Osteonecrosis: a multifactorial etiology

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LETTERS TO THE EDITOR

medical trends with its dental and oral consequences, thus eliminating some empirical, unnecessary, and outdated clinical practice. IAN ZLOTOLOW, DMD San Francisco, CA

doi:10.1016/j.joms.2004.04.004

OSTEONECROSIS: A MULTIFACTORIAL ETIOLOGY To the Editor:—The recent JOMS editorial “New Foundations in Understanding Osteonecrosis of the Jaws” (J Oral Maxillofac Surg 62:225-226, 2004),1 was a timely reminder that ischemic bone disease has multifactorial etiologies, eg, not all cases are secondary to radiotherapy. Bisphosphonates, used to prevent osteoporosis in patients undergoing cancer chemotherapy, are the latest culprits being blamed for ischemic jawbone disease,2-4 but during the preantibiotic era, osteonecrosis of the jaws (infection-induced) was commonplace and treated by curettage and/or local resection.5 A cursory review of an old but seminal paper on the topic cannot help but impress one with the intertwining roles of infection, inflammation, and thrombosis in establishing this end-stage vascular disease of the jaws.6 The popular theories of the time revolved around “an ascending thrombophlebitis” or thrombosis of the “end-arteries” producing marrow compartment infarction.5,6 With the advent of antibiotic therapy for acute osteomyelitis, massive and necrosing infections ceased to be the norm and much of the marrow vasculature was spared. Now we live in a world of preventive dental and periodontal care, conservation of teeth, hyperbaric oxygen therapy, and zealous use of antibiotics by both physicians and dentists, yet we face an apparent “growing epidemic” of jaw osteonecrosis because of the recent introduction of bisphosphonates.2-4 How can this be? The recent communications warning about this problem do not seem to emphasize enough the “multiple-hit” thrombosis model now accepted for ischemic bone disease.7,8 Since such a small number of patients taking bisphosphonates actually develop osteonecrosis of the jaws, it seems logical to look for additional potentiators or etiologic factors which might, in fact, play an even greater role in producing osteonecrosis, not so much by their effects on osteoblastic and osteoclastic activity, but by impairing marrow blood flow and producing chronic marrow ischemia and infarction. There has been a literal explosion of research and advancement in the orthopedic literature relative to ischemic bone disease.9-11 We think that it is time that the dental profession begins to apply the many lessons learned to the jaws, and not just for the extreme forms of the disease, such as osteoradionecrosis and bisphosphonate-induced osteonecrosis, but to the several less severe forms (bone marrow edema, bone marrow infarction, cavitational osteonecrosis, traumatic bone cyst, and bone scars) which often progress asymptomatically until a threshold stimulus triggers symptoms requiring consultation. Many of these are most likely manifestations of several risk factors (both local and systemic) that imperil the jaw’s marrow circulation and its accompanying nerves. There is so much helpful information in the medical literature that we should no longer presume, as a profession, psychosomatic or psychogenic etiologies for jaw pain, for example, merely because we see no obvious dental cause. At the very least we should be savvy enough about

FIGURE 1. Accumulative burden of bone cell stressors which, when they reach the ischemic threshold for an individual, leads to osteonecrosis.

ischemic disease to weigh the use of local anesthetics with potent vasoconstrictors in routine dentoalveolar surgery and avoid their use, as much as possible, in the diagnostic workup and treatment of patients with idiopathic jaw pain,12 especially with cases where bisphosphonates (along with other risk factors) may already have compromised the marrow vasculature and placed it on the brink of necrosis. We have demonstrated that many patients with neuralgiainducing cavitational osteonecrosis (NICO) have heritable prothrombotic tendencies comparable with those of patients with idiopathic osteonecrosis of the femoral head,13 while measures in both groups differ significantly from healthy controls.14-16 Our published data do not represent epiphenomena and we contend that many of the patients cited in the Journal2,3 and Educational Summaries and Outlines of the AAOMS 85th Annual Meeting4 have acquired and/or heritable thrombophilia prior to embarking on a course of cancer chemotherapy. To us, pamidronate (Aredia; Novartis Pharmaceuticals, East Hanover, NJ) and zoledronate (Zometa; Novartis Pharmaceuticals), like exogenous glucocorticosteroids7,17,18 and estrogen,19,20 represent just other stressors of bone health that can tip the scales towards osteonecrosis (Fig 1). Avascular necrosis (AVN) within the jaws can be difficult to diagnose but can respond to treatment if recognized early and thrombogenic risk factors are identified, reduced, or eliminated, but certainly not compounded.21 Cancer chemotherapy not only places the “heaviest weights” on the scale of bone health but often accelerates pathophysiologic events within the microcirculation of the diverse tissues found within the marrow compartment.22,23 AVN of the jaws often has an insidious beginning, usually starting with infarction of small branches of the nutrient artery within the marrow compartment.5,6 As these end arteries thrombose, myeloid elements (including fatty marrow ) liquefy and cancellous bone trabeculae resorb so that bony spaces coalesce and gradually become larger.24-26 The vascular territories of these same nutrient arteries include circulation to dental pulps and surrounding dentoalveolar nerves, and when they thrombose, multiple toothaches occur along with the painful ischemic neuropathy of the alveolar nerves and medullary bone pain. The cause(s) of the pain can be indistinguishable, or, act in concert, often confusing both patient and clinician. It is during this painful period, when the cortices are still intact, but marrow, teeth, and nerves are ischemic or infarcting, that NICO reaches a

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LETTERS TO THE EDITOR crescendo. Painful teeth often become the scapegoat but when endodontic therapy is attempted to help these unfortunate situations, it soon becomes obvious that more is at risk than the tooth and the patient is sent for an emergency extraction.27-29 The oral surgeon inexperienced with the diagnosis of myelonecrosis, ischemic alveolar neuropathy, and /or ischemic pulpalgia may expect some “poor socket healing” because of the cancer chemotherapy but often is ill prepared to deal with the progression of the necrosis into and then throughout the cortical plates.30 Decortication and curettage of the necrotic elements are the primary goals of surgery. If an extraction becomes necessary, it does in some cases serve to begin the decortication procedure, not only providing some pain relief, but also, a window of opportunity to debride through the lamina dura and gain access to the underlying affected (not necessarily infected) cancellous bone. We believe it is imperative that this tissue be submitted for microscopic evaluation to establish a diagnosis and the socket site packed open (weekly if necessary) with an antibiotic dressing after copious irrigation until healing is complete. Systemic antibiotic therapy has limited access to these avascular areas and the need for additional debridement surgery is not uncommon. Consultation with the oncologist is mandatory and consideration for hyperbaric oxygen therapy should be discussed. Prevention of osteonecrosis in cancer patients should be considered the optimal approach. Chronic dental infections should be eliminated before cancer chemotherapy, much as radiation oncologists insist on prior to head and neck radiotherapy to prevent osteoradionecrosis of the facial bones. ROBERT E. MCMAHON, DDS JERRY E. BOUQUOT, DDS, MS, FICD CHARLES J. GLUECK, MD KENNETH J. SPOLNIK, DDS, MSD WILLIAM R. ADAMS, DDS, MSD Merrillville, IN

References 1. Assael LA: New foundations in understanding osteonecrosis of the jaws. J Oral Maxillofac Surg 62:125, 2004 2. Wang J, Goodger NM, Pogrel MA: Osteonecrosis of the jaws associated with cancer chemotherapy. J Oral Maxillofac Surg 61:1104, 2003 3. Marx RE: Pamidronate (Aredia) and zoledromate (Zometa) induced avascular necrosis of the jaws: A growing epidemic. J Oral Maxilofac Surg 61:1115, 2003 (letter) 4. Rosenberg TJ, Ruggiero S: Osteonecrosis of the jaws associated with the use of bisphosphonates. J Oral Maxillofac Surg 61:60, 2003 (suppl 1) 5. Wilensky AO: Osteomyelitis of the jaw. Arch Surg 25:215, 1932 6. Hankey GT: Osteomyelitis (necrosis) of the jaws: Its pathology and treatment. Br Dent J 65:549, 1938 7. Kenzora JE, Glimcher MJ: Accumulative cell stress: The multifactorial etiology of idiopathic osteonecrosis. Orthod Clin North Am 16:669, 1985 8. Jones JP Jr: Risk factors potentially activating intravascular coagulation and causing nontraumatic osteonecrosis, in Jones JP Jr, Urbaniak JR (eds): Osteonecrosis: Etiology, Diagnosis, and Treatment. Rosemont, IL, American Academy of Orthopedic Surgeons, 1997, pp 89-96 9. Arlet J, Mazieres B: Bone Circulation and Bone Necrosis. Heidelberg, Germany, Springer-Verlag, 1990 10. Arnoldi CC: Intraosseous engorgement-pain syndromes: The pathomechanism of pain, in Arlet J, Mazieres B (eds): Bone Circulation and Bone Necrosis. Heidelberg, Germany, SpringerVerlag, 1990

11. Urbaniak JR, Jones JP Jr (eds): Osteonecrosis: Etiology, Diagnosis and Treatment. Rosemont, IL, American Academy of Orthopedic Surgeons, 1997 12. McMahon RE, Griep J, Marfurt CP, et al: Local anesthetic effects in the presence of chronic osteomyelitis/necrosis of the mandible: Implications for localizing the etiologic sites of referred trigeminal pain. J Craniomand Prac 13:212, 1995 13. Glueck CJ, McMahon RE, Bouquot JE, et al: Heterozygosity for the Leiden mutation V gene, a common pathoetiology for osteonecrosis of the jaw with thrombophilia augmented by exogenous estrogens. J Lab Clin Med 130:540, 1997 14. Glueck CJ, Freiberg R, Gruppo R, et al: Thrombophilia and hypofibrinolysis: Reversible pathogenetic etiologies of osteonecrosis in adults and children (Legg-Perthes Disease), in Urbaniak JR, Jones JP Jr (eds): Osteonecrosis: Etiology, Diagnosis, and Treatment. Rosemont, IL, American Academy Orthopaedic Surgeons, 1997, pp 105-110 15. Gruppo R, Glueck CJ, McMahon RE, et al: The pathophysiology of osteonecrosis of the jaw: Anticardiolipin antibodies, thrombophilia, and hypofibrinolysis. J Lab Clin Med 127:481, 1996 16. Glueck CJ, McMahon RE, Bouquot JE, et al: Thrombophilia, hypofibrinolysis and osteonecrosis of the jaws. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 81:557, 1996 17. Taylor LJ: Multifocal avascular necrosis after short-term highdose steroid therapy. J Bone Joint Surg 66:431, 1984 18. McCluskey J, Gutteridge DH: Avascular necrosis of bone after high doses of dexamethasone during neurosurgery. Br Med J 284:333, 1982 19. Glueck CJ, McMahon RE, Bouquot JE, et al: Preliminary pilot study of the treatment of thrombophilia and hypofibrinolysis and the amelioration of the pain of osteonecrosis of the jaws. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 85:64, 1998 20. Glueck CJ, McMahon RE, Bouquot JE, et al: Exogenous estrogen may exacerbate thrombophilia, impair bone healing and contribute to development of chronic facial pain. J Craniomand Prac 16:143, 1998 21. Bouquot JE, McMahon RE: Neuropathic pain in maxillofacial osteonecrosis. J Oral Maxillofac Surg 58:1003, 2000 22. Heit JA: Hereditary thrombotic diseases: Testing and management. Presented at the Conference on Bleeding and Thrombosing Diseases: The Basics and Beyond. Mayo Medical Laboratories, Rochester, MN, August 1-2, 1997 23. Hook CC: Acquired thrombotic diseases. Presented at the Conference on Bleeding and Thrombosing Diseases: The Basics and Beyond. Mayo Medical Laboratories, Rochester, MN, August 1-2, 1997 24. Phemister DB: Repair of bone in the presence of aseptic necrosis resulting from fractures, transplantations, and vascular obstruction. J Bone Joint Surg 12:769, 1930 25. Brosch F: Die histopathologische Grundlage der Symptome bei Keifer- osteomyelitis. Deutsch Zahnartz Zeit 13:426, 1958 26. Hjorting-Hansen E: Decortication in treatment of osteomyelitis of the mandible. J Oral Surg 29:652, 1970 27. Ratner EJ, Person P, Kleinman DJ: Jawbone cavities and trigeminal and atypical facial neuralgias. Oral Surg Oral Med Oral Pathol 48:3, 1979 28. Roberts AM, Person P: Etiology and treatment of idiopathic trigeminal and atypical facial neuralgia. Oral Surg Oral Med Oral Pathol 48:298, 1979 29. Bouquot AM, Roberts AM, Person P, et al: NICO (neuralgiainducing cavitational osteonecrosis): Osteomyelitis in 224 jawbone samples from patients with facial neuralgias. Oral Surg Oral Med Oral Pathol 73:307, 1992 30. Winer HJ, McMahon RE, Olson RE: Palatal necrosis secondary to Cytoxan therapy: Report of a case. J Am Dent Assoc 84:862, 1972

doi:10.1016/j.joms.2004.04.007

TOOTH IN THE LINE OF FRACTURE To the Editor:—I would like to comment on Dr Baykul’s article in the March 2004 Journal of Oral and Maxillofa-