Bisphosphonate-induced osteonecrosis of the jaws refers to a condition characterized by exposure of bone in the mandible or maxilla persisting for more than 8 weeks in a patient who has taken or currently is taking a bisphosphonate and who has no history of radiation therapy to the jaws.1 However, while the exposed bone is indeed dead (osteonecrosis), bone death is actually a secondary result of bisphosphonate bone toxicity, which is similar to the genetic disease osteopetrosis, as explained in chapter 4. Clinically, the disease presents as exposed alveolar bone that occurs spontaneously (Fig 1-1a) or becomes evident following an invasive surgical procedure such as tooth removal (Fig 1-1b), periodontal surgery, apicoectomy, or dental implant placement. The disease manifests mostly in the jaws. To date, it has not been reported in other skeletal sites as exposed bone; however, recent reports have identified femur fractures caused by long-term use (6 years or more) of alendronate (Fosamax, Merck)2,3 (Fig 1-2). Osteonecrosis of the jaws always originates in the alveolar bone and may then extend to the basilar bone or ramus (Figs 1-3 and 1-4). Occasionally, early subclinical radiographic signs—including sclerosis of the lamina dura (Fig 1-5), loss of the lamina dura (Fig 1-6), and/or widening of the periodontal ligament space (Fig 1-7), particularly in association with molars—have been observed.
Fig 1-1a Spontaneous bone exposure of the lingual cortex in the mandibular molar region is a common presentation of bisphosphonate-induced osteonecrosis of the jaws.
Fig 1-1b Nonhealing exposed bone developed after the removal of a maxillary central incisor and the adjacent lateral incisor.
Fig 1-2 Atypical fracture of the femur caused by extended use of alendronate (Fosamax).
Fig 1-3a Radiographic osteosclerosis in the alveolar bone of the mandibular second molar socket.
Fig 1-3b As bisphosphonate-induced osteonecrosis persists, it usually exhibits osteolysis and extends toward the inferior border.
Fig 1-3c Persistent bisphosphonate-induced osteonecrosis. Osteolysis and osteosclerosis become more evident.
Fig 1-3d Further continuation of the bisphosphonate-induced osteonecrosis accompanied by secondary infection can extend into the inferior border, posing a risk of pathologic fracture.
Fig 1-4 Even after a hemimandibular resection, evidence of bisphosphonate-induced osteonecrosis remains in the ramus and condylar neck.
Fig 1-5 Sclerosis of the lamina dura may be seen before exposed bone develops; this is an early sign of bisphosphonate toxicity to the alveolar bone.
Fig 1-6 In some cases, loss of the lamina dura can be an early sign of bisphosphonate toxicity to the alveolar bone.
Fig 1-7 Widening of the periodontal ligament space may be an early or overt sign of bisphosphonate toxicity to the alveolar bone and may also be associated with significant osteolysis.
Bisphosphonate-induced osteonecrosis of the jaws was first described by Marx and Stern in 2002.4 At that time, it was only a curious finding of exposed, nonhealing bone; when debridement was performed, the condition worsened and led to increased amounts of exposed bone. All of the patients described in that report were receiving pamidronate (Aredia, Novartis) for control of malignant tumor deposits in bone. The profession was first formally notified of this drug complication in a medical alert published by the author in 2003 in the Journal of Oral and Maxillofacial Surgery (JOMS), which described 36 cases associated with intravenous bisphosphonates (pamidronate or zoledronate [Zometa, Novartis]).5
Prior to the publication of this medical alert, representatives of Novartis, which produces the two intravenous bisphosphonates (pamidronate and zoledronate) that cause this form of osteonecrosis, were invited to examine 2 of the patients and to discuss the other 34 who were being seen. Although they expressed concern about the plight of these patients, the Novartis representatives denied the possibility that the osteonecrosis was in any way connected with their drugs, because no evidence of bone necrosis was found in their preclinical animal studies or in the more than 3,600 patients enrolled in their human clinical trials. They attributed the bone exposures to the chemotherapy these patients had received and possibly to the dexamethasone that had been given to about 55% of their patients. During that visit, the medical director of Novartis, Dr Peter Tarassoff, was given an advance copy of the medical alert. When it appeared in JOMS, Dr Tarassoff and his Novartis coauthors had already issued a retort strongly denying any causal relationship between the intravenous bisphosphonates produced by Novartis and the osteonecrosis observed in the jaws of these patients.6
The toxicity of chemotherapy was a natural and convenient culprit to blame. Indeed, the very issue of JOMS that carried the medical alert also carried a report by Wang et al of three cases of bone necrosis in the mandible that they too attributed to chemotherapy.7 Yet, it was reported that all three patients had been taking Aredia. Realizing their oversight, these authors later published a retraction article identifying Aredia as the cause of the exposed bone.8 Shortly afterward, compelling findings were reported in the November 2005 issue of JOMS, and three additional reports appeared in the Journal of the American Dental Association in December 2005.9–12 Since the original 2003 publication, more than 1,100 additional reports by over 4,500 authors and at least 14 position papers have been written about what is now accepted as bisphosphonate-induced osteonecrosis of the jaws (BIONJ).
Ironically, the strongest evidence to date of a cause-and-effect relationship between bisphosphonates and osteonecrosis of the jaws is provided by the results of a study Novartis conducted to gain marketing approval by the Food and Drug Administration (FDA). In this study, patients with bone metastasis received either their normal chemotherapy alone or chemotherapy plus a steroid regimen and an intravenous bisphosphonate (either Aredia or Zometa). Patients with the same malignancies but without bone metastasis also received their normal chemotherapy and an identical steroid regimen, but they were not given intravenous bisphosphonates. Interestingly, only those patients who received an intravenous bisphosphonate ever developed exposed bone. This amounted to one of the best randomized, controlled, and truly double-blinded studies in the history of medicine or dentistry.
Flaws in the original study by Novartis are largely the cause of so much disbelief. Their claim that their animal studies failed to show osteonecrosis is likely due to the fact that animal bone physiology is extremely resistant to chemical and physical injury. The profession of oral and maxillofacial surgery has sought to produce a reliable animal model for osteoradionecrosis—its historical nemesis—for four decades. Yet with each attempt, either exposed bone could not be produced or the radiation dose was increased to the point of killing the study animal. In their human clinical trials, Novartis claimed that none of the 3,600+ patients developed exposed bone. This is false; the truth is, they never thought to look for exposed bone in the mouth. Oral examinations before or after intravenous bisphosphonate therapy were never conducted, nor was a dentist or an oral and maxillofacial surgeon assigned to their investigative team. These facts came to light during a special symposium on bisphosphonates and osteonecrosis of the jaws at the 87th Annual Meeting of the American Association of Oral and Maxillofacial Surgeons in Boston in September 2005.13 During that symposium, Dr Noopur Raje, who was a medical oncologist and assistant professor of surgery at Harvard University′s Dana Farber Cancer Institute and formerly a Novartis researcher in their protocol, reported that six patients had complained about exposed bone in the mouth. However, the complaints were not immediately followed up because the protocol did not anticipate this adverse event. It is now known that later other patients in this study also developed exposed bone and were seen by oral and maxillofacial surgeons outside the study but were not included in the study data.
To further disprove the claim that chemotherapy or steroids rather than a bisphosphonate is somehow the cause of osteonecrosis of the jaws, one has only to consider the growing number of patients who have taken oral bisphosphonates for osteopenia or osteoporosis, particularly alendronate (Fosamax, Merck) and, more rarely, risedronate (Actonel, Procter and Gamble), and also developed osteonecrosis of the jaws. These are patients who do not have cancer and were never treated with any chemotherapy or steroid medication. In our study, we examined 180 consecutive patients referred to our practice at the University of Miami Miller School of Medicine who presented with 8 weeks or more of exposed bone but had no exposure to radiation above the clavicles. The results indicated that all 180 patients (100%) were receiving or had received a bisphosphonate (Fosamax), 127 intravenously and 53 orally. None of these patients had a primary osteomyelitis, and no other drug was associated with the bone necrosis more than 28% of the time (51/180 patients). Bisphosphonates are indeed the only cause of this type of osteonecrosis of the jaws. No other drug or comorbidity studied led to the development of exposed bone in the jaws in the absence of a bisphosphonate.
Fig 1-8a The FDA required placement of an adverse-reaction statement on all intravenous bisphosphonates in 2004.
Fig 1-8b The FDA-required adverse-reaction statement specific to Zometa labeling.
Novartis invited a panel of general dentists, oral and maxillofacial surgeons, dental and medical oncologists, dental hygienists, and others in December 2003 and again in April 2004 to review case histories and suggest prevention and treatment protocols. From these conferences emerged recognition by the FDA of the strong link between osteonecrosis of the jaws and the drugs Aredia and, later, Zometa. The FDA promptly issued a so-called black box warning to be placed on these drugs, the strongest possible warning it can issue (Figs 1-8a and 1-8b). In addition, osteonecrosis of the jaws has since been added to the product description and labeling given to practitioners and pharmacists. A white-paper article discussion and recommendations also emerged from these conferences and were published in the Journal of Oncology Practice.14 Unfortunately, this document stopped short of accepting a cause-and-effect relationship, and most of the recommendations were nonspecific and unsupported by any data. In November 2006, Merck also convened a panel of 20+ experts, including the present author. However, no white paper emerged from this meeting.
In January 2005, the FDA identified to Roche (manufacturer of Boniva), Procter and Gamble (manufacturer of Actonel), and Merck (manufacturer of Fosamax) that their package-insert labeling reported to the FDA on December 1, 2003, was inadequate and recommended specific changes and additions to the precautions sections of each. Included in the two-paragraph submission by the FDA was that osteonecrosis of the jaws cases also ″occurred in patients with postmenopausal osteoporosis or other diagnoses.″ Both Roche and Procter and Gamble accepted the recommendation. However, Merck did not and changed the language to eliminate the reference to patients with osteoporosis, thereby deceptively implying that only cancer patients develop osteonecrosis of the jaws, a false belief that has been perpetuated among physicians for many years.
Moreover, as recently as October 2010, the FDA issued a consumer warning about ″possible fracture risk with osteoporosis drugs,″ referring to the growing number of reports of subtrochanteric femur fractures. 14 This warning was issued for all bisphosphonates used to treat osteoporosis and instructed drug labeling changes.
Fig 1-9 An article published in the British Medical Journal in 1899 reported the finding of exposed bone in the jaws and bone necrosis in workers exposed to white phosphorus. Phossy jaw was the name given to the condition.17
Although the textbook by Marx and Stern is credited with first identifying BIONJ, the same disease was recognized more than 100 years earlier as an occupational industrial disease referred to as phossy jaw.4,16,17 Some phosphate miners but mostly match-factory workers in the United States and Great Britain, particularly those who worked in close proximity to the heated phosphate vapors, reportedly developed nonhealing bone exposures only in the mouth related to the length of time they actually worked in the factory17,18 (Fig 1-9). It was recently shown that this chronic daily exposure to airborne phosphates caused an accumulation of bisphosphonate compounds in bone, ultimately producing the same clinical disease now related to medical therapies with bisphosphonates.19–21
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