascular endothelial growth factor at days 7 and 21 after the first administration of N-BPs, which indicates that the antiangiogenic properties of N-BPs are directly linked to BRONJ pathogenesis and that the serum vascular endothelial growth factor levels could represent an effective early predictive marker. The levels of other predictive markers such as morning fasting serum C-terminal telopeptide (CTX) are less than 100 pg/ml in patients who have received or are undergoing N-BP therapy, representing a high risk of BRONJ development 15–17. The immunohistochemical analysis also reveals an increased expression of hDB-1, hDB-2, and hDB-3, reduced expression of TGFβ1, and increased expression of galectin-3 in patients with BRONJ 18,19.
According to previous studies, BRONJ is related to the development of avascular necrosis or dead jaw bones and cannot easily be treated with conventional medical and/or surgical intervention. Therefore, the associated risk factors and preventive measures related to BRONJ play an important role to limit this newly developed clinical condition.
Drug-related risk factors
According to previous studies, heterocyclic N-BPs (zoledronate and risedronate) are more potent compared with alkyl-amino BPs (pamidronate, alendronate, neridronate, olpadronate, and ibandronate) and are more potent compared with non-N-BPs (etidronate, clodronate, and tiludronate) 20. More potent BPs (zoledronate>pamidronate>oral BPs) increase the tendency toward the development of ONJ 5. The i.v. route of administration results in a greater drug exposure (50%) to the jaw compared with the oral route (10%), therefore increasing the tendency toward the development of ONJ 21,22. The incidence rate of BRONJ in cancer patients increases 2.7–4.2 folds if the BPs are administered i.v. compared with cancer patients not exposed to i.v. BPs 2,5.
Duration of therapy
Long-term administration of BPs may associate with an increased risk for the development of ONJ 2.
Local risk factors
Dentoalveolar surgery includes, but is not limited to, extraction, dental implant placement, periapical surgery, and periodontal surgery involving osseous injuries. According to the original position paper, local factors such as having undergone dentoalveolar procedures and the presence of tori and concomitant dental disease increase the risk for the development of BRONJ in the setting of i.v. BP administration. In patients with the above-mentioned conditions, the risk of BRONJ development was seven times higher compared with those who have not undergone dentoalveolar surgery. However, in cancer patients, the administration of i.v. BPs and having undergone dentoalveolar procedures may increase the risk of BRONJ by 5–21 folds compared with cancer patients who were treated with i.v. BPs but had not undergone dentoalveolar procedures 2.
Local anatomical features such as the presence of lingual tori, mylohyoid ridges in the mandible and palatal tori in the maxilla increase the risk for the development of BRONJ. According to previous studies, the occurrence of BRONJ in the mandible is higher compared with the maxilla (2 : 1), and the lesions are more commonly found in areas with a thin mucosa overlying bony prominences such as tori, bony exostoses, and mylohyoid ridges. However, no data are available to estimate the relationship between the occurrence of these anatomical structures and BRONJ 2.
Concomitant oral diseases
Cancer patients exposed to i.v. BPs with a history of inflammatory dental diseases such as periodontal and dental abscesses are at a seven-fold increased risk of developing BRONJ, because inflammatory (possibly infective) dental diseases may lower the pH, which is essential for BRONJ development 2,23.
Demographic and systemic factors
According to the original position paper, the age, sex, ethnicity, and diagnosis of cancer with or without osteoporosis were reported as risk factors for BRONJ 4. However, a recent position paper reported that an increased age of the patient is associated with BRONJ (with each passing decade, there is a 9% increased risk of ONJ in multiple myeloma patients treated with i.v. BPs) 5, that the sex is not statistically associated with BRONJ, and that Whites are at a higher risk of BRONJ compared with blacks 2.
Other systemic factors or conditions such as having undergone renal dialysis and having low hemoglobin levels, obesity, and diabetes increase the risk of BRONJ. The cancer type also plays an important role, for example, patients with multiple myeloma are at the highest risk for development of ONJ, followed by those with breast cancer, followed by those with other cancers and osteopenia/osteoporosis concurrent with cancer 5. Wessel et al. reported an increased risk of BRONJ among tobacco users, but no increased risk was associated with alcohol use 2. The concomitant risk factors include: having undergone renal dialysis; having low hemoglobin levels, obesity, and diabetes; use of tobacco; having poor oral hygiene; and having undergone chemotherapy with cyclophosphamide, erythropoietin, and steroids 5.
Sarasquete et al. reported that genetic perturbations, that is, single-nucleotide polymorphisms in the cytochrome P450-2C (CYP2C8) gene were associated with an increased risk of BRONJ among multiple myeloma patients treated with i.v. BPs 2.
The original position paper recommended that patients must undergo dental evaluations and receive necessary treatment before initiating i.v. BP therapy 4. In addition, given the long-term biological activity of i.v. BPs, one may hypothesize that administration of different dosing regimens may be equally effective and may decrease the risk of BRONJ 2.
Coso et al. evaluated the BRONJ-related and skeletal-related events (SREs), for example, pathological fractures in multiple myeloma patients using different dosing schedules for zoledronate, and reported that alternative dosing schedules reduced i.v. BP exposure and had comparable outcomes in terms of preventing SREs and decreasing the risk of BRONJ 2.
According to the original position paper, the two major risk factors for BRONJ are i.v. BP exposure and having undergone dentoalveolar procedures. Recent studies suggest that manipulation of i.v. BP dosing may be effective in reducing SREs and minimizing the risk of BRONJ. In addition, undergoing preventive dental interventions before initiating i.v. BP treatment can also effectively reduce but does not eliminate the risk of BRONJ 2.
If systemic conditions permit, the clinician may stop oral BPs for a period of 3 months before and 3 months after elective invasive dental surgery to lower the risk of BRONJ. Long-term prospective studies are required to establish the efficacy of a drug holiday in reducing the risk of BRONJ in patients receiving oral BPs, because the risk reduction may depend on the duration of BP exposure 2.
In 2007, studies by Marx on BRONJ provided the following recommendations on the basis of data gained and clinical experience:
- For patients diagnosed with osteopenia or osteoporosis and have been prescribed a BP: administration of oral BPs for less than 3 years has little risk of osteonecrosis; this allows for the dental healthcare provider to achieve optimum oral health and repair the dentition similar to the recommendations (achieve optimum oral health and repair the dentition) provided before the initiation of i.v. BP therapy. The application of preventive measures led to a sustained reduction in BRONJ occurrence from 7.8 to 1.7% (P=0.016) 23.
- Patients who have been taking an oral BP and present for dental treatment: at this level, the dental healthcare provider requires information on the length, dose, indication for which oral BP therapy was advised, and the use of concomitant steroids or other drugs that might affect bone healing. In general, nonsurgical dental procedures are safe at all times in BP-exposed patients. The morning fasting serum CTX levels are less than 100 pg/ml in patients who have received or are receiving N-BP therapy, representing a high risk of BRONJ development; however, an invasive dental procedure is only indicated if the CTX level is greater than 150 pg/ml in order to achieve uncomplicated healing 11,12,17–19.
Bagán et al.24, during the same year, provided guidelines to dental healthcare providers on patients treated with BPs who did not have ONJ and categorized the preventive measures into three subheadings:
- Before initiating BP treatment: All patients with concomitant risk factors who were to begin a treatment with BPs are advised to report to a dental healthcare provider for the proper assessment and management of the recommended dental care before initiating the treatment.
- During BP treatment: In this condition, it is recommended that the patients report to a dental healthcare provider at least once a year to rule out any caries and periodontal diseases at an early stage. Toward the end of the treatment, it is recommended to detect and treat caries using conservative methods (filling/RCT) in cases of periodontal disease to eliminate plaque and periodontal pouches in order to avoid the future need of tooth extractions and any frictional lesions (chronic traumatisms).
- In case of extraction during BP treatment: It is recommended to perform the extraction in the least traumatic manner and suture the wound. In this condition, the antibiotic of choice is oral amoxicillin with clavulanic acid (1000 mg t.d.s.) or clindamycin (300 mg t.d.s./q.i.d.), to be taken 2 days before the extraction and for 10 days after the extraction. After extraction, the patient is advised to maintain good oral hygiene (using 0.12% chlorhexidine twice a day for 15 days).
Kim et al. 10 added a sixth risk factor (cofactor) and reported that the incidence of BRONJ increases because of having undergone corticosteroid treatment, having diabetes, having poor oral hygiene, drinking and smoking habits, and having undergone anticancer therapy. If the patients have been treated with BPs for a long duration and have been prescribed glucocorticosteroids, it can be inferred that there is an increased of the incidence of BRONJ 10.
A summary of all the associated risk factors and prevention of BP-induced ONJ is given below 25.
Conflicts of interest
There are no conflicts of interest.
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