What is Your Diagnosis?

What is Your Diagnosis?

Nelson L. Rhodus, D.M.D., M.P.H., F.I.C.D.:


Case History
The subject is a 57-year-old African American female who has been a smoker for 40 pack-years. She presented with painful, non-healing exposed bone in the mandible following dental extraction of teeth #19 and 20 one year after the dental treatment, as well as a skin lesion extraorally under the left mandible. Her medical history is significant for breast cancer with bone metastases (clavicle) which had been treated two years previously.
Co-Morbid Conditions

Diabetes mellitus
(Type II, 15-year history)
• Hyperlipidemia (10-year history)
• Hypertension (10-year history)
Medications
• Lispro
• Glyburide
• Lisinopril
• Hydrochlorothiazide
• Lipitor
• Dexamethasone

Chemotherapy with Cisplatin/Taxol (2 years ago); Zometa
Differential diagnosis
1. Idiopathic avascular necrosis of bone
2. Osteoradionecrosis
3. Bisphosphonate-related osteonecrosis of the jaw
4. Osteonecrosis of the jaw
5. Osteomyelitis of the jaw

What is your diagnosis?

Diagnosis: Osteonecrosis of the Jaw; Unknown Cause(s)
While this case might seem an apparent case of bisphosphonate-related osteonecrosis of the jaw (BRONJ), from the Zometa therapy, there are several considerations to take into account.
1. There is no universally established definition or medical diagnosis for osteonecrosis of the jaw (ONJ).
2. There is a lack of controlled data from scientifically reliable studies as evidence that bisphosphonate drugs cause ONJ.
3. There are a number of possible risk factors that may lead to ONJ even in the absence of bisphosphonate drugs therapy, including: cancer metastatic to bone, periodontal disease, chemotherapeutic agents, diabetes mellitus, corticosteroid use, smoking tobacco, alcohol abuse, anemia, osteomyelitis, vitamin D or calcium deficiency, genetic factors, dental extractions, dento-alveolar surgery, and trauma.
4. There is no established biological mechanism for ONJ arising in patients exposed to bisphosphonate
drugs therapy.
5. Many people have used bisphos-phonate drugs without ever developing ONJ, while others have developed ONJ without having used bisphosphonate drugs. Therefore, one needs controlled data from scientifically reliable studies to determine whether those drugs cause ONJ.
Many of the publications con-
cerning ONJ in persons exposed to bisphosphonate drugs are case reports or case series. Many have no actual data, epidemiology, or biostatistics. In an evidence-based critical evaluation, this type of anecdotal information is not reliable to establish direct causation because these reports are not based on a uniform definition for osteonecrosis of the jaw and they do not allow any comparison between patients who were treated with bisphosphonate drugs and patients not exposed to those drugs. Case reports or case series also do not provide reliable evidence of any biological mechanism regarding how ONJ arises. Regardless of the number of case reports or case series, their inherent limitations are the reason science demands higher-quality evidence before causal conclusions can be drawn.1-11
It seems likely that ONJ occurs in some patients who have a primary disease which causes altered bone structure and metabolism, such as Paget’s disease, multiple myeloma, or metastatic breast or prostate cancer, and who may have an inherited genetic predisposition (SNPs) in the presence of several other possible risk factors, including periodontal disease, chemotherapeutic agents, diabetes mellitus, bisphosphonate drug therapy (primarily intravenous), corticosteroid use, smoking tobacco, alcohol abuse, anemia, osteomyelitis, vitamin D or calcium deficiency, genetic factors, dental extractions, dento-alveolar surgery, and trauma.
Osteonecrosis of the jaw has occurred in patients not treated with bisphosphonate drugs. For example, in a very large study of 7,714 patients, the authors found that one patient, who also had diabetes mellitus, acquired ONJ after taking intravenous zoledronic acid, whereas another person developed ONJ without ever having taken the drug. As was stated in that paper, “some cases of osteonecrosis of the jaw occur spontaneously in patients who have never taken bisphosphonates.”12
Other publications have also shown that ONJ occurs in patients who have not been exposed to bisphosphonates.7-11,13-18
In addition to some of the papers cited above, for decades there have been many reports in the scientific literature of osteomyelitis, osteonecrosis (avascular), and idiopathic osteonecrosis, all of which are clinically indistinguishable from ONJ.
Further, the medical literature has identified a number of possible risk factors for ONJ in addition to bisphosphonate therapy14-31, including:

Cancer (renal, breast, lung,
prostate, etc.)
• Diabetes mellitus
• Corticosteriod use
• Chemotherapy
• Smoking tobacco and alcohol abuse
• Periodontal disease
• Poor oral hygiene (bacteria)
• Dento-alveolar surgical treatment
• Osteomyelitis
• Genetic susceptibility = Single Nucleotide Polymorphisms (SNPs)

Diabetes mellitus and ONJ
Diabetes mellitus has been reported in association with ONJ even in the absence of bisphosphonate drugs.41 In the article referenced, the author noted that “debilitating systemic diseases such as diabetes mellitus, predispose an individual to bone infections ...” and postulated that diabetes mellitus may have played an important role in the etiology of the massive necrosis and sequestration of the maxilla in the patient upon whom he reported.
In a different published article, another author noted that, “Micro-vascular disease is a common complication of diabetes and may have impaired bone nutrition through loss of full function of the nutrient vessels in bone ... ” This author went on to further state that “ ... infections of the gingivae and mandibular bone are more common in diabetes ... ” and that “Diabetes may have increased the risk of ONJ through other mechanisms, such as sensitizing or predisposing alveolar bone to necrosis ... by altering the microcirculation.”32
In a recent publication by Khamaisi and Elad titled “Intravenous Bisphosphonate Therapy and Inflammatory Conditions or Surgery of the Jaw: A Population-Based Analysis”, the authors stated, “ ... we found a clear association between diabetes and bisphosphonate-related ONJ. In our study 18 (58%) of the 31 patients with bisphosphonate-related ONJ had diabetes ... a much higher rate than the 14% in the general population. Furthermore, the proportion of diabetes mellitus in a control group of oncologic patients without ONJ was only 12%.”9
An additional recent article noted diabetes as a potential risk factor for ONJ.3

Corticosteroids and ONJ
Corticosteroid therapy is a known possible risk factor for ONJ. The vast majority of patients treated with intravenous bisphosphonates for metastatic cancer also receive corticosteroids.25

Chemotherapy and ONJ
Chemotherapy with several agents has been reported in association with ONJ even in the absence of bisphosphonate drugs.33-40 The vast majority of patients treated with Aredia or Zometa for metastatic cancer also receive various toxic chemotherapeutic regimens.

Smoking and Alcohol Abuse and ONJ
Smoking and alcohol abuse are also possible risk factors for ONJ.10,42

Periodontal Disease and ONJ
Periodontal disease is by definition a bacteria-induced condition of chronically diseased bone. It is plausible that, under certain conditions, periodontal disease alone, but more particularly following oral surgery, may result in osteomyelitis or osteonecrosis.
The effects of tobacco include damage to the microvasculature in bone. Bone remodeling may be impaired due to this process. Additionally, many studies relate tobacco use to periodontal disease in terms of incidence, severity, progression, and poor response to therapy. Further, as noted above, many publications also relate diabetes and periodontal disease. Both may make the patient susceptible to ONJ even in the absence of bisphosphonate drugs.

Osteomyelitis and ONJ
Bacteria and poor oral hygiene can contribute to bone infections (osteomyelitis), particularly following dento-alveolar surgery in immunocompromised patients. Osteomyelitis can lead to osteonecrosis. When a patient presents with both osteonecrosis of the jaw and osteomyelitis of the jaw, it is often impossible to determine which came first.

Tooth Extractions and Other Invasive Dental Procedures and ONJ
Osteonecrosis of the jaw is commonly associated with invasive bone procedures such as dental extractions.3,5,8

Genetics and ONJ
Recent medical science has elucidated certain gene polymorphisms which genetically predispose patients to many diseases. Among these recent discoveries is a gene polymorphism (SNP) which may be associated with ONJ.33 Of potential relevance is data suggesting that “ ... gene polymorphisms MDR1(ABCB1) can be used for predicting the development of steroid-induced osteonecrosis ... ”31 Similarly, data has suggested a role for genetic polymorphisms in osteonecrosis related to thrombophilia and hypofibrinolysis. Glueck reported a “risk ratio x 2.5 (95 % CI) ... the e-NOS T-786C mutant allele present in patients with idiopathic multifocal osteonecrosis and thrombophilia ... multifocal osteonecrosis is similarly associated with hypofibrinolysis and the e-NOS T-786C polymorphism.”34
The science of the role of genetics in ONJ is in its infancy. However, one cannot rule out the possibility that genetic predisposition leads to ONJ even without any exposure to bisphosphonate drugs.

Conclusion
While there is certainly a strong argument for concern and due diligence in recognizing potential medical risk factors which may contribute to a dental patient’s susceptibility to complications from dental therapy, and of course taking every possible precaution to prevent these complications, it is necessary to take into account every possible contributing factor to a particular condition as opposed to simply trying to establish a single cause. Obviously, this is not always possible. Certainly patients who have been treated with intravenous bisphosphonate drugs should be recognized and approached with caution prior to dental treatment (especially oral surgery), and every precaution should be taken to ensure the best outcome in order to avert osteonecrosis of the jaw whenever possible. But equal attention and diligence should be taken in patients with other medical conditions
which might render them just as susceptible. N

References
1. Hay KD, Bishop PA. Association of osteonecrosis of the jaws and bisphosphonate pharmacotherapy: dental implications. NZ Dent J 2006;102(1):4-9.
2. Heras Rincon I et al. Osteonecrosis of the jaws and bisphosphonates. Report of fifteen cases. Therapeutic recommendations. Med Oral Pathol Oral Cir Bucal 2007;12(4):E267-71.
3. Hess LM et al. Factors associated with osteonecrosis of the jaw among bisphosphonate users. Am J Med 2008;121(6):475-483 e3.
4. Hirata, T et al. Low molecular weight phenotype of Apo(a) is a risk factor of corticosteroid-induced osteonecrosis of the femoral head after renal transplant. J Rheumatol 2007;34(3):516-22.
5. Hoff, AO et al. The frequency and risk factors associated with osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonates. J Bone Miner Res 2008.
6. Hong, JM et al. Association study of hypoxia inducible factor 1alpha (HIF1alpha) with osteonecrosis of femoral head in a Korean population. Osteoarthritis Cartilage 2007;15(6):688-94.
7. Hurel, S.J. and P. Kendall-Taylor, Avascular necrosis secondary to postoperative steroid therapy. Br J Neurosurg, 1997,11(4):356-80.
8. Jones, LC, Hungerford DS. The pathogenesis of osteonecrosis. Instr Course Lect 2007;56:179-96.
9. Khamaisi M, Elad S. Re: Intravenous bisphosphonate therapy and inflammatory conditions or surgery of the jaw: a population-based analysis. J Natl Cancer Inst 2008;100(2):155; author reply 155-6.
10. Khosla S et al. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2007;22(10):
1,479-91.
11. Khosla S et al. Oral bisphosphonate-induced osteonecrosis: risk factors, prediction of risk using serum CTX testing, prevention, and treatment. J Oral Maxillofac Surg 2008;66(6):1,320-1; author reply 1,321-2.
12. Grbic JT et al. Incidence of osteonecrosis of the jaw in women with postmenopausal osteoporosis in the health outcomes and reduced incidence with zoledronic acid once yearly pivotal fracture trial. JADA 2008;139(1):32-40.
13. Kim TH et al. Promoter polymorphisms of the vascular endothelial growth factor gene is associated with an osteonecrosis of the femoral head in the Korean population. Osteoarthritis Cartilage 2008;16(3):287-91.
14. Kjaergaard GH, Laursen JO. [Osteonecrosis of a knee joint in a young man with IDDM]. Ugeskr Laeger, 2000;162(35):4,663-4.
15. Koo KH et al. Endothelial nitric oxide synthase gene polymorphisms in patients with nontraumatic femoral head osteonecrosis. J Orthop Res 2006;24(8):1,722-8.
16. Landesberg R, Wilson T, Grbic JT. Bisphosphonate-associated osteonecrosis of the jaw: conclusions based on an analysis of case series. Dent Today 2006;25(8):52, 54-7.
17. Marston SB et al. Osteonecrosis of the femoral head after solid organ transplantation: a prospective study. J Bone Joint Surg Am 2002;84-A(12):2,145-51.
18. Meer S et al. Mandibular osteomyelitis and tooth exfoliation following zoster-CMV co-infection. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006;101(1):70-5.
19. Morse CG, Kovacs JA. Metabolic and skeletal complications of HIV infection: the price of success. JAMA 2006;296(7):844-54.
20. Prenzel KL et al. [Candida infection in hip alloarthroplasty]. Unfallchirurg 2003;106(1):70-2.
21. Price N et al. Prevention and management of osteonecrosis of the jaw associated with bisphosphonate therapy. Support Cancer Ther 2004;2(1):14-7.
22. Rizzoli R et al. Osteonecrosis of the jaw and bisphosphonate treatment for osteoporosis. Bone 2008;42(5):841-7.
23. Ruggiero SL. Bisphosphonate-related osteonecrosis of the jaws. Compend Contin Educ Dent 2008;29(2):96-8, 100-2, 104-5.
24. Ruggiero SL, Drew SJ. Osteonecrosis of the jaws and bisphosphonate therapy. J Dent Res 2007;86(11):1,013-21.
25. Ruggiero SL, Fantasia J, Carlson E. Bisphosphonate-related osteonecrosis of the jaw: background and guidelines for diagnosis, staging and management. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006;102(4):433-41.
26. Ruggiero SL, Mehrotra B. Bisphosphonate-related osteonecrosis of the jaw: diagnosis, prevention, and treatment. Annu Rev Med, 2008.
27. Sarasquete ME et al. Bisphosphonate-related osteonecrosis of the jaw is associated with polymorphisms of the cytochrome P450 CYP2C8 in multiple myeloma: a genome-wide single nucleotide polymorphism analysis. Blood 2008;112(7):2,709-12.
28. Su P et al. Age at onset-dependent presentations of premature hip osteoarthritis, avascular necrosis of the femoral head, or Legg-Calve-Perthes disease in a single family, consequent upon a p.Gly1170Ser mutation of COL2A1. Arthritis Rheum 2008;58(6):1,701-6.
29. Watts NB, Marciani RD. Osteonecrosis of the jaw. South Med J 2008;101(2):160-5.
30. Wilkinson GS et al. Intravenous bisphosphonate therapy and inflammatory conditions or surgery of the jaw: a population-based analysis. J Natl Cancer Inst 2007;99(13):1,016-24.
31. Yang XY, Xu DH. MDR1(ABCB1) gene polymorphisms associated with steroid-induced osteonecrosis of femoral head in systemic lupus erythematosus. Pharmazie 2007;62(12):930-2.
32. Favus MJ. Diabetes and the risk of osteonecrosis of the jaw. J Clin Endocrinol Metab 2007;92(3): p.817-8.
33. French D et al. A PAI-1 (SERPINE1) polymorphism predicts osteonecrosis in children with acute lymphoblastic leukemia: a report from the Children’s Oncology Group. Blood 2008;111(9):4,496-9.
34. Glueck CJ et al. Thrombophilia, hypofibrinolysis, the eNOS T-786C polymorphism, and multifocal osteonecrosis. J Bone Joint Surg Am 2008;90(10):2,220-9.
35. Estilo C et al. Osteonecrosis of the jaw related to Bevacizumab. J Clin Oncol 2008;26:4,037-38.
36. Greuter S et al. Bevacizumab-associated osteonecrosis of the jaw. Annals of Oncolog Advance access; e-published October 31, 2008.
37. Lenz J et al. Does avascular necrosis of the jaws in cancer patients only occur following treatment with bisphosphonates? J Craniomaxillofac Surg 2003;33:395-403.
38. Pires FR et al. Oral avascular bone necrosis associated with chemotherapy and bisphosphonate therapy. Oral Dis 2005;11:365-369.
39. Schwartz HC. Osteonecrosis of the jaws: a complication of cancer chemotherapy. Head Neck Surg 1982;4:251-253.
40. Winer HJ et al. Palatal necrosis secondary to cytotoxin therapy: report of a case. JADA 1972;84:862-866.
41. Nandakumar H. Massive sequestration of the upper jaw: a case report. Br J Oral & Max Surg 28;1990:55-56.
42. American Association of Oral and Maxillofacial Surgeons: American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 2007;65(3):369-376.

*Dr. Rhodus is Professor and Director, Division of Oral Medicine, University of Minnesota School of Dentistry, and Adjunct Professor, Department of Otolaryngology, University of Minnesota School of Medicine, University of Minnesota, 55455. E-mail is rhodu001@umn.edu.