Table of Contents Author Guidelines Submit a Manuscript
International Journal of Dentistry
Volume 2014 (2014), Article ID 107690, 8 pages
http://dx.doi.org/10.1155/2014/107690
Clinical Study

Conservative Surgical Management of Stage I Bisphosphonate-Related Osteonecrosis of the Jaw

1Unit of Oral Pathology and Laser-Assisted Oral Surgery, Department of Biomedical, Biotechnological and Translational Sciences, University of Parma, 43100 Parma, Italy
2Université de Liège, 4000 Liège, Belgium
3University of Valencia, 46010 Valencia, Spain

Received 31 October 2013; Accepted 21 December 2013; Published 6 February 2014

Academic Editor: Toni Zeinoun

Copyright © 2014 Paolo Vescovi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Purpose. To report the efficacy of conservative surgical treatment for stage I bisphosphonate-related osteonecrosis of the jaw (BRONJ). Materials and Methods. This study reports the clinical outcomes of 63 patients treated for BRONJ stage I (according to Ruggiero's staging system) at the Oral Pathology and Laser-Assisted Surgery Unit of the University of Parma between January 2004 and January 2011. Surgical interventions were performed, under local analgesia, in patients unresponsive for a period of six months to noninvasive treatments such as cycles of local or systemic antibacterial therapy combined or not to low level laser therapy, ozone therapy, or Hyperbaric Oxygen Therapy. All interventions were performed after the consultation of oncologist or physician. Results. In our experience, conservative surgical treatment is associated with the highest number of BRONJ healed sites in stage I disease. Complete healing was observed in 92.6% of sites surgically treated. Conclusions. This study confirms that treatment of patients affected by minimal bone exposition, (stage I of BRONJ), through conservative surgical strategies, possibly with laser, may result in a high control of the disease in the long term.

1. Introduction

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is currently defined as an area of exposed bone in the maxillofacial region that has persisted for more than 8 weeks in a patient on previous or current treatment with a bisphosphonate and without history of radiation therapy to the jaws. Despite this definition, many cases of nonexposed variant of BRONJ have been reported.

Many pathogenetic hypotheses have been put forward but none of them could explain the peculiar character of this disorder. Osteoclasts are the main target of bisphosphonates, with the suppression of osteoclast-mediated bone remodelling. Because remodelling is high in the jaw, remodelling suppression hypothesis has been firstly proposed [1].

Even if BRONJ seems to be a primarily bone condition, some studies showed a toxic effect of bisphosphonates (BP) on the oral epithelium with inhibition of normal soft tissue healing. Because epithelialisation is an essential step in postintervention wound healing, it has been hypothesized that the soft tissue of the oral mucosa could be a key factor in BRONJ development. Moreover, a relevant role has been advocate for the antiangiogenetic effect of BP, particularly for the possible failure of healing processes with exposure of bone, which could then become necrotic. Other factors likely involved in the BRONJ etiopathogenesis are the anatomic site, bacterial infection, diabetes, smoking, concurrent medications, and genetic predisposition [1].

BRONJ is a multifactorial disease and it is therefore difficult to develop an aetiological therapy.

BRONJ management is controversial: there are no evidence-based guidelines in the literature associated with good results for a long-term followup, in particular regarding surgical procedures [2]. The main purposes of each treatment are to reduce pain and infection and slow the progression of the disease. Most of the authors privilege a noninvasive approach especially for asymptomatic stages of BRONJ (stage I in Ruggiero’staging system) (Table 1) [3].

tab1
Table 1: Clinical classification of BRONJ by Ruggiero et al. [3] (2009).

Temporary suspension of BPs offers no short-term benefit, whilst long-term discontinuation may be beneficial in stabilizing sites of ONJ and reducing clinical symptoms [3].

The position paper of AAOMS suggested the use of oral antimicrobial rinses for stage I and systemic antibiotic therapy (penicillin, metronidazole, quinolones, clindamycin, doxycycline, and erythromycin) for symptomatic stages (stages 0, II, and III) (Table 1).

The main problem of local or systemic antibacterial therapy is the shortness of clinical results producing improvement of abscess, pain, and swelling which are usually followed by a relapse of infection and symptoms after an average of three weeks. Another aspect is that these patients are usually old and under chemotherapy, are debilitated by malignancies, and are thus not able to bear the side effects of prolonged (and sometimes permanent) antibiotic schedules. Furthermore, the evolution of disease and the uncontrollable transition from stage I to advanced stages of BRONJ are not unlikely [4].

Recently, Teriparatide (N-terminal 34 amino acids of recombinant human parathyroid hormone) was reported for medical treatment of BRONJ [5]. This compound increases bone density stimulating osteoblastic bone formation and as well as bone remodelling [6]. However the treatment with such a drug should be limited to 2 years because preclinical studies showed increased risk of osteosarcoma for long-term exposure. For this reason Teriparatide should not be recommended for patients with metastatic cancer [5, 6].

Pentoxifylline and -tocopherol in addition to antimicrobial therapy induced a 74% decrease in area of bone exposure and symptoms in BRONJ patients also in early stages of disease [7].

In vitro studies support the hypothesis that local or systemic treatment with Geranylgeraniol (GGOH) improves viability and migration capacity of osteoblasts, fibroblasts, and endothelial cells with possible mucosal healing also in stage I of BRONJ [8].

Ozone therapy (OT) and Hyperbaric Oxygen Therapy (HBO) may stimulate cell proliferation and soft tissue healing reducing pain [912]. Laser applications at low intensity (low level laser therapy (LLLT)) have been reported in the literature for the treatment of BRONJ. Biostimulant effects of laser improve reparative process, increase inorganic matrix of bone and osteoblast mitotic index, and stimulate lymphatic and blood capillaries growth [1316]. OT, HBO, and LLLT are in general recommended in addition to medical or surgical therapy: good clinical results are probably associated with an improvement of traditional treatments by these adjunctive therapies.

Surgical necrotic bone debridement or resection in combination with antibiotic therapy may offer long-term palliation with resolution of acute infection and pain [17]. Mobile segments of bony sequestrum and necrotic tissue should be removed extending surgery until unaffected bone is reached [18]. For diffuse BRONJ, the resection of mandible followed by reconstruction with free fibula flaps has been proposed [1719]. In the case of large and complex surgical interventions a careful evaluation of the general conditions of each patient should be performed, including disease severity, age, and life expectancy.

The position paper of AAOMS suggested to limit surgical procedures to stage III BRONJ, but many subsequent studies reported very good results of surgery also in early stages of BRONJ.

Currently, there is no agreement with regard to the treatment of choice for stage I BRONJ and no effective unique therapy has yet been developed. The noninvasive management of these conditions is related to the prevention of the possible extension of the necrotic process, but many authors reported better results with surgical therapy than with medical treatment alone and proposed an implementation of surgical procedures, in the cases uncontrolled by local or general therapy, to limit the risk of evolution to stage III [2023] (Table 2).

tab2
Table 2: Clinical staging and management strategies by Bagan et al. [22] (2009).

A limited surgical approach in patients not responding to noninvasive medical or adjunctive therapy (OT, HBO, and LLLT) represents a good solution. Such a treatment is rapid, poorly invasive and can be performed under local analgesia in day-surgery regimen. Here we report our experience of surgical conservative treatment of stage I in a cohort of cancer and noncancer patients under BPT with long-term followup.

2. Materials and Methods

This study reports the clinical outcomes of 63 patients treated for BRONJ stage I (according to Ruggiero’s staging system) at the Oral Pathology and Laser-Assisted Surgery Unit of the University of Parma, Italy, between January 2004 and January 2011.

This study was approved by the Parma Hospital IRB and all participants signed an informed consent agreement.

In this retrospective analysis we included patients under BPT for malignancies or osteoporosis, with asymptomatic bone exposure in the maxillofacial region persisted for more than 8 weeks, without history of radiation therapy in the cervicofacial area.

Eligibility criteria for the retrospective analysis are shown as follows.

Inclusion Criteria(1)Patients under BPT for malignancies or osteoporosis with diagnosis of BRONJ in stage I.(2)Patients unresponsive to noninvasive treatments (namely, local antiseptics, antibiotic therapy, and low level laser therapy) for six months.(3)Patients considered sufficiently in health status to tolerate the surgical intervention (ASA score < 3).(4)Absence of metastasis in the region of bone exposure and the absence of deeper involvement of BRONJ.(5)Minimum followup of 6 months after surgery.

Exclusion Criteria(1)Presence of symptoms (pain) or clinical/radiological findings typical for different stages of BRONJ (erythema, purulent drainage, necrotic bone extending beyond the region of alveolar bone resulting in pathologic fracture, extraoral fistula, oral antral/oral nasal communication, or osteolysis extending to the inferior border of the mandible or the sinus floor).(2)Patients with history of radiation therapy in the maxillofacial region.(3)Patients immunocompromised (white blood cells < 2000 cells/mm3), debilitated (ASA score ≥ 3), or with serious problems of haemostasis not able to tolerate surgical intervention (platelets count < 50000 ptl/mL or INR > 3,5).(4)Patients not in agreement with specific informed consensus for surgical intervention.

Surgical interventions were performed, under local analgesia, in patients unresponsive to a period of six months of noninvasive treatments such as cycles of local or systemic antibacterial therapy combined or not to LLLT, OT, or HBO. All interventions were performed after the consultation of oncologist or physician.

For all patients all exams previously performed by their specialists (blood exams, magnetic nuclear resonance, scintigraphy, PET, and MOC) were obtained. Specific exams for BRONJ were dental X-rays, orthopantomographs, and computed tomography in order to exclude metastases in the region of bone exposure and deeper involvement of BRONJ (maxillary sinus, mandibular body and bone fractures).

The decision of BPT discontinuation before and after surgical intervention was made by the oncologist or internist.

The outcome parameters of clinical success of treatment were the absence of symptoms (pain, dysesthesia, or anaesthesia) and the presence of intact mucosa in the previous site of BRONJ without signs of infection (swelling, abscess, and fistulas) (stage 0) (Table 3) and the absence of new exposed bone near surgical area.

tab3
Table 3: Staging system of “clinical success” in the BRONJ management by Vescovi et al. [13] (2006).

Data about patients, BRONJ features, and clinical outcome after surgery were summarized in tables.

Surgical Management of Stage I BRONJ. On the basis of BRONJ pathogenesis the aim of intervention is the complete elimination of necrotic bone followed by covering of the presumptive healthy tissue with the vascularized soft tissue of the access flap.

All surgical interventions were performed under local analgesia. Prophylactic antibiotics were administered for 4 days before surgery (amoxicillin and clavulanic acid 1 gr twice a day and metronidazole 500 mg twice a day) and continued postoperatively for two weeks. The surgical procedure included a mucoperiosteal flap through a linear mucoperiosteal cut surrounding bone exposure without lateral incisions to limit the risk of reduction of vascularization. The inflamed margins of the mucosa were eliminated for two millimetres to obtain a better quality tissue to cover bone surgical area. Necrotic bone was resected with surgical drills or evaporated with an erbium laser (Er:YAG laser, wave length 2940 nm, parameters: 250 mJ 20 Hz (VSP) with a fluence of 50 J/cm2 up to 300 mJ, 30 Hz, and fluence of 60 J/cm2) until the appearance of bleeding bone under sterile saline solution irrigation (Figures 1, 2, and 3).

107690.fig.001
Figure 1: Maxillary stage I BRONJ developed in a patient who received infusions of zoledronic acid for metastasis of a breast cancer. Successfull treatment with Er:YAG laser.
107690.fig.002
Figure 2: BRONJ on the left mylohyoid crest in a patient affected by multiple myeloma—complete healing achieved after Er:YAG surgery.
107690.fig.003
Figure 3: Left maxillar BRONJ stage I in a patient treated with zoledronic acid for brest cancer.

Bone fragments and spikes were eliminated to obtain a smooth surface in order to avoid local traumatisms and to facilitate soft tissue healing over the surgical site. The surgical sites were abundantly rinsed with iodopovidone solution (10%). All surgical specimens underwent histopathological examination to confirm BRONJ diagnosis and to exclude the presence of metastasis or myeloma localization.

Wound closure was obtained by a tension-free mucosal flap sitting passively over the bone with silk suture. The sutures were removed 10 to 14 days after surgical intervention.

In the postoperative period nonsteroid anti-inflammatory drugs (NSAID), in the case of necessity, and chlorhexidine 1% gel, four times a day, were recommended.

During the post-operative follow-up each patient was visited weekly during the first month, twice a month for the two following months and once a month for the following six months. The followup was maintained every four months. Photographs were obtained before surgical interventions and during the follow-up period. The orthopantomographs, in the cases of complete mucosal healing, were obtained after six months from the surgical intervention. In cases of worsening or relapses of BRONJ new imaging exams were suddenly required.

For each patient, conforming to a protocol that satisfied the ethical standard as described by the Azienda Ospedaliero-Universitaria di Parma and University General Hospital of Valencia, Spain, we collected specific informed consensus for surgical intervention.

The algorithm of management of BRONJ in stage I is resumed as follows.

Algorithm of Stage I BRONJ Management(1)Diagnosis of stage I BRONJ: asymptomatic bone exposure in the maxillofacial region after 8 weeks of observation without history of radiation therapy in the cervicofacial area.(2)Photographs: at the first visit and during the follow-up period.(3)Prescription of radiographic exams: endoral RX, orthopantomographs and computed tomography.(4)Noninvasive treatment: for six months medical therapy (intermittent cycles of local or systemic antibacterial therapy) combined or not to alternative therapies (LLLT, OT, or HBO).(5)Evaluation of laboratory exams (blood exams including full blood count and hemostasis, epatic and renal function, magnetic nuclear resonance, scintigraphy, PET scan, MOC, etc.), and consultation with specialists (oncologists, physicians) required by their specialists.(6)Evaluation of evolution of disease: age, performance status and life expectancy.(7)Collection of informed consensus for surgical intervention.(8)BPT interruption (drug holiday): not in every case. The decision was made by the oncologists or internists on the basis of each single condition and necessity.(9)Prophylactic antibiotic therapy: amoxicillin and clavulanic acid 2 gr a day and metronidazole 1 gr a day starting 4 days before surgery.(10)Local analgesia: articaine 4%.(11)Mucoperiosteal envelope flap through a linear cut surrounding bone exposure without lateral discharge incisions.(12)Elimination of necrotic bone: with surgical drills or erbium laser to obtain a smooth surface of bleeding bone.(13)Irrigation of surgical site: with 10% iodopovidone solution.(14)Suture: 4 zero silk, tension free mucosal flap.(15)Removing of sutures: between 10 and 14 days after surgery.(16)Postoperative medical therapy: antibiotics for two weeks postoperatively, chlorhexidine 1% gel 4 times daily, and NSAID (if necessary).(17)Histopathological analysis of bony fragment: to confirm BRONJ and to exclude cancer diagnosis.

Followup is as follows:once a week during the first month, twice a month for the two following months, and once a month for six months. The followup will be maintained every four months.

3. Results

Nineteen patients were affected by multiple myeloma (MM), 29 were treated for bone metastases (BM) (48 patients, Cancer Group—CG), and 15 were taking BPs for osteoporosis (Noncancer Group—NCG). Mean BPT duration was 25.65 months for patients in CG and 90.85 months for NCG (Table 4).

tab4
Table 4: Patients with stage I BRONJ evaluated in the present study.

According to oral subsite involved, 8 and 7 patients of CG had maxillary and mandibular involvement, respectively. In NCG, 20 patients had maxillary BRONJ while 28 had mandibular involvement. A number of patients with stage 0 disease and months of followup are shown in Table 5.

tab5
Table 5: Sites of occurrence of BRONJ.

Table 6 reports the number of cases in stage I, stage II, and stage III, subclassified according site of involvement, primary disease of the patients, and treatment modality (surgical treatment, nonsurgical treatment).

tab6
Table 6: Outcome of surgical and nonsurgical treatments.

Number of sites as well as percentage of complete healing are reported in Table 7.

tab7
Table 7: Number and percentage of healed sites after BRONJ treatment.

4. Discussion

Marx et al. suggested in 2007 morning fasting serum c-terminal telopeptide (CTX)-guided drug holiday protocol for planning surgical procedures in patients under BPT [24]. Nowadays CTX test represents a controversial matter because it is not reliable in the cancer or rheumatoid patients under previous treatment with methotrexate, prednisone, and raloxafene because drugs and malignancy effects on bone confound the results of the test. In fact studies showed higher level of CTX in patients with bone metastasis and lower level of CTX in patients under suppressive therapies [25]. On the other hand different authors found normal rate of CTX or other bone turnover markers in BRONJ patients showing the absence of specific relationship between serum levels and severity of disease [2629]. Some authors reported that BPs discontinuation for a variable period (one to six months) before and after interventions favoured the surgical outcome [30]. It is still unclear if long-term drug holiday can be beneficial in stabilizing sites of BRONJ or can improve the healing after surgical procedures. The discontinuation of BPT could result in a recurrence of bone pain, progression of metastases or osteolytic lesions, or increase of related skeletal events (RSE) [31, 32]. Based on the above-mentioned considerations we did not use bone metabolism markers in our case series. To plan surgical intervention we judged general health status and blood exams. Discontinuation of BPT before surgery seems not to influence the outcome in patients with stage I disease.

Some authors reported that surgery is more successful in patients with osteoporosis or multiple myeloma than in those with solid tumors. In our experience, patients treated with early surgical approach had similar percentages of healing in the 2 groups.

Wutzl et al. and Curi et al. reported that surgical procedures in patients suffering from BRONJ (also in the cases of stage I) were made under general anaesthesia. In our experience it was possible to perform interventions in day surgery under local analgesia in all cases [30, 33].

Laser can be used for conservative surgery whereby necrotic bone is vaporised, until healthy bone is reached. The erbium laser penetrates the hard tissue for 0.1 mm, providing safety guarantees and allowing precision [34]. A gradual evaporation of the necrotic bone can be performed till healthy bleeding bone is seen. The minimally invasive technique of evaporation allows the sectioned bone surfaces to be regular and can be used to create microperforations at the base for stimulating new vascularization [35]. The additional advantages of laser surgery are the bactericidal and biostimulatory actions of the laser beam with a better postoperative recovery [36].

The percentages of clinical success in BRONJ treatment reported in the literature with this technique are very high in comparison to conventional surgery [3739]. The results in the present study confirm that the laser surgery represents a valid therapeutic option for BRONJ and enables the minimally invasive treatment of the early stages of the disease.

5. Conclusions

When making the decision to perform surgical procedures for the treatment of BRONJ, the deal between benefit and potential risks according to clinical circumstances of each patient should be considered. Surgical operations for advanced stages of BRONJ are invasive and extensive and must be performed under general anaesthesia. Only few patients may undergo this type of surgery. On the other hand a minimal and faster intervention under local analgesia is useful also for aged and immunocompromised patients. Less invasive surgery may determine a complete mucosal healing containing the microbial infection and the risk of spread of the disease.

Our result confirms that treatment of patients affected by minimal bone exposition, (stage I of BRONJ), through conservative surgical strategies, possibly with laser, may determine a higher control of lesions in the long term.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

References

  1. R. Landesberg, V. Woo, S. Cremers et al., “Potential pathophysiological mechanisms in osteonecrosis of the jaw,” Annals of the New York Academy of Sciences, vol. 1218, no. 1, pp. 62–79, 2011. View at Publisher · View at Google Scholar · View at Scopus
  2. J. Bagan, C. Scully, V. Sabater, and Y. Jimenez, “Osteonecrosis of the jaws in patients treated with intravenous bisphosphonates (BRONJ): a concise update,” Oral Oncology, vol. 45, no. 7, pp. 551–554, 2009. View at Publisher · View at Google Scholar · View at Scopus
  3. S. L. Ruggiero, T. B. Dodson, L. A. Assael, R. Landesberg, R. E. Marx, and B. Mehrotra, “American association of oral and maxillofacial surgeons position paper on bisphosphonate-related osteonecrosis of the jaws—2009 update,” Journal of Oral and Maxillofacial Surgery, vol. 67, no. 5, supplement, pp. 2–12, 2009. View at Publisher · View at Google Scholar · View at Scopus
  4. P. Vescovi, E. Merigo, M. Meleti, and M. Manfredi, “Early surgical approach preferable to medical therapy for bisphosphonate-related osteonecrosis of the jaws,” Journal of Oral and Maxillofacial Surgery, vol. 66, no. 4, pp. 831–832, 2008. View at Publisher · View at Google Scholar · View at Scopus
  5. J. D. Bashutski, R. M. Eber, J. S. Kinney et al., “Teriparatide and osseous regeneration in the oral cavity,” The New England Journal of Medicine, vol. 363, no. 25, pp. 2396–2405, 2010. View at Publisher · View at Google Scholar · View at Scopus
  6. A. Cheung and E. Seeman, “Teriparatide therapy for alendronate-associated osteonecrosis of the jaw,” The New England Journal of Medicine, vol. 363, no. 25, pp. 2473–2474, 2010. View at Publisher · View at Google Scholar · View at Scopus
  7. M. S. Epstein, F. W. Wicknick, J. B. Epstein, J. R. Berenson, and M. Gorsky, “Management of bisphosphonate-associated osteonecrosis: pentoxifylline and tocopherol in addition to antimicrobial therapy. An initial case series,” Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology and Endodontology, vol. 110, no. 5, pp. 593–596, 2010. View at Publisher · View at Google Scholar · View at Scopus
  8. T. Ziebart, F. Koch, M. O. Klein et al., “Geranylgeraniol—a new potential therapeutic approach to bisphosphonate associated osteonecrosis of the jaw,” Oral Oncology, vol. 47, no. 3, pp. 195–201, 2011. View at Publisher · View at Google Scholar · View at Scopus
  9. A. Agrillo, M. T. Petrucci, M. Tedaldi et al., “New therapeutic protocol in the treatment of avascular necrosis of the jaws,” Journal of Craniofacial Surgery, vol. 17, no. 6, pp. 1080–1083, 2006. View at Publisher · View at Google Scholar · View at Scopus
  10. C. I. Ripamonti, E. Cislaghi, L. Mariani, and M. Maniezzo, “Efficacy and safety of medical ozone (O3) delivered in oil suspension applications for the treatment of osteonecrosis of the jaw in patients with bone metastases treated with bisphosphonates: preliminary results of a phase I-II study,” Oral Oncology, vol. 47, no. 3, pp. 185–190, 2011. View at Publisher · View at Google Scholar · View at Scopus
  11. J. J. Freiberger, R. Padilla-Burgos, A. H. Chhoeu et al., “Hyperbaric oxygen treatment and bisphosphonate-induced osteonecrosis of the jaw: a case series,” Journal of Oral and Maxillofacial Surgery, vol. 65, no. 7, pp. 1321–1327, 2007. View at Publisher · View at Google Scholar · View at Scopus
  12. J. J. Freiberger, “Utility of hyperbaric oxygen in treatment of bisphosphonate-related osteonecrosis of the jaws,” Journal of Oral and Maxillofacial Surgery, vol. 67, no. 5, pp. 96–106, 2009. View at Publisher · View at Google Scholar · View at Scopus
  13. P. Vescovi, E. Merigo, M. Meleti, and M. Manfredi, “Bisphosphonate-associated osteonecrosis (BON) of the jaws: a possible treatment?” Journal of Oral and Maxillofacial Surgery, vol. 64, no. 9, pp. 1460–1462, 2006. View at Publisher · View at Google Scholar · View at Scopus
  14. P. Vescovi, E. Merigo, M. Manfredi et al., “Nd:YAG laser biostimulation in the treatment of bisphosphonate-associated osteonecrosis of the jaw: clinical experience in 28 cases,” Photomedicine and Laser Surgery, vol. 26, no. 1, pp. 37–46, 2008. View at Publisher · View at Google Scholar · View at Scopus
  15. M. Scoletta, P. G. Arduino, L. Reggio, P. Dalmasso, and M. Mozzati, “Effect of low-level laser irradiation on bisphosphonate-induced osteonecrosis of the jaws: preliminary results of a prospective study,” Photomedicine and Laser Surgery, vol. 28, no. 2, pp. 179–184, 2010. View at Publisher · View at Google Scholar · View at Scopus
  16. U. Romeo, A. Galanakis, C. Marias et al., “Observation of pain control in patients with bisphosphonate-induced osteonecrosis using low level laser therapy: preliminary results,” Photomedicine and Laser Surgery, vol. 29, no. 7, pp. 447–452, 2011. View at Publisher · View at Google Scholar · View at Scopus
  17. S. L. Engroff and D. D. Kim, “Treating bisphosphonate osteonecrosis of the jaws: is there a role for resection and vascularized reconstruction?” Journal of Oral and Maxillofacial Surgery, vol. 65, no. 11, pp. 2374–2385, 2007. View at Publisher · View at Google Scholar · View at Scopus
  18. R. Seth, N. D. Futran, D. S. Alam, and P. D. Knott, “Outcomes of vascularized bone graft reconstruction of the mandible in bisphosphonate-related osteonecrosis of the jaws,” Laryngoscope, vol. 120, no. 11, pp. 2165–2171, 2010. View at Publisher · View at Google Scholar · View at Scopus
  19. R. E. Marx, “Reconstruction of defects caused by bisphosphonate-induced osteonecrosis of the jaws,” Journal of Oral and Maxillofacial Surgery, vol. 67, no. 5, supplement, pp. 107–119, 2009. View at Publisher · View at Google Scholar · View at Scopus
  20. E. Merigo, M. Manfredi, M. Meleti et al., “Bone necrosis of the jaws associated with the use of bisphosphonates (pamidronate and zoledronate): a report of 29 cases,” Acta Bio Medica, vol. 77, no. 2, pp. 109–117, 2006. View at Google Scholar
  21. S. B. Pérez, M. V. Barreo, M. S. Hernàndez, M. Knezevic, J. M. Navarro, and J. R. Millares, “Bisphosphonate-associated osteonecrosis of the jaw. A proposal for conservative treatment,” Medicina Oral Patologia Oral y Cirugia Bucal, vol. 13, no. 12, pp. E770–E773, 2008. View at Google Scholar
  22. J. V. Bagan, Y. Jimenez, J. M. Diaz et al., “Osteonecrosis of the jaws in intravenous bisphosphonate use: proposal for a modification of the clinical classification,” Oral Oncology, vol. 45, no. 7, pp. 645–646, 2009. View at Publisher · View at Google Scholar · View at Scopus
  23. F. Wilde, M. Heufelder, K. Winter et al., “The role of surgical therapy in the management of intravenous bisphosphonates-related osteonecrosis of the jaw,” Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology and Endodontology, vol. 111, no. 2, pp. 153–163, 2011. View at Publisher · View at Google Scholar · View at Scopus
  24. R. E. Marx, J. E. Cillo Jr., and J. J. Ulloa, “Oral bisphosphonate-induced osteonecrosis: risk factors, prediction of risk using serum CTX testing, prevention, and treatment,” Journal of Oral and Maxillofacial Surgery, vol. 65, no. 12, pp. 2397–2410, 2007. View at Publisher · View at Google Scholar · View at Scopus
  25. F. Lumachi, D. A. Santeufemia, A. Del Conte et al., “Carboxy-terminal telopeptide (CTX) and amino-terminal propeptide (PINP) of type I collagen as markers of bone metastases in patients with non-small cell lung cancer,” Anticancer Research, vol. 33, no. 6, pp. 2593–2596, 2013. View at Google Scholar
  26. J. V. Bagan, Y. Jiménez, D. Gómez, R. Sirera, R. Poveda, and C. Scully, “Collagen telopeptide (serum CTX) and its relationship with the size and number of lesions in osteonecrosis of the jaws in cancer patients on intravenous bisphosphonates,” Oral Oncology, vol. 44, no. 11, pp. 1088–1089, 2008. View at Publisher · View at Google Scholar · View at Scopus
  27. S. Lehrer, A. Montazem, L. Ramanathan et al., “Normal serum bone markers in bisphosphonate-induced osteonecrosis of the jaws,” Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology and Endodontology, vol. 106, no. 3, pp. 389–391, 2008. View at Publisher · View at Google Scholar · View at Scopus
  28. T. S. Lazarovici, S. Mesilaty-Gross, I. Vered et al., “Serologic bone markers for predicting development of osteonecrosis of the jaw in patients receiving bisphosphonates,” Journal of Oral and Maxillofacial Surgery, vol. 68, no. 9, pp. 2241–2247, 2010. View at Google Scholar · View at Scopus
  29. K. E. Fleisher, G. Welch, S. Kottal, R. G. Craig, D. Saxena, and R. S. Glickman, “Predicting risk for bisphosphonate-related osteonecrosis of the jaws: CTX versus radiographic markers,” Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology and Endodontology, vol. 110, no. 4, pp. 509–516, 2010. View at Publisher · View at Google Scholar · View at Scopus
  30. A. Wutzl, S. Pohl, I. Sulzbacher et al., “Factors influencing surgical treatment of bisphosphonate-related osteonecrosis of the jaws,” Head and Neck, vol. 34, no. 2, pp. 194–200, 2012. View at Publisher · View at Google Scholar · View at Scopus
  31. L. Gallego and L. Junquera, “Consequence of therapy discontinuation in bisphosphonate-associated osteonecrosis of the jaws,” The British Journal of Oral and Maxillofacial Surgery, vol. 47, no. 1, pp. 67–68, 2009. View at Publisher · View at Google Scholar · View at Scopus
  32. T. Mawatari, “Bisphosphonates (BP) and osteonecrosis of the jaws; continuous treatment with Bisphosphonates should be considered,” Clinical Calcium, vol. 20, no. 11, pp. 1743–1747, 2010. View at Google Scholar · View at Scopus
  33. M. M. Curi, G. S. I. Cossolin, D. H. Koga et al., “Bisphosphonate-related osteonecrosis of the jaws—an initial case series report of treatment combining partial bone resection and autologous platelet-rich plasma,” Journal of Oral and Maxillofacial Surgery, vol. 69, no. 9, pp. 2465–2472, 2011. View at Publisher · View at Google Scholar · View at Scopus
  34. P. Vescovi and S. Nammour, “Bisphosphonate-related osteonecrosis of the jaw (BRONJ) therapy. A critical review,” Minerva Stomatologica, vol. 59, no. 4, pp. 181–213, 2010. View at Google Scholar · View at Scopus
  35. P. Rugani, S. Acham, A. Truschnegg, B. Obermayer-Pietsch, and N. Jakse, “Bisphosphonate-associated osteonecrosis of the jaws: surgical treatment with ErCrYSGG-laser. Case report,” Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology and Endodontology, vol. 110, no. 6, pp. e1–e6, 2010. View at Publisher · View at Google Scholar · View at Scopus
  36. P. Vescovi, M. Manfredi, E. Merigo et al., “Surgical approach with Er: YAG laser on osteonecrosis of the jaws (ONJ) in patients under bisphosphonate therapy (BPT),” Lasers in Medical Science, vol. 25, no. 1, pp. 101–113, 2010. View at Publisher · View at Google Scholar · View at Scopus
  37. P. Vescovi, E. Merigo, M. Manfredi et al., “Surgical treatment of maxillary osteonecrosis due to bisphosphonates using an Er:YAG (2940 nm) laser. Discussion of 17 clinical cases,” Revue Belge de Médecine Dentaire, vol. 64, no. 2, pp. 87–95, 2009. View at Google Scholar · View at Scopus
  38. F. Angiero, C. Sannino, R. Borloni, R. Crippa, S. Benedicenti, and G. E. Romanos, “Osteonecrosis of the jaws caused by bisphosphonates: evaluation of a new therapeutic approach using the Er:YAG laser,” Lasers in Medical Science, vol. 24, no. 6, pp. 849–856, 2009. View at Publisher · View at Google Scholar · View at Scopus
  39. S. Stübinger, J. Dissmann, N. C. Pinho, B. Saldamli, O. Seitz, and R. Sader, “A preliminary report about treatment of bisphosphonate related osteonecrosis of the jaw with Er:YAG laser ablation,” Lasers in Surgery and Medicine, vol. 41, no. 1, pp. 26–30, 2009. View at Publisher · View at Google Scholar · View at Scopus