Bisphosphonates and osteonecrosis of the jaw: Innocent association or significant risk?
ABSTRACTPublished case series and systematic reviews have documented an association between bisphosphonates and osteonecrosis of the jaw. However, a cause-and-effect relationship has not been established, and most of the reported cases have been in patients with cancer who were receiving much higher doses than those used to treat osteoporosis or Paget disease of bone. The risk, if any, to patients with these latter conditions receiving these drugs appears to be very small.
KEY POINTS
- Recently published data do not support the hypothesis that these drugs cause osteonecrosis of the jaw.
- There is no evidence to support routine dental examinations for all patients before starting bisphosphonate therapy for osteoporosis or Paget disease, but heightened concern seems warranted for cancer patients.
- Clinical experience suggests that dental work by experienced dentists and surgeons can be carried out safely with very little risk to patients taking bisphosphonates.
The risk, if any, is probably very small
This information suggests that if these drugs, used at the recommended dose, really do pose a risk, it is probably very small: less than 1 case in 100,000 patient-years if taking an oral bisphosphonate such as alendronate.14,17 This is significantly less than the risk of fracture in these patients (which may be higher than 1 in 10), the risk of death following such a fracture,22–30 or the risk of death from drowning, house fire, or motor vehicle accident.52
The cases of osteonecrosis of the jaw that we have personally seen—all in cancer patients treated with chemotherapy and highdose bisphosphonates—all showed histologic evidence of necrosis and concomitant infections, suggesting the actual diagnosis was osteomyelitis. Bone biopsies from affected but macroscopically normal mandibles at the time of surgical debridement for osteonecrosis of the jaw showed normal or increased osteoclastic activity, in contrast to what one would expect if there were oversuppression of bone turnover (unpublished data, J. Christian, J. Carey, Cleveland Clinic).
Recently, this family of drugs has shown some promise in limiting the progression of alveolar bone loss in periodontal disease (though they are not approved for this indication).53–55 Finally, published studies suggest bisphosphonate therapy may even be beneficial in animals and humans with osteonecrosis,56–58 and in conditions that mimic osteonecrosis such as SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis) of the mandible, in which the histologic appearance may resemble that of osteonecrosis.59
WHAT SHOULD WE TELL OUR PATIENTS?
Several things are worth emphasizing from the published data and guidelines:
- Many things are unknown about osteonecrosis of the jaw and the risk in people taking bisphosphonates.
- The best evidence today does not support a cause-and-effect relationship between osteonecrosis of the jaw and bisphosphonate therapy.
- If bisphosphonates are causative, the risk appears very low in patients without cancer.
- It is important to distinguish between cancer and noncancer patients because of different risk factors, the markedly higher doses of bisphosphonates used in cancer patients, and the much greater incidence of osteonecrosis of the jaw seen in cancer patients irrespective of the cause.
- The higher risk in cancer patients is likely modified or confounded by additional risk factors, possibly including long-term use of high-dose intravenous bisphosphonates.
- About 90% of cases of bisphosphonate-associated osteonecrosis of the jaw have been in cancer patients, in whom a substantial temporal relationship to bisphosphonate therapy has been seen.9–12,15–17,19,49,54–57
- Prevention will likely be the most effective management strategy because of the significant morbidity associated with and the refractory nature of osteonecrosis of the jaw.
- Prophylactic dental examinations and any needed repair work are probably best done before starting bisphosphonate therapy in cancer patients; however, studies supporting such a strategy are needed.
- There is no evidence to support routine dental examinations before starting such therapy for disorders other than cancer, or for stopping such therapy before, during, or after dental surgery. Whether this is true for patients who have been taking these drugs for several years or more is unclear.
- Good communication between patients and their physicians, dentists, periodontists, and surgeons will help provide them with the best possible care.
Clearly, much further research is needed on the causes, risks, diagnosis, and management of this disorder to optimize patient outcomes.
