Nature and Frequency of Bisphosphonate-Associated Osteonecrosis of the Jaws in Australia

University of Adelaide, Tarndarnya, South Australia, Australia
Journal of Oral and Maxillofacial Surgery (Impact Factor: 1.43). 04/2007; 65(3):415-23. DOI: 10.1016/j.joms.2006.10.061
Source: PubMed


The purpose of this study is to estimate the frequency and describe the clinical characteristics of patients diagnosed with bisphosphonate-associated osteonecrosis of the jaws (ONJ) in Australia.
Cases of ONJ were identified in 2004 and 2005 primarily by a postal survey of Australian Oral and Maxillofacial Surgeons (OMS) with additional cases from other dental specialists and the Commonwealth of Australia Adverse Drug Reaction Committee (ADRAC). The clinical characteristics were recorded. The frequency of ONJ cases was estimated from prescription and dental extraction data. Univariate and bivariate statistics were calculated.
One hundred fifty-eight cases of ONJ were identified. These were primarily in patients with bone malignancy (72%) and the main trigger was dental extraction (73%). The reported number of cases varied between different Australian States with the highest frequency being reported in the States with the best integrated health systems. The frequency of ONJ in osteoporotic patients, mainly on weekly oral alendronate was 1 in 2,260 to 8,470 (0.01% to 0.04%) patients. If extractions were carried out, the calculated frequency was 1 in 296 to 1,130 cases (0.09% to 0.34%). The total dose of oral alendronate at the onset of ONJ was 9,060 (+/-7,269) mg. The frequency of ONJ for Paget's disease cases was 1 in 56 to 380 (0.26% to 1.8%). If extractions were carried out, the calculated frequency of ONJ was 1 in 7.4 to 48 (2.1% to 13.5%). The frequency of ONJ in bone malignancy cases, treated with mainly intravenous zoledronate or pamidronate was 1 in 87 to 114 (0.88% to 1.15%). If extractions were carried out, the calculated frequency of ONJ was 1 in 11 to 15 (6.67% to 9.1%) The total dose of pamidronate was 3,285 (+/-2,530) mg and zoledronate 62 (+/-54.28) mg at the onset of ONJ. The median time to onset of ONJ was 12 months for zoledronate, 24 months for pamidronate, and 24 months alendronate.
Before the prescription of bisphosphonates for bone disease the patient should be made dentally fit so that the need for subsequent dental extractions is minimized. Appropriate informed consent for the risk of ONJ for different bisphosphonates, for osteoporosis, and malignancy both in general and in particular for dental extractions can be provided using this data.

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Available from: Brian Neil Stein, Aug 12, 2014
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    • "Clinical reports describe surgical dental treatments in patients receiving BP treatment as being associated with osteonecrosis of the jaw (ONJ) [8] [9] [10]. ONJ occasionally causes worsening of the quality of life and general status because of unbearable pain and eating dysfunction, but the role of BPs in this mechanism is unknown [11] [12]. However, with regard to the correlation of ONJ incidence with BP potency, it appears that inhibition of osteoclast function and differentiation may be a key factor in the underlying pathomechanism [13]. "
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    ABSTRACT: Bisphosphonates (BPs) are widely used in the prevention of skeletal-related events (SRE), including osteoporosis, skeletal metastases of malignant tumours, and multiple myeloma. Osteonecrosis of the jaw (ONJ) is frequently reported as a major adverse effect induced by BP treatment. The receptor activator of the nuclear factor kappa-B ligand (RANKL) inhibitor, denosumab, has recently been used to prevent SRE, but the frequency of ONJ induced by denosumab is similar to that by BPs. This finding suggests that the inhibition of RANKL-mediated osteoclastogenesis may have a close relationship with the occurrence of ONJ. We therefore investigated the expression status of RANKL-inducible genes in zoledronate-treated mouse osteoclast precursor cells. The molecular targets of zoledronate in the RANKL signal pathway and additional factors associated with osteoclastogenesis were analysed by genome-wide screening. Microarray analysis identified that among 31 genes on 44 entities of RANKL-inducible genes, the mRNA expression level of two genes, i.e., nuclear factor of activated T-cells c1 (NFATc1) and carbonic anhydrase 2 (CAII), was decreased in zoledronate-treated cells. Subsequent analyses verified that these two genes were significantly silenced by zoledronate treatment and that their expression was restored following inhibition of zoledronate action by geranylgeraniol. Zoledronate inhibited RANKL-induced osteoclast differentiation by suppression of NFATc1 and CAII gene expression. Our results suggest that these genes might be common targets for zoledronate and denosumab in the mechanism underlying RANKL-induced osteoclast differentiation. A clear understanding of the common molecular mechanisms of bone-remodelling agents is thus essential for prevention of ONJ.
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    • "By using postmarketing surveillance method Abtahi et al. identified one case of ONJ among 952 patients, who had received chronic oral bisphosphonate therapy [75]. Moreover, these findings contrast to those from an Australian study, which identified ONJ cases by nationwide maxillofacial surgeon survey [70]. "
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    ABSTRACT: Osteonecrosis of the jaw in patients treated with bisphosphonates is a relatively rare but well known complication at maxillofacial units around the world. It has been speculated that the medication, especially long-term i.v. bisphosphonate treatment, could cause sterile necrosis of the jaws. The aim of this narrative review of the literature was to elaborate on the pathological mechanisms behind the condition and also to gather an update on incidence, risk factors, and treatment of bisphosphonate associated osteonecrosis of the jaw. In total, ninety-one articles were reviewed. All were published in internationally recognized journals with referee systems. We can conclude that necrotic lesions in the jaw seem to be following upon exposure of bone, for example, after tooth extractions, while other interventions like implant placement do not increase the risk of osteonecrosis. Since exposure to the bacterial environment in the oral cavity seems essential for the development of necrotic lesions, we believe that the condition is in fact chronic osteomyelitis and should be treated accordingly.
    International Journal of Dentistry 09/2014; 2014:471035. DOI:10.1155/2014/471035
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    • "While the correlation between use of intravenous injection bisphosphonates and the development of BRONJ is by now widely affirmed in the literature and was reported from 2003 by Marx,4 less clear and predictable is the correlation between BRONJ and orally administered bisphosphonates.22 What remains secure, however, is that dental surgical interventions on patients who take bisphosphonates on a long-term basis orally, present an elevated risk of BRONJ. "
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