Clinical study of diagnosis and treatment of bisphosphonate-related osteonecrosis of the jaws

Kyung-Wook Kim; Beom-Jin Kim; Chung-Hyun Lee

doi:10.5125/jkaoms.2011.37.1.54

Journal List > J Korean Assoc Oral Maxillofac Surg > v.37(1) > 1032518

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Kim, Kim, and Lee: Clinical study of diagnosis and treatment of bisphosphonate-related osteonecrosis of the jaws

Original Article

J Korean Assoc Oral Maxillofac Surg 2011;37(1):54-61.

Published online: 10 January 2011

DOI: https://doi.org/10.5125/jkaoms.2011.37.1.54

Clinical study of diagnosis and treatment of bisphosphonate-related osteonecrosis of the jaws

Kyung-Wook Kim, Beom-Jin Kim, Chung-Hyun Lee

Department of Oral and Maxillofacial Surgery, College of Dentistry, Dankook University, Choenan, Korea

Kyung-Wook Kim Department of Oral and Maxillofacial Surgery, Dental Hospital, Dankook University San 7-1 Sinbu-dong, Choenan, 330-716, Korea TEL: +82-41-550-1994 FAX: +82-41-551-8988 E-mail: kkwoms@dankook.ac.kr

Received 3 August 2010 Revised 20 December 2010 Accepted 7 February 2011

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Introduction

Bisphosphonates is used widely for the treatment of the Paget's disease, multiple myeloma, bone metastases of malignant tumors with the prevention of pain and their pathological fracture. However, it was recently suggested that bisphosphonates related osteonecrosis of the jaw (BRONJ) is a side effect of bisphosphonate use.

Materials and Methods

Twenty-four individuals, who were referred to the Department of Oral and Maxillofacial surgery, Dankook University Dental Hospital, were selected from those who had exposed bone associated with bisphosphonates from January, 2005 to December, 2009 according to the criteria of American Association of Oral and Maxillofacial Surgeons (AAOMS) for BRONJ. The patients group consisted of 7 males and 17 females between the age of 46 to 78 years (average 61.8 years). Each patient had panoramic imaging, computed tomography (CT), whole body bone scanning performed for a diagnosis and biopsy sampling from the necrotizing tissue. C-terminal cross-linking telopeptide of type I collagen (CTX) level of patients who had undergone surgical intervention was measured 7 days before surgery.

Results

The main cause of bone exposure was post-extraction (15), chronic periodontitis (4), persistent irritation of the denture (3). Twenty people had undergone BRONJ treatment for two to eight months except for 4 people who had to maintain the bisphosphonates treatment to prevent a metastasis and bone trabecular pain with medical treatment. When the bisphosphonate treatment was suspended at least for 3 months and followed up according to the AAOMS protocols, the exposed necrotizing bones were found to be covered by soft tissue.

Conclusion

Prevention therapy, interruption of bisphophonates for at least 3 months and cooperation with the physician for conservative treatment are the essential for treating BRONJ patient with high risk factors. The CTX level of BRONJ patients should be checked before undergoing surgical intervention. Surgical treatments should be delayed in the case of a CTX level <150 pg/mL.

Keywords: Bisphosphonates, Osteonecrosis, Jaw Diseases, Therapeutics

References

1. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg. 2004; 62:527–34.

2. Badros A, Weikel D, Salama A, Goloubeva O, Schneider A, Rapoport A, et al. Osteonecrosis of the jaw in multiple myeloma patients: clinical features and risk factors. J Clin Oncol. 2006; 24:945–52.

3. Epstein S. Update of current therapeutic options for the treatment of postmenopausal osteoporosis. Clin Ther. 2006; 28:151–73.

4. Saad F, Lipton A. Clinical benefits and considerations of bisphosphonate treatment in metastatic bone disease. Semin Oncol. 2007; 34(6 Suppl 4):S17–23.

5. Owens G, Jackson R, Lewiecki EM. An integrated approach: bisphosphonate management for the treatment of osteoporosis. Am J Manag Care. 2007; 13(Suppl 11):S290–308. quiz S309–12.

6. Migliorati CA, Casiglia J, Epstein J, Jacobsen PL, Siegel MA, Woo SB. Managing the care of patients with bisphosphonateassociated osteonecrosis: an American Academy of Oral Medicine position paper. J Am Dent Assoc. 2005; 136:1658–68.

7. Woo SB, Hellstein JW, Kalmar JR. Narrative [corrected] review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med. 2006; 144:753–61.

8. Brooks JK, Gilson AJ, Sindler AJ, Ashman SG, Schwartz KG, Nikitakis NG. Osteonecrosis of the jaws associated with use of risedronate: report of 2 new cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007; 103:780–6.

9. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg. 2003; 61:1115–7.

10. Migliorati CA. Bisphosphanates and oral cavity avascular bone necrosis. J Clin Oncol. 2003; 21:4253–4.

11. Diel IJ, Bergner R, Gro¨tz KA. Adverse effects of bisphosphonates: current issues. J Support Oncol. 2007; 5:475–82.

12. Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR, Felsenberg D, et al. American Society for Bone and Mineral Research. 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; 22:1479–91.

13. Advisory Task Force on Bisphosphonate-Related Ostenonecrosis of the Jaws, 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; 65:369–76.

14. Bedogni A, Blandamura S, Lokmic Z, Palumbo C, Ragazzo M, Ferrari F, et al. Bisphosphonate-associated jawbone osteonecrosis: a correlation between imaging techniques and histopathology. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2008; 105:358–64.

15. Green JR. Bisphosphonates: preclinical review. Oncologist. 2004; 9(Suppl 4):3–13.

16. Mavrokokki T, Cheng A, Stein B, Goss A. Nature and frequency of bisphosphonateassociated osteonecrosis of the jaws in Australia. J Oral Maxillofac Surg. 2007; 65:415–23.

17. McClung MR. Bisphosphonates. Endocrinol Metab Clin North Am. 2003; 32:253–71.

18. Lehenkari PP, Kellinsalmi M, Na¨pa¨nkangas JP, Ylitalo KV, Mo¨nkko¨nen J, Rogers MJ, et al. Further insight into mechanism of action of clodronate: inhibition of mitochondrial ADP/ATP translocase by a nonhydrolyzable, adenine-containing metabolite. Mol Pharmacol. 2002; 61:1255–62.

19. Alakangas A, Selander K, Mulari M, Halleen J, Lehenkari P, Mo¨nkko¨nen J, et al. Alendronate disturbs vesicular trafficking in osteoclasts. Calcif Tissue Int. 2002; 70:40–7.

20. Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, et al. .;. HORIZON Pivotal Fracture Trial. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007; 356:1809–22.

21. Marx RE, Sawatari Y, Fortin M, Broumand V. Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment. J Oral Maxillofac Surg. 2005; 63:1567–75.

22. Reid IR, Bolland MJ, Grey AB. Is bisphosphonateassociated osteonecrosis of the jaw caused by soft tissue toxicity? Bone. 2007; 41:318–20.

23. Sawatari Y, Marx RE. Bisphosphonates and bisphosphonate induced osteonecrosis. Oral Maxillofac Surg Clin North Am. 2007; 19:487–98. v-vi.

24. Lam DK, Sa ′ ndor GK, Holmes HI, Evans AW, Clokie CM. A review of bisphosphonateassociated osteonecrosis of the jaws and its management. J Can Dent Assoc. 2007; 73:417–22.

25. Yarom N, Yahalom R, Shoshani Y, Hamed W, Regev E, Elad S. Osteonecrosis of the jaw induced by orally administered bisphosphonates: incidence, clinical features, predisposing factors and treatment outcome. Osteoporos Int. 2007; 18:1363–70.

26. Phal PM, Myall RW, Assael LA, Weissman JL. Imaging findings of bisphosphonateassociated osteonecrosis of the jaws. AJNR Am J Neuroradiol. 2007; 28:1139–45.

27. Bisdas S, Chambron Pinho N, Smolarz A, Sader R, Vogl TJ, Mack MG. Biphosphonate-induced osteonecrosis of the jaws: CT and MRI spectrum of findings in 32 patients. Clin Radiol. 2008; 63:71–7.

28. Hansen T, Kunkel M, Springer E, Walter C, Weber A, Siegel E, et al. Actinomycosis of the jaws-histopathological study of 45 patients shows significant involvement in bisphosphonateassociated osteonecrosis and infected osteoradionecrosis. Virchows Arch. 2007; 451:1009–17.

29. Marx RE, Cillo JE Jr, Ulloa JJ. Oral bisphosphonate-induced osteonecrosis: risk factors, prediction of risk using serum CTX testing, prevention, and treatment. J Oral Maxillofac Surg. 2007; 65:2397–410.

30. Rosen HN, Moses AC, Garber J, Iloputaife ID, Ross DS, Lee SL, et al. Serum CTX: a new marker of bone resorption that shows treatment effect more often than other markers because of low coefficient of variability and large changes with bisphosphonate therapy. Calcif Tissue Int. 2000; 66:100–3.

31. Bize R, Lamy O, Peytremann-Bridevaux I. Osteoporotic fracture in menopausal women: alendronate reduces the risk. Rev Med Suisse. 2008; 4:2703.

Fig. 1.

Necrotic bone.

Fig. 2.

Purulent exudate and necrotic bone.

Fig. 3.

After extraction, the extraction socket remains.

Fig. 4.

With disappearing of lamina dura and widening of periodontal space, signs of osteolysis are shown on a panoramic view.

Fig. 5.

The bony trabecula deformation of the alveolar bone in the left anterior maxilla and the large sequestrum with poor cor-ticomedullary differntiation are shown on CT scan image.(CT: computed tomography)

Fig. 6.

Periosteal reaction is shown with bone sequestration.

Fig. 7.

Many plasma cells, neutrophils and capillaries in granulation tissue are seen.(H&E staining, original magnification×200).

Fig. 8.

Empty osteocytic lacuna.(H&E staining, original magnification ×100)

Fig. 9.

The temporal muscle flap reconstruction was performed after segmental resection of the right posterior maxilla. A complete wound healing was achieved.

Fig. 10.

The R-plate reconstruction was performed after segmental resection of the right posterior mandible. A complete wound healing was achieved.

Fig. 11.

Chemical fomula of basic bisphosphonates structure.

Table 1.

Patients and clinical information

Patient	Sex	Age	Reason for bisphosphonate use	Bisphosphonate	(months) Duration	Site	Etiologic factor
1	F	63	Osteoporosis	Alendronate (PO)	38	Lt. Mn. Molar	Teeth extraction
2	M	71	Prostate cancer	Zoledronate (IV)	11	Rt. Mn. Premolar	Chronic periodontitis
3	F	68	Osteoporosis	Alendronate (PO)	47	Rt. Mx. Incisor	Teeth extraction
4	F	46	Breast cancer	Zoledronate (IV)	23	Rt. Mn. Molar	Teeth extraction
5	F	67	Osteoporosis	Alendronate (PO)	51	Rt. Mn. Molar	Curettage
6	M	54	Multiple myeloma	Zoledronate (IV)	17	Lt. Mx. Molar	Teeth extraction
7	F	67	Osteoporosis	Residronate (PO)	38	Rt. Mn. Molar	Teeth extraction
8	F	62	Breast cancer	Zoledronate (IV)	29	Lt. Mn. Premolar	Chronic periodontitis
9	M	59	Prostate cancer	Zoledronate (IV)	23	Rt. Mn. Molar	Teeth extraction
10	F	78	Osteoporosis	Alendronate (PO)	41	Rt. Mx. buccal eminence	Denture trauma
11	F	56	Breast cancer	Pamidronate (IV) Zoledronate (IV)	34	Lt. Mx. Premolar	Teeth extraction
			Breast cancer	Pamidronate (IV) Zoledronate (IV)	34	Lt. Mn. Molar	Teeth extraction
12	F	64	Osteoporosis	Alendronate (PO)	35	Rt. Mn. Molar	Curettage
13	F	48	Multiple myeloma	Zoledronate (IV)	16	Lt. Mx. Incisor	Teeth extraction
14	M	68	Osteoporosis	Alendronate (PO)	43	Lt. Mn. lingual eminence	Denture trauma
15	F	75	Osteoporosis	Ibadronate (PO)	51	Lt. Mn. Premolar	Teeth extraction
16	F	65	Breast cancer	Pamidronate (IV) Zoledronate (IV)	27	Rt. Mx. Molar	Teeth extraction
				Pamidronate (IV) Zoledronate (IV)		Rt. Mn. Molar
17	F	62	Multiple myeloma	Pamidronate (IV)	23	Lt. Mn. Molar	Teeth extraction
18	F	58	Osteoporosis	Alendronate (PO)	31	Lt. Mx. buccal eminence	Denture trauma
19	M	51	Multiple myeloma	Pamidronate (IV)	17	Rt. Mn. Premolar	Teeth extraction
20	F	67	Osteoporosis	Alendronate (PO)	63	Lt. Mn. Molar	Chronic periodontitis
21	M	61	Lung cancer	Zoledronate (IV)	26	Rt. Mx. Molar	Teeth extraction
22	F	53	Breast cancer	Zoledronate (IV)	14	Lt. Mn. Premolar	Teeth extraction
23	F	63	Osteoporosis	Alendronate (PO)	37	Lt. Mx. Incisor	Teeth extraction
24	M	58	Prostate cancer	Zoledronate (IV)	21	Rt. Mn. Molar	Chronic periodontitis

(PO: per oral, IV: intravenous, Mn: mandible, Mx: maxilla)

Table 2.

Results of the proposed therapeutic protocol

Patient	Stage	Cessation of BP (months)	CTX (pg/mL)	Treatment	Results
1	3	6	178	Sequestrectomy	Complete wound healing
2	1	4	317	No	Complete wound healing
3	3	3	215	Segmental resection	Complete wound healing
4	3	No	168	Sequestrectomy	Recurrence¹
5	3	3	142	Sequestrectomy	Progressive necrosis²
6	1	4	351	No	Complete wound healing
7	3	3	135	Sequestrectomy	Complete wound healing
8	3	3	113	Sequestrectomy	Recurrence
9	2	8	215	Debridement	Complete wound healing
10	1	3	273	No	Complete wound healing
11	3	No	162	Sequestrectomy	Recurrence
12	2	5	261	Debridement	Complete wound healing
13	2	No	183	Debridement	Recurrence
14	3	3	84	No	Progressive necrosis
15	3	6	278	Sequestrectomy	Complete wound healing
16	2	2	314	Debridement	Progressive necrosis
17	1	4	372	No	Complete wound healing
18	3	8	236	Sequestrectomy	Complete wound healing
19	3	3	121	Sequestrectomy	Recurrence
20	3	4	328	Sequestrectomy	Complete wound healing
21	2	No	271	Debridement	Progressive necrosis
22	1	5	325	No	Complete wound healing
23	2	3	96	No	Progressive necrosis
24	2	6	217	Debridement	Complete wound healing

BP: bisphosphonate, CTX: C-terminal cross-linking telopeptied of type I collagen, Recurrence

¹ exposure of newly formed necrotic bone on the adjacent sites, Progressive necrosis

² prolonged exposure of necrotic bone in the lesion area)

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