- Bisphosphonates: An Introduction
- Bisphosphonates and Jaw Necrosis
- Assessing the Risks of Bisphosphonates
- Assessing the Risks of Bisphosphonate Alternatives
- Treatment of Jaw Necrosis
- Weighing the Risks and Benefits of Bisphosphonates
- Conclusion
Bisphosphonates: An Introduction
Bisphosphonates have been used commonly for more than a decade for the treatment and prevention of osteoporosis, and are administered in two ways: orally and intravenously.
Alendronate (Fosamax), risedronate (Actonel) and ibandronate (Boniva) are available orally. The former two agents can be taken daily or weekly; the later agent can be taken daily or monthly. These drugs are generally well-tolerated, but a small percentage of patients note upper gastrointestinal irritation.
Pamidronate (Aredia), ibandronate (Boniva) and zoledronic acid (Zometa) are given intravenously. The former two agents are generally given every 3-4 months, and the later agent yearly, for the treatment of osteoporosis. While patients can develop a short-lived syndrome of low grade temperature as well as muscle and joint pain, these agents were, in general, felt to be well-tolerated and beneficial for the improvement of bone density and reduction in the rate of insufficiency fractures.
Bisphosphonates and Jaw Necrosis
Over the past several years, a concept concerning the use of bisphosphonates and the possible association of jaw necrosis (an area of bone which has lost its blood supply) has emerged. This entity has been termed “osteonecrosis” of the jaw. Patients with this condition develop exposed bone in the jaw. The overlying tooth often falls out and a nonhealing, often painful lesion remains. Also, an associated drainage tract may be present, connecting the area of damaged bone to the gum surface.
X-rays may initially be normal, but areas of thinned bone (radiolucencies) commonly develop subsequently. Surgery for these areas of abnormal bone (debridement) can increase the size of the involved area. If a patient develops necrosis of the jaw, efforts are made to avoid any dental procedures in that area
Osteonecrosis of the jaw is more common in the lower than in the upper jaw. Although this entity has been termed “osteonecrosis of the jaw”, bone pathologists agree that the pathology (disease development) is not similar to the “avascular necrosis,” which is classically seen in the femoral head of the bone, often in association with corticosteroid or alcohol use. Necrosis in the jaw seems to be associated with underlying infection.
Assessing the Risks of Bisphosphonates
Recent attention of the media to this condition has led to tremendous concern by patients who are taking these agents. Health care workers are trying as best as possible to assess the overall risk and to determine predictors of risk in any one patient. Osteoporosis is an ever growing concern for health providers and, as the population ages, there will be a greater number of insufficiency fractures, which means that more patients who will be candidates for bisphosphonate therapy.
A recent meta-analysis (Ann Intern Med 2006, 144: 753-761) reviewed the literature on the risks of bisphosphonate therapy. Ninety four percent of the cases of osteonecrosis of the jaw occurred in patients receiving high dose intravenous therapy (primarily pamidronate and zoledronic acid). The risks for females was shown to be slightly higher (3:2 female to male ratio). Sixty percent of the cases occurred after dental extraction or other dental surgery. There are less than 20 cases in the world’s literature associated with oral bisphosphonate therapy for treating conditions such as Paget’s disease or osteoporosis.
Although it is unclear how many cases were not reported, it seems to be quite uncommon, given the large number of patients that have taken these medications.
Assessing the Risks of Bisphosphonate Alternatives
There are clearly no perfect alternatives to bisphosphonate therapy. The Women’s Health Initiative Study questions the use of hormone replacement therapy (e.g. Premarin) for the treatment of osteoporosis due to the associated risk of breast cancer, myocardial infarction and stroke. The SERMs (estrogen-like drugs, such as raloxifene (Evista) which have some characteristics different than estrogen, and which do not appear to increase breast cancer risk have been shown to reduce the risk of vertebral fractures, but not hip fractures. Calcitonin is felt to be of minimal efficacy in reducing fracture risk. The bone-building agent teriparatide (Forteo) does reduce the risk of both vertebral and hip fractures; the original study by Neer (NEJM 2001) was stopped early due to study rats developing osteosarcoma. Although this has not been demonstrated in humans, both patients and health care workers still grapple with this concern. On the other hand, bisphosphonates were felt to be a safe treatment for the treatment and prevention of osteoporosis. Millions of patients have used these agents worldwide.
Treatment of Jaw Necrosis
When avascular necrosis of the jaw develops, it remains unclear how best to treat it. This has lead to the great concern that both patients and health care providers are experiencing. Treatment protocols are being designed; however, they have not been tested.
It seems prudent that all patients should have a dental exam and cleaning prior to beginning bisphosphonate therapy, and regular dental cleaning should continue throughout the duration of use. As infection is felt to trigger this condition, it is hoped that proper dental care will reduce the incidence of osteonecrosis of the jaw.
Discontinuing bisphosphonate therapy for low turnover state of bone may help prevent this condition (one way to measure turnover state in bone is the urinary N-Telopeptide, and some physicians suggest stopping bisphosphonate therapy if this result is less than 10).
If osteonecrosis does develop, there is some thought that acrylic stents (cavity supports) - with or without soft liners - may benefit exposed bone. Gentle surgical debridement (cleaning away of dead areas of bone) may also help, and oral antimicrobial rinses are frequently used as well. Bisphosphonate therapy is generally discontinued if this condition occurs, although there is no data to show that this leads to resolution of the problem.
Weighing the Risks and Benefits of Bisphosphonates
As when any medication is prescribed, the risks and benefits of that medication must be considered. For the treatment of osteoporosis, patients must understand that hip fractures can lead to significant disability and death (e.g., from clots in the lung related to leg clots that develop after fracture), and that multiple vertebral fractures can cause very significant pain and disability. This must be weighed against what appears to be a probable very low risk of osteonecrosis of the jaw. Oncologists treating patients with multiple myeloma and metastatic breast cancer have a different set of concerns, and use of bisphosphonates in the patient with cancer requires that a different set of issues be weighed. In patients being treated for osteoporosis, the consequences of untreated disease, with resultant fractures, must not be forgotten when striking the proper balance.
Conclusion
Osteonecrosis of the jaw is a newly recognized condition that we continue to learn more about. The exact incidence and the relation to bisphosphonate use, especially the risk with oral bisphosphonates, still needs more study. We especially need more data on how the development of necrosis relates to the duration of bisphosphonate use. The bisphosphonates clearly reduce the risk of osteoporotic fractures and reduce mortality in many patients with malignancies, and they reduce osteoporosis-related disability and can reduce the risk of mortality related to hip fracture. However, it’s worth reiterating that further study is clearly needed. At present, the overall risk associated with the use of oral bisphosphonate therapy for the treatment of osteoporosis appears to be low.
After balancing the risks and benefits, bisphosphonates will likely remain the best choice for most patients with osteoporosis. However, the decision regarding the optimal drug for managing osteoporosis in each patient is quite individual and should be determined on a case by case basis.
Read more on this topic in an ACR Hotline.
