Commentary (Berenson/Yeh): Osteonecrosis of the Jaw in Cancer Patients Receiving IV Bisphosphonates

During the past decade, there has been a dramatic change in the lives of patients with metastatic bone disease as a result of the use of intravenous monthly infusions of pamidronate (Aredia) and more recently zoledronic acid (Zometa). First, in the mid-1990s, pamidronate was shown to reduce skeletal complications among multiple myeloma patients with lytic lesions[1] and breast cancer patients with metastatic bone disease receiving either chemotherapy[2] or hormonal therapy.[3] More recently, zoledronic acid was shown to be effective not only in these patient populations[4] but also among patients with metastatic bone disease from other types of cancer, including prostate,[5,6] whereas other bisphosphonates had not shown efficacy in these patients. This led to the development of specific American Society of Clinical Oncology guidelines recommending the use of these agents for breast cancer patients with metastatic bone disease[7] and myeloma patients with demonstrated loss of bone.[8]

Prevalence of ONJ

Recently, cases of osteonecrosis of the jaw (ONJ) have been reported among patients with metastatic bone disease who were receiving intravenously administered bisphosphonates monthly as outlined in the comprehensive review from Van Poznak and Estilo. These reports were initially made by oral surgeons who were seeing these patients in their practice.[9] In addition, an internet survey involving patients receiving these agents reported a high proportion of myeloma patients who were developing this complication with a lower risk among breast cancer patients.[10] The authors also suggested a higher risk with zoledronic acid than with pamidronate. More recently, retrospective and prospective studies have attempted to determine the risk of this complication at several major institutions that treat large numbers of patients with metastatic cancer to bone with these agents.[11-13]

Since these drugs are being increasingly used for patients with metastatic bone disease and patients are living longer with bony involvement of their cancers, resulting in longer use with more prolonged exposure to these drugs, the reports of ONJ are only likely to increase. Thus, it will become increasingly important to better define this entity, its spectrum of severity, clinical consequences, course over time, other risk factors, and possible ways to prevent or at the very least delay its onset and reduce its sequelae; and determine whether bisphosphonates should be discontinued in patients who develop this complication.

Moving Toward a Uniform Definition

At this point, there is still no clear definition of what constitutes ONJ. Certainly, patients with exposed mandibular or maxillary bone who have been exposed to these agents are likely to be victims of this complication but many published reports include patients with only jaw pain that were never properly evaluated and confirmed to result from ONJ. In order to get a handle on this problem, we need to have a uniform definition of what the problem is, which will require the input of a qualified group of oral surgeons and pathologists.

Moreover, although attempts have been made to develop a staging system for ONJ and estimate the relative proportions of patients that are in each of the stages,[14] this has not garnered widespread acceptance in either the dental or oncology communities. This is imperative if we are to make intelligent decisions about the relative clinical consequences of this complication weighed against the development of skeletal problems resulting from the discontinuation or lack of use of these agents altogether.

In our experience, this complication can have a wide range in terms of its relative clinical significance for the patient. In some patients ONJ is relatively quiescent over many years whereas other patients rapidly develop severe bone loss and ongoing infections that can be debilitating and greatly affect the quality of life. At this point, there are no data to show that continuing, discontinuing, or modifying dose or schedule of the bisphosphonate treatment changes the course of this complication. Obviously, the consequences of withdrawal of these agents among patients with minimal ONJ but severe bone problems that are being controlled with bisphosphonate treatment may be quite different than among patients with severe ONJ and minimal bone disease.

Factors That Influence Risk and Severity

It will also be important to define other risk factors in order to try and reduce the frequency of ONJ in this setting. Certainly, it is recognized that tobacco and alcohol use as well as poor dental hygiene are risk factors for the development of ONJ. In addition, chemotherapy and radiotherapy are also known risk factors for this complication. Whether these factors increase the risk of patients developing bisphosphonate-associated ONJ as well as other factors needs to be determined. If specific agents that are being used to treat the patient's cancer are identified as risk factors, alternative therapies may need to be used. The type of cancer may be a risk factor in that myeloma patients seem to have a higher incidence of ONJ than patients with other types of cancer [10,11]. Whether this is a result of the disease, disease-specific treatments, or patient factors unrelated to the cancer is unknown at this point.

Factors that may worsen or improve the course of this disorder also need to be identified. For example, it has been shown that surgical intervention is largely ineffective and may, in fact, exacerbate the condition. However, there may be circumstances requiring surgical intervention;these should be defined for the dental and oncology communities. Moreover, use of antibiotic, antiviral, and antifungal therapies have all been used but have never been evaluated in a clinical trial for this condition. In fact, if these treatments or other potential interventions lead to long-term control of the problem, then the consequences of ONJ may be minimized. Hence the patient could enjoy the benefit of bisphosphonate therapy without the worry of devastating effects from jaw problems with ongoing bisphosphonate treatment.

Although some studies have suggested differences in risk between the different bisphosphonates,[10,11] these studies suffer from their inadequate design, small numbers of cases and/or lack of a clear definition of ONJ. It will be important to determine if there are differences in risk between these different agents so that bisphosphonate options that may be equally effective for patients with a specific type of cancer associated with bone metastases may receive drugs that will minimize the risk of ONJ. However, physicians should not be duped into believing that all bisphosphonates are equal in terms of efficacy in the setting of metastatic bone disease. Clearly potency, dose, schedule, and route of administration matter when it comes to the ability of these drugs to prevent skeletal problems for cancer patients with metastatic bone disease.

Conclusions

The review by Van Pozak and Estilo provides an excellent overview of the current literature regarding a recently identified complication in cancer patients with metastatic bone disease who receive intravenously administered bisphosphonates. Although the authors have provided a very comprehensive report of what is currently known about its incidence, risk factors, and treatment, much more needs to be learned so that the risk of this complication can be reduced and its clinical consequences minimized. This will be important to cancer patients with metastatic bone disease so that they can continue to enjoy the improved quality of life from the reduction in skeletal problems that has resulted from bisphosphonate use during the past 10 years.

-James R. Berenson, MD-Howard S. Yeh, MD

Financial Disclosure:Dr. Berenson is a member of the speakers' bureau, is a consultant for and receives research grants from Novartis Pharmaceuticals.

References:

1. Berenson JR, Lichtenstein A, Porter L, et al: Efficacy of pamidronate in reducing the skeletal events in patients with advanced multiple myeloma. N Engl J Med 334:488-493, 1996.

2. Hortobagyi GN, Theriault RL, Porter L, et al: Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone lesions. N Engl J Med 335:1785-1791, 1996.

3. Theriault RL, Lipton A, Hortobagyi GN, et al: Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: a randomized, placebo-controlled trial. Protocol 18 Aredia Breast Cancer Study Group. J Clin Oncol 17:846-854, 1999.

4. Rosen LS, Gordon D, Kaminski M, et al: Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: A randomized, double-blind, multicenter, comparative trial. Cancer 98:1735-1744, 2003.

5. Rosen LS, Gordon D, Tchekmedyian S, et al: Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: A phase III, double-blind, randomized trial-The Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group. J Clin Oncol 21:3150-3157, 2003.

6. Saad F, Gleason DM, Murray R, et al: A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 94:1458-1468, 2002.

7. Berenson JR, Hillner BE, Kyle RA, et al: American Society of Clinical Oncology Bisphosphonates Expert Panel. American Society of Clinical Oncology clinical practice guidelines: The role of bisphosphonates in multiple myeloma. J Clin Oncol 20(17):3719-3736, 2002.

8. Hillner BE, Ingle JN, Chlebowski RT, et al: American Society of Clinical Oncology. American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 21(21):4042-4057, 2003.

9. Ruggiero SL, Mehrotra B, Rosenberg TJ, et al: Osteonecrosis of the jaws associated with the use of bisphosphonates: A review of 63 cases. J Oral Maxillofac Surg 62:527-534, 2004.

10. Durie BGM, Katz M, Crowley J: Osteonecrosis of the jaw and bisphosphonates. N Engl J Med 353:99, 2005.

11. Bamias A, Kastritis E, Bamia C, et al: Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: Incidence and risk factors. J Clin Oncol 23:8580-8587, 2005.

12. Van Poznak CH, Estilo CL, Sauter NP, et al: Osteonecrosis of the jaw in patients with metastatic breast cancer (abstract 3057). Breast Cancer Res Treat 88(suppl 1):S131, 2004.

13. Hoff AO, Toth B, Altundag K, et al: Osteonecrosis of the jaw in patients receiving intravenous bisphosphonate therapy (abstract 1218). J Bone Miner Res 20(suppl 1):555, 2005.

14. American Association of Oral and Maxillofacial Surgeons: http://www.aaoms.org.