Annals of Oncology Advance Access originally published online on September 2, 2005
Annals of Oncology 2006 17(2):350-352; doi:10.1093/annonc/mdj012
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© 2005 European Society for Medical Oncology
letter to the editor |
Comment on ‘Jaw avascular bone necrosis associated with long-term use of biphosphonates’
We read with interest the recent letter by Sanna et al. [1
] on the avascular necrosis of the jaw as a consequence of long-term use of bisphosphonates and we agree with the authors on the need to understand the mechanisms involved in the process. In March 2003, at our Oncology Unit, a 62-year-old man was diagnosed with prostatic adenocarcinoma metastatic to the bone. At staging, serum prostrate-specific antigen (PSA) value was 275 ng/ml. First-line treatment was hormonal therapy with luteinizing hormone-releasing hormone (LH-RH) agonist and bicalutamide concomitant with monthly i.v. zoledronic acid (Zometa-Novartis). A constant PSA decrease was observed up to February 2004 with a lowest level of 4.7 ng/ml. After this nadir value, a significant progressive increase of PSA was observed until May 2004 when a new bone scan revealed a skeletal disease progression. At the same time, the patient, who had had no history of recent dentoalveolar procedures, presented with spontaneous painful exposure and necrosis of the left maxillary alveolar bone. The patient required maxillar resection of the necrotic bone. Histology revealed necrosis with no presence of neoplastic cells. In August 2004 the patient was started on mitoxantrone 12 mg/m2 i.v. every 21 days and oral prednisone 5 mg b.i.d. continuously. Therapy with zoledronic acid was continued. Six cycles of chemotherapy were administered and, after a transient reduction of PSA, increasing values were observed and reached 682 ng/ml in December 2004. While continuing zoledronic acid and oral prednisone, a second-line chemotherapy regimen with docetaxel 75 mg/m2 i.v. every 21 days was started in January 2005.
In March 2005 a second episode of osteonecrosis occurred in a different region of the bone that this time involved the right side of the maxilla. The patient required a new surgical procedure to remove all of the involved bone. After this second event, zoledronic acid administration was definitively discontinued, as we had learned from scientific literature of a possible correlation between avascular osteonecrosis of the jaw and use of bisphosphonates. Nevertheless, the clinical benefit of this approach has not yet been proven. The tumor of our patient appeared particularly sensitive to docetaxel and chemotherapy with this drug is still ongoing. In fact, a significant response has been obtained both for PSA, which decreased to 5.24 ng/ml in June 2005, and pain control. To our knowledge, this is the second report in the literature of bilateral necrosis of the jaw in a metastatic prostate cancer patient.
In a group of 63 patients with osteonecrosis of the jaw associated with the use of bisphosphonates reported by Ruggiero et al. [2], 56 of them with some type of tumor, only three patients had prostate cancer. All three patients had received pamidronate and one of them had bilateral jaw osteonecrosis similarly to our patient. Marx [3] reported for the first time a case series in which he supposed that amino-bisphosphonates, such as pamidronate and zoledronic acid, are the direct factors in a multifactorial aetiology leading to avascular necrosis in the jaw. On the other hand, no cases of osteonecrosis of the mandible or maxilla were reported with the use of clodronate in an analysis that reviewed the spontaneous adverse event of this non-amino-bisphosphonate drug [4]. Migliorati [5] postulated that bisphosphonates may cause oral avascular bone necrosis due to antiangiogenic effect leading to inhibition of osteoclasts. Docetaxel, with its antiangiogenic effect [6], and prednisone, continuously administered to our patient, can be considered as possible etiological co-factors. In particular, prednisone was found to be an additional and separate risk factor, not time-dependent, for osteonecrosis of the jaw in myeloma patients treated with i.v. bisphosphonates [7].
In June 2004, although at that time a causal relationship between bisphosphonates therapy and osteonecrosis of the jaws had not been established, an expert panel developed clinical guidelines for prevention, early diagnosis, management and multidisciplinary treatment of this complication in patients with cancer [8]. It was only in March 2005, in Italy, that Novartis included this serious complication in the caution and adverse reactions list of Drug Prescribing Information.
Although there had been an increasing number of case series reporting this complication, the majority of them, until recently by Sanna et al. [1], had been published in short reports [5, 7, 9] or in journals not oncology-related. We think it is important to alert clinicians to a possible adverse reaction in the oral cavity by a group of drugs that are commonly prescribed, in particular, by medical oncologists. We also think it is mandatory to evaluate the precise incidence of this complication both in patients with myeloma and solid tumors.
Moreover, if we believe that the pathogenetic mechanism involves antiangiogenesis, an increased incidence of this complication has to be expected, particularly in patients with hormonoresistant prostate cancer with bone metastases. These patients, in fact, are meant to receive bisphosphonates together with docetaxel plus prednisone, which has been established as the new standard chemotherapy regimen in this setting.
It can be hypothesized that in the near future a number of factors might intervene in raising the risk of this complication: (a) taxanes are increasingly used to treat patients affected by several types of tumors; (b) thalidomide, a drug with an antiangiogenic mechanism, is widely used to treat myeloma patients who are also receiving bisphosphonates; (c) due to the prolonged survival of cancer patients, they are to receive bisphosphonates for longer periods of time, without ‘bisphosphonate holiday’; (d) trials are ongoing to evaluate the efficacy of some bisphosphonates in the adjuvant setting, such as zoledronic acid in patients with breast cancer, and might contribute to a wider use of these drugs; (e) the availability of potent oral bisphosphonates, such as ibandronate, while rendering more convenient the administration of the drug, might make this complication pass unnoticed or delay its diagnosis.
1 Division of Medical Oncology, Ospedale Civile, Vittorio Veneto; 2 Division of Oral and Maxillofacial Surgery, Ospedale Civile, Pordenone, Italy
* (E-mail: domenico.errante{at}ulss7.it)
References
1. Sanna G, Zampino MG, Pelosi G, Nolè F, Goldhirsch A. Jaw avascular bone necrosis associated with long-term use of biphosphonates. Ann Oncol 2005; 16: 1207–1208.
2. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 2004; 62: 527–534.[CrossRef][Web of Science][Medline]
3. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 2003; 61: 1115–1118.[CrossRef][Web of Science][Medline]
4. Jones GR, Lehtinen T, Riphagen FE, von Roemeling R. Adverse event reporting of oral clodronate with emphasis on osteonecrosis of the jaw. Am Soc Clin Oncol 2005; 23: 77S (Abstr 799).
5. Migliorati CA. Bisphosphonates and oral cavity avascular bone necrosis. J Clin Oncol 2003; 21: 4253–4254.
6. Hotchkiss KA, Ashton AW, Mahmood R, Russell RG, Sparano JA, Schwartz EL. Inhibition of endothelial cell function in vitro and angiogenesis in vivo by docetaxel (Taxotere): association with impaired repositioning of the microtubule organizing center. Mol Cancer Ther 2002; 1: 1191–1200.
7. Durie BGM, Katz M, McCoy J, Crowley J. Osteonecrosis of the jaws in myeloma: time dependent correlation with Aredia and Zometa use. Am Soc Hematol 2004; 104: 216a (Abstr 756).
8. Damato K, Gralow J, Hoff A et al. Expert panel recommendations for the prevention, diagnosis, and treatment of osteonecrosis of the jaws. Dockets Management, US Food and Drink Administration, June 2004; www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4095B2_02_12-Novartis-Zometa-App-11.pdf.
9. Travis K, Zielinski SL. In Brief. J Natl Cancer Inst 2004; 96: 1572.
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