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Bisphosphonate Osteochemonecrosis (Bis-Phossy Jaw): Is This Phossy Jaw of the 21st Century?
CURRENT THERAPY J Oral Maxillofac Surg 63:682-689, 2005
Bisphosphonate Osteochemonecrosis (Bis-Phossy Jaw): Is This Phossy Jaw of the 21st Century? John W. Hellstein, DDS, MS,* and Cindy L. Marek, BS Pharm, PharmD† Purpose: Bisphosphonates are being implicated in a growing number of complications of the jaws. A
number of terms are being applied to this phenomenon and perhaps the descriptive term bisphosphonate osteochemonecrosis has the most merit. But the eerie similarity of this 21st century disease process with the 19th century disease known as phossy jaw is striking. As the nomenclature continues to evolve, the term used in this article will be bis-phossy jaw. This article will explore historical and current aspects of these diseases. Although there may be other mitigating factors, such as oral health, chemotherapy history, immune status, Karnofsky performance status, or Kaplan-Feinstein index, bisphosphonates appear to be the necessary component in cases of bis-phossy jaw. Materials: This is primarily a review article on reported cases of bis-phossy jaw, with historical looks at phossy jaw and osteoradionecrosis. Our laboratory has reviewed 20 suspected cases of bis-phossy jaw and the typical histopathologic features of bis-phossy jaw are presented. Results: Descriptions of phossy jaw and current bis-phossy jaw cases are remarkably similar. Histopathologic features of bis-phossy jaw showed intact vascular channels, even in areas with acute inflammatory infiltrates and bacterial overgrowth. Non-vital bone fragments with reduced evidence of osteoclastic action were also noted. Conclusion: Bis-phossy jaw may have more of a bacterial cofactor risk than osteoradionecrosis, and though altered angiogenesis may yet prove to be a factor, avascularity does not appear to be a major cofactor. The historical disease phossy jaw appears to serve as a possible analogous disease for current research and treatment of bis-phossy jaw. Prevention and early identification of patients at risk should be of prime concern. © 2005 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 63:682-689, 2005 Bisphosphonate therapy is becoming a mainstay of therapy in various clinical settings.1 Most reported cases of osteomyelitis or necrosis of the jaws associated with bisphosphonate use involve injectable bisphosphonates such as pamidronate and zoledronic acid. But Ruggerio et al2 also reports 7 of 63 cases associated with “chronic” oral bisphosphonate use. In
2003, alendronate was listed as the 19th most commonly prescribed drug, with 17 million prescriptions; risidronate was 72nd with 6 million prescriptions. With such large numbers, even oral bisphosphonates may yet prove to be of significant clinical concern for oral health care providers.3 As of now, the injectable bisphosphonates (pamidronate and zoledronic acid) appear to be of most concern. Zoledronic acid has been used in over 300,000 patients worldwide and is a mainstay for the treatment of hypercalcemia of malignancy.4 As the incidence and prevalence of bisphosphonate associated complications of the jaw (bis-phossy jaw) continues to be elucidated, proper workup and therapeutic management of patients may be affected by thinking of how bisphosphonates affect the jaws. Science is still trying to deduce all the physiologic/molecular effects of bisphosphonates, although the end goal is to increase medullary bone density. What is known is that the oral administration of
Received from the Departments of Oral Pathology, Radiology, and Medicine, University of Iowa, Iowa City, IA. *Clinical Professor. †Clinical Associate Professor. Address correspondence and reprint requests to Dr Hellstein: University of Iowa, Oral Pathology, Radiology and Medicine, 356 Dental Science S, Iowa City, IA 52242; e-mail; [email protected] © 2005 American Association of Oral and Maxillofacial Surgeons
0278-2391/05/6305-0010$30.00/0 doi:10.1016/j.joms.2005.01.010
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bisphosphonates generally creates a bisphosphonate bioavailability of less than 5%.5 We also know the relative in vitro potencies of various bisphosphonates are approximately as follows: 1 for etidronate, 10 for clodronate, 100 for pamidronate, 100 to 1,000 for alendronate, 1,000 to 10,000 for risedronate and ibandronate, and 10,000⫹ for zoledronate.6 We do not know enough to conclude the long-term risks of oral or injected bisphosphonates or which patient subpopulation is susceptible to those risks. Bisphosphonate inhibition of farnesyl diphosphate synthase and the resulting effect of that enzyme on bone resorption is one popular physiologic area being studied.7,8 In addition, inhibition of angiogenesis is being actively investigated.9,10 Researchers also realize the need to study the results of therapy as well as the biomedical considerations.11,12 At this time, there are many unanswered questions, and the effects on the jaws may very well be a completely different issue than in other skeletal locations. Some authors have focused on actions related to angiogenesis and drawn analogies to osteoradionecrosis or avascular necrosis.2,13,14 Physiologically, angiogenesis is important in many systems and may provide no analogy of bisphossy jaw to avascular necrosis, neuralgia-inducing cavitational necrosis, or osteoradionecrosis.2,14-18 The importance of the effects of bisphosphonates on angiogenesis in the establishment of bis-phossy jaw is yet to be determined The ratio of osteoblastic action may not just be increased because of reduction of osteoclastic action, but also because of an earlier commitment of osteoblasts.19-21 The parenteral varieties of bisphosphonates, such as zoledronic acid and pamidronate, probably pose the greatest risk of inducing bis-phossy jaw. But the nitrogen containing bisphosphonates, which also include alendronate, risidronate, and ibandronate, may also have special metabolic activity.7 At this time we should consider all varieties of bisphosphonates to have some bis-phossy jaw risk associated with their use, but we should be most suspicious of injectable bisphosphonates. Chemotherapeutic cofactors in the patients at risk for hypercalcemia of malignancy may have additional or synergistic effects with bisphosphonates. Age, immune status, nutrition, Karnofsky performance status, or Kaplan-Feinstein index may additionally affect what I am calling the osteoclast/osteoblast axis. Bone physiology is of course amazingly complex, but the osteoblasts and osteoclasts are important at the cellular level. Changes in the osteoclast/osteoblast axis may be the major predicating risk factor, with the bisphosphonates acting as modifiers of that axis. The jaw’s unique demands require adaptability and “upregulation” of the osteoclast/ osteoblast axis not usually seen in other skeletal sites.
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Historical Aspects and Nomenclature History may help us in our endeavors to diagnose and treat bisphosphonate associated effects of the jaws. White phosphorus, the cause of phossy jaw, appears to have had similar skeletal effects as bisphosphonate therapy. Phossy jaw has interesting historical aspects and was known by several nomenclature variations. Phosphorus necrosis was perhaps the most common and proper term used in publication. However, “phossy” jaw was also commonly used and appears to have been the term used most often in oral communications, and is the term handed down to generations of oral pathologists and oral surgeons. The term “osteochemonecrosis,” or the more descriptive, “bisphosphonate osteochemonecrosis of the jaws” may be the best nominee(s) for the problems we are now seeing in patients being administered bisphosphonates. (NOTE: the term osteochemonecrosis was coined orally at the 2004 American Academy of Oral Medicine meeting in Key Biscayne, FL, by Dr. Cesar Migliorati. But, the term “bis-phossy jaw” has a certain historical caché and for simplicity this will be the term used in this article. In addition, the use of terms such as bisphosphonate avascular necrosis, bisphosphonate osteomyelitis, bisphosphonate osteonecrosis, or bisphosphonate necrosis may prove much too simplistic or restrictive. Those terms may actually limit our thoughts on what will likely be complicated physiologic, etiologic, and clinical factors. They may also be completely or partially wrong. As discussed later, I believe we will likely find that there will be a need to classify bis-phossy jaw into at least early and late forms. There will also likely be a spectrum of involvement, ranging from mild to severe. It is hoped that this article will show that phossy jaw offers itself as a model to base current therapies for bis-phossy jaw. The jaws present unique challenges, especially in terms of bone turnover and exposure to bacteria. It is hoped that protocols may be developed to better predict patients at risk for bisphossy jaw, and that preventive measures are developed to decrease the incidence of the disease. Time will tell whether bones other than the jaws will also be at some increased risk from bisphosphonate therapy, but in the case of phosphorus necrosis, involvement of bones outside the jaws was relatively uncommon. Dearden22,23 described some risk of femoral fracture associated with chronic phosphorus necrosis and reports pathologic fractures following minimal trauma, such as tripping on a board. Such reports are rare and the jaws were well known to be unique in incidence, treatment challenges, and presentation.
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Phossy Jaw Review Phossy jaw was first described in the mid portion of the 19th century, when it became apparent that workers in the matchmaking industry were being afflicted with an unusual necrosis of the jaws. Lorinser first reported these cases in 1845.24 The victims were often young and otherwise healthy. Eventually, the workers were diagnosed with what became known as phossy jaw or phosphorus necrosis. The morbidity and mortality associated with phossy jaw were significant. Severe pain and deformity were hallmarks of the disease, and as reported by Miles, Hunter estimated the mortality rate in the preantibiotic era as 20%.25 The treatment and prevention of phossy jaw has ties to early socially active groups such as the Salvation Army,26 as well as with early efforts in industrial hygiene.27,28 Descriptions of phossy jaw lesions included observations of an initial dull red area on the gingiva which was often overlying an “infected” tooth. As related by Hughes,29 the initial presenting symptoms were described as follows: “the disease it was noticed, began usually with aching in one of the teeth. At first, this was probably mistaken for ordinary toothache, and would, indeed, at times intermit. Sooner or later, however, recurrence of pain necessitated the extraction of the tooth, and the pain and annoyance for a time probably ceased. The wound in the gum, however, was found not to heal; offensive matter began to ooze from it, and ere long a portion of the alveolus became exposed.” The course of the disease could continue for several years. In another scenario, an indolent ulcer was often seen associated with the socket of a recently extracted tooth. The socket would be indolently involved with associated inflammation.30 In either scenario, there would be progressive extension of the initial lesion with greater and greater areas of bone exposure and eventual sequestration. Multiple episodes of sequestration would be expected during the disease course. The sequestra were often described as porous and light in weight, and sometimes portrayed as either worm-eaten or pumice-like.25 Please note, this description is of the sequestra only. In contrast, the medullary bone was often observed to display increased trabeculations.31 Some also described the starkly white bone surrounding the sequestrum.32 In fact, they also described that chronic phosphorus exposure produced a hyperostosis of the entire skeletal structure, and that the spongy bone is transformed to sclerotic bone.33 In 1944, Kennon and Hallem32 described what they perceived to be 2 different eras of phossy jaw presentation. In their discussion, they describe an “era of extensive necrosis and suppuration” as well as a “modern era of small sequestra.” These observations
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may be because of the changes in exposure levels or perhaps to changes in access of care. Phossy jaw authors also described severe osteomyelitis with formation of both sequestra and involucra. The involved bone would sometimes become surrounded by a new shell. This was sometimes referred to as bone “casket” formation.34,32 The casket formation may have been more common in the mandible than the maxilla.35 Kennon and Hallem reported that, radiographically, the areas of involvement showed more contrast of the affected bone from the unaffected bone, as compared with standard osteomyelitis.32 Also of note is the finding that like bis-phossy jaw, phossy jaw affected both the maxilla and the mandible, though the mandible was affected slightly more often. Even more interesting than finding phosphorus as the prime causative factor in phossy jaw, was that the risk was only associated with the metabolically active white phosphorus and not with red phosphorus. Although both are elemental phosphorus, red and white phosphorus are allotropes of each other. The allotrope of white phosphorus is a simple tetrahedral configuration, whereas red phosphorus consists of tetrahedral polymers of variable lengths. The allotropic variants result in significant differences in physical and chemical properties.36 Except for the vague comment that white phosphorus is more metabolically active than red phosphorus, the physiologic basis of how white phosphorus causes phossy jaw remains unresolved.37 Even today it might be helpful to answer the question of how white phosphorus behaved at the molecular and cellular level and how that compares with the actions and pathways affected by the bisphosphonates. We do know from reports that white phosphorus appeared to accumulate in the oral region. Whether this accumulation was because the oral cavity was the initial portal and thus was exposed more than other regions, and/or whether the bone turnover needs of the jaws resulted in phosphorus returning to the area, is unknown. There are remarkable stories of politicians and activists being swayed into action by seeing a victim of phossy jaw. First they would see the disfiguring evidence of the disease as the patient was presented to them. Then the lights would be turned off and the patient would open their mouth. In the darkened setting, the spectators would then see an eerie glow emanating from the mouth. That glow was evidence of how phosphorus was named. It indeed glows at room temperature without the need of any additional external heat.38 Although white phosphorus was used most notably in the matchmaking industry, other industries were also involved in the phossy jaw epidemic. The fireworks manufacturers, brass manufacturers, and mak-
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ers of tracer type war munitions also utilized white phosphorus.26,32,38 Even into the 21st century, dental examinations and preventive dental measures remain in place at Pine Bluff Arsenal in Arkansas, where white phosphorus munitions were/are still manufactured. With that said, modern ventilation, containment measures, and other industrial hygiene measures are the most viable reasons why none of these workers has had a case of phossy jaw in at least several decades. (This personal opinion is made unofficially, and to the best of my memory, as a former US Army Oral and Maxillofacial Pathologist. It is not necessarily the opinion of the US Army or the Department of Defense.) Of clinical importance in studying bis-phossy jaw, the clinician must also be aware that it usually took white phosphorus exposure of months to years before phossy jaw would be manifested. In addition, the risk remained for years after the workers left their jobs and therefore their phosphorous exposure could be relatively remote.39 I cannot help but think that we may be only witnessing the tip of the iceberg in a possible bis-phossy jaw epidemic. The phossy jaw treatment paradigm was to preach prevention, patience, and minimal surgical intervention. That is not to say that the surgical interventions were not significant. There are reports of entire mandibles being sequestered. “Minimal,” as I interpret the reports, meant removing sequestra, involucra, and necrotic bone only, with very little soft tissue manipulation and no attempt to extend surgery to “uninvolved” bone with epithelial coverage. But the sequestra were often measured in centimeters and many operations would not be considered insignificant by any measure. As more and more cases of bisphosphonate associated jaw necrosis are being detected, described, and treated, it is also becoming evident that the therapeutic paradigm associated with phossy jaw may also apply to what I am calling bisphossy jaw. Of clinical significance in phossy jaw was the finding of a significant bacterially based component of the disease process. This may be an important etiologic cofactor when comparing and contrasting osteoradionecrosis with bis-phossy jaw. This comparison to osteoradionecrosis is important because there seems to be a contemporary predilection to compare bisphossy jaw with osteoradionecrosis. This is somewhat ironic, because when osteoradionecrosis was first being elucidated in the 1920s the first thing some compared it with was phossy jaw.24,40-42 It took some time for the early analogies of osteoradionecrosis to phossy jaw to change. But the differences were noted in Thoma’s first text on oral pathology in 194135 and the disease processes were separated even further by the Fourth edition of Thoma’s Oral Pathology text in 1954.43 Tiecke’s 1965 text44 also recognized the dif-
FIGURE 1. This clinical photograph shows a large maxillary torus which first became painful following a burn caused by hot food. The mucosa over the torus was a somewhat darker red than the adjacent oral mucosa. Multiple small pustular elevations were seen submucosally. The posterior aspect is dominated by exposed bone. Hellstein and Marek. Is This Phossy Jaw of the 21st Century? J Oral Maxillofac Surg 2005.
fering presentations of osteoradionecrosis and phossy jaw. He noted that suppuration was uncommon and usually minimal in osteoradionecrosis, whereas he noted that phossy jaw was almost invariably complicated by bacterial infection. Coincidentally, osteoradionecrosis caused by exposure of workers painting luminous watch dials with radium, also played a significant role in the field of industrial hygiene.42,45
Modern Bis-Phossy Jaw Findings and Further Review In comparing modern cases of bis-phossy jaw with osteoradionecrosis, we are also seeing differences. In the last year, 20 cases of osteomyelitis in patients with a history of breast cancer, prostate cancer, or multiple myeloma have been reviewed at the University of Iowa Surgical Oral Pathology Laboratory (Iowa City, IA). Bisphosphonates were confirmed or suspected as cofactors in these cases. A review showed that bacteria were commonly associated with the non-vital bone fragments. In addition, in 1 case of bis-phossy jaw seen clinically and microscopically at our institution, multiple small pustular areas were seen overlying a maxillary torus with bis-phossy jaw (Fig 1). In that case, the overlying mucosa was indeed a rather unique dull, ruddy red similar to that described in phossy jaw. Histopathologic sections displayed subepithelial bacterial colonies and small non-vital bone fragments. The patient had multiple bony metastases secondary to prostate cancer and had been getting zoledronic acid injections for 15 months. He believes he burnt the mucosa over the torus before the development of signs and symptoms about 6 weeks prior to the photograph.
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FIGURE 2. This photomicrograph shows congested vascular spaces with associated acute inflammatory infiltrates. The bone still displays some osteocytes though osteocyte “dropout” is apparently ongoing. There is past evidence of apparent osteoclastic or resorptive action. There is single apparent osteoclast in a Howship’s lacuna in the lower center of the field. (Hematoxylin-eosin stain of demineralized tissue; original magnification ⫻100.) Hellstein and Marek. Is This Phossy Jaw of the 21st Century? J Oral Maxillofac Surg 2005.
In all cases of confirmed bis-phossy jaw there was a relative paucity of Howship’s lacunae, although, osteoclasts were sometimes noted. Active reversal lines were likewise present but relatively sparse. In areas of vital bone, the vascularity of the connective tissue appeared to be intact, though venules were often congested with erythrocytes (Fig 2). In acutely affected areas, inflammatory cells were often the dominant feature in any given microscopic field and bacterial colonies were evident (Fig 3). Osteoblastic rimming was noted in some areas of acute inflammation but was not a notable feature. In contrast, cases of osteoradionecrosis reviewed from archival files, were seen to have a higher incidence of Howship’s lacunae and reversal lines in more normal proportions. Unfortunately, data on whether these osteoradionecrosis patients had already had hyperbaric oxygen therapy was not available. In osteoradionecrosis, inflammation and bacteria were seen around sequestra and on superficial bone surfaces. But bacteria and inflammatory infiltrates were not common in deeper portions of the trabeculae. In deeper areas showing connective tissue elements, the vascularity was diminished. While bacteria were erroneously thought for decades to be a prime cofactor in osteoradionecrosis, the foul smell and purulence associated with phossy jaw, along with bacterial colonies seen in current cases of bis-phossy jaw, may be important clues of why we should separate bis-phossy jaw from osteoradionecrosis.40,46
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Treatment modalities for phossy jaw in the era before antibiotics were generally conservative, with moderate debridement and topical solutions being the mainstays of therapy.30 We do know that topical solutions such as copper sulfate acted as topical antibiotics and thus support a bacterial cofactor hypothesis. One could also hypothesize that usual therapeutic success, despite the non-availability of systemic antibiotics, mitigates against bacterial cofactors being a major component. In our cases, the submitting clinicians invariably have reported purulence or suspected infection and given a clinical impression of osteomyelitis. I cannot help but believe that a bacterial component is significant in bis-phossy jaw. There are significant reports of death because of phossy jaw (estimated up to 20%), but most cases appear to have been ultimately managed with conservative therapy.25,29,30,32,46,47 We must also remember phossy jaw was primarily a disease that preceded systemic antibiotics. Although the descriptions of foul smells and death associated with phossy jaw lend credence to a bacterial cofactor, it is impossible to rule out bacterial osteomyelitis as only an occasional sequela, or bacteria as an occasional but not necessary cofactor. I believe it will take some time and multiple studies to see whether bacteria play a primary role or merely represent secondary infections in cases of bisphossy jaw. Our laboratory examples, cited above, and the reported observation that topical chlorhexidine has proven therapeutically beneficial seem to at least indicate that control of surface bacteria may help the body recover denuded areas of bone. In addition,
FIGURE 3. This photomicrograph shows bacterial colonies and acute inflammatory infiltrates. This is a transition area with vital bone seen in the upper portion and non-vital bone seen in the lower portion of the photomicrograph. (Hematoxylin-eosin stain of demineralized tissue; original magnification ⫻200.) Hellstein and Marek. Is This Phossy Jaw of the 21st Century? J Oral Maxillofac Surg 2005.
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it suggests an increased bacterial role as compared with osteoradionecrosis. This would differ greatly from the bases and sequence offered by Dr Marx in his 1983 article on osteoradionecrosis.48 In that article, he described a causative sequence for osteoradionecrosis of 1) radiation, 2) hypoxic-hypocellular-hypovascular tissue, 3) tissue breakdown, and 4) chronic nonhealing wound. This landmark article on osteoradionecrosis has now stood the test of clinical practice, but in fact it took a number of years for clinicians to change the paradigm of treatment. Treatment for osteoradionecrosis, especially before the advent of hyperbaric oxygen, was primarily based on preventative measures with surgical and/or bacterial control protocols being applied when necessary.46,48,49 Today, hyperbaric oxygen remains a mainstay of therapy for osteoradionecrosis, but if surgical correction is deemed necessary an “aggressive” approach is advocated to reach bone unaffected by high dose radiation. If surgery is necessary it is performed in conjunction with adjunctive hyperbaric oxygen.50-52 It is becoming clear with reports by Ruggiero et al,2 Asseal,14 and Marx16 that the avascular clinical appearance of bis-phossy jaw sequestra may produce an analogy to osteoradionecrosis. While avascularity may indeed be a factor at some stages of bis-phossy jaw, we believe this is most likely a misplaced analogy. This is evident in tissue sections of bis-phossy jaw because vessels appear to be present in normal numbers, albeit congested numbers (Fig 2). In osteoradionecrosis, the remodeling process is related to reduction of both osteoclastic and osteoblastic actions, which are in turn the result of the hypocellularity/ hypovascularity/hypoxic nature of the postradiation tissue effects. In the Marx sequence and his therapeutic protocol for osteoradionecrosis, the success of hyperbaric oxygen therapy is beneficial to both the osteoclasts as well as the osteoclasts.50 In addition, in histologic samples of osteoradionecrosis, it is common to see evidence of osteoclastic action and although some inflammatory cells may be seen, the setting is usually remarkably non-inflammatory in nonsurface areas. Of course, this is not the case if secondary infection occurs as in cases of Marx’s stage III osteoradionecrosis. In patients being administered bisphosphonates, the osteoclast/osteoblast axis or feedback loop is a completely different scenario. In bis-phossy jaw, osteoclastic action is reduced but osteoblastic production continues. In fact, a complication of bisphosphonate therapy is progression to drug induced osteopetrosis.53 Osteopetrosis is in and of itself a risk factor for osteomyelitis. In addition, oral and maxillofacial surgeons are well aware of the different healing characteristics and osteomyelitis risks in any area of
687 bony sclerosis. Such sclerosis may be seen in florid cemento-osseous dysplasia and other benign fibroosseous lesions. This increased medullary bone density may indicate some potential differences in bisphossy jaw cases that present early in bisphosphonate therapy and those that present late. In early cases, the dense bone problems may not be a factor, whereas in late cases dense sclerotic bone may be present. In both instances, decreased osteoclastic action will be a factor but dense medullary bone may be an additional factor in cases where it is present. Remember that (although not to the state of osteopetrosis) increased medullary bone density was a common finding in the historic descriptions of phossy jaw.33 And, of course, the reason to use bisphosphonates is exactly for the purpose of increasing medullary bone density. Although I am putting forth a theory that the primary problem in bis-phossy jaw is the inability of osteoclasts to remove, and thus repair or contain areas of “diseased” bone, the contribution of the osteoblasts to “overbuilding” and walling off of diseased bone should not be overlooked. The adaptability of dense medullary bone is simply different than normal medullary bone. Perhaps the sequence for development of bisphossy jaw might be: 1) bisphosphonate alteration of the osteoclast/osteoblast axis. This increases relative osteoblastic activity and decreases relative osteoclast activity. 2a) Active periodontal disease, 2b) periapical/periradicular disease, 2c) oral surgical procedure resulting in bone exposure and need for remodeling to accomplish normal healing, 2d) easily traumatized mucosa over bone, eg, internal oblique ridge, palatal tori, mandibular tori, denture flange support areas, 3) osteoclasts can not activate or aggregate enough to remove contaminated and/or necrotic bone. Note: Destruction of the periosteal interface may be especially important in surface based erosions. 4a) Osteoblasts previously or subsequently lay down dense bone with altered proportions of bone to connective tissue elements (vessels, fibroblasts, and so forth). This diminishes the adaptability seen in normal medullary bone and probably also affects periosteal surfaces as well. 4b) Even with the ability of osteoblasts to build new bone, the failure of osteoclasts to remove diseased bone results in a situation where there is not sufficient “scaffolding” on which to lay down healthy bone. 5) A sufficient volume of necrotic bone results which produces local changes sufficient to destroy bony, vascular, and connective tissue structures necessary for self-repair. 6) Pre-existing, superimposed, or metachronous bacterial cofactors produce sequestration, possible osteomyelitis, and prevents or inhibits periosteal and/or epithelial regeneration over exposed bone.
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Therapy and Prevention First, as related to the above sequence, we as oral health care providers should be able to apply the criteria we currently use in patients before artificial replacement of large joints, head and neck radiation, bone marrow transplant, and organ transplant patients. Second, at least in the case of widespread metastatic disease, nuclear medicine scans of the jaws should be available on most patients being worked up for such metastatic diseases. We must immediately require nuclear medicine specialists to never ignore what has traditionally been interpreted as normal technetium99 uptake in the jaws. We can no longer ignore the possibility that increased uptake of radionucleotides in the jaws may be an indicator of bisphosphonate susceptible bone. Whether this technetium99 uptake and therefore bone turnover is from periodontal disease, endodontic related disease, or recent extraction sites, the data may prove to be telling. Technetium99 uptake could be an important predictor of bis-phossy jaw susceptibility. Such areas of radionucleotide uptake essentially represent asymptomatic siege warfare of the osteoclasts and osteoblasts with or without a bacterial component. If bisphosphonates are applied, a tipping point may occur in this stalemate war. Cold spots of the jaws may be less important, but at this point cold spots are also worthy of more study and should be annotated on nuclear medicine reports as well. These cold spots may merely indicate a decrease in osteoblast activity. However, such cold spots have been indicated as possible indicators of neuralgia-inducing cavitational necrosis. No matter your opinion on neuralgia-inducing cavitational osteonecrosis, at this point of investigating causation and risk factors associated with bis-phossy jaw, we must keep track of any changes of the osteoclast/osteoblast axis.54,55 In addition to the preventive measures mentioned above, surgical intervention will undoubtedly play a role in bis-phossy jaw therapy. We may need to develop a staging protocol as to when surgical intervention should be considered. As described by Ruggiero et al,2 extensive involvement may necessitate large areas of debridement to include segmental mandibulectomy and partial maxillectomy, but it appears that our profession is still exploring what the best modality of treatment should be for bis-phossy jaw. Sequential removal of sequestra as necessary seems to be the current conservative approach, but if large volume debridement becomes necessary the goal should be to remove as little bone as possible. Marx16 reports the futility of trying to cover the exposed areas with tissue flaps. When removing bone the clinician must realize that there is no periphery of “normal” bone because the entire skeleton is being treated with the
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bisphosphonate. Maintenance of as much periosteum as possible should also serve to minimize the amount of bone exposed to the oral microbiologic cesspool. As the profession attempts to find the best method to treat bis-phossy jaw, multiple treatment protocols may need to be attempted. When these treatment protocols are developed for bis-phossy jaw, multiple factors should be taken into consideration and recorded. Patient attributes, clinical findings, clinical and medical cofactors, patient compliance issues, follow-up intervals, and therapeutic modalities used should all be annotated in each case. Bisphosphonate therapy is already a common treatment modality in a number of clinical settings. One of the advantages of zoledronic acid is that it may be administered monthly and in a 15 minute infusion.56 Although a longer infusion period is used, pamidronate also has proven beneficial in the prevention of hypercalcemia of malignancy, skeletal morbidity, and reducing the burdens of advanced cancers. But head to head tests of zoledronic acid and pamidronate have shown advantages to the use of zoledronic acid, and this has become a much more popular choice. By early 2004, at least 300,000 patients worldwide have been treated with zoledronic acid.4,57 Novartis (Basel, Switzerland), the primary manufacturer of these 2 most commonly used injectable bisphosphonates, has released post-marketing warnings of “osteonecrosis (primarily of the jaws).”58,59 The company is also applauded for holding a conference to discuss the problem. Whether the manufacturers of the orally administered bisphosphonates will need to issue similar statements in the future will be fodder for future debate. We will need much more research to see what population groups or oral factors are the best risk predictors of bis-phossy jaw. There is no doubt that bisphosphonate therapy will continue to show substantial clinical benefits and grow in use. It would also be predicted that the percentage of people affected with bis-phossy jaw may ultimately prove to be relatively low, but the overall number affected will be clinically significant. The morbidity of those patients that are affected is proving to be very significant. We need to discover the ideal dosage, delivery route, and bisphosphonate for each patient category. In addition, it is imperative that we establish predictive and preventive dental metrics along with treatment categories and protocols.
References 1. Kessel B: Hip fracture prevention in postmenopausal women. Obstet Gynecol Surv 59:446, 2004 2. Ruggiero SL, Mehrotra B, Rosenberg TJ, et al: Osteonecrosis of the jaws associated with the use of bisphosphonates: A review of 63 cases. J Oral Maxillofac Surg 62:527, 2004
HELLSTEIN AND MAREK 3. Marketos M: The top 200 brand drugs in 2003 (by units). Drug Topics 148:76, 2004 4. Berenson J, Hirschberg R: Safety and convenience of a 15minute infusion of zoledronic acid. Oncologist 9:319, 2004 5. Conte P, Guarneri V: Safety of intravenous and oral bisphosphonates and compliance with dosing regimens. Oncologist 9:28, 2004 (suppl 4) 6. O’Connell MB, Elliot ME: Osteoporosis and osteomalacia, in DiPiro T (ed): Pharmacotherapy: A Pathophysiologic Approach (5th ed). New York, NY, McGraw-Hill, 2002, p 1690 7. Dunford JE, Thompson K, Coxon FP, et al: Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogencontaining bisphosphonates. J Pharmacol Exp Ther 296:235, 2001 8. Vitte C, Fleisch H, Guenther HL: Bisphosphonates induce osteoblasts to secrete an inhibitor of osteoclast-mediated resorption. Endocrinology 137:2324, 1996 9. Fournier P, Boissier S, Filleur S, et al: Bisphosphonates inhibit angiogenesis in vitro and testosterone-stimulated vascular regrowth in the ventral prostate in castrated rats. Cancer Res 62:6538, 2002 10. Wood J, Bonjean K, Ruetz S, et al: Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther 302:1055, 2002 11. Pioletti DP, Rakotomanana LR: Can the increase of bone mineral density following bisphosphonates treatments be explained by biomechanical considerations? Clin Biomech 19: 170, 2004 12. Smith JA: Bone histology at autopsy and matched bone scintigraphy findings in patients with hormone refractory prostate cancer: The effect of bisphosphonate therapy on bone scintigraphy results. Urol Oncol 21:483, 2003 13. Oh HK, Chambers MS, Garden AS, et al: Risk of osteoradionecrosis after extraction of impacted third molars in irradiated head and neck cancer patients. J Oral Maxillofac Surg 62:139, 2004 14. Assael LA: New foundations in understanding osteonecrosis of the jaws. J Oral Maxillofac Surg 62:125, 2004 15. Carter GD, Goss AN: Bisphosphonates and avascular necrosis of the jaws. Aust Dent J 48:268, 2003 16. Marx RE: Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: A growing epidemic. J Oral Maxillofac Surg 61:1115, 2003 17. Migliorati CA: Bisphosphonates and oral cavity avascular bone necrosis. J Clin Oncol 21:4253, 2003 18. Tarassoff P, Csermak K: Avascular necrosis of the jaws: Risk factors in metastatic cancer patients. J Oral Maxillofac Surg 61:1238, 2003 19. Reinholz GG, Getz B, Sanders ES, et al: Distinct mechanisms of bisphosphonate action between osteoblasts and breast cancer cells: Identity of a potent new bisphosphonate analogue. Breast Cancer Res Treat 71:257, 2002 20. Reinholz GG, Getz B, Pederson L, et al: Bisphosphonates directly regulate cell proliferation, differentiation, and gene expression in human osteoblasts. Cancer Res 60:6001, 2000 21. Im GI, Qureshi SA, Kenney J, et al: Osteoblast proliferation and maturation by bisphosphonates. Biomaterials 25:4105, 2004 22. Dearden WF: The causation of phosphorus necrosis. BMJ 2:408, 1901 23. Dearden WF: Fragilitas ossium amongst workers in Lucifer match factories. BMJ 2:270, 1899 24. Editor’s Note: Phosphorus necrosis under control. B Dent J 76:343, 1944 25. Miles AE: Phosphorus necrosis of the jaw: ‘Phossy jaw.’ Br Dent J 133:203, 1972 26. Aronson SM: The Salvation Army and phossy jaw. Med Health R I 80:315, 1997 27. Hamilton A, Hardy HL: Industrial Toxicology (2nd ed). New York, NY, Paul B. Hoeber, Inc, 1949, pp 138-144 28. Hamilton A, Hardy HL, Finkel AJ: Hamilton and Hardy’s Industrial Toxicology (4th ed). Boston, MA, John Wright, PSG Inc, 1983, pp 116-120
689 29. Hughes JP, Baron R, Buckland DH: Phosphorus necrosis of the jaw: A present-day study. Br J Ind Med 19:83, 1962 30. Wakefield BG: Phosphorus necrosis of the mandible. J Oral Surg 6:264, 1948 31. Adams CO, Sarnat BG: Effects of yellow phosphorus and arsenic trioxide on growing bones and growing teeth. Arch Pathol 30:1192, 1940 32. Kennon R, Hallam JW: Modern phosphorus caries and necrosis. Br Dent J 76:321, 1944 33. Heiman H: Chronic phosphorus poisoning. J Indust Hyg 28: 142, 1946 34. Thoma KH, Goldman HM: Oral Pathology (5th ed). St Louis, MO, Mosby, 1960, p 709 35. Thoma KH: Oral Pathology. St Louis, MO, Mosby, 1941, pp 815-836 36. NationMaster.com: Phosphorus. www.nationmaster.com/encyclopedia/Phosphorus. Accessed March 8, 2005 37. US Department of Health and Human Services: Toxicological profile for white phosphorus. http://www.atsdr.cdc.gov/toxprofiles/tp103.pdf. Agency for toxic substances and disease registry. Accessed March 31, 2005 38. Myers ML, McGlothlin JD: Matchmakers’ “phossy jaw” eradicated. Am Ind Hyg Assoc J 57:330, 1996 39. Ward EF: Phosphorus necrosis in the manufacture of fireworks. J Indust Hyg 10:314, 1928 40. Blum T: Osteomyelitis of the mandible and maxilla. J Am Dent Assoc 11:802, 1924 41. Bernier JL, Goldman HM: Atlas of Dental and Oral Pathology (3rd ed). Washington, DC, Armed Forces Institute of Pathology, 1944, pp 156-157 42. Clark C: Radium Girls. Chapel Hill, NC, The University of North Carolina Press, 1997, pp 65-86 43. Thoma KH: Oral Pathology (4th ed). St Louis, MO, Mosby, 1954, pp 760-767 44. Tiecke RW: Oral Pathology. New York, NY, McGraw-Hill, 1965, pp 545-545 45. Sherk HH, Harrison S, Martland MD: The radium watch-dial workers and the evolution of industrial medicine. N J Med 98:49, 2001 46. Watson WL, Scarborough JE: Osteoradionecrosis in intraoral cancer. Am J Roentgenol Rad Therapy 40:524, 1938 47. Jakhi SA, Parekh BK, Gupta S: Phosphorus necrosis of the maxilla. J Oral Med 38:174, 1983 48. Marx RE: Osteoradionecrosis: A new concept of its pathophysiology. J Oral Maxillofac Surg 41:283, 1983 49. Sunshine I: Dr Alexander O. Gettler’s documentation of a radiation hazard. Am J Forensic Med Pathol 4:307, 1983 50. Cronje FJ: A review of the Marx protocols: Prevention and management of osteoradionecrosis by combining surgery and hyperbaric oxygen therapy. S A Dent J 53:469, 1998 51. Myers RA, Marx RE: Use of hyperbaric oxygen in postradiation head and neck surgery. NCI Monogr 9:151, 1990 52. Vudiniabola S, Pirone C, Williamson J, et al: Hyperbaric oxygen in the therapeutic management of osteoradionecrosis of the facial bones. Int J Oral Maxillofac Surg 29:435, 2000 53. Whyte MP, Wenkert D, Clements KL, et al: Bisphosphonateinduced osteopetrosis. N Engl J Med 349:457, 2003 54. Bouquot JE, McMahon RE: Charlatans in dentistry: Ethics of the NICO wars. J Am Coll Dent 70:38, 2003 55. Zuniga JR: Challenging the neuralgia-inducing cavitational osteonecrosis concept. J Oral Maxillofac Surg 58:1021, 2000 56. Li EC, Davis LE: Zoledronic acid: A new parenteral bisphosphonate. Clin Ther 25:2669, 2003 57. Chern B, Joseph D, Joshua D, et al: Bisphosphonate infusions: Patient preference, safety and clinic use. Support Care Cancer 12:463, 2004 58. Novartis AG: Zometa: (zoledronic acid) injection. Product Information Sheet, Novartis AG, p 1, 2004 59. Novartis AG: Aredia: pamidronate disodium for injection, For intravenous infusion. Product Information Sheet, Novartis AG, p 1, 2004
Bisphosphonate Osteochemonecrosis (Bis-Phossy Jaw): Is This Phossy Jaw of the 21st Century? John W. Hellstein, DDS, MS,* and Cindy L. Marek, BS Pharm, PharmD† Purpose: Bisphosphonates are being implicated in a growing number of complications of the jaws. A
number of terms are being applied to this phenomenon and perhaps the descriptive term bisphosphonate osteochemonecrosis has the most merit. But the eerie similarity of this 21st century disease process with the 19th century disease known as phossy jaw is striking. As the nomenclature continues to evolve, the term used in this article will be bis-phossy jaw. This article will explore historical and current aspects of these diseases. Although there may be other mitigating factors, such as oral health, chemotherapy history, immune status, Karnofsky performance status, or Kaplan-Feinstein index, bisphosphonates appear to be the necessary component in cases of bis-phossy jaw. Materials: This is primarily a review article on reported cases of bis-phossy jaw, with historical looks at phossy jaw and osteoradionecrosis. Our laboratory has reviewed 20 suspected cases of bis-phossy jaw and the typical histopathologic features of bis-phossy jaw are presented. Results: Descriptions of phossy jaw and current bis-phossy jaw cases are remarkably similar. Histopathologic features of bis-phossy jaw showed intact vascular channels, even in areas with acute inflammatory infiltrates and bacterial overgrowth. Non-vital bone fragments with reduced evidence of osteoclastic action were also noted. Conclusion: Bis-phossy jaw may have more of a bacterial cofactor risk than osteoradionecrosis, and though altered angiogenesis may yet prove to be a factor, avascularity does not appear to be a major cofactor. The historical disease phossy jaw appears to serve as a possible analogous disease for current research and treatment of bis-phossy jaw. Prevention and early identification of patients at risk should be of prime concern. © 2005 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 63:682-689, 2005 Bisphosphonate therapy is becoming a mainstay of therapy in various clinical settings.1 Most reported cases of osteomyelitis or necrosis of the jaws associated with bisphosphonate use involve injectable bisphosphonates such as pamidronate and zoledronic acid. But Ruggerio et al2 also reports 7 of 63 cases associated with “chronic” oral bisphosphonate use. In
2003, alendronate was listed as the 19th most commonly prescribed drug, with 17 million prescriptions; risidronate was 72nd with 6 million prescriptions. With such large numbers, even oral bisphosphonates may yet prove to be of significant clinical concern for oral health care providers.3 As of now, the injectable bisphosphonates (pamidronate and zoledronic acid) appear to be of most concern. Zoledronic acid has been used in over 300,000 patients worldwide and is a mainstay for the treatment of hypercalcemia of malignancy.4 As the incidence and prevalence of bisphosphonate associated complications of the jaw (bis-phossy jaw) continues to be elucidated, proper workup and therapeutic management of patients may be affected by thinking of how bisphosphonates affect the jaws. Science is still trying to deduce all the physiologic/molecular effects of bisphosphonates, although the end goal is to increase medullary bone density. What is known is that the oral administration of
Received from the Departments of Oral Pathology, Radiology, and Medicine, University of Iowa, Iowa City, IA. *Clinical Professor. †Clinical Associate Professor. Address correspondence and reprint requests to Dr Hellstein: University of Iowa, Oral Pathology, Radiology and Medicine, 356 Dental Science S, Iowa City, IA 52242; e-mail; [email protected] © 2005 American Association of Oral and Maxillofacial Surgeons
0278-2391/05/6305-0010$30.00/0 doi:10.1016/j.joms.2005.01.010
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bisphosphonates generally creates a bisphosphonate bioavailability of less than 5%.5 We also know the relative in vitro potencies of various bisphosphonates are approximately as follows: 1 for etidronate, 10 for clodronate, 100 for pamidronate, 100 to 1,000 for alendronate, 1,000 to 10,000 for risedronate and ibandronate, and 10,000⫹ for zoledronate.6 We do not know enough to conclude the long-term risks of oral or injected bisphosphonates or which patient subpopulation is susceptible to those risks. Bisphosphonate inhibition of farnesyl diphosphate synthase and the resulting effect of that enzyme on bone resorption is one popular physiologic area being studied.7,8 In addition, inhibition of angiogenesis is being actively investigated.9,10 Researchers also realize the need to study the results of therapy as well as the biomedical considerations.11,12 At this time, there are many unanswered questions, and the effects on the jaws may very well be a completely different issue than in other skeletal locations. Some authors have focused on actions related to angiogenesis and drawn analogies to osteoradionecrosis or avascular necrosis.2,13,14 Physiologically, angiogenesis is important in many systems and may provide no analogy of bisphossy jaw to avascular necrosis, neuralgia-inducing cavitational necrosis, or osteoradionecrosis.2,14-18 The importance of the effects of bisphosphonates on angiogenesis in the establishment of bis-phossy jaw is yet to be determined The ratio of osteoblastic action may not just be increased because of reduction of osteoclastic action, but also because of an earlier commitment of osteoblasts.19-21 The parenteral varieties of bisphosphonates, such as zoledronic acid and pamidronate, probably pose the greatest risk of inducing bis-phossy jaw. But the nitrogen containing bisphosphonates, which also include alendronate, risidronate, and ibandronate, may also have special metabolic activity.7 At this time we should consider all varieties of bisphosphonates to have some bis-phossy jaw risk associated with their use, but we should be most suspicious of injectable bisphosphonates. Chemotherapeutic cofactors in the patients at risk for hypercalcemia of malignancy may have additional or synergistic effects with bisphosphonates. Age, immune status, nutrition, Karnofsky performance status, or Kaplan-Feinstein index may additionally affect what I am calling the osteoclast/osteoblast axis. Bone physiology is of course amazingly complex, but the osteoblasts and osteoclasts are important at the cellular level. Changes in the osteoclast/osteoblast axis may be the major predicating risk factor, with the bisphosphonates acting as modifiers of that axis. The jaw’s unique demands require adaptability and “upregulation” of the osteoclast/ osteoblast axis not usually seen in other skeletal sites.
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Historical Aspects and Nomenclature History may help us in our endeavors to diagnose and treat bisphosphonate associated effects of the jaws. White phosphorus, the cause of phossy jaw, appears to have had similar skeletal effects as bisphosphonate therapy. Phossy jaw has interesting historical aspects and was known by several nomenclature variations. Phosphorus necrosis was perhaps the most common and proper term used in publication. However, “phossy” jaw was also commonly used and appears to have been the term used most often in oral communications, and is the term handed down to generations of oral pathologists and oral surgeons. The term “osteochemonecrosis,” or the more descriptive, “bisphosphonate osteochemonecrosis of the jaws” may be the best nominee(s) for the problems we are now seeing in patients being administered bisphosphonates. (NOTE: the term osteochemonecrosis was coined orally at the 2004 American Academy of Oral Medicine meeting in Key Biscayne, FL, by Dr. Cesar Migliorati. But, the term “bis-phossy jaw” has a certain historical caché and for simplicity this will be the term used in this article. In addition, the use of terms such as bisphosphonate avascular necrosis, bisphosphonate osteomyelitis, bisphosphonate osteonecrosis, or bisphosphonate necrosis may prove much too simplistic or restrictive. Those terms may actually limit our thoughts on what will likely be complicated physiologic, etiologic, and clinical factors. They may also be completely or partially wrong. As discussed later, I believe we will likely find that there will be a need to classify bis-phossy jaw into at least early and late forms. There will also likely be a spectrum of involvement, ranging from mild to severe. It is hoped that this article will show that phossy jaw offers itself as a model to base current therapies for bis-phossy jaw. The jaws present unique challenges, especially in terms of bone turnover and exposure to bacteria. It is hoped that protocols may be developed to better predict patients at risk for bisphossy jaw, and that preventive measures are developed to decrease the incidence of the disease. Time will tell whether bones other than the jaws will also be at some increased risk from bisphosphonate therapy, but in the case of phosphorus necrosis, involvement of bones outside the jaws was relatively uncommon. Dearden22,23 described some risk of femoral fracture associated with chronic phosphorus necrosis and reports pathologic fractures following minimal trauma, such as tripping on a board. Such reports are rare and the jaws were well known to be unique in incidence, treatment challenges, and presentation.
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Phossy Jaw Review Phossy jaw was first described in the mid portion of the 19th century, when it became apparent that workers in the matchmaking industry were being afflicted with an unusual necrosis of the jaws. Lorinser first reported these cases in 1845.24 The victims were often young and otherwise healthy. Eventually, the workers were diagnosed with what became known as phossy jaw or phosphorus necrosis. The morbidity and mortality associated with phossy jaw were significant. Severe pain and deformity were hallmarks of the disease, and as reported by Miles, Hunter estimated the mortality rate in the preantibiotic era as 20%.25 The treatment and prevention of phossy jaw has ties to early socially active groups such as the Salvation Army,26 as well as with early efforts in industrial hygiene.27,28 Descriptions of phossy jaw lesions included observations of an initial dull red area on the gingiva which was often overlying an “infected” tooth. As related by Hughes,29 the initial presenting symptoms were described as follows: “the disease it was noticed, began usually with aching in one of the teeth. At first, this was probably mistaken for ordinary toothache, and would, indeed, at times intermit. Sooner or later, however, recurrence of pain necessitated the extraction of the tooth, and the pain and annoyance for a time probably ceased. The wound in the gum, however, was found not to heal; offensive matter began to ooze from it, and ere long a portion of the alveolus became exposed.” The course of the disease could continue for several years. In another scenario, an indolent ulcer was often seen associated with the socket of a recently extracted tooth. The socket would be indolently involved with associated inflammation.30 In either scenario, there would be progressive extension of the initial lesion with greater and greater areas of bone exposure and eventual sequestration. Multiple episodes of sequestration would be expected during the disease course. The sequestra were often described as porous and light in weight, and sometimes portrayed as either worm-eaten or pumice-like.25 Please note, this description is of the sequestra only. In contrast, the medullary bone was often observed to display increased trabeculations.31 Some also described the starkly white bone surrounding the sequestrum.32 In fact, they also described that chronic phosphorus exposure produced a hyperostosis of the entire skeletal structure, and that the spongy bone is transformed to sclerotic bone.33 In 1944, Kennon and Hallem32 described what they perceived to be 2 different eras of phossy jaw presentation. In their discussion, they describe an “era of extensive necrosis and suppuration” as well as a “modern era of small sequestra.” These observations
IS THIS PHOSSY JAW OF THE 21ST CENTURY?
may be because of the changes in exposure levels or perhaps to changes in access of care. Phossy jaw authors also described severe osteomyelitis with formation of both sequestra and involucra. The involved bone would sometimes become surrounded by a new shell. This was sometimes referred to as bone “casket” formation.34,32 The casket formation may have been more common in the mandible than the maxilla.35 Kennon and Hallem reported that, radiographically, the areas of involvement showed more contrast of the affected bone from the unaffected bone, as compared with standard osteomyelitis.32 Also of note is the finding that like bis-phossy jaw, phossy jaw affected both the maxilla and the mandible, though the mandible was affected slightly more often. Even more interesting than finding phosphorus as the prime causative factor in phossy jaw, was that the risk was only associated with the metabolically active white phosphorus and not with red phosphorus. Although both are elemental phosphorus, red and white phosphorus are allotropes of each other. The allotrope of white phosphorus is a simple tetrahedral configuration, whereas red phosphorus consists of tetrahedral polymers of variable lengths. The allotropic variants result in significant differences in physical and chemical properties.36 Except for the vague comment that white phosphorus is more metabolically active than red phosphorus, the physiologic basis of how white phosphorus causes phossy jaw remains unresolved.37 Even today it might be helpful to answer the question of how white phosphorus behaved at the molecular and cellular level and how that compares with the actions and pathways affected by the bisphosphonates. We do know from reports that white phosphorus appeared to accumulate in the oral region. Whether this accumulation was because the oral cavity was the initial portal and thus was exposed more than other regions, and/or whether the bone turnover needs of the jaws resulted in phosphorus returning to the area, is unknown. There are remarkable stories of politicians and activists being swayed into action by seeing a victim of phossy jaw. First they would see the disfiguring evidence of the disease as the patient was presented to them. Then the lights would be turned off and the patient would open their mouth. In the darkened setting, the spectators would then see an eerie glow emanating from the mouth. That glow was evidence of how phosphorus was named. It indeed glows at room temperature without the need of any additional external heat.38 Although white phosphorus was used most notably in the matchmaking industry, other industries were also involved in the phossy jaw epidemic. The fireworks manufacturers, brass manufacturers, and mak-
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ers of tracer type war munitions also utilized white phosphorus.26,32,38 Even into the 21st century, dental examinations and preventive dental measures remain in place at Pine Bluff Arsenal in Arkansas, where white phosphorus munitions were/are still manufactured. With that said, modern ventilation, containment measures, and other industrial hygiene measures are the most viable reasons why none of these workers has had a case of phossy jaw in at least several decades. (This personal opinion is made unofficially, and to the best of my memory, as a former US Army Oral and Maxillofacial Pathologist. It is not necessarily the opinion of the US Army or the Department of Defense.) Of clinical importance in studying bis-phossy jaw, the clinician must also be aware that it usually took white phosphorus exposure of months to years before phossy jaw would be manifested. In addition, the risk remained for years after the workers left their jobs and therefore their phosphorous exposure could be relatively remote.39 I cannot help but think that we may be only witnessing the tip of the iceberg in a possible bis-phossy jaw epidemic. The phossy jaw treatment paradigm was to preach prevention, patience, and minimal surgical intervention. That is not to say that the surgical interventions were not significant. There are reports of entire mandibles being sequestered. “Minimal,” as I interpret the reports, meant removing sequestra, involucra, and necrotic bone only, with very little soft tissue manipulation and no attempt to extend surgery to “uninvolved” bone with epithelial coverage. But the sequestra were often measured in centimeters and many operations would not be considered insignificant by any measure. As more and more cases of bisphosphonate associated jaw necrosis are being detected, described, and treated, it is also becoming evident that the therapeutic paradigm associated with phossy jaw may also apply to what I am calling bisphossy jaw. Of clinical significance in phossy jaw was the finding of a significant bacterially based component of the disease process. This may be an important etiologic cofactor when comparing and contrasting osteoradionecrosis with bis-phossy jaw. This comparison to osteoradionecrosis is important because there seems to be a contemporary predilection to compare bisphossy jaw with osteoradionecrosis. This is somewhat ironic, because when osteoradionecrosis was first being elucidated in the 1920s the first thing some compared it with was phossy jaw.24,40-42 It took some time for the early analogies of osteoradionecrosis to phossy jaw to change. But the differences were noted in Thoma’s first text on oral pathology in 194135 and the disease processes were separated even further by the Fourth edition of Thoma’s Oral Pathology text in 1954.43 Tiecke’s 1965 text44 also recognized the dif-
FIGURE 1. This clinical photograph shows a large maxillary torus which first became painful following a burn caused by hot food. The mucosa over the torus was a somewhat darker red than the adjacent oral mucosa. Multiple small pustular elevations were seen submucosally. The posterior aspect is dominated by exposed bone. Hellstein and Marek. Is This Phossy Jaw of the 21st Century? J Oral Maxillofac Surg 2005.
fering presentations of osteoradionecrosis and phossy jaw. He noted that suppuration was uncommon and usually minimal in osteoradionecrosis, whereas he noted that phossy jaw was almost invariably complicated by bacterial infection. Coincidentally, osteoradionecrosis caused by exposure of workers painting luminous watch dials with radium, also played a significant role in the field of industrial hygiene.42,45
Modern Bis-Phossy Jaw Findings and Further Review In comparing modern cases of bis-phossy jaw with osteoradionecrosis, we are also seeing differences. In the last year, 20 cases of osteomyelitis in patients with a history of breast cancer, prostate cancer, or multiple myeloma have been reviewed at the University of Iowa Surgical Oral Pathology Laboratory (Iowa City, IA). Bisphosphonates were confirmed or suspected as cofactors in these cases. A review showed that bacteria were commonly associated with the non-vital bone fragments. In addition, in 1 case of bis-phossy jaw seen clinically and microscopically at our institution, multiple small pustular areas were seen overlying a maxillary torus with bis-phossy jaw (Fig 1). In that case, the overlying mucosa was indeed a rather unique dull, ruddy red similar to that described in phossy jaw. Histopathologic sections displayed subepithelial bacterial colonies and small non-vital bone fragments. The patient had multiple bony metastases secondary to prostate cancer and had been getting zoledronic acid injections for 15 months. He believes he burnt the mucosa over the torus before the development of signs and symptoms about 6 weeks prior to the photograph.
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FIGURE 2. This photomicrograph shows congested vascular spaces with associated acute inflammatory infiltrates. The bone still displays some osteocytes though osteocyte “dropout” is apparently ongoing. There is past evidence of apparent osteoclastic or resorptive action. There is single apparent osteoclast in a Howship’s lacuna in the lower center of the field. (Hematoxylin-eosin stain of demineralized tissue; original magnification ⫻100.) Hellstein and Marek. Is This Phossy Jaw of the 21st Century? J Oral Maxillofac Surg 2005.
In all cases of confirmed bis-phossy jaw there was a relative paucity of Howship’s lacunae, although, osteoclasts were sometimes noted. Active reversal lines were likewise present but relatively sparse. In areas of vital bone, the vascularity of the connective tissue appeared to be intact, though venules were often congested with erythrocytes (Fig 2). In acutely affected areas, inflammatory cells were often the dominant feature in any given microscopic field and bacterial colonies were evident (Fig 3). Osteoblastic rimming was noted in some areas of acute inflammation but was not a notable feature. In contrast, cases of osteoradionecrosis reviewed from archival files, were seen to have a higher incidence of Howship’s lacunae and reversal lines in more normal proportions. Unfortunately, data on whether these osteoradionecrosis patients had already had hyperbaric oxygen therapy was not available. In osteoradionecrosis, inflammation and bacteria were seen around sequestra and on superficial bone surfaces. But bacteria and inflammatory infiltrates were not common in deeper portions of the trabeculae. In deeper areas showing connective tissue elements, the vascularity was diminished. While bacteria were erroneously thought for decades to be a prime cofactor in osteoradionecrosis, the foul smell and purulence associated with phossy jaw, along with bacterial colonies seen in current cases of bis-phossy jaw, may be important clues of why we should separate bis-phossy jaw from osteoradionecrosis.40,46
IS THIS PHOSSY JAW OF THE 21ST CENTURY?
Treatment modalities for phossy jaw in the era before antibiotics were generally conservative, with moderate debridement and topical solutions being the mainstays of therapy.30 We do know that topical solutions such as copper sulfate acted as topical antibiotics and thus support a bacterial cofactor hypothesis. One could also hypothesize that usual therapeutic success, despite the non-availability of systemic antibiotics, mitigates against bacterial cofactors being a major component. In our cases, the submitting clinicians invariably have reported purulence or suspected infection and given a clinical impression of osteomyelitis. I cannot help but believe that a bacterial component is significant in bis-phossy jaw. There are significant reports of death because of phossy jaw (estimated up to 20%), but most cases appear to have been ultimately managed with conservative therapy.25,29,30,32,46,47 We must also remember phossy jaw was primarily a disease that preceded systemic antibiotics. Although the descriptions of foul smells and death associated with phossy jaw lend credence to a bacterial cofactor, it is impossible to rule out bacterial osteomyelitis as only an occasional sequela, or bacteria as an occasional but not necessary cofactor. I believe it will take some time and multiple studies to see whether bacteria play a primary role or merely represent secondary infections in cases of bisphossy jaw. Our laboratory examples, cited above, and the reported observation that topical chlorhexidine has proven therapeutically beneficial seem to at least indicate that control of surface bacteria may help the body recover denuded areas of bone. In addition,
FIGURE 3. This photomicrograph shows bacterial colonies and acute inflammatory infiltrates. This is a transition area with vital bone seen in the upper portion and non-vital bone seen in the lower portion of the photomicrograph. (Hematoxylin-eosin stain of demineralized tissue; original magnification ⫻200.) Hellstein and Marek. Is This Phossy Jaw of the 21st Century? J Oral Maxillofac Surg 2005.
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it suggests an increased bacterial role as compared with osteoradionecrosis. This would differ greatly from the bases and sequence offered by Dr Marx in his 1983 article on osteoradionecrosis.48 In that article, he described a causative sequence for osteoradionecrosis of 1) radiation, 2) hypoxic-hypocellular-hypovascular tissue, 3) tissue breakdown, and 4) chronic nonhealing wound. This landmark article on osteoradionecrosis has now stood the test of clinical practice, but in fact it took a number of years for clinicians to change the paradigm of treatment. Treatment for osteoradionecrosis, especially before the advent of hyperbaric oxygen, was primarily based on preventative measures with surgical and/or bacterial control protocols being applied when necessary.46,48,49 Today, hyperbaric oxygen remains a mainstay of therapy for osteoradionecrosis, but if surgical correction is deemed necessary an “aggressive” approach is advocated to reach bone unaffected by high dose radiation. If surgery is necessary it is performed in conjunction with adjunctive hyperbaric oxygen.50-52 It is becoming clear with reports by Ruggiero et al,2 Asseal,14 and Marx16 that the avascular clinical appearance of bis-phossy jaw sequestra may produce an analogy to osteoradionecrosis. While avascularity may indeed be a factor at some stages of bis-phossy jaw, we believe this is most likely a misplaced analogy. This is evident in tissue sections of bis-phossy jaw because vessels appear to be present in normal numbers, albeit congested numbers (Fig 2). In osteoradionecrosis, the remodeling process is related to reduction of both osteoclastic and osteoblastic actions, which are in turn the result of the hypocellularity/ hypovascularity/hypoxic nature of the postradiation tissue effects. In the Marx sequence and his therapeutic protocol for osteoradionecrosis, the success of hyperbaric oxygen therapy is beneficial to both the osteoclasts as well as the osteoclasts.50 In addition, in histologic samples of osteoradionecrosis, it is common to see evidence of osteoclastic action and although some inflammatory cells may be seen, the setting is usually remarkably non-inflammatory in nonsurface areas. Of course, this is not the case if secondary infection occurs as in cases of Marx’s stage III osteoradionecrosis. In patients being administered bisphosphonates, the osteoclast/osteoblast axis or feedback loop is a completely different scenario. In bis-phossy jaw, osteoclastic action is reduced but osteoblastic production continues. In fact, a complication of bisphosphonate therapy is progression to drug induced osteopetrosis.53 Osteopetrosis is in and of itself a risk factor for osteomyelitis. In addition, oral and maxillofacial surgeons are well aware of the different healing characteristics and osteomyelitis risks in any area of
687 bony sclerosis. Such sclerosis may be seen in florid cemento-osseous dysplasia and other benign fibroosseous lesions. This increased medullary bone density may indicate some potential differences in bisphossy jaw cases that present early in bisphosphonate therapy and those that present late. In early cases, the dense bone problems may not be a factor, whereas in late cases dense sclerotic bone may be present. In both instances, decreased osteoclastic action will be a factor but dense medullary bone may be an additional factor in cases where it is present. Remember that (although not to the state of osteopetrosis) increased medullary bone density was a common finding in the historic descriptions of phossy jaw.33 And, of course, the reason to use bisphosphonates is exactly for the purpose of increasing medullary bone density. Although I am putting forth a theory that the primary problem in bis-phossy jaw is the inability of osteoclasts to remove, and thus repair or contain areas of “diseased” bone, the contribution of the osteoblasts to “overbuilding” and walling off of diseased bone should not be overlooked. The adaptability of dense medullary bone is simply different than normal medullary bone. Perhaps the sequence for development of bisphossy jaw might be: 1) bisphosphonate alteration of the osteoclast/osteoblast axis. This increases relative osteoblastic activity and decreases relative osteoclast activity. 2a) Active periodontal disease, 2b) periapical/periradicular disease, 2c) oral surgical procedure resulting in bone exposure and need for remodeling to accomplish normal healing, 2d) easily traumatized mucosa over bone, eg, internal oblique ridge, palatal tori, mandibular tori, denture flange support areas, 3) osteoclasts can not activate or aggregate enough to remove contaminated and/or necrotic bone. Note: Destruction of the periosteal interface may be especially important in surface based erosions. 4a) Osteoblasts previously or subsequently lay down dense bone with altered proportions of bone to connective tissue elements (vessels, fibroblasts, and so forth). This diminishes the adaptability seen in normal medullary bone and probably also affects periosteal surfaces as well. 4b) Even with the ability of osteoblasts to build new bone, the failure of osteoclasts to remove diseased bone results in a situation where there is not sufficient “scaffolding” on which to lay down healthy bone. 5) A sufficient volume of necrotic bone results which produces local changes sufficient to destroy bony, vascular, and connective tissue structures necessary for self-repair. 6) Pre-existing, superimposed, or metachronous bacterial cofactors produce sequestration, possible osteomyelitis, and prevents or inhibits periosteal and/or epithelial regeneration over exposed bone.
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Therapy and Prevention First, as related to the above sequence, we as oral health care providers should be able to apply the criteria we currently use in patients before artificial replacement of large joints, head and neck radiation, bone marrow transplant, and organ transplant patients. Second, at least in the case of widespread metastatic disease, nuclear medicine scans of the jaws should be available on most patients being worked up for such metastatic diseases. We must immediately require nuclear medicine specialists to never ignore what has traditionally been interpreted as normal technetium99 uptake in the jaws. We can no longer ignore the possibility that increased uptake of radionucleotides in the jaws may be an indicator of bisphosphonate susceptible bone. Whether this technetium99 uptake and therefore bone turnover is from periodontal disease, endodontic related disease, or recent extraction sites, the data may prove to be telling. Technetium99 uptake could be an important predictor of bis-phossy jaw susceptibility. Such areas of radionucleotide uptake essentially represent asymptomatic siege warfare of the osteoclasts and osteoblasts with or without a bacterial component. If bisphosphonates are applied, a tipping point may occur in this stalemate war. Cold spots of the jaws may be less important, but at this point cold spots are also worthy of more study and should be annotated on nuclear medicine reports as well. These cold spots may merely indicate a decrease in osteoblast activity. However, such cold spots have been indicated as possible indicators of neuralgia-inducing cavitational necrosis. No matter your opinion on neuralgia-inducing cavitational osteonecrosis, at this point of investigating causation and risk factors associated with bis-phossy jaw, we must keep track of any changes of the osteoclast/osteoblast axis.54,55 In addition to the preventive measures mentioned above, surgical intervention will undoubtedly play a role in bis-phossy jaw therapy. We may need to develop a staging protocol as to when surgical intervention should be considered. As described by Ruggiero et al,2 extensive involvement may necessitate large areas of debridement to include segmental mandibulectomy and partial maxillectomy, but it appears that our profession is still exploring what the best modality of treatment should be for bis-phossy jaw. Sequential removal of sequestra as necessary seems to be the current conservative approach, but if large volume debridement becomes necessary the goal should be to remove as little bone as possible. Marx16 reports the futility of trying to cover the exposed areas with tissue flaps. When removing bone the clinician must realize that there is no periphery of “normal” bone because the entire skeleton is being treated with the
IS THIS PHOSSY JAW OF THE 21ST CENTURY?
bisphosphonate. Maintenance of as much periosteum as possible should also serve to minimize the amount of bone exposed to the oral microbiologic cesspool. As the profession attempts to find the best method to treat bis-phossy jaw, multiple treatment protocols may need to be attempted. When these treatment protocols are developed for bis-phossy jaw, multiple factors should be taken into consideration and recorded. Patient attributes, clinical findings, clinical and medical cofactors, patient compliance issues, follow-up intervals, and therapeutic modalities used should all be annotated in each case. Bisphosphonate therapy is already a common treatment modality in a number of clinical settings. One of the advantages of zoledronic acid is that it may be administered monthly and in a 15 minute infusion.56 Although a longer infusion period is used, pamidronate also has proven beneficial in the prevention of hypercalcemia of malignancy, skeletal morbidity, and reducing the burdens of advanced cancers. But head to head tests of zoledronic acid and pamidronate have shown advantages to the use of zoledronic acid, and this has become a much more popular choice. By early 2004, at least 300,000 patients worldwide have been treated with zoledronic acid.4,57 Novartis (Basel, Switzerland), the primary manufacturer of these 2 most commonly used injectable bisphosphonates, has released post-marketing warnings of “osteonecrosis (primarily of the jaws).”58,59 The company is also applauded for holding a conference to discuss the problem. Whether the manufacturers of the orally administered bisphosphonates will need to issue similar statements in the future will be fodder for future debate. We will need much more research to see what population groups or oral factors are the best risk predictors of bis-phossy jaw. There is no doubt that bisphosphonate therapy will continue to show substantial clinical benefits and grow in use. It would also be predicted that the percentage of people affected with bis-phossy jaw may ultimately prove to be relatively low, but the overall number affected will be clinically significant. The morbidity of those patients that are affected is proving to be very significant. We need to discover the ideal dosage, delivery route, and bisphosphonate for each patient category. In addition, it is imperative that we establish predictive and preventive dental metrics along with treatment categories and protocols.
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