Bisphosphonates are non-metabolized analogs of pyrophosphate with a long period of retention in the bone (up to 10 years). Bisphosphonates can be chemically grouped into two main categories based on side chains.
The first category is the group containing nitrogen (which prevents metabolization; allowing them to accumulate with ongoing effects) and are considered more potent. Elendronate, risedronate, pamidronate, ibandronate and zoledronate are all members of this category. The medications inhibit farnesyl pyrophosphate synthesis and block the mevolanate pathway in osteoclasts.
The second group of medications is without the nitrogen side chain; and are considered less potent. This category includes etidronate, clodronate, and tiludronate.
Bisphosphonates induce osteoclast cell death by formation of cytotoxic metabolites of ATP-bisphosphonate analogs that interfere with intracellular metabolic enzymes. These medications are widely used among many medical disciplines with remarkable improvement in the overall quality of life in several conditions, including osteoporosis, Paget's disease, otosclerosis, immobilization due to malignancy-related hypercalcemia, fibrous dysplasia and osteolytic bone lesions of malignant myeloma and malignant diseases in which bone resorption is the main component of the disease.
Reports of Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ) were recognized as early as 2003. Currently, the American Academy of Oral & Maxillofacial Surgeons (AAOMS) define BRONJ as
- Current or previous treatment with a bisphosphonate;
- Exposed, necrotic bone in the maxillofacial region that has persisted for more than eight weeks; and
- No history of radiation therapy to the jaws.
BRONJ may be mistaken for several other conditions including alveolar osteitis, sinusitis, gingivitis/periodontitis, caries, periapical pathology and TMJ disorders.
Overall, the risk of developing BRONJ is estimated to be between 0.01% and 34%. Increased risk of developing BRONJ is increased with the potency of the medications and the duration of the therapy. Additionally, dentoalveolar surgery, extraction, dental implants, periapical, and other jaw surgeries are known local risk factors in causing the disease.
Precautions and Recommendations
The following must be kept in mind whenever clinicians see patients who are on bisphosphonates:
- Optimum OHI should be always emphasized, at all times, whether the patient is on or will be taking the medication. Patients who report history of diabetes, alcohol and tobacco usage taking corticosteroids or those receiving chemotherapeutic agents are considered at higher risk for developing BRONJ.
- Prior to treatment with IV bisphosphonates, a thorough oral examination with extraction of unsalvageable teeth, as well as the performance of any other invasive surgical procedures, should be completed.
- Discontinuation of oral bisphosphonates for a period of three months prior to and three months following elective invasive dental surgery may lower the risk of BRONJ. It is important, however, to remember that this medication is given for the presence of advanced metastatic carcinoma and multiple myeloma, among other serious conditions. Additionally, responses to discontinuing the medication vary with no concrete guarantees.
- When the clinician is planning to start the patient on bisphosphonates, it is highly preferred to delay dental treatments until optimal dental health is achieved. Again, this is done when a patient's systemic condition permits. Nevertheless, unsalvageable teeth and necessary surgical procedures should be completed. If the patient is already on IV-bisphosphonates and they are asymptomatic, invasive dentoalveolar surgeries or dental implants should be avoided. Non-restorable teeth may be treated by removal of the crown and endodontic treatment of the remaining roots.
- When the patient presents with convincing evidence of BRONJ, the necrotic bone and soft tissues should be debrided and all measures should be taken to achieve patient comfort and elimination of pain, with the understanding that there may be mixed results in response. Al elective surgical procedures must be delayed. Exposing uninvolved bone should be avoided at all times. Hyperbaric oxygen may or may not be effective. Discontinuation of the medication may potentially have a beneficial role in preventing BRONJ. However, clinicians must always weigh the benefits versus potential risk, providing that most patients receiving this class of medications have an advanced metastatic malignancy that requires long-term bisphosphonates therapy.
Detailed information on BRONJ can be found in the two position papers of the American Academy of Oral & Maxillofacial Pathology and the American Academy of Oral & Maxillofacial Surgery.