Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic

To the Editor:—Preliminary to a manuscript submitted to a refereed scientific journal, this preliminary communication is being issued by the Division of Oral and Maxillofacial Surgery at the University of Miami School of Medicine. It identifies 36 cases of painful bone exposure in the mandible, maxilla, or both, that were unresponsive to surgical or medical treatments. All patients were receiving pamidronate (Aredia; Novartis Pharmaceuticals, East Hanover, NJ) or zoledronate (Zometa; Novartis Pharmaceuticals) therapy. It represents a heretofore unrecognized and unreported serious adverse affect; caution should be used when prescribing these drugs. Of the 36 patients, 24 had received pamidronate (Aredia) at the prescribed dose of 90 mg intravenously (IV) monthly, 6 had received pamidronate (Aredia) at the same dose in the past but were receiving zoledronate (Zometa) 4 mg IV monthly at the time of presentation and 6 received only zoledronate (Zometa) 4 mg IV monthly. Eighteen patients received these drugs for the indication of hypercalcemia related to multiple myeloma, 17 for the indication of hypercalcemia related to metastatic breast carcinoma, and 1 reportedly for osteoporosis. Although each of these patients was also taking other medications, some of which negatively affect wound healing, only pamidronate or zoledronate as a single class of drugs appeared in all 36 cases. Twenty-two (61%) patients were also receiving dexamethasone (Decadron; Merck & Company, West Point, PA), 24 (67%) were receiving maintenance chemotherapy, and 4 (11%) had received radiotherapy in the past. Most patients present with painful exposed avascular bone in the mandible (29 [80.5%]), in the maxilla (5 [14%]), or both (2 [5.5%]). The presentations simulate dental abscesses, “tooth aches,” denture sore spots, and osteomyelitis. Removal of painful teeth is often the initiator of the exposed nonhealing bone (Fig 1). This was the case in 28 (77.7%) patients; the remaining 8 patients (22.3%) developed exposed bone spontaneously (Fig 2). FIGURE 2Exposed necrotic bone in the maxilla in a patient who was taking pamidronate (Aredia). Exposed bone occurred spontaneously.View Large Image Figure ViewerDownload (PPT) Pamidronate (Aredia) and zoledronate (Zometa) are in a class of drugs referred to as bisphosphonate-mediated bone resorption inhibitors. Their affects are mediated through osteoclastic inhibition. Their specific mode of osteoclastic inhibition is unknown but several mechanisms have been supported by investigations. These include inhibition of osteoclast development from monocytes,1Hughes D.E. Wright K.R. Uy H.L. et al.Bisphosphonates promotes apoptosis in murine osteoclasts in vitro and in vivo.J Bone Miner Res. 1995; 10: 1478Crossref PubMed Scopus (935) Google Scholar increased osteoclast apoptosis,1Hughes D.E. Wright K.R. Uy H.L. et al.Bisphosphonates promotes apoptosis in murine osteoclasts in vitro and in vivo.J Bone Miner Res. 1995; 10: 1478Crossref PubMed Scopus (935) Google Scholar stimulation of osteoclast inhibitory factor,2Vitte C. Fleisch H. Guenthes H.L. Bisphosphonates induce osteoblasts to secrete an inhibitor of osteoclastic mediated resorption.Endocrinology. 1996; 137: 2324Crossref PubMed Google Scholar prevention of osteoclast development from bone marrow precursors,3Hughes D.E. MacDonald B.R. Russell R.G. et al.Inhibition of osteoclast-like cell formation by bisphosphonates in long-term cultures of human bone marrow.J Clin Invest. 1989; 83: 1930Crossref PubMed Scopus (330) Google Scholar reduction of osteoclast activity,4Sato M. Grasser W. Effects of bisphosphonates on isolated cat osteoclast as examined by reflected light microscopy.J Bone Miner Res. 1990; 5: 31Crossref PubMed Scopus (232) Google Scholar and down regulation of matrix metlalloproteinases.5Teronen O. Heikkila P. Konttinenn Y.T. et al.MMP inhibition and down regulation by bisphosphonates.Ann NY Acad Sci. 1999; 878: 453Crossref PubMed Scopus (185) Google Scholar Their resultant reduction in osteoclastic activity reduces bone resorption and thus supports their published indications, which includes reducing the hypercalcemia in some malignancies and reducing osteolysis in bone metastases and in some cases of Paget’s disease. However, normal osteoclasis is vital to bone turnover and bone viability. Osteocytes develop from osteoblasts, which have secreted hydroxyapatite crystals into a collagen matrix known as mineralized bone, which then encases the osteocyte. The osteocyte is a terminal cell with a life span of about 150 days.6Schenk R.K. Bone regeneration Biologic basis.in: Buser D. Dahlin C. Schenk R.K. Guided Bone Regeneration in Implant Dentistry. Quintessence, Chicago, IL1994: 49-100Google Scholar As the osteocyte lives out its normal life span it no longer can maintain its mineral matrix which surrounds it and microfractures develop. Normal osteoclasis resorbs nonvital bone and releases cytokines such as bone morphogenetic protein (BMP) and insulin-like growth factors 1 and 2 (ILG1 and ILG2), which normally induce mesenchymal stem cells and the premitotic osteoblast to differentiate into active bone forming osteoblasts.7Parfett A.M. Osteonal and hemiosteonal remodeling, The spatial and temporal framework for signal traffic in adult human bone.J Cellular Biochem. 1994; 55: 273Crossref PubMed Scopus (769) Google Scholar Interruption of this homeostatic cycle by overly effective inhibition of bone resorption results in the accumulation of nonvital osteocytes and micro fractures of old mineral matrix. Bisphosphonates are not new and no other bisphosphonates used to treat osteoporosis have been associated with avascular bone necrosis in the jaws. Indeed, etidronate (Didronel; Proctor & Gamble, Mason, OH), residronate (Actonel; Proctor & Gamble), and tiludronate (Skelid; Sanofi Weinthrop [Sanofi-Sythe Labo Inc], New York, NY) are in common usage today and do not cause bone necrosis. However, these drugs are non-nitrogen containing bisphosphonates and are rapidly metabolized.8Frith J.C. Monkkonen J. Blackburn G.M. et al.Clodronate and liposome-encapsulated clodronate are metabolized to a toxic ATP analog, adenosire 5”-(beta,gamma-dichloromethylene) triphosphate, by mammalian cells in vitro.J Bone Miner Res. 1997; 12: 1358Crossref PubMed Scopus (399) Google Scholar Pamidronate (Aredia) and zoledronate (Zometa) are nitrogen containing bisphosphonates, are much more potent and are not metabolized.8Frith J.C. Monkkonen J. Blackburn G.M. et al.Clodronate and liposome-encapsulated clodronate are metabolized to a toxic ATP analog, adenosire 5”-(beta,gamma-dichloromethylene) triphosphate, by mammalian cells in vitro.J Bone Miner Res. 1997; 12: 1358Crossref PubMed Scopus (399) Google Scholar, 9Tenenbaum H.C. Shelemay A. Girard B. et al.Bisphosphonates and periodontics potential applications for regulation of bone mass in the periodontium and other therapeutic/diagnostic uses.J Periodontol. 2002; 73: 813Crossref PubMed Scopus (65) Google Scholar Therefore, they accumulate in bone and have an ongoing affect that results in bone necrosis.10Fleisch H. Bisphosphonates in Bone Disease From the Laboratory to the Patient. Academic Press, San Diego, CA2000: 34-55Google Scholar In the 36 patients in this alert, none had any other bone exposed and no reports of bone exposure in other bones could be found in the literature. The explanation for this is the mere presence of teeth. The jaws are the only bones in the skeleton exposed to the external environment, ie, via the teeth, which frequently have periodontal inflammation, dental abscesses, root canal treatments, and other pathologies that increases the demand for and the rate of bone turnover. Supporting this explanation is our observation that 28 of these 36 cases (77.7%) were initiated by a tooth removal surgery. The remaining “spontaneous” bone exposures are likely due to the thinness of the oral mucosa since most of these occurred on the lingual surface of the posterior mandible, a known area of thin mucosa. The location limited to the jaws or having its highest incidence in the jaws correlates well with 2 other diseases that clinically produce nonhealing avascular exposed bone, osteoradionecrosis and osteopetrosis. Both have their highest incidence in the jaws due to these same 2 factors. The clinical dilemma relates mainly to the 3 professions of medical oncology, oral and maxillofacial surgery, and dentistry. That is, most medical oncologists have found a great benefit for patients using these drugs but are unaware of this adverse effect. Indeed, the drug evaluation monographs for these drugs do not include this serious complication, either in the cautions or adverse reactions list. Knowledge of this previously unreported adverse reaction should prompt specific further research into these drugs, a risk versus benefit analysis before prescribing these drugs, a consideration of alternative drugs, and an informed consent identifying the potential occurrence of this adverse reaction. The oral and maxillofacial surgeon or dentist may be the practitioner who initiates the clinical disease. The oral and maxillofacial surgeon is usually the one who must treat it. The difficulty in treating this disease is that debridement cannot be carried out to uninvolved bone and may actually cause further exposure of bone. In addition, removal of painful teeth may alleviate pain but may also cause further exposure of bone and pain of some degree related to the bone exposure. Covering such exposed bone with tissue flaps has not been effective due to the development of fistulas around these flaps and possible complete dehiscence, which leads to more bone exposure. Although no definite cause and effect relationship has yet been established, these 2 drugs are the direct factors in a multifactorial etiology leading to avascular necrosis in the jaws. At present, there is no known resolution for this drug-induced avascular necrosis of bone. Prevention by limiting the use of pamidronate (Aredia) and zolendrontate (Zometa) to treatment of documented hypercalcemic states and multiple bone metastases with close monitoring seems prudent. It seems prudent that these drugs should not be used in normal calcemic states or in static bone metastases. In addition, use of alternative drugs unassociated with these complications may be useful. Prevention, surgically by avoiding tooth removals if possible, control of periodontal disease by nonsurgical means, avoiding dental implants, and using soft liners on dentures also seems prudent. In addition, major debridement surgeries are to be avoided if at all possible. Treatment of established cases is recommended to begin with an identification that palliation and control of osteomyelitis are the primary goals. Control and limitation of progression has been obtained in most cases with long-term or intermittent courses of penicillin-type antibiotics (erythromycins or tetracyclines if penicillin allergic), 0.12% chlorhexidine mouthwash (Peridex; Proctor & Gamble), and periodic minor debridement of soft-textured sequestrating bone and wound irrigation.