- Email: [email protected]
New foundations in understanding osteonecrosis of the jaws
EDITORIAL J Oral Maxillofac Surg 62:125-126, 2004
New Foundations in Understanding Osteonecrosis of the Jaws Objects and ideas have much in common. An object (or idea) pressed on too heavily will inevitably fall under its own weight. Unidirectional force causes motion, but not always in the best direction. Unidirectional ideas also produce a clear direction for research and practice. However, the result may be uncompromising opinions that carry great weight until their moment of collapse. Additionally, reliance on a single direction of research may suppress important new areas of inquiry. As an idea further progresses in a single direction, the impelling force multiplies. The promoters of the original idea often forcefully disagree with research that does not support their accepted direction. Investigators with original ideas may find it difficult to obtain funding for research endeavors that do not conform to the conventional direction. The more research succeeds in a single-minded direction, the more likely it will eventually need new foundations. The failure to critically evaluate opposing views makes research ever more vulnerable to sudden refutation. Objects and ideas are only stable when they are joined by forces/research that provide balance. They also rely upon their foundations; ideas that may be called into question by new information that does not fit the conventional direction. New foundations are then created as new information gains its proper interpretation in a new universe. The tremendous force and eventual collapse of Newtonian physics early in the 20th century provides the best example of these phenomena in the history of science. As scientific measurement became more precise, at first in seeming celebration of Newtonian order, more errors were found. For centuries, these errors were attributed to the shortcomings of scientists, their methods, or their instruments. When it became clear that the Newtonian foundation could no longer explain the physical universe, the responses of physicists included forceful rebuttal, befuddlement, and even religious attribution. The emergence of Einstein’s theory of relativity created a new foundation to support 20th century measurements of matter, space, and time. Conventional inquiry and invention could now proceed with a new seemingly stable foundation. In an irony only the passage of time can produce, a century later, the shortcomings of Einstein’s view are now becoming apparent. Quantum mechanics, the origins of the universe, and gravity do not fit
Einstein’s foundation. String theory is emerging to produce a new foundation.1 Many areas in oral and maxillofacial surgery depend upon foundation concepts on which we may lean too heavily. This month’s Journal of Oral and Maxillofacial Surgery provides good examples of ideas that provide balance to these unidirectional concepts. They should open our minds toward critical examination of the existing foundation ideas that provide the basis for our views on patient care. In 1983, a new understanding of the pathophysiology of osteonecrosis in head and neck cancer patients emerged. At the University of Miami, Marx described a rational foundation idea, namely that radiation, tissue hypoxia, hypocellularity and hypovascularity, tissue breakdown, and chronic nonhealing wounds are the pathogenesis of osteoradionecrosis.2 This concept of radiation-induced necrosis de-emphasized the role of bacteria, host response, other concomitant diseases, and chemotherapy. Kanthak’s theory of radiation, trauma, and infection as the etiology of osteoradionecrosis was relegated to the past. With this new foundation, hyperbaric oxygen (HBO) was developed as a means to prevent and treat osteoradionecrosis. In his 1985 paper, Marx reduced the incidence of persistent exposed bone in the socket (his definition of osteoradionecrosis in this paper) from 29% to 6% with 30 perioperative HBO treatments.3 No prophylactic antibiotics were used in the HBO group. In this and subsequent papers, Marx’s foundation concept on the pathophysiology of bone necrosis in the radiated patient appeared to explain most if not all of the events surrounding bone necrosis and treatment in the radiated head and neck cancer patient. Yet research continues to appear that indicates that this foundation idea may not explain all there is to know about osteonecrosis in radiated head and neck cancer patients. In this issue of JOMS, Oh et al at the M.D. Anderson Cancer Center have inquired into the incidence of osteoradionecrosis after third molar removal in radiated patients.4 This paper was of special interest because, based upon the foundation ideas on the etiology of bone necrosis in radiated patients, these patients would appear to be at particularly high risk. All of their patients received prophylactic antibiotics and none had preoperative HBO. Only 4 patients developed osteoradionecrosis (2 of them in sites not 125
126 related to the extraction and one as an apparent result of a pericoronal infection) for an incidence of 4.9%. Recently, Sulaiman et al at Memorial Sloan Kettering Cancer Center reported on 951 dental extractions in 187 patients that occurred either before or after head and neck radiation.5 Less than a quarter of the patients received prophylactic antibiotics and only 7 patients received HBO therapy as a prophylactic protocol. The incidence of osteoradionecrosis was just 2%. At the time of these investigations, other clinician scientists have observed findings in a similar but not identical osteonecrosis of the jaws. After an alert initial observation by Wang, Goodger, and Pogrel at University of California San Francisco, Rosenberg and Ruggiero at Long Island Jewish Medical Center as well as Marx have reported osteonecrosis of the jaws in a new set of patients.6-8 These patients may provide insight into the foundation ideas that support our clinical experience with osteoradionecrosis. The clinical appearance and behavior of osteonecrosis in these patients bears a striking resemblance to osteoradionecrosis with exposed bone and sequestration nonresponsive to conventional surgical management. These osteonecrosis patients have undergone suppression of osteoclasia with bisphosphonates. Some have simultaneous cytotoxic chemotherapy and some patients have known metastases or severe osteoporosis. How these pieces all fit remains unclear, but it is certain that osteoclasts play a role in osteonecrosis that has heretofore been unexplored. The elements of a new foundation for understanding osteonecrosis in head and neck cancer are in place. The new foundation expands upon the existing one in a way that helps create greater understanding of the clinical picture of osteoradionecrosis. For example, it has always seemed odd that technetium, gallium, and indium scans nearly always showed sharply increased uptake in osteoradionecrosis, indicating increased (not decreased) bone turnover, inflammation, and infection. Another interesting clinical finding in osteoradionecrosis is the increased subperiosteal bone deposition and increased thickness of the jaw in the radiated zone indicating altered remodeling. Sequestrum formation is severely delayed and only occurs when very dense surrounding new bone appears to cut off the central core blood supply. Also, bone grafting of the affected site seems to do well when the soft tissue bed has been restored either
EDITORIAL
through flap or HBO. Hypovascularity, hypocellularity, and hypoxia would not seem to be the only explanations for these findings. Perhaps the selective suppression of osteoclasts in radiated bone is a key element in osteoradionecrosis. Therapy that selectively restores osteoclasia in the affected site might restore a remodeling process essential to healing. The truth is never simple. A universal and simple explanation for a clinical phenomenon is rarely possible. Radiation dose, portals, voltage, host immune response, concomitant therapy, cardiovascular disease, diabetes, atherosclerotic heart disease, cytotoxic drugs, cancer stage, surgical method, bisphosphonates, nutrition, endocrine response, or other yet unknown alterations of bone physiology may all play a part in the development of osteoradionecrosis. Osteonecrosis presents with a similar but not identical set of issues. We will not advance in this endeavor until we develop a new foundation for understanding the pathogenesis of these diseases. New information appearing now in JOMS is generating the elements of a new foundation that will support the effective balanced therapies of the future. LEON A. ASSAEL, DMD
References 1. Schwarz P: The official string theory website. Available at www. superstringtheory.com/index.html. Accessed December 2, 2003 2. Marx RE: Osteoradionecrosis: A new concept of its pathophysiology. J Oral Maxillofac Surg 41:283, 1983 3. Marx RE, Johnson RP, Kline SN: Prevention of osteoradionecrosis: A randomized prospective clinical trial of hyperbaric oxygen versus penicillin. J Am Dent Assoc 111:49, 1985 4. 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 5. Sulaiman F, Huryn J, Zlotolow IM: Dental extractions in the irradiated head and neck patient: A retrospective analysis of Memorial Sloan-Kettering Cancer Center protocols, criteria, and end results. J Oral Maxillofac Surg 61:1123, 2003 6. Wang J, Goodger NM, Pogrel MA: Osteonecrosis of the jaws associated with cancer chemotherapy. J Oral Maxillofac Surg 61:1104, 2003 7. Rosenberg TJ, Ruggiero S: Osteonecrosis of the jaws associated with the use of biphosphonates. J Oral Maxillofac Surg 61:60, 2003 (suppl 1) 8. Marx RE: Pamidronate (Aredia)- and zoledronate (Zometa)-induced avascular necrosis of the jaws: A growing epidemic (letter to the editor). J Oral Maxillofac Surg 61:1115, 2003
© 2004 American Association of Oral and Maxillofacial Surgeons doi:10.1016/j.joms.2003.11.009
New Foundations in Understanding Osteonecrosis of the Jaws Objects and ideas have much in common. An object (or idea) pressed on too heavily will inevitably fall under its own weight. Unidirectional force causes motion, but not always in the best direction. Unidirectional ideas also produce a clear direction for research and practice. However, the result may be uncompromising opinions that carry great weight until their moment of collapse. Additionally, reliance on a single direction of research may suppress important new areas of inquiry. As an idea further progresses in a single direction, the impelling force multiplies. The promoters of the original idea often forcefully disagree with research that does not support their accepted direction. Investigators with original ideas may find it difficult to obtain funding for research endeavors that do not conform to the conventional direction. The more research succeeds in a single-minded direction, the more likely it will eventually need new foundations. The failure to critically evaluate opposing views makes research ever more vulnerable to sudden refutation. Objects and ideas are only stable when they are joined by forces/research that provide balance. They also rely upon their foundations; ideas that may be called into question by new information that does not fit the conventional direction. New foundations are then created as new information gains its proper interpretation in a new universe. The tremendous force and eventual collapse of Newtonian physics early in the 20th century provides the best example of these phenomena in the history of science. As scientific measurement became more precise, at first in seeming celebration of Newtonian order, more errors were found. For centuries, these errors were attributed to the shortcomings of scientists, their methods, or their instruments. When it became clear that the Newtonian foundation could no longer explain the physical universe, the responses of physicists included forceful rebuttal, befuddlement, and even religious attribution. The emergence of Einstein’s theory of relativity created a new foundation to support 20th century measurements of matter, space, and time. Conventional inquiry and invention could now proceed with a new seemingly stable foundation. In an irony only the passage of time can produce, a century later, the shortcomings of Einstein’s view are now becoming apparent. Quantum mechanics, the origins of the universe, and gravity do not fit
Einstein’s foundation. String theory is emerging to produce a new foundation.1 Many areas in oral and maxillofacial surgery depend upon foundation concepts on which we may lean too heavily. This month’s Journal of Oral and Maxillofacial Surgery provides good examples of ideas that provide balance to these unidirectional concepts. They should open our minds toward critical examination of the existing foundation ideas that provide the basis for our views on patient care. In 1983, a new understanding of the pathophysiology of osteonecrosis in head and neck cancer patients emerged. At the University of Miami, Marx described a rational foundation idea, namely that radiation, tissue hypoxia, hypocellularity and hypovascularity, tissue breakdown, and chronic nonhealing wounds are the pathogenesis of osteoradionecrosis.2 This concept of radiation-induced necrosis de-emphasized the role of bacteria, host response, other concomitant diseases, and chemotherapy. Kanthak’s theory of radiation, trauma, and infection as the etiology of osteoradionecrosis was relegated to the past. With this new foundation, hyperbaric oxygen (HBO) was developed as a means to prevent and treat osteoradionecrosis. In his 1985 paper, Marx reduced the incidence of persistent exposed bone in the socket (his definition of osteoradionecrosis in this paper) from 29% to 6% with 30 perioperative HBO treatments.3 No prophylactic antibiotics were used in the HBO group. In this and subsequent papers, Marx’s foundation concept on the pathophysiology of bone necrosis in the radiated patient appeared to explain most if not all of the events surrounding bone necrosis and treatment in the radiated head and neck cancer patient. Yet research continues to appear that indicates that this foundation idea may not explain all there is to know about osteonecrosis in radiated head and neck cancer patients. In this issue of JOMS, Oh et al at the M.D. Anderson Cancer Center have inquired into the incidence of osteoradionecrosis after third molar removal in radiated patients.4 This paper was of special interest because, based upon the foundation ideas on the etiology of bone necrosis in radiated patients, these patients would appear to be at particularly high risk. All of their patients received prophylactic antibiotics and none had preoperative HBO. Only 4 patients developed osteoradionecrosis (2 of them in sites not 125
126 related to the extraction and one as an apparent result of a pericoronal infection) for an incidence of 4.9%. Recently, Sulaiman et al at Memorial Sloan Kettering Cancer Center reported on 951 dental extractions in 187 patients that occurred either before or after head and neck radiation.5 Less than a quarter of the patients received prophylactic antibiotics and only 7 patients received HBO therapy as a prophylactic protocol. The incidence of osteoradionecrosis was just 2%. At the time of these investigations, other clinician scientists have observed findings in a similar but not identical osteonecrosis of the jaws. After an alert initial observation by Wang, Goodger, and Pogrel at University of California San Francisco, Rosenberg and Ruggiero at Long Island Jewish Medical Center as well as Marx have reported osteonecrosis of the jaws in a new set of patients.6-8 These patients may provide insight into the foundation ideas that support our clinical experience with osteoradionecrosis. The clinical appearance and behavior of osteonecrosis in these patients bears a striking resemblance to osteoradionecrosis with exposed bone and sequestration nonresponsive to conventional surgical management. These osteonecrosis patients have undergone suppression of osteoclasia with bisphosphonates. Some have simultaneous cytotoxic chemotherapy and some patients have known metastases or severe osteoporosis. How these pieces all fit remains unclear, but it is certain that osteoclasts play a role in osteonecrosis that has heretofore been unexplored. The elements of a new foundation for understanding osteonecrosis in head and neck cancer are in place. The new foundation expands upon the existing one in a way that helps create greater understanding of the clinical picture of osteoradionecrosis. For example, it has always seemed odd that technetium, gallium, and indium scans nearly always showed sharply increased uptake in osteoradionecrosis, indicating increased (not decreased) bone turnover, inflammation, and infection. Another interesting clinical finding in osteoradionecrosis is the increased subperiosteal bone deposition and increased thickness of the jaw in the radiated zone indicating altered remodeling. Sequestrum formation is severely delayed and only occurs when very dense surrounding new bone appears to cut off the central core blood supply. Also, bone grafting of the affected site seems to do well when the soft tissue bed has been restored either
EDITORIAL
through flap or HBO. Hypovascularity, hypocellularity, and hypoxia would not seem to be the only explanations for these findings. Perhaps the selective suppression of osteoclasts in radiated bone is a key element in osteoradionecrosis. Therapy that selectively restores osteoclasia in the affected site might restore a remodeling process essential to healing. The truth is never simple. A universal and simple explanation for a clinical phenomenon is rarely possible. Radiation dose, portals, voltage, host immune response, concomitant therapy, cardiovascular disease, diabetes, atherosclerotic heart disease, cytotoxic drugs, cancer stage, surgical method, bisphosphonates, nutrition, endocrine response, or other yet unknown alterations of bone physiology may all play a part in the development of osteoradionecrosis. Osteonecrosis presents with a similar but not identical set of issues. We will not advance in this endeavor until we develop a new foundation for understanding the pathogenesis of these diseases. New information appearing now in JOMS is generating the elements of a new foundation that will support the effective balanced therapies of the future. LEON A. ASSAEL, DMD
References 1. Schwarz P: The official string theory website. Available at www. superstringtheory.com/index.html. Accessed December 2, 2003 2. Marx RE: Osteoradionecrosis: A new concept of its pathophysiology. J Oral Maxillofac Surg 41:283, 1983 3. Marx RE, Johnson RP, Kline SN: Prevention of osteoradionecrosis: A randomized prospective clinical trial of hyperbaric oxygen versus penicillin. J Am Dent Assoc 111:49, 1985 4. 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 5. Sulaiman F, Huryn J, Zlotolow IM: Dental extractions in the irradiated head and neck patient: A retrospective analysis of Memorial Sloan-Kettering Cancer Center protocols, criteria, and end results. J Oral Maxillofac Surg 61:1123, 2003 6. Wang J, Goodger NM, Pogrel MA: Osteonecrosis of the jaws associated with cancer chemotherapy. J Oral Maxillofac Surg 61:1104, 2003 7. Rosenberg TJ, Ruggiero S: Osteonecrosis of the jaws associated with the use of biphosphonates. J Oral Maxillofac Surg 61:60, 2003 (suppl 1) 8. Marx RE: Pamidronate (Aredia)- and zoledronate (Zometa)-induced avascular necrosis of the jaws: A growing epidemic (letter to the editor). J Oral Maxillofac Surg 61:1115, 2003
© 2004 American Association of Oral and Maxillofacial Surgeons doi:10.1016/j.joms.2003.11.009