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Bis-phossy jaw, phossy jaw, and the 21st century: Bisphosphonate-associated complications of the jaws

2004; Elsevier BV; Volume: 62; Issue: 12 Linguagem: Inglês

10.1016/j.joms.2004.09.004

1531-5053

John W. Hellstein, Cindy L. Marek,

Pharmacological Effects and Toxicity Studies

Preliminary to a manuscript, which is being submitted along with this letter for peer review, this commentary and advisory is submitted.Imagine the following scenario: A dentist begins seeing a series of patients who present with spontaneous (or postextraction) development of exposed bone. Over time, the patients present with purulence, sequestration, pain, and osteomyelitis. Eventually, it is discovered that the patients had all been exposed to the same chemical. This chemical had various systemic effects in addition to the sometimes devastating complications in the alveolar processes. But even though other portions of the skeleton could be involved, the jaws, overwhelmingly, seemed to be the most common area to present with complications. The skeleton, including the jaws, showed increased density, particularly of the medullary bone. The bone surrounding jaw sequestra was often described as dense and white.Alas, these descriptors are not from the 21st century, but instead are from patients exposed to white phosphorus. The descriptions actually represent cases of the 19th and early 20th centuries. The disease was called phossy jaw.1Dearden W.F. The causation of phosphorus necrosis.BMJ. 1901; 2: 408Google Scholar, 2Dearden W.F. Fragilitas ossium amongst workers in Lucifer match factories.BMJ. 1899; 2: 270Crossref PubMed Scopus (18) Google Scholar, 3Adams C.O. Sarnat B.G. Effects of yellow phosphorus and arsenic trioxide on growing bones and growing teeth.Arch Pathol. 1940; 30: 1192Google Scholar, 4Editor's Note Phosphorus necrosis under control.B Dent J. 1944; 76: 343Google Scholar, 5Heiman H. Chronic phosphorus poisoning.J Indust Hyg. 1946; 28: 142PubMed Google Scholar, 6Kennon R. Hallam J.W. Modern phosphorus caries and necrosis.Br Dent J. 1944; 76: 321Google ScholarPhossy jaw has interesting historical aspects and was known by several nomenclature variations. Phosphorus necrosis was perhaps the most common designation and was the more 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.7Aronson S.M. The Salvation Army and phossy jaw.Med Health R I. 1997; 80: 315PubMed Google Scholar, 8Miles A.E. Phosphorus necrosis of the jaw ‘phossy jaw’.Br Dent J. 1972; 133: 203Crossref PubMed Scopus (25) Google Scholar, 9Myers M.L. McGlothlin J.D. Matchmakers' “phossy jaw” eradicated.Am Ind Hyg Assoc J. 1996; 57: 330Crossref PubMed Scopus (40) Google ScholarBut now, many clinically similar cases are presenting in patients who are being administered bisphosphonates for metastatic cancer or other potential bone loss conditions. I believe the term bis-phossy jaw is the proper term for the current “epidemic.” This is because the bony pathoses seen in the jaws secondary to bisphosphonate therapy may have analogous findings to the historical disease of phossy jaw. I believe the term bis-phossy jaw has a certain historical niche. But 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 also limit our thoughts on what may actually be complicated etiologic and clinical settings.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. The term bis-phossy jaw will allow usto think of the unique challenges the jaws present, especially in terms of bone turnover and exposure to bacteria.The nascent field of industrial hygiene found phossy jaw to be an early instance of why workers needed protection and why governments should assert regulatory controls. The controls and regulations they instituted have been successful in relegating phossy jaw to what is essentially a historical footnote.10Ward E.F. Phosphorus necrosis in the manufacture of fireworks.J Indust Hyg. 1928; 10: 314Google Scholar, 11Jakhi S.A. Parekh B.K. Gupta S. Phosphorus necrosis of the maxilla.J Oral Med. 1983; 38: 174PubMed Google Scholar, 12Hamilton A. Hardy H.L. Phosphorus.in: Hamilton A. Hardy H.L. Industrial Toxicology. ed 2. Paul B. Hoeber, Inc, New York, NY1949: 138-145Google Scholar We can only hope we will be as fortunate with bis-phossy jaw. Today, questions must be asked about the mechanisms of bisphosphonates and whether we can learn from some of the treatment rendered to phossy jaw patients. Certainly earlier clinicians practiced avoidance of the chemical, but where exposure had occurred, or was inevitable, they also found that preventive dental care was beneficial. They sought to avoid extractions, periodontal disease, and abscesses. When phossy jaw did occur, topical antimicrobials, conservative debridement of sequestra, and minimization of surgery was advised. Please note that conservative refers to “minimal removal of bone other than the sequestra.” Conservative does not imply that the sequestra were not sometimes extremely large or that the procedures were not complicated.13Hughes J.P. Baron R. Buckland D.H. Phosphorus necrosis of the jaw A present-day study.Br J Ind Med. 1962; 19: 83PubMed Google Scholar, 14Bernier J.L. Goldman H.M. Atlas of Dental and Oral Pathology. ed 3. Armed Forces Institute of Pathology, Washington, DC1944: 156Google ScholarThe complex physiologic actions of osteoclasts and osteoblasts as they relate to bone turnover, regulation of minerals in the serum, and removal contaminants can be called the osteoclast/osteoblast axis. The unique challenges the jaws present as related to the osteoclast/osteoblast axis appear to be extremely important. Unlike avascular necrosis, the histopathologically bis-phossy jaw appears to retain vascularity even as sequestration is occurring (Fig 1). Unlike osteoradionecrosis, bacteria appear to be a common feature (Fig 2).FIGURE 2This photomicrograph shows bacterial colonies, acute inflammatory infiltrates, and non-vital bone. (Hematoxylin-eosin stain of demineralized tissue; original magnification ×40.)Show full captionHellstein and Marek. Letter to the Editor. J Oral Maxillofac Surg 2004.View Large Image Figure ViewerDownload (PPT)In the cases of cancer, osteoporosis, and other clinical settings, bisphosphonates are used to maintain bone density, regulate serum calcium, and decrease tumor burden.15Berenson J. Hirschberg R. Safety and convenience of a 15-minute infusion of zoledronic acid.Oncologist. 2004; 9: 319Crossref PubMed Scopus (41) Google Scholar, 16Li E.C. Davis L.E. Zoledronic acid A new parenteral bisphosphonate.Clin Ther. 2003; 25: 2669Abstract Full Text PDF PubMed Scopus (102) Google Scholar, 17Day J.S. Ding M. Bednarz P. et al.Bisphosphonate treatment affects trabecular bone apparent modulus through micro-architecture rather than matrix properties.J Orthop Res. 2004; 22: 465Crossref PubMed Scopus (60) Google Scholar, 18Di Leo G. Neri E. Ventura A. Using pamidronate for osteoporosis.J Pediatr. 2004; 144: 689Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar, 19Srivastava T. Alon U.S. The role of bisphosphonates in diseases of childhood.Eur J Pediatr. 2003; 162: 735Crossref PubMed Scopus (57) Google Scholar We must now wonder whether the metabolic pathways affected by white phosphorus are similar to, or the same as, modern “metabolically active” bisphosphonates. We must also consider the sample of patients who are being prescribed injectable bisphosphonates. It would not be unexpected for such patients to have had a complicated series of chemotherapeutic agents. Overall, measures of immunocompetency along with such measures as the Karnofsky performance score or the Kaplan-Feinstein Index may prove to be risk indicators as well. Though bisphosphonates may be a necessary component of bis-phossy jaw, oral health status, oral hygiene, and dental IQ may also prove to be important.Health care providers must be aware that there are probable significant differences between bis-phossy jaw and osteoradionecrosis. Treatment modalities for the 2 diseases will not be a one-size-fits-all solution. Prevention will most likely be a mainstay of “treatment” for bis-phossy jaw. Even in the era of phossy jaw (an era where industrially supported dentistry was rare), preventive dental care was given to factory workers at risk of white phosphorus exposure.10Ward E.F. Phosphorus necrosis in the manufacture of fireworks.J Indust Hyg. 1928; 10: 314Google Scholar Similar preventive measures and increased awareness of the patient, dentist, internist, and oncologist should also be the starting point in patients being administered potent bisphosphonates in the 21st century.I believe we should begin by proactively applying preventive dental protocols similar to those for transplant patients or for patients being evaluated for large artificial joint replacement. In addition, we should be especially cognizant of “hot” areas in the jaws as seen on nuclear medicine scans. Right now we have no proof that techetium99 “hot spots” relate directly to bis-phossy jaw. But I believe we can longer allow jaw uptake abnormalities to be considered “normal,” and let such hot spots go without comment in people being evaluated for metastatic disease. All such patients are currently candidates for potent bisphosphonate therapy. Osteopetrosis-like changes are risks of bisphosphonates and surgeons are well aware of the osteomyelitis risks associated with dense bone in general.20Whyte M.P. Wenkert D. Clements K.L. et al.Bisphosphonate-induced osteopetrosis.N Engl J Med. 2003; 349: 457Crossref PubMed Scopus (393) Google ScholarClinicians will continue to explore therapies before the establishment of defined protocols of bis-phossy jaw by disease stage. But during this time period, where the profession is exploring the best therapeutic protocols, we should apply some basic considerations to patient treatment. Considerations before treatment should include at least: 1) Bisphosphonate therapy affects the entire skeleton. It is impossible to surgically reach an area of normal osteoclastic activity in bis-phossy jaw. 2) Osteoblasts retain near normal or increased capabilities and bisphosphonates increase the denominator in the ratio of osteoblastic activity, as related to the osteoclast:osteoblast axis. 3) Osteoclastic activity and abilities are reduced. 4) With the above predicating factors, the bacterial cesspool represented by the oral cavity creates a situation where exposed bone is difficult to recover with periosteum, connective tissue elements, and epithelium. 5) True osteomyelitis may occur from a pre-existing periodontal or endodontic problem or secondary to surgery/trauma. In any case, the osteomyelitis may become the major treatment modifier.All clinicians must become aware of early signs and symptoms of bis-phossy jaw, which may include ulceration, irritation, or pain. On patients being administered injectable (and perhaps oral) bisphosphonates, informed consent issues should be given before extraction of teeth or other invasive procedures. Preliminary to a manuscript, which is being submitted along with this letter for peer review, this commentary and advisory is submitted. Imagine the following scenario: A dentist begins seeing a series of patients who present with spontaneous (or postextraction) development of exposed bone. Over time, the patients present with purulence, sequestration, pain, and osteomyelitis. Eventually, it is discovered that the patients had all been exposed to the same chemical. This chemical had various systemic effects in addition to the sometimes devastating complications in the alveolar processes. But even though other portions of the skeleton could be involved, the jaws, overwhelmingly, seemed to be the most common area to present with complications. The skeleton, including the jaws, showed increased density, particularly of the medullary bone. The bone surrounding jaw sequestra was often described as dense and white. Alas, these descriptors are not from the 21st century, but instead are from patients exposed to white phosphorus. The descriptions actually represent cases of the 19th and early 20th centuries. The disease was called phossy jaw.1Dearden W.F. The causation of phosphorus necrosis.BMJ. 1901; 2: 408Google Scholar, 2Dearden W.F. Fragilitas ossium amongst workers in Lucifer match factories.BMJ. 1899; 2: 270Crossref PubMed Scopus (18) Google Scholar, 3Adams C.O. Sarnat B.G. Effects of yellow phosphorus and arsenic trioxide on growing bones and growing teeth.Arch Pathol. 1940; 30: 1192Google Scholar, 4Editor's Note Phosphorus necrosis under control.B Dent J. 1944; 76: 343Google Scholar, 5Heiman H. Chronic phosphorus poisoning.J Indust Hyg. 1946; 28: 142PubMed Google Scholar, 6Kennon R. Hallam J.W. Modern phosphorus caries and necrosis.Br Dent J. 1944; 76: 321Google Scholar Phossy jaw has interesting historical aspects and was known by several nomenclature variations. Phosphorus necrosis was perhaps the most common designation and was the more 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.7Aronson S.M. The Salvation Army and phossy jaw.Med Health R I. 1997; 80: 315PubMed Google Scholar, 8Miles A.E. Phosphorus necrosis of the jaw ‘phossy jaw’.Br Dent J. 1972; 133: 203Crossref PubMed Scopus (25) Google Scholar, 9Myers M.L. McGlothlin J.D. Matchmakers' “phossy jaw” eradicated.Am Ind Hyg Assoc J. 1996; 57: 330Crossref PubMed Scopus (40) Google Scholar But now, many clinically similar cases are presenting in patients who are being administered bisphosphonates for metastatic cancer or other potential bone loss conditions. I believe the term bis-phossy jaw is the proper term for the current “epidemic.” This is because the bony pathoses seen in the jaws secondary to bisphosphonate therapy may have analogous findings to the historical disease of phossy jaw. I believe the term bis-phossy jaw has a certain historical niche. But 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 also limit our thoughts on what may actually be complicated etiologic and clinical settings. 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. The term bis-phossy jaw will allow usto think of the unique challenges the jaws present, especially in terms of bone turnover and exposure to bacteria. The nascent field of industrial hygiene found phossy jaw to be an early instance of why workers needed protection and why governments should assert regulatory controls. The controls and regulations they instituted have been successful in relegating phossy jaw to what is essentially a historical footnote.10Ward E.F. Phosphorus necrosis in the manufacture of fireworks.J Indust Hyg. 1928; 10: 314Google Scholar, 11Jakhi S.A. Parekh B.K. Gupta S. Phosphorus necrosis of the maxilla.J Oral Med. 1983; 38: 174PubMed Google Scholar, 12Hamilton A. Hardy H.L. Phosphorus.in: Hamilton A. Hardy H.L. Industrial Toxicology. ed 2. Paul B. Hoeber, Inc, New York, NY1949: 138-145Google Scholar We can only hope we will be as fortunate with bis-phossy jaw. Today, questions must be asked about the mechanisms of bisphosphonates and whether we can learn from some of the treatment rendered to phossy jaw patients. Certainly earlier clinicians practiced avoidance of the chemical, but where exposure had occurred, or was inevitable, they also found that preventive dental care was beneficial. They sought to avoid extractions, periodontal disease, and abscesses. When phossy jaw did occur, topical antimicrobials, conservative debridement of sequestra, and minimization of surgery was advised. Please note that conservative refers to “minimal removal of bone other than the sequestra.” Conservative does not imply that the sequestra were not sometimes extremely large or that the procedures were not complicated.13Hughes J.P. Baron R. Buckland D.H. Phosphorus necrosis of the jaw A present-day study.Br J Ind Med. 1962; 19: 83PubMed Google Scholar, 14Bernier J.L. Goldman H.M. Atlas of Dental and Oral Pathology. ed 3. Armed Forces Institute of Pathology, Washington, DC1944: 156Google Scholar The complex physiologic actions of osteoclasts and osteoblasts as they relate to bone turnover, regulation of minerals in the serum, and removal contaminants can be called the osteoclast/osteoblast axis. The unique challenges the jaws present as related to the osteoclast/osteoblast axis appear to be extremely important. Unlike avascular necrosis, the histopathologically bis-phossy jaw appears to retain vascularity even as sequestration is occurring (Fig 1). Unlike osteoradionecrosis, bacteria appear to be a common feature (Fig 2). Hellstein and Marek. Letter to the Editor. J Oral Maxillofac Surg 2004. In the cases of cancer, osteoporosis, and other clinical settings, bisphosphonates are used to maintain bone density, regulate serum calcium, and decrease tumor burden.15Berenson J. Hirschberg R. Safety and convenience of a 15-minute infusion of zoledronic acid.Oncologist. 2004; 9: 319Crossref PubMed Scopus (41) Google Scholar, 16Li E.C. Davis L.E. Zoledronic acid A new parenteral bisphosphonate.Clin Ther. 2003; 25: 2669Abstract Full Text PDF PubMed Scopus (102) Google Scholar, 17Day J.S. Ding M. Bednarz P. et al.Bisphosphonate treatment affects trabecular bone apparent modulus through micro-architecture rather than matrix properties.J Orthop Res. 2004; 22: 465Crossref PubMed Scopus (60) Google Scholar, 18Di Leo G. Neri E. Ventura A. Using pamidronate for osteoporosis.J Pediatr. 2004; 144: 689Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar, 19Srivastava T. Alon U.S. The role of bisphosphonates in diseases of childhood.Eur J Pediatr. 2003; 162: 735Crossref PubMed Scopus (57) Google Scholar We must now wonder whether the metabolic pathways affected by white phosphorus are similar to, or the same as, modern “metabolically active” bisphosphonates. We must also consider the sample of patients who are being prescribed injectable bisphosphonates. It would not be unexpected for such patients to have had a complicated series of chemotherapeutic agents. Overall, measures of immunocompetency along with such measures as the Karnofsky performance score or the Kaplan-Feinstein Index may prove to be risk indicators as well. Though bisphosphonates may be a necessary component of bis-phossy jaw, oral health status, oral hygiene, and dental IQ may also prove to be important. Health care providers must be aware that there are probable significant differences between bis-phossy jaw and osteoradionecrosis. Treatment modalities for the 2 diseases will not be a one-size-fits-all solution. Prevention will most likely be a mainstay of “treatment” for bis-phossy jaw. Even in the era of phossy jaw (an era where industrially supported dentistry was rare), preventive dental care was given to factory workers at risk of white phosphorus exposure.10Ward E.F. Phosphorus necrosis in the manufacture of fireworks.J Indust Hyg. 1928; 10: 314Google Scholar Similar preventive measures and increased awareness of the patient, dentist, internist, and oncologist should also be the starting point in patients being administered potent bisphosphonates in the 21st century. I believe we should begin by proactively applying preventive dental protocols similar to those for transplant patients or for patients being evaluated for large artificial joint replacement. In addition, we should be especially cognizant of “hot” areas in the jaws as seen on nuclear medicine scans. Right now we have no proof that techetium99 “hot spots” relate directly to bis-phossy jaw. But I believe we can longer allow jaw uptake abnormalities to be considered “normal,” and let such hot spots go without comment in people being evaluated for metastatic disease. All such patients are currently candidates for potent bisphosphonate therapy. Osteopetrosis-like changes are risks of bisphosphonates and surgeons are well aware of the osteomyelitis risks associated with dense bone in general.20Whyte M.P. Wenkert D. Clements K.L. et al.Bisphosphonate-induced osteopetrosis.N Engl J Med. 2003; 349: 457Crossref PubMed Scopus (393) Google Scholar Clinicians will continue to explore therapies before the establishment of defined protocols of bis-phossy jaw by disease stage. But during this time period, where the profession is exploring the best therapeutic protocols, we should apply some basic considerations to patient treatment. Considerations before treatment should include at least: 1) Bisphosphonate therapy affects the entire skeleton. It is impossible to surgically reach an area of normal osteoclastic activity in bis-phossy jaw. 2) Osteoblasts retain near normal or increased capabilities and bisphosphonates increase the denominator in the ratio of osteoblastic activity, as related to the osteoclast:osteoblast axis. 3) Osteoclastic activity and abilities are reduced. 4) With the above predicating factors, the bacterial cesspool represented by the oral cavity creates a situation where exposed bone is difficult to recover with periosteum, connective tissue elements, and epithelium. 5) True osteomyelitis may occur from a pre-existing periodontal or endodontic problem or secondary to surgery/trauma. In any case, the osteomyelitis may become the major treatment modifier. All clinicians must become aware of early signs and symptoms of bis-phossy jaw, which may include ulceration, irritation, or pain. On patients being administered injectable (and perhaps oral) bisphosphonates, informed consent issues should be given before extraction of teeth or other invasive procedures.