Systematic review: Bisphosphonates and Osteonecrosis of the Jaws
Ann Int Med 2006;144:753-761, Woo, SB and others. PMID: 16702591. There is a previous Update on jaw osteonecrosis caused by bisphosphonates on this site. “Osteonecrosis” literally translates to mean “bone death.” It has recently been described as an adverse effect of bisphosphonate therapy, especially from intravenous nitrogen-containing bisphosphonates, but there are a few cases related to oral bisphosphonates such as Fosamax or Actonel. The Woo and others article reviews all the previous articles on this topic, so it is worthwhile reading. Because of the importance of this topic, and since most of you probably can't find the full-text article, the following coverage will be more detailed than usual. First the key summary points from the article:
1. “Osteonecrosis of the jaws is strongly associated with the use of aminobisphosphonates, and the mechanism of disease is probably severe suppression of bone turnover.”
2. “Ninety-four percent of patients are treated with zoledronic acid or pamidronate or both; 85% of affected patients have multiple myeloma or metastatic breast cancer, and 4% have osteoporosis.”
3. “The prevalence of osteonecrosis in patients with cancer is 6% to 10% and the prevalence in those taking alendronate for osteoporosis is unknown; osteonecrosis seems to be time- and dose-dependent because of the long half-life of aminobisphosphonates.”
4. “More than half of all cases (60%) occur after dentoalveolar surgery (such as tooth extraction) to treat infections, and the remaining 40% are probably related to infection, denture trauma, or other physical trauma.”
5. “Preventive strategies include removing all foci of dental infection before starting bisphosphonate therapy.”
6. “Treatment is directed toward control of pain and infection and careful local debridement of dead bone, but not wide excision of lesions.”
Actions of bisphosphonates. Bisphosphonates powerfully inhibit osteoclastic activity. That is, they stop osteoclasts from resorbing bone. This allows osteoblasts (bone-forming cells) to continue to function, thus increasing bone mineral density (BMD). Bisphosphonate half-life has been reported to be as much as 12 years. Alendronate, risedronate, pamidronate, zoledronic acid, and ibandronate, the aminobisphosphonates, have much higher potency due to their nitrogen side chain. The authors allude to several other actions of the bisphosphonates not discussed here. However, there are two important functions that are highlighted: they exert antitumor effects (thus their use for multiple myeloma and breast cancer; and they have antiangiogensis properties (they prevent blood vessels from developing). Decreased blood vessels in the area makes healing more difficult in the presence of infection or trauma. Intravenous bisphosphonates have improved bioavailability without gastrointestinal side effects which gives better patient adherence. They are the standard therapy for managing multiple myeloma and metastatic cancer.
Potential adverse effects. Prolonged use of bisphosphonates may suppress bone turnover enough to allow microdamage of bone to develop. Some researchers suggest this could lead to bone less able to cope with stress and strain with an increased risk of fracture. There are, however, researchers who say this won't affect bone mineralization or mechanical properties.
Oral complications of bisphosphonate therapy. Osteonecrosis of the jaw is reported in 368 cases. This is reported as exposure of portions of the bone of the mandible (lower jaw) in 65% of cases, of the maxilla (upper jaw) 26% of the time, and both 9%. About 1/3 of the lesions were painless and often involved multiple sites on one side of the jaw or was on both sides. Most lesions were on the posterior lingual mandible near the mylohyoid ridge. This is on the tongue side of the lower jaw in back of your last molar where you can feel this ridge with your own tongue. Important to note is that 60% of the cases occurred after a tooth extraction or other dental surgery and the other cases were spontaneous. The latter cases often involved patients with dentures, which may cause local trauma. Often bony exostoses (outgrowths of bone that are easily traumatized) were reported as the cause in spontaneous cases. Most cases (94%) involved patients treated with intravenous bisphosphonates. The remaining 6% of patients were taking oral bisphosphonates for osteoporosis or Paget disease of bone.
Clinical appearance. The exposed bone appears as areas of yellow-white, hard bone with smooth or ragged borders. There may be extra- or intraoral sinus tracts (drainage openings). Painful ulcers may develop in soft tissue that touches the ragged bone.
Radiographic appearance. Results may be negative early or may appear as subtle periodontal ligament widening equal to the findings in periodontal disease. Advanced cases show a moth-eaten, poorly defined radiolucency, with or without radio-opaque sequestra. Pathologic jaw fracture is a possibility. The presentation of bisphosphonate-associated osteonecrosis may present similarly to osteoradionecrosis (osteonecrosis caused by excessive radiation exposure).
Risk factors and etiopathogenesis. The two most important factors for developing bisphosphonate-associated osteonecrosis of the jaws are the type and total dose of bisphosphonate and a history of trauma, dental surgery, or dental infection. Note that 94% of patients received pamidronate or zoledronic acid for cancer therapy with dosages up to 12 times higher than that used for osteoporosis. Clodronate, a nonaminobisphosphonate has not been implicated in jaw osteonecrosis. With intravenous aminobisphosphonates lesions have developed in four months, but the median therapy duration is from 22 to 39 months and the mean is from 9 to 14 months. In one year the cumulative hazard was 1% but it increased to 21% at 3 years of treatment when using zoledronic acid. With patients using pamidronate either alone or with subsequent zoledronic acid, these hazards decreased to 0% at 1 year and 4% in the third year. A few cases were reported in patients taking 10 mg/day of alendronate. One patient had taken alendronate for only 2 years. Trauma to oral tori (bony outgrowths) and patients (60%) having dentoalveolar surgery resulted in nonhealing of the surgical site and necrosis of bone.
Susceptibility of the jaws to osteonecrosis. Why the jaws? This appears to be due to the jaw bones being separated from a trauma-intense and microbiologically diverse oral environment by a thin mucosa and periosteum. It is thought that even minor damage to the mucosal or periodontal covering can lead to bone necrosis. Additionally the teeth can readily be infected by bacteria that cause caries and periodontal disease, common oral infections. Only a 2 mm periodontal covering separates the teeth from the bone. The authors state, “We suggest that bisphosphonate-associated osteonecrosis of the jaws results from marked suppression of bone metabolism that results in accumulation of physiologic microdamage to the jawbones, compromising biomechanical properties. Trauma and infection increase demand for osseous repair that exceeds the capacity of the hypodynamic bone, resulting in localized bone necrosis. The antiangiogenic property of bisphosphonates and the other medications and the presence of other comorbid factors may promote the risk for or persistence and progression of this condition.”
Management recommendations. There are no clinical trials yet that show any management strategy superior to others. With this in mind the authors suggest three therapies based upon when the patients begin/began bisphosphonate therapy:
Group 1. Patients about to begin aminobisphosphonate therapy. Treat active oral infections, eliminate sites at high risk for infection such as partially impacted wisdom teeth, nonrestorable teeth, or teeth with substantial periodontal disease.
Group 2. Patients without osteonecrosis of the jaws who are receiving intravenous aminobisphosphonate therapy. With less than 3 months of drug therapy treat as group 1. With more than three months of drug therapy, seek conservative alternatives to surgical procedures (endodontic therapy with or without decoronation, scaling, and debridement) with appropriate local and systemic antibiotics. Perform extractions and other surgery using minimal bone manipulation with appropriate local and systemic antibiotics; follow up to assure healing.
Group 3. Patients with osteonecrosis of the jaws. Same as group 2 with more than 3 months of drug therapy. Consider additional imaging studies, such as computed tomography scans. Perform conservative removal of dead bone as necessary with minimal trauma to adjacent hard and soft tissues. Prescribe oral rinses (0.12% chlorhexidine rinse, hydrogen peroxide). Prescribe systemic antibiotic therapy. Prescribe systemic analgesics as indicated. Prescribe a soft acrylic stent. Suggest discontinuation of bisphosphonate therapy until osteonecrosis heals or underlying disease progresses.
Discontinuation of bisphosphonate therapy. There are no published studies to show the superiority of discontinuation of bisphosphonates over continuing them. The authors, however, suggest that the patient may benefit from bisphosphonates being withdrawn since anecdotal reports suggest this sometimes works.
Editor's comments
Brief summary of jaw osteonecrosis and bisphosphonate relationship: There appear to be two requirements for osteonecrosis of the jaw to develop: 1) A condition that requires aminobisphosphonates therapy. 2) An oral infection or trauma to the jaw bones when patients are on aminobisphosphonate therapy.
Other thoughts: Osteonecrosis of the jaws is obviously a very serious condition that individuals should strive to prevent. For those of us with osteoporosis taking oral bisphosphonates, the number of cases of osteonecrosis that have been reported is quite small. Considering that Fosamax has been an approved FDA medication for over ten years and clinical trials used it for several years before that, the chance of getting osteonecrosis from oral bisphosphonates is minimal with only 4% of the reported cases due to oral bisphosphonates. This is apparently due to the fact that oral doses of aminobisphosphonates probably don't suppress bone turnover as much as the intravenous methods do.
The importance of proper dental preventive therapy and treatment to prevent aminobisphosphonate-associated jaw osteonecrosis. Although there are no clinical trials to assure us that careful preventive measures will decrease the chance of getting osteonecrosis, wisdom dictates that we should meticulously follow the three management guidelines given by the authors. This means that dental examination and therapy should become an integral part of osteoporosis treatment. When you are first diagnosed with osteoporosis, if your physician doesn't recommend a thorough dental examination, you need to have that done yourself. Then show your physician the abstract for the Woo and others study in order to educate him or her about the necessity of combining dental and osteoporosis diagnosis and treatments if aminobisphosphonates are used for osteoporosis therapy. If you are receiving aminobisphosphonates and develop a dental problem, be sure your dentist knows you are being treated for osteoporosis with aminobisphosphonates. Keep your mouth meticulously clean with proper brushing, flossing and other methods such as antimicrobial mouth rinses. If you wear a dental prosthetic device (full or partial denture), have any sore spots or irritations checked immediately. Avoid extensive dental therapies, especially those involving bone surgery, if at all possible. If you must have the surgery, be sure you have received an antibiotic mouth rinse and antibiotics before undergoing oral surgery. Remember that root canal therapy (endodontics) causes much less trauma to the bone and surrounding tissues than an extraction. This should always be the primary treatment choice (rather than an extraction) for individuals on long-term or intravenous aminobisphosphonate therapy. And antibiotic therapy is probably warranted as a precaution even when doing endodontics until studies provide more guidance on this topic. This would be especially true on teeth with periapical radiolucencies which probably indicates a infection is present in the jaw bone.
Reporting cases of jaw bone osteonecrosis to the FDA. Consumers or dentists can report cases of osteonecrosis to the FDA at http://www.fda.gov/medwatch/report/consumer/consumer.htm.