Open access peer-reviewed chapter

Bisphosphonate-Related Osteonecrosis of the Jaw Around Dental Implants

Written By

Tatsuo Shirota, Atsushi Nakamura, Yoshiro Matsui, Masashi Hatori, Masanori Nakamura and Satoru Shintani

Submitted: October 14th, 2010 Reviewed: March 11th, 2011 Published: August 29th, 2011

DOI: 10.5772/16607

Chapter metrics overview

4,508 Chapter Downloads

View Full Metrics

1. Introduction

Bisphosphonate is the collective name for compounds in which the backbone of pyrophosphoric acid, a P-O-P structure, is converted to chemically stable P-C-P, and this structure shows the affinity of bisphosphonate for bone hydroxyapatite in the body (Fleisch et al. 2002). Administered bisphosphonate preparations (BPs) transfer to and deposit in bone, exhibiting a bone resorption-inhibitory effect. The chemical structure of the side chain bound to the carbon atom of P-C-P markedly influences bisphosphonate activity, and, particularly, side chains containing nitrogen molecules not only markedly increase the affinity for HA but also bone resorption-inhibitory activity (Migliorati et al. 2005). Because of this potent bone resorption-inhibitory effect, BPs are the first-choice treatment for osteoporosis worldwide (Russell et al. 2007), and their efficacy for malignant tumor-associated hypercalcemia (Body et al.1999), ostealgia complicating bone metastasis of solid tumors (Hortobagyi et al. 1998), and multiple myeloma accompanied by bone destruction (Berenson et al. 1996) has been shown. Adverse effects of BPs were previously considered to be relatively mild, such as digestive symptoms induced by oral preparations and fever induced by injections (Berenson et al. 1996), but the association of BPs with osteonecrosis of the jaw has been frequently described since Marx (2003) initially reported it (Ruggiero et al. 2004; Marx et al. 2005; Khosla et al. 2007)

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is clinically diagnosed when the following 3 conditions are met: 1) current or previous treatment with BPs, 2) persistent exposure of necrotized bone in the maxillofacial region for 8 weeks or longer, 3) no past medical history of radiotherapy for the jaw bone (AAOMS 2007; Ruggiero et al. 2009). BPs inducing BRONJ mostly contain nitrogen (NBPs). BRONJ frequently develops in patients under NBP treatment upon dental treatment, such as tooth extraction, implant placement, and surgical periodontal treatment accompanied by bone invasion, and inflammatory diseases, such as periodontal disease and abscess (Ruggiero et al. 2009; Vahtsevanos et al. 2009; Yoneda et al. 2010). BRONJ shows poor responses to the standard treatment for common osteomyelitis of the jaw, such as curettage/resection of necrotized tissue and antimicrobial drugs, and its intractability is the most serious problem.

Stack & Epker (1995) initially reported the influence of BPs on dental implant treatment. They introduced a case in which all 5 favorably functioning implants in the lower anterior tooth region were lost after the 5-month administration of a BP containing no nitrogen, etidronatedisodium (Didronel; Procter and Gamble, Cincinnati, OH), for osteoporosis. The details of the bone wound healing process after implant loss or whether BRONJ developed were not described, but the author concluded that Didronel administration is a risk factor for implant treatment. However, several recent studies reported that implant treatment in the presence of NBPs was possible when the NBPs were oral drugs. Fugazzotto et al (2007) evaluated that a retrospective analysis of case records of patients with a history of oral BPs therapy treated as part of routine periodontal and implant treatment. They reported that no osteonecrosis was noted immediately postoperatively or during follow-up period 61 patients, and all implants were functioning successfully 12 to 24 months post-insertion.Grant et al. (2008) evaluated the clinical results of 115 patients who received oral BPs during implant treatment. They showed that there was no significant difference in treatment results between patients with and without oral BPs during implant treatment. It was also reported that no patients developed ONJ after implant treatment. Bell & Bell (2008) reported that bone grafting for implant treatment in 42 patients who received oral BPs for osteoporosis treatment was conducted safely. Therefore, no conclusion has been reached regarding whether oral BPs are contraindicated for implant treatment. On the other hand, it has been clarified that the risk of developing BRONJ upon open dental treatment rises in patients treated with NBP intravenous injection showing a potent bone adsorption-inhibitory action, and implant treatment is considered contraindicated for such cases (Khan et al. 2008; Ruggiero et al. 2009). However, there have been fewer reports on the influence of intravenous BPs on implants which have already acquired osseointegration and are favorably functioning, and the actual state is unclear.

We experienced the case of a patient who developed ONJ around implants in the maxilla, considered to be caused by intravenous BP administration for osteometastasis treatment of breast cancer, and underwent partial maxillectomy to relieve inflammation (Shirota et al. 2009). This chapter introduces clinical findings, the treatment and its outcome, and peri-implant histopathological findings in the patient, and the developmental mechanism of peri-implant BRONJ is discussed with a literature review.


2. Patient and methods

2.1. Outline of the patient

The patient was a 54-year-old female who visited our hospital for chief complaints of peri-implant pain in the upper left molar region and bone exposure. The patient developed breast cancer about 6 years ago and underwent left mastectomy followed by irradiation and chemotherapy. However, multiple cancer metastases occurred about 2 years ago, and the patient underwent cancer chemotherapy and intravenous BPs injection.

The patient underwent implant treatment for the upper left molar region at a dental clinic immediately before the development of breast cancer, in which 2 implants were placed. These implants functioned without a problem for about 6 years, but peri-implant gingival recession, bone exposure, and pain appeared about one month ago, and the patient received antimicrobial drug administration, irrigation, and disinfection at a clinic, but the symptoms did not improve. Thus, the patient visited our department. On the first examination, brown-colored necrotized bone was exposed in the upper left first molar region on the buccal side. The peri-implant gingiva was painful and swollen with slight flare, but no implant mobility was observed (Fig.1). On panoramic radiography, mild bone resorption was noted in alveolar bone in the implant neck. Computed tomography (CT) revealed sequestration with an irregular trabecular bone structure around the implant (Fig.2). Biopsy was performed in consideration of metastasis of breast cancer to the oral cavity, but only inflammatory cell infiltration was observed without tumor cells.

Figure 1.

Radiograph showing slight bone resorption around the implants.

Figure 2.

Computed tomography (CT) image around the implants (arrow).

2.2. Diagnosis and treatment

It is well-known that curative chemotherapy or long-term adrenocortical steroid administration for lymphoblastic leukemia and Hodgkin and non-Hodgkin lymphomas induces osteonecrosis of the femoral head (Kubo et al. 2001; Bojko et al 2003; Karimova et al. 2008). Many anticancer drugs were administered for breast cancer metastasis in this patient, but no osteonecrosis of the jaw caused by these drugs has been reported. In addition, the clinical symptoms of this patient met all diagnostic criteria of BRONJ proposed by AAOMS (AAOMS 2007; Ruggiero et al. 2009). Based on these findings, BP-induced osteonecrosis was diagnosed.

In the treatment, morbid bone tissue including implants was resected in consideration of the following 3 conditions: 1) early chemotherapy for metastatic cancer was necessary, for which removal of the infected lesion was necessary, 2) there was a possibility that continuation of the withdrawal of BPs would aggravate metastatic cancer-associated bone destruction and hypercalcemia, and 3) it was difficult to remit inflammation by employing conservative treatment proposed by the American Association of Oral and Maxillofacial Surgeons (AAOMS 2007; Ruggiero et al. 2009). After considering these points, sequestrectomy of the left maxilla was selected. The gingival margin was incised between the upper left first premolar and implant towards the maxillary tuberosity, and the lesion area was exposed by forming a buccal and palatal mucoperiosteal flap. The bone cortex of the lesion was brownish black, and necrotic bone was confirmed between the distal surface of the second premolar and mesial surface of the implant placed in the second molar area, but particularly around the implant placed in the first molar area (Fig.3a). The area for resection around the living bone in the lesion was determined after the extraction of the second premolar, and the pathological bone tissue including the implant was removed with a Lindeman bar and bone chisel, followed by the grinding of the bone surface of the resection stump until bleeding was confirmed. As a result, the instrument partially perforated the maxillary sinus floor, and the thickened maxillary sinus mucosa was exposed. This sinus mucosa was spared, and the surgical wound was completely closed by suturing the mucoperiosteal flaps (Fig.3b)

Figure 3.

Intraoperative view of the sequestomy of the left maxilla. (a) Pathological bone including the implants was removed, and maxillary sinus mucosa was exposed. (b) The surgical wound was completely closed by suturing the mucoperiosteal flap.

After surgery, antibiotic was intravenously administered for 3 days and oral antibiotic was administered for 3 days. In addition, hyperbaric oxygen therapy was performed. The efficacy of hyperbaric oxygen therapy for BRONJ is controversial (Ruggiero et al. 2004; Freiberger et al 2009), but, at least, it may be effective to promote mucoepithelial wound healing in the sequestration-resected region. The wound was completely covered with healthy mucosa 2 weeks after surgery (Fig.4.). Since the remission of inflammation could be confirmed, anticancer drug and BP administration was initiated for metastatic cancer and bone metastasis-associated bone destruction. The patient died of multiorgan failure associated with multiple cancer metastasis 8 months after surgery, but BRONJ did not recur before death.

Figure 4.

Intraoral view at 4 weeks after surgery.

2.3. Macroscopic and μCT findings of the resected specimen

Implants were strongly fixed to the bone, and areas of brown sequestration were observed around them (Fig.5.). On μCT, no apparent abnormality, such as trabecular destruction, was observed, and the implant surface was in direct contact with the trabecula at various sites (Fig.6.).

Figure 5.

The resected specimen shows a portion of the left maxilla including two implants.

Figure 6.

μCT findings of the resected specimen.

2.4. Histopathological analysis

2.4.1. Histologic preparation

The resected specimen was divided into the lesion including the implants and peri-lesion, i.e., healthy tissue in the resected stump. The bone tissue around the implants was fixed, dehydrated, and embedded in polyester resin (Ligorac®, Wako Pure Chemical Industries, Ltd., Tokyo, Japan). Undecalcified ground sections 15 μm in thickness were cut along the long axis of the implant using the EXAKT Cutting-Grinding System (EXAKT, Norderstedt, Germany) and stained with 1% toluidine blue (pH 7.2), then the bone tissue around the implant was observed under light microscopy. Meanwhile, the bone tissue around the lesion was dehydrated and embedded in paraffin according to the conventional procedure. Some of the sections were stained with hematoxylin-eosin (HE) and AZAAN. Other sections were processed for immunohistochemical analysis by immunostaining with anti-human CD3, CD20, CD45 and CD68 (Daco, Carpinteria, CA).

2.4.2. Peri-implant histopathological findings in undecalcified ground sections

The implant surface was mostly in direct contact with bone tissue, suggesting that osseointegration was maintained until BRONJ development (Fig.7a). No osteocyte was present in the cavity of bone contacting implants or the surrounding trabeculae, nor were there cellular components on the bone surface, and bone tissue mostly showed sequestration (Fig.7b). The marrow cavity was filled with aggregates of actinomycete-like microorganisms, neutrophils, and other necrotized soft tissue (Fig.8a). In addition, adsorption cavities with a worm-eaten appearance were widely present. Normally, bone tissue necrotized in the body is absorbed by osteoclasts, shows sequestration, and is naturally excreted. However, no osteoclasts were present in the resorption cavity, suggesting that active resorption of the bone occurred in the BRONJ developmental process, rather than the resorption of necrotized bone by osteoclasts (Fig.8b).

2.4.3. Histopathological findings around lesions in decalcified sections

Osteocytes were present in the bone cavity (Fig.9a,b). The trabecular surface was smooth, and osteoid formation and osteoblast arrangement were observed. Reactive bone formation was also observed at various trabecular sites. Granulation tissue rich in capillary blood

Figure 7.

Histological findings of the tissue from the implants in an undecalcofied sections stained with toluidine blue. (a) Most of the implant surfaces are in direct contact with the bone (× 40). (b) The bone in contact with the implant sureface is necrotic (× 200).

Figure 8.

Histological findings of the tissue from the implants in an undecalcofied sections stained with toluidine blue. (a) Growth of a bacterial colony into the marrow cavity is observed (× 200). (b) Marked bone destruction with a moth eaten appearance is observed on the necrotic trabecular bone surface (× 200).

vessels invaded the bone marrow region (Fig.10a,b). On immunohistological staining, lymphocytes infiltrating the bone marrow were mostly CD3-positive, showing that the cells were derived from T cells. In contrast, only a few lymphoctyes were positive for CD20 and CD45 (Fig.11a,b), but they were considered not to be significant. Multinucleated giant cells strongly positive for CD68, assumed to be osteoclasts, were present at various sites on the trabecular surface (Fig.12a,b).


3. Discussion on the peri-implant BRONJ developmental mechanism

No viewpoint regarding the pathogenesis of BRONJ has been established. Based on clinical experience, mucosal injuries caused by poorly fitting dentures and oral surgical treatment, such as that for periodontal disease and tooth extraction, have been reported as local risk factors, but this patient received no surgical dental treatment during the BP administration

Figure 9.

Histological findings of the tissue around the lesion in a decalcified thin section. (a) The trabecular bone surface are smooth (HE stain; × 40); b) Growth of fibrous connective tissue and vascular formation are observed in the marrow(HE stain, × 100).

Figure 10.

Histological findings of the tissue around the lesion in a decalcified thin section. (a) Numerous lymphoid cells are observed in the marrow (HE stain; × 200). (b) Lining cells and osteoid formation are observed (AZAN; × 100).

Figure 11.

Immunohistological staining ot hte tissue around the lesion in a decalcified thin section. (a) Many lymphoid cells are positive for anti-human CD3 (× 200). (b) Only a few lymphoctyes are positive for CD20 (× 200).

Figure 12.

Immunohistological staining ot hte tissue around the lesion in a decalcified thin section. (a) Only a few lymphoctyes are positive for CD45 (× 200). (b) Multinuclear cells are strongly positive for anti-human CD68 antibody (× 200).

period, and no implant mobility was observed in the BRONJ site. Histologically, oseointegration was widely maintained on the implant surface, and no deep overgrowth of gingival epithelium was noted, suggesting that BRONJ in this patient suddenly occurred around favorably functioning implants, and was not induced by peri-implant inflammation.

Necrosis of the femoral head (Kerachian et al. 2006) and irradiation-induced osteonecrosis of the jaw (Marx 1983) are widely known as osteonecrotic lesions, and the cause is insufficiency of vascular formation in both diseases. Reportedly, zoledronate exhibits a potent vascularization-inhibitory effect (Giraudo et al. 2004), and the BP-induced obstruction of blood vessels in bone and necrosis of osteocytes around them have been reported (Hansen et al. 2007). Based on these findings, it is hypothesized that insufficiency of the blood supply is also involved in BRONJ, but, histologically, the absence of vascularization inhibition in BRONJ has been reported (Bedogni et al. 2008). Another important hypothesis suggests an influence of reduced bone remodeling due to the BP-induced inhibition of bone resorption by osteoclasts. It has been reported that osteocyte mortality increases when bone remodeling declines, i.e., BPs reduce bone remodeling, increasing osteocyte death, which is involved in BRONJ (Allen et al. 2009). However, many resorption cavities were present on the peri-implant-sequestered bone surface, and the growth of granulation tissue containing abundant capillary blood vessels and reactive bone formation in the resected stump were confirmed in this patient. Thus, it is difficult to explain the cause of BRONJ with insufficient blood supply and the bone remodeling-inhibitory effect of BPs alone.

Pamidronate and zoledronate administered intravenously to this patient are BPs that incorporate nitrogen. BPs containing nitrogen (NBPs) induce an inflammatory reaction by stimulating cells (Hewit et al. 2005; Endo et al. 1993; Nakamura et al. 1996). NBPs also exist on the surface of gram-negative cell walls, and increase inflammatory reactions to lipopolysaccharide (LPS), which has a strong inflammatory effect (Yamaguchi et al. 2000). Therefore, BRONJ may be caused by interactions among several factors differing among cases, not by a single cause. For example, in this patient, the following conditions may have influenced each other and caused BRONJ: 1) the excessive inhibition of bone turnover due to the NBP-related inhibition of bone resorption; 2) the occlusal force loaded on implants was directly transmitted to the bone, which activated local bone metabolism in the surrounding region, releasing BP accumulated in the bone at a high level; 3) free NBP-induced inflammatory reactions, induction of osteoclast apoptosis (Roelofs et al. 2006), and inhibition of epithelial activity (Landesberg et al. 2009); 4) increased risk of bacterial infection due to suppression of the immune system; 5) enhanced inflammatory reactions due to interactions between gram-negative bacterial lipopolysaccharides and NBPs and 6) reduced local blood flow by vascularization inhibition and vascular obstruction (Fig.13).

Figure 13.

Hypothetical mechanism of BRONJ aroud the implants.


4. Conclusion

BRONJ is intractable, and no treatment method has been established. Only guidelines mainly concerning prevention and conservative treatment have been proposed. When peri-implant BRONJ occurs, firstly, conservative treatment should be selected following the AAOMS treatment guidelines, placing great importance on the prevention of exacerbation of BRONJ, but when NBPs are administered to control bone metastasis, it should be a priority to re-start BP administration and prevent any delay in cancer chemotherapy. Accordingly, although the appropriateness and timing of sequestration site resection should be carefully investigated, active surgical treatment may be one choice for some patients. Implant treatment is no longer special treatment. It is widely introduced into routine dental practice as a method to recover the occlusal function of defective teeth. Therefore, NBP intravenous injections will be increasingly administered to patients with a past medical history of implant treatment, for which the establishment of a practical clinical policy for the prevention and treatment of BRONJ is strongly desired.


  1. 1. 0278-2391367943950AAOMS. (2007) American association of oral and maxillofacial surgeons position paper on bisphosphonate-related osteonecrosis of the jaws. The Journal of Oral and Maxillofacial Surgery, Vol. 67, No.3, (March 2007), pp. 943-950, ISSN 0278-2391
  2. 2. AllenM. R.BurrD. B.2009The pathogenesis of bisphosphonate-related osteonecrosis of the jaw: so many hypotheses, so few data.The Journal of Oral and Maxillofacial surgaery,675Supplement 1, (May 2009),61700278-2391
  3. 3. BedogniA.BlandamuraS.LokmicZ.PalumboC.RagazzoM.FerrariF.TregnaghiA.PietrograndeF.ProcopioO.SaiaG.FerrettiM.BedogniG.ChiariniL.FerronatoG.NinfoV.LoRusso. L.LoMuzio. L.NociniP. F.2008Bisphosphonate-associated jawbone osteonecrosis: a correlation between imaging techniques and histopathology.Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology and Endodontology,1053March 2009),3583641079-2104
  4. 4. BellB. M.BellR. E.2008Oral bisphosphonates and dental implants: a retrospective study.The Journal of Oral and Maxillofacial Surgaery,665May 2008),102210241079-2104
  5. 5. BerensonJ. R.LichtensteinA.PorterL.DimopoulosM. A.BordoniR.GeorgeS.LiptonA.KellerA.BallesterO.KovacsM. J.BlacklockH. A.BellR.SimeoneJ.ReitsmaD. J.HeffermanM.SeamanJ.KnightR. D.1996Efficacy of pamidronate in reducing skeletal event in patients with advanced multiple myeloma. Myeloma Aredia Study Group.The New England Journal of Medicine,3348Feburuary 1996),4884930028-4793
  6. 6. BodyJ. J.LortholaryA.RomieuG.VigneronA. M.FordJ.1999A dose-finding sudy of zoledronate in hypercalcemic cancer patients.Journal of Bone and Mineral Research,1419September 1999),155715611523-4681
  7. 7. BojkoP.HilgerR. A.RuehmS. G.DirschO.SeeberS.ScheulenM. E.2003Femoral head necrosis in three patients with relapsed ovarian cancer receiving high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation.Bone Marrow Teansplantation,316March 2003),4874910268-3369
  8. 8. EndoY.NakamuraM.KikuchiT.ShinodaH.TakedaY.NittaY.KumagaiK.1993Aminoalkylbisphosphonates, potent inhibitors of bone resorption, induce a prolonged stimulation of histamine synthesis and increase macrophages, granulocytes, and osteoclasts in vivo.Calcified Tissue International523March 1993),2482540017-1967X
  9. 9. FleischH.ReszkaA.RodanG.RogersM.2002Bisphosphonates: Mechanisms of action,Principles of Bone Biology, Bilezikian, J. P., Raisz, L. G. & Rodan, G.A.,1316111385Academic Press,0-12098-652-3Diego
  10. 10. FreibergerJ. J.2009Utility of hyperbaric oxygen in treatment of bisphosphonate-related osteonecrosis of the jaws.The Journal of Oral Maxillofacial Surgery.675Supplement 1, (March 2009),961061079-2104
  11. 11. FugazzottoP. A.LightfootW. S.JaffinR.KumarA.2007Implant placement with or without simultaneous tooth extraction in patients taking oral bisphosphonates: postoperative healing, early follow-up, and the incidence of complications in two private practices.Journal of Periodontology,789September 2007),166416690022-3492
  12. 12. GiraudoE.InoueM.HanahanD.2004An amino-bisphosphonate targets MMP-9-expressing macrophages and angiogenesis to impair cervical carcinogenesis.The Journal of Clinical Investigation,1145September 1 2004),623633ISSN, 0021-9738
  13. 13. GrantB. T.AmenedoC.FreemanK.KrautR. A.2008Outcomes of placing dental implants in patients taking oral bisphosphonates: a review of 115 cases.The Journal of Oral and Maxillofacial Surgery,662February 2008),2232300278-2391
  14. 14. HansenT.KunkelM.SpringerE.WalterC.WeberA.SiegelE.KirkpatrickC. J.2007Actinomycosis of the jaws--histopathological study of 45 patients shows significant involvement in bisphosphonate-associated osteonecrosis and infected osteoradionecrosisVirchows Archiv4516December 2007),100910170945-6317
  15. 15. HewitR. E.LissinaA.GreenA. E.SlayE. S.PriceD. A.SewellD. A.2005The bisphosphonate acute phase response: rapid and copious production of proinflammatory cytokines by peripheral blood gd T cells in response to aminobisphosphonates is inhibited by statins.Clinical Experimental Immunology,1391January 2005),1011110009-9104
  16. 16. HortobagyiG. N.TheriaultR. L.LiptonA.PorterL.BlayneyD.SinoffC.WheelerH.SimeoneJ. F.SeamanJ. J.KnightR. D.HeffernanM.MellarsK.ReitsmaD. J.1998Long-term prevention of skeletal complications of metastatic brest cancer with pamidronate. Protocol 19 Aredia Brest Cancer Study Group.Journal of Clinical Oncology,166June 1998),203820440073-2183X
  17. 17. KarimovaE. J.RaiS. N.WuJ.BrittonL.KasteS. C.NeelM. D.2008Femoral resurfacing inyoung patients with hematologic cancer and osteonecrosis.Clinical Orthopaedics Related Research,46612December 2008),304430501528-1132
  18. 18. KerachianM. A.HarveyE. J.CournoyerD.ChowT. Y.SéguinC.2006A vascular necrosis of the femoral head: vascular hypotheses.Journal of Endothelial Cell Research,234July-August 2006),2372441062-3329
  19. 19. KhanA. A.SándorG. K.DoreE.MorrisonA. D.AlsahliM.AminF.PetersE.HanleyD. A.ChaudryS. R.DempsterD. W.GlorieuxF. H.NevilleA. J.TalwarR. M.ClokieC. M.AlMardini. M.PaulT.KhoslaS.JosseR. G.SutherlandS.LamD. K.CarmichaelR. P.BlanasN.KendlerD.PetakS.St-MarieL. G.BrownJ.EvansA. W.RiosL.CompstonJ. E.CanadianAssociation.ofOral.MaxillofacialSurgeons.2008Canadian consensus practice guidelines for bisphosphonate associated osteonecrosis of the jaw.The Journal of Rheumatology,357July 2008),139113970031-5162X
  20. 20. KhoslaS.BurrD.CauleyJ.DempsterD. W.EbelingP. R.FelsenbergD.GagelR. F.GilsanzV.GuiseT.KokaS.Mc CauleyL. K.Mc GowanJ.Mc KeeM. D.MohlaS.PendrysD. G.RaiszL. G.RuggieroS. L.ShaferD. M.ShumL.SilvermanS. L.Van PoznakC. H.WattsN.WooS. B.ShaneE.AmericanSociety.forBone.MineralResearch.2007Bisphosphonate-associated osteonecrosis of the jaw: Report of a task force of the American Society for Bone and Mineral Research.Journal of Bone and Mineral Research,2210October 2007),147914911523-4681
  21. 21. KuboT.KojimaA.YamazoeS.UeshimaK.YamamotoT.HirasawaY.2001Osteonecrosis of the femoral head that developed after long-term topical application.Journal of Orthopaedic Science,61January 2001),92940949-2658
  22. 22. LandesbergR.EisigS.FennoyI.SirisE.2009Alternative indications for bisphosphonate therapy.The Journal of Oral and Maxillofacial Surgery,675Supplement 1, (May 2009),27341079-2104
  23. 23. MarxR. E.1983Osteonecrosis: a new concept of its pathophysiology. JThe Journal of Oral and Maxillofacial Surgery,415May 1983),2832881079-2104
  24. 24. MarxR. E.2003Pamidronate (Aredia) and Zoledronate (Zometa) Induced Avascular Necrosis of the Jaws: A growing epidemic.Journal of Oral and Maxillofacial Surgery,619September 2003),111511171079-2104
  25. 25. MarxR. E.SawatariY.FortinM.BroumandN.2005Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws. Journal of Oral and Maxillofacial Surgery,6311November 2005),156715751079-2104
  26. 26. MiglioratiC. A.CasigliaJ.EpsteinJ.JacobsenP. L.SiegelM. A.WooS. B.2005Managing the care of patients with bisphosphonate-associated osteonecrosis: an American Academy of Oral Medicine position paper.Journal of the American Dental Association,13612December 2005),165816680002-8177
  27. 27. NakamuraM.AndoT.AbeM.KumagaiK.EndoY.1996Contrast between effects of aminobisphosphonates and non-aminobisphosphonates on collagen-induced arthritis in mice.British Journal of Pharmacology,1192September 1996),2052121476-5381
  28. 28. RoelofsA. J.ThompsonK.GordonS.RogersM. J.2006Molecular mechanisms of action of bisphosphonates: current status.Clinical Cancer Research,1220Pt 2, (October 2006 ),6222s6230s1557-3265
  29. 29. RuggieroS. L.MehrotraB.RosenbergT. J.EngroffS. L.2004Osteonecrosis of the Jaws associated with the use of bisphosphonates: a review of 63 cases.The Journal of Oral and Maxillofacial Surgery,6255275341079-2104
  30. 30. RuggieroS. L.DodsonT. B.AssaelL. A.LandesbergR.MarxR. E.MehrotraB.AmericanAssociation.oforal.MaxillofacialSurgeons.2009American Association of Oral and Maxillofacial Surgeons Position Paper on Bisphosphonate-Related Osteonecrosis of the Jaws- 2009 update.The Journal of Oral and Maxillofacial Surgery,675Supplement,2121079-2104
  31. 31. RussellR. G.XiaZ.DunfordJ. E.OppermannU.KwaasiA.HulleyP. A.KavanaghK. L.TriffittJ. T.LundyM. W.PhippsR. J.BarnetB. L.CoxonF. P.RogersM. J.WattssN. B.EbetinoF. H.2007Bisphosphonates an update on mechanisms of action and how these relate to clinical efficacy.Annals of the New York Academy of Sciences1117November 2007),2092571749-6632
  32. 32. ShirotaT.NakamuraA.MatsuiY.HatoriM.NakamuraM.ShintaniS.2009Bisphosphonate-related osteonecrosis of the jaw around dental implants in the maxilla: report of a case.Clinical Oral Implants Ressearch,2012December 2009),140214080905-7161
  33. 33. StarckW. J.EpkerB. N.1995Failure of osseointegrated dental implants after diphosphonate therapy for osteoporosis: a case report.The International Journal of Oral & Maxillofacacial Implants,101January-February 1995),7478
  34. 34. VahtsevanosK.KyrgidisA.VerrouE.KatodritouE.TriaridisS.AndreadisC. G.BoukovinasI.KoloutsosG. E.TeleioudisZ.KitikidouK.ParaskevopoulosP.ZervasK.AntoniadesK.2009Longitudinal cohort study of risk factors in cancer patients of bisphosphonate-related osteonecrosis of the jaw. Journal ofClinical Oncology,2732November 2009),535653620073-2183X
  35. 35. YamaguchiK.MotegiK.IwakuraY.EndoY.2000Involvement of interleukin-1 in the inflammatory actions of aminobisphosphonates in mice.British Journal of Pharmacology,1307August 2000),164616541476-5381
  36. 36. YonedaT.HaginoH.SugimotoT.OhtaH.TakahashiS.SoenS.TaguchiA.ToyosawaS.NagataT.UradeM.2010Bisphosphonate-related osteonecrosis of the jaw: position paper from the Allied Task Force Committee of Japanese Society for Bone and Mineral Research, Japan Osteoporosis Society, Japanese Society of Periodontology, Japanese Society for Oral and Maxillofacial Radiology, and Japanese Society of Oral and Maxillofacial Surgeons.Journal of Bone and Mineral Metabolism,2843653831435-5604

Written By

Tatsuo Shirota, Atsushi Nakamura, Yoshiro Matsui, Masashi Hatori, Masanori Nakamura and Satoru Shintani

Submitted: October 14th, 2010 Reviewed: March 11th, 2011 Published: August 29th, 2011