- Email: [email protected]
Bone Regeneration Without Bone Grafting After Resection of a Segment of the Mandible to Treat Bisphosphonate-Related Osteonecrosis of the Jaw
SURGICAL ONCOLOGY AND RECONSTRUCTION J Oral Maxillofac Surg 69:2657-2662, 2011
Bone Regeneration Without Bone Grafting After Resection of a Segment of the Mandible to Treat BisphosphonateRelated Osteonecrosis of the Jaw Frank Wilde, MD, DMD,* Jörg Hendricks, MD, DMD,† Christoph Riese, MD, DMD,‡ Niels Christian Pausch, MD, DMD, PhD,§ Alexander Schramm, MD, DMD, PhD,储 and Marcus Heufelder, MD, DMD¶ In 2003, Marx first described an association of exposed necrotic bone of the jaw with long-term application of bisphosphonates (BPh).1 Bisphosphonaterelated osteonecrosis of the jaw (BRONJ) seems to be resistant to customary dental anti-infective treatment, for example, antimicrobiological rinsing (chlorhexidine, peroxide, etc), curettage of the exposed bone followed by simple closure of the mucosa, or open wound management with regular changing of a gauze wick. Often the severity and stage of the BRONJ is worsened by these procedures. Several articles in the recent literature deal with the question of the most *Assistant Medical Director, Department of Oral and Maxillofacial Surgery, Facial Plastic Surgery, Military Hospital Ulm and Academic Hospital University Ulm, Ulm, Germany. †Resident, Department of Oral and Maxillofacial Surgery, Facial Plastic Surgery, University of Leipzig, Leipzig, Germany. ‡Resident, Department of Oral and Maxillofacial Surgery, Facial Plastic Surgery, Military Hospital Ulm and Academic Hospital University Ulm, Ulm, Germany. §Consultant, Department of Oral and Maxillofacial Surgery, Facial Plastic Surgery, University of Leipzig, Leipzig, Germany. 储Professor and Head, Department of Oral and Maxillofacial Surgery, Facial Plastic Surgery, Military Hospital Ulm and Academic Hospital University Ulm, Ulm, Germany. ¶Senior Physician, Department of Oral and Maxillofacial Surgery, Facial Plastic Surgery, Military Hospital Ulm and Academic Hospital University Ulm, Ulm, Germany. Address correspondence and reprint requests to Dr Wilde: Department of Oral and Maxillofacial Surgery, Facial Plastic Surgery, Military Hospital and Academic Hospital University, Oberer Eselsberg 40, D-89081 Ulm, Germany; e-mail: [email protected] © 2011 American Association of Oral and Maxillofacial Surgeons
0278-2391/11/6910-0033$36.00/0 doi:10.1016/j.joms.2011.02.037
effective treatment for BRONJ. Current concepts described in the literature are based on expert opinion and vary from conservative approaches with antimicrobiological rinsing and oral antibiotics to radical surgery.2-10 Increasing evidence seems to indicate, however, that surgical therapy of BRONJ, by resection of the infected and necrotic bone and sealing as primary wound closure, can lead to long-term healing of BRONJ.6,10-13 However, the question remains of how to reconstruct the mandible when continuous resection is necessary because of extension of the BRONJ. We discuss a case with successful long-term healing over nearly 4 years, after continuous resection of the part of the anterior mandible affected by severe BRONJ. One year postsurgery, bone regeneration, in the form of complete bone bridging along a 2.4 tita-
FIGURE 1. Clinical picture at the first examination (August 2005) with typical nonhealing bone and signs of local infection of the surrounding soft tissue. Wilde et al. Bisphosphonate-Related Osteonecrosis of the Jaw. J Oral Maxillofac Surg 2011.
2657
2658
BISPHOSPHONATE-RELATED OSTEONECROSIS OF THE JAW
FIGURE 2. Extraoral picture in September 2006 with painful, red submental swelling and numbness of the right lower lip. Wilde et al. Bisphosphonate-Related Osteonecrosis of the Jaw. J Oral Maxillofac Surg 2011.
nium reconstruction plate from resection margin to resection margin, was found at recall.
Case Presentation We describe the case of a 55-year-old woman who developed BRONJ in the right mandible after 3 years of zoledronate therapy. Intravenous zoledronate therapy was administered monthly by an oncologist to treat a non-Hodgkin lymphoma. The BRONJ developed in the right mandible in the region 45 to 44
FIGURE 4. The radiological findings in September 2006 showed severe osteolyses with sequestration and periostal reaction along the inferior border of the mandible. A, axial view; B, sagittal view. Wilde et al. Bisphosphonate-Related Osteonecrosis of the Jaw. J Oral Maxillofac Surg 2011.
FIGURE 3. Intraoral view in September 2006 with multiple fistulas and discharge of pus. Wilde et al. Bisphosphonate-Related Osteonecrosis of the Jaw. J Oral Maxillofac Surg 2011.
(Fédération Dentaire Internationale [FDI] tooth numbering system) after a tooth extraction and denture wear. In August 2005, the clinical picture showed typical nonhealing bone and signs of local infection of the surrounding soft tissue (Fig 1). The first attempts at conservative treatment, with antimicrobiological rinse and the use of oral antibiotics, and then curettage and superficial osteotomy of the exposed bone followed by simple wound closure, were unsuccessful. In September 2006, the patient attended the clinic
2659
WILDE ET AL
FIGURE 5. A, Intraoperative picture after dissection of the mandible with pathologic fracture and reactive periostal reaction. B, Intraoperative picture after segment resection of the entire anterior mandible and primary reconstruction with a 2.4 titanium reconstruction plate. Wilde et al. Bisphosphonate-Related Osteonecrosis of the Jaw. J Oral Maxillofac Surg 2011.
with painful, red submental swelling and numbness of the right lower lip (Fig 2). The intraoral picture showed multiple fistulas with pus discharge (Fig 3). Radiological findings showed severe osteolyses with sequestration and periosteal reaction along the inferior border of the mandible (Fig 4A,B). After an extraoral incision, drainage of the submental abscess, and intravenous administration of antibiotics (amoxicillin with sulbactam), the acute symptoms decreased. After 3 weeks, surgery was performed with segment resection of the entire anterior mandible. For primary mandible reconstruction, a 2.4 titanium reconstruction plate was implanted, without bone transplant (Fig 5A,B). Intraoral closure was achieved with absorbable suture material. The result was a seal suture free from tension. Primary healing was uncomplicated. Since then, the patient has been followed up consistently. From September 2006 until the writing, there were no signs of recurrence of BRONJ. Instead, bone regeneration in the form of complete bone bridging along the 2.4 titanium reconstruction plate from resection margin to resection margin was revealed by x-ray monitoring 1 year after primary surgery (Fig 6). This bone regeneration was still stable 3 years postoperatively (Fig 7), and there were no signs of plate fracture or plate exposure.
Discussion As mentioned earlier, there is increasing evidence in the literature that surgical therapy for BRONJ, with com-
FIGURE 6. Panoramic x-ray 1 year after primary surgery with bone regeneration in the form of complete bone bridging along the 2.4 titanium reconstruction plate from resection margin to resection. Wilde et al. Bisphosphonate-Related Osteonecrosis of the Jaw. J Oral Maxillofac Surg 2011.
2660
BISPHOSPHONATE-RELATED OSTEONECROSIS OF THE JAW
FIGURE 7. Cone beam computed tomography 3 years after primary surgery with still-stable bone regeneration along the 2.4 titanium reconstruction plate. Wilde et al. Bisphosphonate-Related Osteonecrosis of the Jaw. J Oral Maxillofac Surg 2011.
plete resection of all infected and necrotic bone and sealing for primary wound closure is successful.6,10-13 This is corroborated by the case described. In all these studies, however, there has been no focus on how to deal with BRONJ of the mandible if segment resection is necessary because of the severity and extension of the BRONJ. The results from our case suggest that after segment resection of the mandible, osseous regeneration, in the form of complete bone bridging from resection margin to resection margin along a titanium reconstruction plate, may be expected. This can be supported by a second BRONJ case of a 70-year-old woman in
whom we also observed bone regeneration after mandible segment resection 6 months postoperatively. However, we do not yet have long-term results for this case (Fig 8). Whether such bone regeneration can be expected regularly or in isolated patients must be investigated in a larger number of cases. In all probability, this phenomenon of bone regeneration may be explained by the continued presence of the periostal tube after bone resection in BRONJ cases, which is different from tumor cases in which the mandible is usually resected with the entire periosteum. The persistent periostal tube is a type of internal periostal flap or, stated better, a periostal
2661
WILDE ET AL
FIGURE 8. Newly formed bone from resection margin to resection margin 6 months after segment resection of the left mandible in a second case of bisphosphonate-related osteonecrosis of the jaw in a 70-year-old woman. Wilde et al. Bisphosphonate-Related Osteonecrosis of the Jaw. J Oral Maxillofac Surg 2011.
pouch. In many studies, it has been proved that vascularized periostal grafts or flaps have osteogenic capacities.14-17 This periostal bone regeneration seems explainable by the anatomical structure of the periosteum. Histologically, it consists of 2 layers. The outer layer is composed of fibroblasts, collagen, and elastin fibers,18,19 along with a distinctive nerve and microvascular network.18,20,21 The inner cambium layer consists of cellrich connective tissue that contains adult mesenchymal progenitor cells, differentiated osteogenic progenitor cells and osteoblasts,18,22 fibroblasts,18,23 as well as microvessels18,20 and sympathetic nerves.18,21 Because of its high vascularity, the periosteum contains a multiplicity of endothelial pericytes18,24 that have the ability to differentiate into numerous cell types, including osteoblasts.18,25,26 These cells may serve as supplementary sources for osteoprogenitor cells18,24 and may be important in periostal bone formation.18,25 Apart from the osteogenic capacities of the periosteum, the osseo-inductive and osseo-conductive potential of the titanium plate and/or the effects of the BPh on bone metabolism may also affect bone regeneration. All of these possibilities, and perhaps others, must be considered and should be the focus of further research on this phenomenon.
If research provides evidence that bone regeneration along titanium reconstruction plates is normal in cases in which the periostal tube can be preserved during the operation, the authors believe that free or microvascular bone grafting should, if possible, be avoided in BRONJ cases. Instead, mandible bridging with load-bearing reconstruction plates alone, with regular clinical and radiological recall, should be the first choice for mandible reconstruction. In making this suggestion, the authors considered published case reports of microvascular reconstruction with fibula bone grafts,27-29 and the authors have also had positive results with fibula grafts in BRONJ patients. Nevertheless, microvascular bone transfer is a high-risk procedure in BRONJ patients. We believe, therefore, that microvascular bony reconstruction should be used only for young patients with a stable primary disease when almost the entire mandible must be reconstructed.
References 1. Marx RE: Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis: A growing epidemic. J Oral Maxillofac Surg 61:1115, 2005 2. Ruggiero SL, Fantasia J, Carlson E: Bisphosphonate-related osteonecrosis of the jaw. Background and guidelines for diagno-
2662
3. 4.
5.
6. 7. 8. 9. 10.
11. 12. 13.
14. 15.
sis, staging and management. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 102:433, 2006 American Association of Oral and Maxillofacial Surgeons (AAOMS): Position paper on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 65:369, 2007 American Association of Oral and Maxillofacial Surgeons: Position paper on bisphosphonate-related osteonecrosis of the jaw—2009 Update; August 2010. Available at http:// www.aaoms.org/docs/position_papers/bronj_update.pdf. Montebugnoli L, Felicetti L, Gissi DB, et al: Biphosphonateassociated osteonecrosis can be controlled by nonsurgical management. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 104:473, 2007 Abu-Id MH, Warnke PH, Gottschalk J, et al: “Bis-phossy jaws”— High and low risk factors for bisphosphonate-induced osteonecrosis of the jaw. J Craniomaxillofac Surg 36:95, 2008 Khan AA, Sándor GK, Dore E, Morrison AD, Alsahli M, Amin F, et al: Canadian consensus practice guidelines for bisphosphonate associated osteonecrosis of the jaw. J Rheumatol 35:1391, 2008 Khan AA, Sándor GK, Dore E, et al: Bisphosphonate associated osteonecrosis of the jaw. J Rheumatol 36:478, 2009 Wutzl A, Biedermann E, Wanschitz F, et al: Treatment results of bisphosphonate-related osteonecrosis of the jaws. Head Neck 30:1224, 2008 Stockmann P, Vairaktaris E, Wehrhan F, et al: Osteotomy and primary wound closure in bisphosphonate-associated osteonecrosis of the jaw: A prospective clinical study with 12-months follow-up. Support Care Cancer 18:449, 2010 Carlson ER, Basile JD: The role of surgical resection in the management of bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 67:85, 2009 Williamson RA: Surgical management of bisphosphonate induced osteonecrosis of the jaws. Int J Oral Maxillofac Surg 39:251, 2010 Wilde F, Heufelder M, Winter K, et al: The role of surgical therapy in the management of intravenous bisphosphonatesrelated osteonecrosis of the jaw. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 111:153, 2011 Ortak T, Ozdemir R, Uysal A, et al: Osteogenic capacities of periost grafts, periost flaps and prefabricated periosteal flaps: Experimental study. J Craniofac Surg 16:594, 2009 Chen AC, Lin SS, Chan YS, et al: Osteogenesis of prefabricated vascularized periosteal graft in rabbits. J Trauma 67:165, 2009
BISPHOSPHONATE-RELATED OSTEONECROSIS OF THE JAW 16. Stock W, Hierner R, Wolf K: Vascularized periosteal transplant. A review of a new therapeutic possibility. Handchir Mikrochir Plast Chir 23:149, 1991 17. Dailiana ZH, Shiamishis G, Niokou D, et al: Heterotopic neoosteogenesis from vascularized periosteum and bone grafts. J Trauma 53:934, 2002 18. Allen MR, Hock JM, Burr DB: Periosteum: Biology, regulation, and response to osteoporosis therapies. Bone 35:1003, 2004 19. Taylor JF: The periosteum and bone growth, in Hall BK (ed): Bone Growth, Vol. 6. Boca Raton, FL, CRC Press, 1992, pp 21-52 20. Ellender G, Feik SA, Carach BJ: Periostal structure and development in a rat caudal vertebra. J Anat 158:173, 1988 21. Hohmann EL, Elde RP, Rysavy JA, et al: Innervation of periosteum and bone by sympathetic vasoactive intestinal peptide-containing nerve fibers. Science 232:868, 1986 22. Aubin J, Triffitt J: Mesenchymal stem cells and osteoblast differentiation, in Bilezikian J, Raisz LG, Rodan GA (eds): Principles of Bone Biology. San Diego, CA, Academic Press, 2002, pp 59-81 23. Squier C, Ghoneim S, Kremenak C: Ultrastructure of the periosteum from membrane bone. J Anat 171:233, 1990 24. Diaz-Flores L, Gutierrez R, Lopez-Alonso A, et al: Pericytes as a supplementary source of osteoblasts in periosteal osteogenesis. Clin Orthop Relat Res 275:280, 1992 25. Bianco P, Riminucci M, Gronthos S, et al: Bone marrow stromal stem cells: Nature, biology, and potential applications. Stem Cells 19:180, 2001 26. Reilly TM, Seldes R, Luchetti W, et al: Similarities in the phenotypic expression of pericytes and bone cells. Clin Orthop Relat Res 346:95, 1998 27. Mücke T, Haarmann S, Wolff KD, et al: Bisphosphonate related osteonecrosis of the jaws treated by surgical resection and immediate osseous microvascular reconstruction. J Craniomaxillofac Surg 37:291, 2009 28. Ferrari S, Bianchi B, Savi A, et al: Fibula free flap with endosseous implants for reconstructing a resected mandible in bisphosphonate osteonecrosis. J Oral Maxillofac Surg 66:999, 2008 29. Nocini PF, Saia G, Bettini G, et al: Vascularized fibula flap reconstruction of the mandible in bisphosphonate-related osteonecrosis. Eur J Surg Oncol 35:373, 2009
Bone Regeneration Without Bone Grafting After Resection of a Segment of the Mandible to Treat BisphosphonateRelated Osteonecrosis of the Jaw Frank Wilde, MD, DMD,* Jörg Hendricks, MD, DMD,† Christoph Riese, MD, DMD,‡ Niels Christian Pausch, MD, DMD, PhD,§ Alexander Schramm, MD, DMD, PhD,储 and Marcus Heufelder, MD, DMD¶ In 2003, Marx first described an association of exposed necrotic bone of the jaw with long-term application of bisphosphonates (BPh).1 Bisphosphonaterelated osteonecrosis of the jaw (BRONJ) seems to be resistant to customary dental anti-infective treatment, for example, antimicrobiological rinsing (chlorhexidine, peroxide, etc), curettage of the exposed bone followed by simple closure of the mucosa, or open wound management with regular changing of a gauze wick. Often the severity and stage of the BRONJ is worsened by these procedures. Several articles in the recent literature deal with the question of the most *Assistant Medical Director, Department of Oral and Maxillofacial Surgery, Facial Plastic Surgery, Military Hospital Ulm and Academic Hospital University Ulm, Ulm, Germany. †Resident, Department of Oral and Maxillofacial Surgery, Facial Plastic Surgery, University of Leipzig, Leipzig, Germany. ‡Resident, Department of Oral and Maxillofacial Surgery, Facial Plastic Surgery, Military Hospital Ulm and Academic Hospital University Ulm, Ulm, Germany. §Consultant, Department of Oral and Maxillofacial Surgery, Facial Plastic Surgery, University of Leipzig, Leipzig, Germany. 储Professor and Head, Department of Oral and Maxillofacial Surgery, Facial Plastic Surgery, Military Hospital Ulm and Academic Hospital University Ulm, Ulm, Germany. ¶Senior Physician, Department of Oral and Maxillofacial Surgery, Facial Plastic Surgery, Military Hospital Ulm and Academic Hospital University Ulm, Ulm, Germany. Address correspondence and reprint requests to Dr Wilde: Department of Oral and Maxillofacial Surgery, Facial Plastic Surgery, Military Hospital and Academic Hospital University, Oberer Eselsberg 40, D-89081 Ulm, Germany; e-mail: [email protected] © 2011 American Association of Oral and Maxillofacial Surgeons
0278-2391/11/6910-0033$36.00/0 doi:10.1016/j.joms.2011.02.037
effective treatment for BRONJ. Current concepts described in the literature are based on expert opinion and vary from conservative approaches with antimicrobiological rinsing and oral antibiotics to radical surgery.2-10 Increasing evidence seems to indicate, however, that surgical therapy of BRONJ, by resection of the infected and necrotic bone and sealing as primary wound closure, can lead to long-term healing of BRONJ.6,10-13 However, the question remains of how to reconstruct the mandible when continuous resection is necessary because of extension of the BRONJ. We discuss a case with successful long-term healing over nearly 4 years, after continuous resection of the part of the anterior mandible affected by severe BRONJ. One year postsurgery, bone regeneration, in the form of complete bone bridging along a 2.4 tita-
FIGURE 1. Clinical picture at the first examination (August 2005) with typical nonhealing bone and signs of local infection of the surrounding soft tissue. Wilde et al. Bisphosphonate-Related Osteonecrosis of the Jaw. J Oral Maxillofac Surg 2011.
2657
2658
BISPHOSPHONATE-RELATED OSTEONECROSIS OF THE JAW
FIGURE 2. Extraoral picture in September 2006 with painful, red submental swelling and numbness of the right lower lip. Wilde et al. Bisphosphonate-Related Osteonecrosis of the Jaw. J Oral Maxillofac Surg 2011.
nium reconstruction plate from resection margin to resection margin, was found at recall.
Case Presentation We describe the case of a 55-year-old woman who developed BRONJ in the right mandible after 3 years of zoledronate therapy. Intravenous zoledronate therapy was administered monthly by an oncologist to treat a non-Hodgkin lymphoma. The BRONJ developed in the right mandible in the region 45 to 44
FIGURE 4. The radiological findings in September 2006 showed severe osteolyses with sequestration and periostal reaction along the inferior border of the mandible. A, axial view; B, sagittal view. Wilde et al. Bisphosphonate-Related Osteonecrosis of the Jaw. J Oral Maxillofac Surg 2011.
FIGURE 3. Intraoral view in September 2006 with multiple fistulas and discharge of pus. Wilde et al. Bisphosphonate-Related Osteonecrosis of the Jaw. J Oral Maxillofac Surg 2011.
(Fédération Dentaire Internationale [FDI] tooth numbering system) after a tooth extraction and denture wear. In August 2005, the clinical picture showed typical nonhealing bone and signs of local infection of the surrounding soft tissue (Fig 1). The first attempts at conservative treatment, with antimicrobiological rinse and the use of oral antibiotics, and then curettage and superficial osteotomy of the exposed bone followed by simple wound closure, were unsuccessful. In September 2006, the patient attended the clinic
2659
WILDE ET AL
FIGURE 5. A, Intraoperative picture after dissection of the mandible with pathologic fracture and reactive periostal reaction. B, Intraoperative picture after segment resection of the entire anterior mandible and primary reconstruction with a 2.4 titanium reconstruction plate. Wilde et al. Bisphosphonate-Related Osteonecrosis of the Jaw. J Oral Maxillofac Surg 2011.
with painful, red submental swelling and numbness of the right lower lip (Fig 2). The intraoral picture showed multiple fistulas with pus discharge (Fig 3). Radiological findings showed severe osteolyses with sequestration and periosteal reaction along the inferior border of the mandible (Fig 4A,B). After an extraoral incision, drainage of the submental abscess, and intravenous administration of antibiotics (amoxicillin with sulbactam), the acute symptoms decreased. After 3 weeks, surgery was performed with segment resection of the entire anterior mandible. For primary mandible reconstruction, a 2.4 titanium reconstruction plate was implanted, without bone transplant (Fig 5A,B). Intraoral closure was achieved with absorbable suture material. The result was a seal suture free from tension. Primary healing was uncomplicated. Since then, the patient has been followed up consistently. From September 2006 until the writing, there were no signs of recurrence of BRONJ. Instead, bone regeneration in the form of complete bone bridging along the 2.4 titanium reconstruction plate from resection margin to resection margin was revealed by x-ray monitoring 1 year after primary surgery (Fig 6). This bone regeneration was still stable 3 years postoperatively (Fig 7), and there were no signs of plate fracture or plate exposure.
Discussion As mentioned earlier, there is increasing evidence in the literature that surgical therapy for BRONJ, with com-
FIGURE 6. Panoramic x-ray 1 year after primary surgery with bone regeneration in the form of complete bone bridging along the 2.4 titanium reconstruction plate from resection margin to resection. Wilde et al. Bisphosphonate-Related Osteonecrosis of the Jaw. J Oral Maxillofac Surg 2011.
2660
BISPHOSPHONATE-RELATED OSTEONECROSIS OF THE JAW
FIGURE 7. Cone beam computed tomography 3 years after primary surgery with still-stable bone regeneration along the 2.4 titanium reconstruction plate. Wilde et al. Bisphosphonate-Related Osteonecrosis of the Jaw. J Oral Maxillofac Surg 2011.
plete resection of all infected and necrotic bone and sealing for primary wound closure is successful.6,10-13 This is corroborated by the case described. In all these studies, however, there has been no focus on how to deal with BRONJ of the mandible if segment resection is necessary because of the severity and extension of the BRONJ. The results from our case suggest that after segment resection of the mandible, osseous regeneration, in the form of complete bone bridging from resection margin to resection margin along a titanium reconstruction plate, may be expected. This can be supported by a second BRONJ case of a 70-year-old woman in
whom we also observed bone regeneration after mandible segment resection 6 months postoperatively. However, we do not yet have long-term results for this case (Fig 8). Whether such bone regeneration can be expected regularly or in isolated patients must be investigated in a larger number of cases. In all probability, this phenomenon of bone regeneration may be explained by the continued presence of the periostal tube after bone resection in BRONJ cases, which is different from tumor cases in which the mandible is usually resected with the entire periosteum. The persistent periostal tube is a type of internal periostal flap or, stated better, a periostal
2661
WILDE ET AL
FIGURE 8. Newly formed bone from resection margin to resection margin 6 months after segment resection of the left mandible in a second case of bisphosphonate-related osteonecrosis of the jaw in a 70-year-old woman. Wilde et al. Bisphosphonate-Related Osteonecrosis of the Jaw. J Oral Maxillofac Surg 2011.
pouch. In many studies, it has been proved that vascularized periostal grafts or flaps have osteogenic capacities.14-17 This periostal bone regeneration seems explainable by the anatomical structure of the periosteum. Histologically, it consists of 2 layers. The outer layer is composed of fibroblasts, collagen, and elastin fibers,18,19 along with a distinctive nerve and microvascular network.18,20,21 The inner cambium layer consists of cellrich connective tissue that contains adult mesenchymal progenitor cells, differentiated osteogenic progenitor cells and osteoblasts,18,22 fibroblasts,18,23 as well as microvessels18,20 and sympathetic nerves.18,21 Because of its high vascularity, the periosteum contains a multiplicity of endothelial pericytes18,24 that have the ability to differentiate into numerous cell types, including osteoblasts.18,25,26 These cells may serve as supplementary sources for osteoprogenitor cells18,24 and may be important in periostal bone formation.18,25 Apart from the osteogenic capacities of the periosteum, the osseo-inductive and osseo-conductive potential of the titanium plate and/or the effects of the BPh on bone metabolism may also affect bone regeneration. All of these possibilities, and perhaps others, must be considered and should be the focus of further research on this phenomenon.
If research provides evidence that bone regeneration along titanium reconstruction plates is normal in cases in which the periostal tube can be preserved during the operation, the authors believe that free or microvascular bone grafting should, if possible, be avoided in BRONJ cases. Instead, mandible bridging with load-bearing reconstruction plates alone, with regular clinical and radiological recall, should be the first choice for mandible reconstruction. In making this suggestion, the authors considered published case reports of microvascular reconstruction with fibula bone grafts,27-29 and the authors have also had positive results with fibula grafts in BRONJ patients. Nevertheless, microvascular bone transfer is a high-risk procedure in BRONJ patients. We believe, therefore, that microvascular bony reconstruction should be used only for young patients with a stable primary disease when almost the entire mandible must be reconstructed.
References 1. Marx RE: Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis: A growing epidemic. J Oral Maxillofac Surg 61:1115, 2005 2. Ruggiero SL, Fantasia J, Carlson E: Bisphosphonate-related osteonecrosis of the jaw. Background and guidelines for diagno-
2662
3. 4.
5.
6. 7. 8. 9. 10.
11. 12. 13.
14. 15.
sis, staging and management. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 102:433, 2006 American Association of Oral and Maxillofacial Surgeons (AAOMS): Position paper on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 65:369, 2007 American Association of Oral and Maxillofacial Surgeons: Position paper on bisphosphonate-related osteonecrosis of the jaw—2009 Update; August 2010. Available at http:// www.aaoms.org/docs/position_papers/bronj_update.pdf. Montebugnoli L, Felicetti L, Gissi DB, et al: Biphosphonateassociated osteonecrosis can be controlled by nonsurgical management. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 104:473, 2007 Abu-Id MH, Warnke PH, Gottschalk J, et al: “Bis-phossy jaws”— High and low risk factors for bisphosphonate-induced osteonecrosis of the jaw. J Craniomaxillofac Surg 36:95, 2008 Khan AA, Sándor GK, Dore E, Morrison AD, Alsahli M, Amin F, et al: Canadian consensus practice guidelines for bisphosphonate associated osteonecrosis of the jaw. J Rheumatol 35:1391, 2008 Khan AA, Sándor GK, Dore E, et al: Bisphosphonate associated osteonecrosis of the jaw. J Rheumatol 36:478, 2009 Wutzl A, Biedermann E, Wanschitz F, et al: Treatment results of bisphosphonate-related osteonecrosis of the jaws. Head Neck 30:1224, 2008 Stockmann P, Vairaktaris E, Wehrhan F, et al: Osteotomy and primary wound closure in bisphosphonate-associated osteonecrosis of the jaw: A prospective clinical study with 12-months follow-up. Support Care Cancer 18:449, 2010 Carlson ER, Basile JD: The role of surgical resection in the management of bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 67:85, 2009 Williamson RA: Surgical management of bisphosphonate induced osteonecrosis of the jaws. Int J Oral Maxillofac Surg 39:251, 2010 Wilde F, Heufelder M, Winter K, et al: The role of surgical therapy in the management of intravenous bisphosphonatesrelated osteonecrosis of the jaw. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 111:153, 2011 Ortak T, Ozdemir R, Uysal A, et al: Osteogenic capacities of periost grafts, periost flaps and prefabricated periosteal flaps: Experimental study. J Craniofac Surg 16:594, 2009 Chen AC, Lin SS, Chan YS, et al: Osteogenesis of prefabricated vascularized periosteal graft in rabbits. J Trauma 67:165, 2009
BISPHOSPHONATE-RELATED OSTEONECROSIS OF THE JAW 16. Stock W, Hierner R, Wolf K: Vascularized periosteal transplant. A review of a new therapeutic possibility. Handchir Mikrochir Plast Chir 23:149, 1991 17. Dailiana ZH, Shiamishis G, Niokou D, et al: Heterotopic neoosteogenesis from vascularized periosteum and bone grafts. J Trauma 53:934, 2002 18. Allen MR, Hock JM, Burr DB: Periosteum: Biology, regulation, and response to osteoporosis therapies. Bone 35:1003, 2004 19. Taylor JF: The periosteum and bone growth, in Hall BK (ed): Bone Growth, Vol. 6. Boca Raton, FL, CRC Press, 1992, pp 21-52 20. Ellender G, Feik SA, Carach BJ: Periostal structure and development in a rat caudal vertebra. J Anat 158:173, 1988 21. Hohmann EL, Elde RP, Rysavy JA, et al: Innervation of periosteum and bone by sympathetic vasoactive intestinal peptide-containing nerve fibers. Science 232:868, 1986 22. Aubin J, Triffitt J: Mesenchymal stem cells and osteoblast differentiation, in Bilezikian J, Raisz LG, Rodan GA (eds): Principles of Bone Biology. San Diego, CA, Academic Press, 2002, pp 59-81 23. Squier C, Ghoneim S, Kremenak C: Ultrastructure of the periosteum from membrane bone. J Anat 171:233, 1990 24. Diaz-Flores L, Gutierrez R, Lopez-Alonso A, et al: Pericytes as a supplementary source of osteoblasts in periosteal osteogenesis. Clin Orthop Relat Res 275:280, 1992 25. Bianco P, Riminucci M, Gronthos S, et al: Bone marrow stromal stem cells: Nature, biology, and potential applications. Stem Cells 19:180, 2001 26. Reilly TM, Seldes R, Luchetti W, et al: Similarities in the phenotypic expression of pericytes and bone cells. Clin Orthop Relat Res 346:95, 1998 27. Mücke T, Haarmann S, Wolff KD, et al: Bisphosphonate related osteonecrosis of the jaws treated by surgical resection and immediate osseous microvascular reconstruction. J Craniomaxillofac Surg 37:291, 2009 28. Ferrari S, Bianchi B, Savi A, et al: Fibula free flap with endosseous implants for reconstructing a resected mandible in bisphosphonate osteonecrosis. J Oral Maxillofac Surg 66:999, 2008 29. Nocini PF, Saia G, Bettini G, et al: Vascularized fibula flap reconstruction of the mandible in bisphosphonate-related osteonecrosis. Eur J Surg Oncol 35:373, 2009