Pathophysiology, risk factors and management of bisphosphonate-associated osteonecrosis of the jaw: Is there a diverse relationship of amino- and non-aminobisphosphonates?

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Abstract

Reports of osteonecrosis of the jaw (ONJ) in patients receiving long-term bisphosphonate therapy have appeared in the literature since 2003. This condition involves avascular necrotic bone in the area of maxilla or mandibula and there may be a secondary infection. Most cases of ONJ have been reported in cancer patients receiving the intravenous aminobisphosphonates zoledronic acid and pamidronate monthly or q 3 week; of note these are also the two most commonly used agents of this class. Risk factors for ONJ include a history of trauma, dental surgery or dental infection and intravenous bisphosphonate administration; in addition, the extent and duration of exposure to bisphosphonates also seem to correlate with the risk. Although a direct causal relationship with bisphosphonates cannot be assumed, these agents may possibly contribute to the development of ONJ by suppression of bone remodeling in the jaw which leads to increased rates of bone mineralisation and accumulation of microfractures. Clodronate, a non-aminobisphosphonate, appears to have a different mechanism of suppressing bone remodeling compared with aminobisphosphonates, and this may explain why few cases of ONJ have been reported with clodronate despite extensive use over the past 20 years; however, the potential of clodronate to reduce the risk of ONJ while providing equivalent clinical benefit to the aminobisphosphonates needs to be substantiated in controlled clinical trials. Use of bisphosphonate therapy should be carefully planned in patients with metastatic bone disease who have risk factors for ONJ, and appropriate preventive measures taken to avoid the development of this condition.

Introduction

Osteonecrosis of the jaw (ONJ) is a painful condition characterised by avascular necrosis of the bone in the oral cavity that is commonly associated with localised swelling and, in some cases, a purulent discharge [1], [2]. This is not a new phenomenon. In the mid-19th century, the term “phossy jaw” was coined to describe the maxillofacial necrosis that was seen in factory workers exposed to the white phosphorus used in matches [3]. Subsequently, the development of safety matches, which use amorphous red phosphorus, led to a decline in “phossy jaw” from the 1850s onwards.

Since 2003, a condition that bears some similarities to “phossy jaw” has been reported in patients with various cancers (reviewed by Woo et al. [4]). A common feature among these cases has been use of aminobisphosphonates—agents used in conjunction with standard cancer therapy to treat osteolysis or hypercalcaemia due to malignancy. Indeed, it has been suggested that bisphosphonate-associated ONJ is a new complication of supportive care in cancer, and little attention has been given to the fact these agents exist in different forms that may differ in their characteristics [5], [6].

This review discusses the biological basis for a causal relationship between the use of the two classes of bisphosphonates (aminobisphosphonates and non-aminobisphosphonates) in malignancy and the development of ONJ, the clinical presentation of the condition, and appropriate strategies for its prevention and management.

Section snippets

Bisphosphonates

Bisphosphonates are widely used for the treatment of diseases involving excessive bone resorption, such as osteoporosis, Paget's disease and osteolysis associated with metastatic bone disease. These agents inhibit bone resorption through interactions with osteoclasts, the cells responsible for mediating this process.

Bisphosphonate-associated osteonecrosis of the jaw

Bisphosphonate-associated ONJ can be defined as the unexpected development of necrosis in the oral cavity of a patient who has received bisphosphonates but not radiotherapy to the head and neck [21]. It can either appear spontaneously or after a dental procedure. The first report of this painful avascular necrosis of the bone in the mandible and maxilla in patients receiving the aminobisphosphonates pamidronate or zoledronic acid was published by Marx et al. in 2003 [22], and has since been

Prevention and management of bisphosphonate-associated osteonecrosis of the jaw

As yet, there have been no randomised, controlled trials that have evaluated strategies to prevent or manage ONJ in individuals receiving long-term high-dose bisphosphonate therapy. Published recommendations are based upon expert experience from a variety of sources [4], [21], [23], [36], [37], [38], including our own. These are summarised in Table 1. It is important to recognise that effective strategies for prevention and management of bisphosphonate-associated ONJ will require a combined

Conclusions

The emergence of ONJ as a possible adverse effect of long-term, high-dose bisphosphonate therapy has raised serious concerns within the medical and dental communities. While a direct causal relationship with bisphosphonates cannot be assumed, it is important that research into this phenomenon is prioritised to further characterise risk factors and inciting factors, and develop and test effective treatment strategies. In particular, it will be important to determine whether ONJ is predominantly

Reviewers

Prof. Luis A.M. Costa, Unidade de Oncologia Hospital de Santa Maria, Piso 3, PT-1649-035 Lisbon, Portugal.

Prof. Jean-Jacques Body, Department of Internal Medicine, Institut J. Bordet, Universite Libre de Bruxelles, rue Heger-Bordet 1, B-1000 Brussels, Belgium.

Rosh Dias, M.D., MRCP, Global Medical Affairs, Oncology Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ 07936-1080, United States.

Conflict of interest

Authors have no conflict of interest. Ingo J. Diel is Consultant to Roche and Bayer Schering. Matti Aapro is Consultant to Novartis and Roche.

Acknowledgement

The development of the manuscript has been supported with an unrestricted educational grant by Bayer Schering.

Ingo J. Diel, M.D., is associated professor of gynecology and obstetrics, co-director of the Institute for Gynecologic Oncology at the Center for Comprehensive Gynecology (CCG-Clinic), Mannheim, Germany. Dr. Diel attended medical school in Leuven, Belgium, as well as at the University of Heidelberg in Heidelberg, Germany. After receiving his diploma in medicine, he completed residencies at both the Institute of Pathology and the Women's Hospital at the University of Heidelberg, where he also

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    Ingo J. Diel, M.D., is associated professor of gynecology and obstetrics, co-director of the Institute for Gynecologic Oncology at the Center for Comprehensive Gynecology (CCG-Clinic), Mannheim, Germany. Dr. Diel attended medical school in Leuven, Belgium, as well as at the University of Heidelberg in Heidelberg, Germany. After receiving his diploma in medicine, he completed residencies at both the Institute of Pathology and the Women's Hospital at the University of Heidelberg, where he also served before his current position as assistant medical director. He is also board-certified in gynecology and obstetrics. Dr. Diel's primary fields of research include the detection of disseminated tumor cells in the bone marrow and peripheral blood of breast cancer patients, the pathogenesis of bone metastases, the role of PTHrP and cytokines in metastasis, and the prognostic impact of minimal residual disease in breast cancer patients. He has been an investigator for several clinical studies of breast cancer therapies, including agents used in primary chemotherapy, antiangiogenic agents, and bisphosphonates for the treatment and prophylaxis of bone metastases. Other areas of interest include osteoporosis and bone metabolism, the endocrinology of menopause, and breast cancer prevention. Dr. Diel is a member of the American Society of Clinical Oncology (ASCO) and the European Society of Medical Oncology (ESMO). He has lectured extensively and published numerous breast cancer-related articles in peer-reviewed journals.

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