Osteonecrosis – associated with biphosphonates

Support Care Cancer. 2016 Feb;24(2):807-13. doi: 10.1007/s00520-015-2847-x. Epub 2015 Jul 21.

The effect of laser therapy on the expression of osteocalcin and osteopontin after tooth extraction in rats treated with zoledronate and dexamethasone.

Mergoni G1, Vescovi P2, Sala R3, Merigo E2, Passerini P2, Maestri R4, Corradi D4, Govoni P5, Nammour S6, Bianchi MG3.

Author information

  • 1Unit of Oral Pathology and Laser-Assisted Oral Surgery, Department of Biomedical, Biotechnological and Translational Sciences, University of Parma, Viale Gramsci 14, 43100, Parma, Italy. gmergon@gmail.com.
  • 2Unit of Oral Pathology and Laser-Assisted Oral Surgery, Department of Biomedical, Biotechnological and Translational Sciences, University of Parma, Viale Gramsci 14, 43100, Parma, Italy.
  • 3Unit of General Pathology, Department of Biomedical, Biotechnological and Translational Sciences, University of Parma, Parma, Italy.
  • 4Unit of Pathology, Department of Biomedical, Biotechnological, and Translational Sciences, University of Parma, Parma, Italy.
  • 5Unit of Anatomy Histology and Embryology, Department of Biomedical, Biotechnological and Translational Sciences (S.Bi.Bi.T), University of Parma, Parma, Italy.
  • 6Department of Dental Sciences, Faculty of Medicine, University of Liège, Liège, Belgium.



Laser therapy has been used for the prevention and management of medication-related ostenecrosis of the jaw (MRONJ). The aim of this paper was to investigate the action of laser therapy on extraction socket healing in rats in conditions at risk for MRONJ, evaluating the expression of markers of bone metabolism.


Thirty male Sprague-Dawley rats were divided in four groups: control group (C, n?=?5), laser group (L, n?=?5), treatment group (T, n?=?10), and treatment plus laser group (T?+?L, n?=?10). Rats of group T and T?+?L received zoledronate 0.1 mg/kg and dexamethasone 1 mg/kg every 2 days for 10 weeks. Rats of group C and L were infused with vehicle. After 9 weeks, the left maxillary molars were extracted in all rats. Rats of groups L and T?+?L received laser therapy (Nd:YAG, 1064 nm, 1.25 W, 15 Hz, 5 min, 14.37 J/cm(2)) in the socket area at days 0, 2, 4, and 6 after surgery. Western blot analysis was performed to evaluate the alveolar expression of osteopontin (OPN) and osteocalcin (OCN) 8 days after extraction.


Rats of groups L and T?+?L showed a significant higher expression of OCN compared to rats of groups C and T (+348 and +400 %, respectively; P?=?0.013 and P?=?0.002, respectively). The expression of OPN did not show significant differences among the different groups.


Our findings suggest that laser irradiation after tooth extraction can promote osteoblast differentiation, as demonstrated by the higher expression of OCN. Thus, laser irradiation could be considered a way to improve socket healing in conditions at risk for MRONJ development.

Support Care Cancer. 2016 Mar 31. [Epub ahead of print]

Bisphosphonate-related osteonecrosis of the jaw: a review of the potential efficacy of low-level laser therapy.

Latifyan S1, Genot MT1, Klastersky J2.

Author information

  • 1Institut Jules Bordet, Centre des Tumeurs de l’Université Libre de Bruxelles, Bruxelles, Belgique, 1, Rue Heger-Bordet, 1000, Brussels, Belgium.
  • 2Institut Jules Bordet, Centre des Tumeurs de l’Université Libre de Bruxelles, Bruxelles, Belgique, 1, Rue Heger-Bordet, 1000, Brussels, Belgium. jean.klastersky@bordet.be.


Osteonecrosis of the jaw (ONJ) resulting from administration of bisphosphonates (BP) or denosumab is a rare but severe complication in cancer patients. Complete remission depends on the stage of ONJ; it can be estimated in the range of 20-30 %. Low-level laser therapy (LLLT) is a logical additional option, as it has been recognized effective for the management of chemotherapy and/or radiotherapy-induced mucositis. LLLT irradiation has anti-inflammatory actions and thus can help to control pain, as well as biostimulating properties with favorable actions on bacterial control and wound healing. We review the results of seven published studies of LLLT in BP-associated ONJ. LLLT results in an overall response rate of 55 % superior to that observed in controls (30 %). Our review suggests that there might be an advantage to add LLLT to the “classical” management of ONJ. This therapy is easy to administer and is not associated with any known side effects. Further research is needed to remove any doubt of protection or enhancement of carcinogenic processes. We believe that prospective well-controlled studies of LLLT in ONJ are warranted. If the positive results are confirmed, it would represent a great improvement for the quality of life of many patients.

Lasers Med Sci. 2016 Mar 30. [Epub ahead of print]

Efficacy of laser therapy in the management of bisphosphonate-related osteonecrosis of the jaw (BRONJ): a systematic review.

Weber JB1, Camilotti RS2, Ponte ME2.

Author information

  • 1School of Dentistry, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Av. Ipiranga, 6681-Building 6, Partenon, Porto Alegre, RS, 90619-900, Brazil. jbbweber@terra.com.br.
  • 2School of Dentistry, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Av. Ipiranga, 6681-Building 6, Partenon, Porto Alegre, RS, 90619-900, Brazil.


Bisphosphonate-related osteonecrosis of the jaw is a well-known potential side effect of long-term bisphosphonate therapy; the primary objective of the treatment should be to improve patient quality of life through pain and infection management, to prevent the development of new lesions, and to slow disease progression. In recent years, the use of laser for bisphosphonate-related osteonecrosis of the jaw has become more widespread, due to its use of administration and widely reported beneficial effects on tissue healing. The present systematic review of the literature sought to elucidate whether low-level laser therapy has positive effects on the treatment of bisphosphonate-related osteonecrosis of the jaw. We conducted a systematic search of the PubMed, EMBASE, and Cochrane Library electronic databases, with no restrictions on language or year of publication. Search strategies were formulated using keywords and Boolean operators. The electronic search strategy retrieved 55 records. From 55 articles, 16 were selected for full-text review, and of these, 10 were ultimately included for data analysis in this review. Our findings show that treatment modalities including laser were associated with superior outcomes in terms of cure or improvement of bisphosphonate-related osteonecrosis of the jaw lesions as compared with conventional surgical and/or conservative drug therapy. It can be concluded that combined treatment with antibiotics, minimally invasive surgery (including Er:YAG laser surgery), and low-level laser therapy in the early stages of the disease should be the gold standard for bisphosphonate-related osteonecrosis of the jaw management.

Photomed Laser Surg. 2014 Jul 21. [Epub ahead of print]

Low-Level Laser Therapy Supported Surgical Treatment of Bisphosphonate Related Osteonecrosis of Jaws: A Retrospective Analysis of 11 Cases.

Altay MA1, Tasar F, Tosun E, Kan B.

Author information

  • 11 Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Akdeniz University , Antalya, Turkey .


Abstract Objective: The aim of this study is to evaluate and report on low-level laser therapy (LLLT) supported medical-surgical treatment outcomes of 11 patients with bisphosphonate related osteonecrosis of the jaws (BRONJ) lesions.

Background data: BRONJ is a severe clinical condition, which adversely affects patients’ lives. Even though various treatment modalities have been proposed, the ideal approach still remains to be debated. LLLT stands out among supportive approaches because of its favorable effects on tissue healing.

Materials and methods: Eleven patients diagnosed with Stage II or III lesions (American Association of Oral and Maxillofacial Surgeons [AAOMS] classification) were included in the study. All patients received LLLT applications during the postoperative period in addition to medical and surgical treatment. Laser applications covering the entirety of the surgical site were performed with GaAlAs diode laser with the following parameters: 808?nm wavelength, 0.5 W power, continuous wave, noncontact mode at 0.5-1?cm distance from the oral mucosa, spot size 0.28?cm2 (R=6?mm), for 3?sec per point (10?sec per cm2), and energy density of 5?J/cm2(energy per point,1.4?J).

Results: Elimination of previously recorded symptoms and a stable mucosal closure was achieved in all patients. Primary healing was achieved in seven patients and secondary healing course was observed in four patients. Permanence of obtained positive outcomes was noted in follow-up periods.

Conclusions: Treatment of advanced BRONJ lesions with a combination of antibiotic therapy, surgical removal of the lesion, and consecutive low-level diode laser applications provided favorable results in all patients. In consideration of our findings, it can be assumed that LLLT may serve as a safe and effective adjunct to medical-surgical treatment of BRONJ lesions.

Photomed Laser Surg.  2012 May;30(5):293-7. Epub 2012 Apr 17.

Laser GaAlAs (860 nm) photobiomodulation for the treatment of bisphosphonate-induced osteonecrosis of the jaw.

da Guarda MG, Paraguassú GM, Cerqueira NS, Cury PR, Farias JG, Ramalho LM.


School of Dentistry, Graduation Program, Federal University of Bahia, Salvador, Bahia, Brazil.



The aim of this article is to report a case of bisphosphonate-induced osteonecrosis (ONJ-BP) of the jaw treated by curettage of the necrotic bone, low-level laser therapy (LLLT), and antibiotic therapy.


ONJ-BP is characterized by painful ulcerations of the oral mucosa, is prone to bone necrosis that does not heal within 8 weeks after diagnosis, and is often difficult to treat. No definitive standard of care has been established for ONJ-BP. LLLT improves wound healing, relieves pain, and appears to be a promising treatment modality for patients with ONJ-BP.


An 82-year-old man taking intravenous bisphosphonate presented with ONJ-BP after tooth extraction. The patient was treated by LLLT using a GaAlAs diode laser with the following settings: wavelength, 860 nm; 70 mW; continuous wave; and spot size 4 mm(2). An energy density of 4.2 J/cm(2) per point was applied in a punctual contact manner every 48 h for 10 days, in association with antibiotic therapy and curettage of the necrotic bone. Reduction in painful symptoms was reported after the second irradiation session, and tissue healing was complete at the end of the third week following oral curettage. The patient was followed up for 12 months and exhibited good oral health and quality of life.


The therapeutic protocol used in this study had a positive effect on tissue healing and remission of painful symptoms, resulting in better oral health and quality of life for the patient.


J Osteoporos. 2012;2012:585434. Epub 2012 May 8.

Surgical Approach and Laser Applications in BRONJ Osteoporotic and Cancer Patients.

Vescovi P, Merigo E, Meleti M, Manfredi M, Fornaini C, Nammour S.


Oral Medicine, Pathology and Laser-Assisted Surgery Unit and Section of Dentistry, Department of ENT/Dental/Ophthalmological and Cervico-Facial Sciences, University of Parma, Via Gramsci, 14-43100 Parma, Italy.


Bisphosphonates-related Osteonecrosis of the Jaw (BRONJ) has been reported with increasing frequency in literature over last years, but its therapy is still a dilemma. One hundred ninety patients affected by BRONJ were observed between January 2004 and November 2011 and 166 treated sites were subdivided in five groups on the basis of the therapeutical approach (medical or surgical, traditional or laser-assisted approach, with or without Low Level Laser Therapy (LLLT)). Clinical success has been defined for each treatment performed as clinical improvement or complete mucosal healing. Combination of antibiotic therapy, conservative surgery performed with Er:YAG laser and LLLT applications showed best results for cancer and noncancer patients. Nonsurgical approach performed on 69 sites induced an improvement in 35 sites (50.7%) and the complete healing in 19 sites (27.5%), while surgical approach on 97 sites induced an improvement in 84 sites (86.6%) and the complete healing in 78 sites (80.41%). Improvement and healing were recorded in 31 (81.5%) and 27 (71.5%) out of the 38 BRONJ sites treated in noncancer patients and in 88 (68.75%) and in 69 (53.9%) out of the 128 in cancer patients.

Photomed Laser Surg. 2011 Jan 16. [Epub ahead of print]

Observation of Pain Control in Patients with Bisphosphonate-Induced Osteonecrosis Using Low Level Laser Therapy: Preliminary Results.

Romeo U, Galanakis A, Marias C, Vecchio AD, Tenore G, Palaia G, Vescovi P, Polimeni A.

1 Department of Oral Sciences, “Sapienza” University of Rome , Rome, Italy .


Abstract Background: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is an adverse side effect associated with bisphosphonate (BP) therapy, especially when parenteral BP administration is used. Patients affected by BRONJ present wide areas of exposed necrotic bone, particularly after surgical oral procedures. The main symptom is pain that is poorly controlled by common analgesic drugs. Recently, many studies have pointed to the beneficial effect of low-level laser therapy (LLLT) in pain reduction for many pathological conditions. The purpose of this study is to investigate whether LLLT could be helpful in managing BRONJ by reducing the problems associated with this condition and the use of analgesic drugs. Methods: Twelve patients affected by BRONJ were monitored at the Complex Operative Unit of Oral Pathology. Among these patients, only seven referred to pain in necrotic areas and were recruited for LLLT. Laser applications were performed with a double diode laser simultaneously emitting at two different wavelengths (??=?650?nm and ??=?904-910?nm, spot size?=?8?mm). All of the patients were irradiated with a fluence of 0.053?J/cm(2) for 15?min five times over a period of 2 weeks, in a non-contact mode, ?1?mm from the pathologic area. The patient’s maximum and minimum pain was recorded using a numeric rating scale (NRS) evaluation before and after the treatment. Statistical analysis was performed using the Kruskal-Wallis test. Results: Six patients showed significant pain reduction, and only one patient indicated a worsening of the symptoms, which was probably related to a reinfection of the BRONJ site, which occurred during the study. A statistically significant difference (p?<?0.05) was found between the NRS rates before and after the protocol. Conclusions: This pilot study suggests that LLLT may be a valid technique to support the treatment of BRONJ-related pain, even though the low number of cases in this study does not permit any conclusive consideration.

Lasers Med Sci. 2010 Jul 29. [Epub ahead of print]

Low-level laser therapy supported teeth extractions of two patients receiving IV zoldendroate.

Kan B, Altay MA, Ta?ar F, Akova M.

Faculty of Dentistry, Department of Oral and Maxillofacial Surgery, Hacettepe University, Ankara, Turkey, bahadirk@hacettepe.edu.tr.


BRONJ (bisphosphonate-related osteonecrosis of jaws) is a frequently encountered disease, particularly in the maxillofacial region, and a consequence of bisphosphonate use. Treatment of BRONJ remains controversial, as efficiency of medical and surgical approaches as well as a combination of these methods with supportive treatments have not been clearly demonstrated in the literature. In recent years, laser usage alone or in combination with the main therapy methods, has become popular for the treatment of bisphosphonate-related osteo-necrosis of jaws. In this article, we present the successful management of two dental patients who had high potentials for BRONJ development as a result of chemo and radiotherapy combined with IV zoledronic acid application. Multiple consecutive teeth extractions followed with primary wound closure and LLLT applications were performed under high doses of antibiotics prophylaxis. Satisfactory wound healing in both the surrounding soft and hard tissues was achieved. LLLT application combined with atraumatic surgical interventions under antibiotics prophylaxis is a preferable approach in patients with a risk of BRONJ development. Adjunctive effect of LLLT in addition to careful infection control on preventing BRONJ was reported and concluded.

Minerva Stomatol. 2010 Apr;59(4):181-213.

Biphosphonate-Related Osteonecrosis of the Jaw (BRONJ) therapy.  A critical review.

Vescovi P, Nammour S.

Director of EMDOLA (European Master Degree on Oral Laser Applications), Unit of Oral Pathology and Medicine and laser-assisted Oral Surgery, Section of Dentistry – paolo.vescovi@unipr.it.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is an area of uncovered bone in the maxillo-facial region that did not heal within 8 weeks after identification by health care provider, in a patient who was receiving or had been exposed to Bisphosphonate Therapy (BPT) without previous radiation therapy to the craniofacial region. Low-grade risk of ONJ is connected with oral BPT used in the treatment of osteopenia, osteoporosis and Paget’s disease (from 0.01% to 0.04%) while higher-grade risk is associated with intravenous (IV) administration in the treatment of multiple myeloma and bone metastases (from 0.8% to 12%). The management of BRONJ currently is a dilemma. No effective treatment has yet been developed and interrupting BPT does not seem to be beneficial. Temporary suspension of BPs offers no short-term benefit, whilst long term discontinuation (if systemic conditions permit it) may be beneficial in stabilizing sites of ONJ and reducing clinical symptoms. The use of oral antimicrobial rinses in combination with oral systemic antibiotic therapy -penicillin, metronidazole, quinolones, clindamycin, doxycycline, erythromycin- is indicated for Stages I and II of Ruggiero’s Staging. The role of hyperbaric oxygen therapy is still unclear but some benefits of this treatment have recently been described in association with discontinuation of BPT and conventional therapy (medical or/and surgical). Surgical treatment, in accordance to the AAOMS Position Paper, is reserved to patients affected by Stage III of BRONJ even if in the last version (2009) a superficial debridement is indicated to relieve soft tissue irritation also in the stage II (lesions being unresponsive to antibiotic treatment). Aggressive surgical treatment may occasionally results in even larger areas of exposed and painful infected bone. Surgical debridement or resection in combination with antibiotic therapy may offer long-term palliation with resolution of acute infection and pain. Mobile segments of bony sequestrum should be removed without exposing unaffected bone. If pathological fractures or complete mandibular involvement are observed, if the medical condition of the patients allows it the affected bone portion may be resected and primary bone reconstruction or revascularization graft may be carried out. Ozone therapy in the management of bone necrosis or in extractive sites during and after oral surgery in patients treated with BPs may stimulate cell proliferation and soft tissue healing. 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. Laser can be used for conservative surgery, whereby necrotic bone is vaporized, until healthy bone is reached. The Er:YAG laser wavelength has a high degree of affinity for water and hydroxyapatite, hence both soft and bone tissues can be easily treated. An additional advantage of the Er:YAG laser is its bactericidal and possible biostimulatory action, accelerating the healing of both soft and bone tissues, in comparison to conventional treatments. Long-term, prospective studies are required to establish the efficacy of drug holidays in reducing the risk of BRONJ for patients receiving oral BPs even if it has been suggested that BPT may be discontinued for three months before the surgical procedures and bone turnover markers (CTx, NTx, PTH, 1,25-dihydroxy vitamin D) may be checked. However it must be recognized that interindividual variability, gender, age, physical activity, and seasonal and circadian variation exist that can result in difficulty in interpreting these assays and more research is needed. Laser application (LLLT and laser surgery) nowadays appears to be a promising modality of BRONJ treatment, being safe and well tolerated, and it permits the minimally invasive treatment of early stages of the disease.

Photomed Laser Surg. 2010 Apr;28(2):179-84.

Effect of low-level laser irradiation on bisphosphonate-induced osteonecrosis of the jaws: preliminary results of a prospective study.

Scoletta M, Arduino PG, Reggio L, Dalmasso P, Mozzati M.

Oral Surgery Unit, Dentistry Section, Department of Clinical Physiopathology, University of Turin, Turin, Italy.


OBJECTIVE: The aim of this study was to detail the clinical efficacy of low-level laser therapy (LLLT) for the management of bisphosphonate-induced osteonecrosis of the jaws (ONJ-BP).

BACKGROUND: ONJ-BP is the correct term, recently emerged, to describe a significant complication in a subset of patients receiving drugs such as zoledronic acid, pamidronate, and alendronate. No definitive standard of care has been set for ONJ-BP and no definitively agreed guidelines have been provided. There is currently no consensus on the correct approach to the issue.

MATERIALS AND METHODS: The investigators studied a prospective cohort of 20 patients affected by ONJ-BP, who received biostimulation with a pulsed diode laser (GaAs). Patients were exposed to a 904-nm infrared laser (50 kHz, 28.4 J/cm(2) energy density, 40% duty cycle, spot size 0.8 cm). Outcome variables were the size of lesions, edema, visual analogue score of pain, presence of pus, fistulas, and halitosis. Preoperative results were compared with the postoperative outcome and statistically evaluated.

RESULTS: Four weeks after LLLT, a statistically significant difference was observed for reported pain (p = 0.0001), clinical size (p = 0.0034), edema (p = 0.0005), and presence of pus and fistulas (p = 0.0078 and p = 0.03, respectively).

CONCLUSION: This study suggests that LLLT would appear to be a promising modality of treatment for patients with ONJ-BP, providing that clinical efficacy is safe and well tolerated, especially by those patients who require conservative treatment. Of course, this needs to be addressed further in larger and randomly controlled studies in different clinical settings.

Lasers Med Sci. 2010 Jan;25(1):101-13. Epub 2009 Jun 19.

Surgical approach with Er:YAG laser on osteonecrosis of the jaws (ONJ) in patients under biphosphonate therapy (BPT).

Vescovi P, Manfredi M, Merigo E, Meleti M, Fornaini C, Rocca JP, Nammour S.

Oral Medicine and Laser-Assisted Surgery Unit- Section of Dentistry – Department of ENT/Dental/Ophtalmological and Cervico-Facial Sciences, EMDOLA (European Master Degree on Oral Laser Applications) – University of Parma, Parma, Italy. paolo.vescovi@unipr.it.

Osteonecrosis of the jaw (ONJ) in patients on long-term bisphosphonate Therapy (BPT) has been reported with increasing frequency in literature over the past 4 years. Therapy for this condition is still a dilemma. Temporary suspension of BPT offers no short-term benefits; hyperbaric oxygen has no proven efficacy and therefore is not recommended. Intermittent or continuous antibiotic therapy with surgical debridement can be beneficial to palliate the symptoms. Er:YAG laser can be used to eliminate necrotic bone portions by partial or total resection as an alternative to conventional rotary devices. In our study, 91 patients affected by ONJ-BP lesion, for a total of 115 ONJ sites were observed between January 2004 and May 2008 (Department of Odontostomatology, University of Parma). Fifty-five ONJ sites were considered for this study in four different groups, retrospectively identified on the basis of treatment performed (G1-G4). G1: 13 ONJ-BP sites were treated with medical therapy (amoxicillin 1gr x 3/die per os with metronidazole 250 mg x 2/die per os) for at least 2 weeks; G2: 17 ONJ-BP sites received medical treatment in association with cycles of low-level laser therapy (LLLT) applications performed using an Nd:YAG laser (1,064 nm) once a week for 2 months; G3: 13 ONJ-BP sites were surgically treated (sequestrectomy of necrotic bone, debridement, corticotomy/surgical removal of alveolar and/or cortical bone); G4: 12 ONJ-BP sites were treated with surgical therapy performed using an Er:YAG laser (2,940 nm) in association with LLLT. Clinical success has been defined for each treatment performed as: (a) complete mucosal healing free from signs and symptoms (classified as stage “0”) or (b) transition from a higher to a lower stage (Ruggiero staging) for at least 3 months. All the ONJ-BP sites treated with Er:YAG laser (G4 group) had a clinical improvement (100%) and 87.5% of sites had a complete mucosal healing with a mean follow-up of 13 months. The result obtained in the G4 is extremely significant in comparison with those obtained by medical treatment alone or in a traditional surgical approach. Thanks to the high degree of affinity of this wavelength for water and hydroxyapatite, both soft and bone tissues can be easily treated. This technique can also be used for conservative operations whereby necrotic bone is vaporized until healthy bone is reached. In addition, an additional advantage of the Er:YAG laser is its bactericidal and possible biostimulatory action, accelerating the healing of both soft tissues and bone tissues, in comparison to conventional treatments. In conclusion, from our experience, it is possible to observe that an early conservative surgical approach with Er:YAG laser associated with LLLT, for BP-induced ONJ could be considered as more efficient in comparison with medical therapy or other conventional techniques.

Ther Clin Risk Manag. 2009; 5: 217–227.Published online 2009 March 26. PMCID: PMC2697532

Copyright © 2009 Borgioli et al, publisher and licensee Dove Medical Press Ltd.

Biphosphonates-related osteonecrosis of the jaw: Clinical and physiopathological considerations.

Alberto Borgioli,1 Christian Viviani,1 Marco Duvina,1 Leila Brancato,1 Giuseppe Spinelli,1 Maria Luisa Brandi,2,3 and Paolo Tonelli1

1Department of Odontostomatology, Dental School; 2Department of Internal Medicine; 3DeGene Spin-off, Medical School, University of Florence, Florence, ItalyCorrespondence: Maria Luisa Brandi, Department of Internal Medicine, University of Florence, Medical School, Viale Pieraccini, 6. 50139 Florence Italy, Tel +39 0554 296 586, Fax +39 0554 296 585, Email m.brandi@dmi.unifi.it

This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.


Since osteonecrosis of the jaw was related to biphosphonate administration by Marx, studies showing clinical symptoms, drug and surgical therapies overwhelmed the literature. Furthermore, the literature demonstrated the correlation between chronic biphosphonate adsumption and osteonecrosis of the jaw onset. Nitrogen-containing biphosphonates are widely used for the management of metastatic cancer, for prevention and treatment of osteoporosis, for the treatment of Paget’s disease, and for the management of acute hypercalcemia. According to our experience, the treatment of BRON-J’s lesions is difficult and prolonged. For this reason, in order to avoid these complications it is mandatory to perform a risk staging in patients who must undergo biphosphonate administration. When pharmacologic treatments with antibiotics and local antiseptics are not able to control the development of BRON-J’s complications, the clinicians should perform radical surgical treatments such as the resection of the bone involved.

Keywords: osteonecrosis of the jaw, biphosphonates, BRON-J


Osteonecrosis of the jaw is a chronic osteomielitis that recognizes a multifactorial genesis, connected to both local and systemic factors. The relevant systemic factors capable to influence development of osteonecrosis of the jaw encompass immunosuppression, chemotherapy, corticosteroid therapy, and endocrine diseases.

Pharmacologic-related osteonecrosis of the jaw (BRON-J) in oncologic patients treated with intravenous biphosphonates was an unknown clinical entity until 2003, when Marx described 36 cases of BRON-J in patients affected by malignant tumors.1 Biphosphonates stand as an important group of drugs for the treatment of metabolic and oncologic pathologies involving the skeletal system. Biphophonates act by inhibiting osteoclastic bone resorption. The most common drugs utilized in the prevention and therapy of osteoporosis are: alendronate, risendronate, ibandronate, and clodronate. Pamidronate and zolendronate are utilized in the prophylaxis of bone complications and in the hypercalcemia associated to multiple myeloma and to metastatic bone disease due to breast and prostatic cancer. All these chemical substances are characterized by a high power and selectivity. Nowadays, the literature demonstrates the correlation between chronic biphosphonate assumption and onset of osteonecrosis of the jaw.

BRON-J: history and definition

Since Marx’s study other studies on BRON-J have been published. In 2004, Ruggiero and colleagues published 63 cases of BRON-J, with the majority of cases being dependent on the use of intravenous biphosphonate administration in cancer patients and only few patients treated with oral biphosphonates for osteoporosis.2

In 2005, Marx published 119 cases of BRON-J and correlated it to the type of drug used, to the invasiveness of the oral treatments, to the dose, and to the assumption length for a given drug.3 In the same year, Scientific Societies published the first position paper on the topic. The American Academy of Oral Medicine described clinical manifestations of these lesions, suggested potential clinical ways to prevent and to treat the affected patients.4

Several authors later reported extensive revisions of myeloma and metastatic cancer disease treated with intravenous biphosphonates, correlating the extension and evolution of this complication to the type of drug and to the length of treatment.57

Intravenous biphosphonates became a standard therapy for the control of complications in metastatic bone disease, such as pain, local compression, spontaneous fractures, and hypercalcemia. In several clinical studies, nitrogen-containing molecules (ibandronate, pamidronate, zolendronate) showed to be more effective in controlling manifestations of systemic malignant bone disease if compared to clodronate, with zoledronate being the most potent drug in reducing bone lesions extension and in delaying the development of the first bone metastasis.8,9

Despite the high risk of BRON-J development in oncologic patients the American Society of Clinical Oncology10 recommends the use of zoledronic acid even in patients with asintomatic metastases or disease in progress.11

In 2006, significant data emerged from an American Association of Oral and Maxillofacial Surgeons position paper that reported a consistent incidence of BRON-J, depending on prolonged biphosphonate treatment together with other related risk factors, such as tooth-alveolar bone pathological conditions of inflammatory nature.12 This is especially true for patients suffering from multiple myeloma, and breast or prostatic cancer.

The American Association of Oral and Maxillofacial Surgeons also declared a clear disease staging, from not visible oral lesions to more severe clinical pictures, such as the presence of bone sequestrum and jaw osteolytic complications, proposing different therapeutic protocols based on the stage of this pathology.12

The American Association of Oral and Maxillofacial Surgeons12 established universal criteria for the BRON-J tassonomic picture that was valid when three phenotypes were present:

  • 1) Previous or in progress assumption of biphosphonates;
  • 2) Exposed necrotic bone of the jaws for more than eight weeks;
  • 3) No history of radiotherapy of the maxillofacial region.

A strict correlation between BRON-J and chronic administration of biphosphonates, with incidence ranging from 0.8% to 12% is a well recognized phenomenon.13 Until 2002, however, the incidence was less than a single case out of 10,000 treated patients1 and these data refer to patients treated with nonaminobiphosphonates, such as etidronate or clodronate, at doses used in the therapy of osteoporosis. With the introduction of aminobiphosphonates (risedronate, zoledronate, ibadronate, and aledronate) more powerful in inhibiting bone resorption and in preventing osteoporotic fractures, the incidence of this complication grew to a relevant proportion of patients, especially in these with cancer, with multiple myeloma or metastatic breast, prostatic, or kidney cancer.

As suggested by the American Society of Clinical Oncology,14 zoledronate and pamidronate show a high potency in inhibiting bone and are the chosen therapies in the treatment of the malignant disorders of the skeleton. The potency of these molecules together with their intravenous administration at high dosage in oncologic patients represent the basis for the high incidence of BRON-J in these subjects when compared to osteoporotic patients treated for the prevention of fragility fractures.15 Another potential factor that plays a role in the development of BRON-J is the affinity for the hydroxyapatite crystals by the aminobiphosphonate, with zoledronate showing the highest affinity versus other molecules of this group.

The American Association of Oral and Maxillofacial Surgeons12 pointed out to other potential risk factors for BRON-J onset, such as systemic corticosteroid therapy, smoke, alcohol, bad oral hygiene conditions, chemotherapy, radiotherapy, diabetes, and blood clot diseases. The permissive local factors are: oral surgical treatments, flogistic lesions, and an excessive pressure of the removable denture on a thin mucosa.16

There is no doubt that many factors must occur in BRON-J development, such as intravenous prolonged biphosphonate administration, and a chronic or an acute periodontitis, both responsible for medullary osteomyelitis of the jaw.3

The higher incidence in females than in males could be referred to a longer exposure to oral therapy with biphosphonates in osteoporosis and to a higher incidence of breast cancer17 in women versus men.

From a pathological point of view, BRON-J, such as osteomyelitis, begins in the undifferentiated connective bone tissue, in the Haversian wall vasa, and in the bone marrow spaces. The process progression towards the cortical bone and the periostium leads to the concurring presence of several anatomopathologic aspects of the lesion: osteolysis associated to essudation or to weak growth of granulation tissue; osteonecrosis with slow but progressive bordering of sequestra; suppurated oral/extra-oral fistula caused by superinfection of necrotic tissue; absence of bone remodelling, hence bone condensation at the border of the sequestrum; and hypotrophy or atrophy following loss of the bone sequestra with low coverage of defect by soft tissues.

According to the American Association of Oral and Maxillofacial Surgeons position paper, one can stage BRON-J’s patients in two groups: patients treated with aminobiphosphonates with no exposed bone segments (patients at risk of BRON-J development); and patients presenting BRON-J with exposed and necrotic bone segments.

Bone exposure for more than eight weeks can worse the clinical picture. In fact, the exposed areas located in the lower jaw and having different size (from post-extraction socket site to larger areas or multiple areas) remain asymptomatic and with no signs of flogosis. The necrotic bone areas and exposed bone cause pain due to acute inflammation of surrounding soft tissues. Mucosa is reddish, swollen, bleeding and strongly painful on light pressure. Teeth close to the involved bone are often mobile and a local reactive limphoadenopathy can be noticed. The clinician can still manage this stage of pathology with conservative procedures and medical therapy; including antibacterial agents to fight infections that involve the exposed and necrotic bone.12

Purulent debris are present in endoral abscessual cavities (if the purulent swelling is held by periostium and then by perimaxillary muscels) or in extraoral cavities called perioral phlegmon (if the osteolytic area is beyond perimaxillary muscles insertions). In the first case purulent material drains in the oral cavity. In the second case, purulent material drains in preconstituted anatomical spaces delimited by connective tissue layers of the neck. Maxillary phlegmon can involve canine or buccal spaces. Mandibular phlegmon can involve submental, submaxillary, sublingual, submandibular spaces. In this case the phlogosis exceeding these anatomical limits can spread (for contiguity or through the lymphatic system) to the secondary spaces such as pterygomandibular, lateropharyngeal, masseteric and pterigo-maxillar spaces.18

The different thickness of the cortexes justifies the earlier externalization if the pathologic process is located in the upper jaw. In the lower jaw the osteolytic damage tend to became deeper sometimes reaching the inner edge of the mandibula (Figures 1, ,2).2). The involved bone can fracture spontaneously because of its reduced elasticity. Furtheremore the purulent material can compress nerve endings, causing local paresthesia.19,20 This phase, often following the relapse of the oncologic disease and/or the antiblastic treatment associated to corticosteroid therapy is defined as “complicated phase.”

Figure 1Osteolytic lesion in the lower jaw of patient treated with Zometa® for 12 months (59 years old, female, breast cancer).
Figure 2Worsening of the lesion after sequestrectomy in patient treated with Zometa® for 12 months (59 years old, female, breast cancer).

This phase is characterized by purulent phlogosis, by the presence of fistulae (Figure 3), by spontaneous fractures, by compromized general physical condition with fever, and by reactive adenopathy. In this stage conservative treatments associated to prolonged antibiotic therapy can be useless because of the gravity and the extension of the process, with a radical surgery being more indicated.

Figure 3Cutaneous fistula in patient treated with Aredia® and Zometa® for 24 months (48 years old, female, breast cancer).

BRON-J diagnosis

BRON-J diagnosis is quite clear if one refers to anamnesis, natural history of the oncologic pathology and/or biphosphonates administration. The evidence of the clinical lesion is confirmed with conventional X-rays showing a radiopaque sequestrum usually rounded by diffused radiolucency with a blurred contour due to the higher mineralization of the jaw. This aspect, due to the fixation of calcium in the bone tissue, is responsible for the patchy-ragged multilocular appearance of the involved area and it assumes a higher definition when a radiolucent osteolytic process with a central radiopaque mass of necrotic bone is identified at its periphery.

Computed tomography (CT) can help allow a higher definition of the necrotic foci and their relationships with the surrounding anatomical structures, making possible to quantify the bone sclerosis status. However, CT is not useful either in the staging of the asymptomatic patients or in the differential diagnosis between a primary tumor (with osteolytic aspect and ill-defined borders) and metastatic spreads of prostatic or breast cancer with sclerotic aspect (Figure 4). With CT it can be easier to detect mandibular myeloid lesions in high vascularized areas with their “mould”, regular and well defined characteristics. In these cases the use of a contrast medium can help to better identify the lesions.

Figure 4Computed tomographic scan of the bone sequestrum in patient treated with Zometa® for 5 months (75 years old, female, breast cancer).

Once the sequestrum and the periosteal reactive bone deposition have been identified by CT, magnetic resonance imaging (MRI) is useful to evaluate the quality of overlying soft tissues and the medullary edema, which is a sign of ischemia and bone necrosis.

The scintigraphy (Tc99-scan) is the most sensitive diagnostic device to identify maxillary edema with vascular alterations and to localize bone necrosis even at early stages of the disease. Nevertheless this diagnostic technique has a limit: Tc99-scan is not able to make a differential diagnosis with the metastatic process.21,22

The biopsy of the bone lesions must be carefully evaluated, because the procedure itself may damage bone tissue by creating a wound which can hardly heal.23


Nitrogen-containing biphosphonates are used widely for the management of metastatic cancer in bone (intravenous zoledronic acid or pamidronate), for the prevention and treatment of osteoporosis (oral alendronate, risedronate, and ibandronate) for the treatment of Paget’s disease of bone (intravenous pamidronate and oral aledronate and risedronate), and for the short-term management of acute hypercalcemia (intravenous zoledronic acid and pamidronate).24,25 The nitrogen moiety attached to the side chain of the middle carbon of the phosphorus–carbon–phosphorus biphosphonate backbone renders these drugs much more potent as inhibitors of bone resorption than the bisphosphonates that do not contain nitrogen (etidronate and clodronate). Bisphosphonates reduce the survival and function of osteoclasts, the bone-resorbing cells. These antiresorptive actions largely account for the drugs’efficacy in conditions in which the rate of bone resorption exceeds the rate of bone formation.

Until recently, the only adverse events of substantial consequence associated with the nitrogen-containing bisphosphonates were upper gastrointestinal intolerance (with oral administration) and a short-lived acute phase reaction characterized by fever, myalgias, and an influenza-like syndrome (with intravenous administration). Now another potential complication of these agents–osteonecrosis of the jaw–has surfaced.26,27

The Florence experience

Patient’s characteristics

Based on these premises, the aim of the present study was the description of clinical and anatomopathological aspects of the disease, based on our experience in the management of BRON-J.

From February 2004 to September 2006, 19 patients (14 females and 5 males) with BRON-J undergoing intravenous biphosphonate treatments for cancer were examined at the Oral Surgery Department of the Florence University Hospital.28,29 The mean age was 66.4 ± 11.7.

In 14 patients the used biphosphonate was zolendronate, in one patient pamidronate and in four patients both drugs were administrated. The mean interval administration was 12 months (minimum 5 months, maximum 36 months).

In nine patients (47.4%) the oncologic disease was breast cancer, in six patients (31.5%) myeloma, in three patients (15.8%) prostatic cancer, and in one patient (5%) colon cancer. All the patients were chosen following strict diagnostic criteria. The most frequent symptoms were: spontaneous pain, swelling, odontogenic abscesses, oral fistulas, bone exposure due to mucosal ulcer, post-extraction alveolitis, and local limphoadenopathy.

The trigger factors were considered to be tooth extractions in 10 patients (52.6%), local concussion (inadequate removable total denture, edentulous ridges) in two (10.5%), root canal treatment in two (10.5%), and surgery in three (15.7%). In some cases it was not possible to identify a trigger factor. In 10 patients (52.6%) a pre-existing inflammatory lesions appeared to worsen the development of the disease.

The patients were treated with mouth rinses (chlorhexidine gluconate 0.12% three times/daily); local or systemic antibiotic therapy (amoxicillin 1 g three times/daily; repeated local application of methronidazol) and, in case of mycotic overinfection, with fluconazole 200 mg/daily. Furthermore patients underwent hyperbaric treatment.

The treatment of this lesion is extremely difficult and prolonged. There are no data to support any therapeutic choice: surgery often worsens the pathology.

Surgical curettage to achieve mechanical debridement are indicated in patients with no complications. More invasive surgical treatment (such as deeper courettage, sequestrectomies, large resections, and vascularized bone grafts) are indicated after clinical changes characterized by clinical symptoms (pain, fever), oral or extra oral fistula, necrotic tissue, pathologic fractures and ineffective antibiotic treatment. In our study 13 patients out of 19 were treated with curettage and two with major surgery (segmentary mandibulectomy). Four patients were not operable.

After one-year follow-up, in most of the cases complete healing was not observed, although therapeutic protocol was strictly applied. All cases of maxillary location (two out of 19) reached complete healing thanks to secondary wound closure after two months from surgery. On the contrary we observed only symptoms of improvement in case of mandibular location, probably for the reduced regenerative capacity at this site.

In all patients pharmacological biphosphonate treatment was suspended. The interruption of biphosphonate assumption is one of the most difficult decision and should be taken in agreement with the oncologist. According to Migliorati and colleagues31 the suspension of biphosphonate treatment is mandatory, even though there is no immediate clinical improvement.

Results and discussion

The treatment of these lesions is extremely difficult and prolonged. There are no data to prefer any therapeutic choice over another, even though surgery appears to worsen the disease’s course.

Surgical curettage to achieve mechanical debridement is indicated in patients without complications. Chemical debridement is carried out with antiseptic irrigations and with iodine gauze. Re-infection prevention is improved by local ointment use and 0.12% chlorhexidine daily rinses. Surgical procedures to achieve a mechanical debridement of necrotic tissue, broad spectrum antibiotic treatment for a long period, and local antibiotic use are of benefit before the progression to bone exposure and to small bone sequestra. More invasive surgical treatment (such as deeper curettage, sequestrectomies, large resections and vascularized bone grafts) are indicated in the occurrence of systemic clinical symptoms (pain, fever), of oral or extra-oral fistulas, of necrotic tissue, of pathologic fractures, and of lack of response to antibiotic treatment. The necrotic tissue curettage, sequestrectomy, sliding flap procedure (in two cases with oro-antral communication) and peduncle vascularized bone graft (in case of fracture) were the surgical treatments used in order to stop osteonecrotic lesion progression (Figure 5).

Figure 5Spontaneous fracture of the lower jaw in patient treated with Aredia® and Zometa® for 24 months (43 years old, female, breast cancer).

Metastatic foci were not shown by histological examination both in the lesion core and in the neighbouring bone tissue. Macroscopic healthy bone samples showed cortical necrosis with well preserved lamellar bone. Furthermore, empty osteocytic lacunae were detected and medullary bone tissue appeared necrotic.

All cases of maxillary location reached complete healing. In the majority of the cases of extra-maxillary location, 14 patients (73.6%) complete healing was not achieved, although the therapeutic protocols were strictly applied.28,29 We observed only symptoms of improvement when the location was in the lower jaw: five patients (26.3%), probably for the reduced regenerative capacity at this site.

Following the American Association of Oral and Maxillofacial Surgery’s staging and treatment criteria,12 two different clinical courses have been identified: early clinical course, where a small bone sequestrum was identified (Figure 6); and late clinical course, where large neocrotic areas worsened by suppurative phlogosis were detected (Figure 7).

Figure 6Early clinical picture of the lower jaw in patient treated with Aredia® and Zometa® for 24 months (48 years old, female, breast cancer).
Figure 7Advanced lesion of the upper jaw in patient treated with Zometa® for 12 months (69 years old, male, multiple myeloma).

The present data showed a higher incidence of BRON-J in patients treated with intravenous zolendronate and pamidronate. Clinical pictures varied from a more limited osteonecrosis areas with or without suppurative phlogosis to larger osteonecrotic areas with suppurative phlogosis, jaw fractures and extra-oral fistulae (Figure 8).

Figure 8Abscessual complication of necrotic bone lesion in patient treated with Zometa® for 11 months (61 years old, male, prostatic cancer).

In nine patients (47.3%) we noticed a heavy odontalgia following the extraction of teeth located in the maxillary area involved by BRON-J. Before teeth extraction, the pain was referred to periodontitis involving both the involved teeth and the maxillary area close to them. The role of biphosphonates in the onset of the lesion was confirmed by the time elapsed between drug assumption and the lesions’ development (about 18 months for zoledronate and about six years for pamidronate),30 with reports of lesions initiated even after five months from the beginning of treatment.31,32 All the patients of our study underwent a drug treatment longer than six months. The length of biphosphonate treatment represents a risk factor for BRON-J along with chemotherapy, multiple myeloma, renal failure, corticosteroid treatment, anemia, hypoproteinemia, infections etc.30,34 Six patients out of 14 under chemotherapeutic and radiotherapy treatment presented larger tissue necrosis refractory to the applied therapeutic protocols.

In our study, preferential location of osteonecrotic lesions was in the lower jaw: in 14 patients (73.6%) the location was in the mandible, in two patients (10.6%) was both mandible and maxillary, and in three patients (15.8%) was only maxillary. The location in the mandible seems to be explained by terminal vascularization, lower quantity of trabecular bone in the lower jaw, and more frequent microinjures due to removable denture and masticatory forces.3,20

In order to categorize patients with BRON-J, the American Association of Oral and Maxillofacial Surgeons recognized three stages of the disease.12 In stage 1, the bone is exposed but there is no soft tissue inflammatory swelling. Sometimes there is pain before bone exposure. In stage 2, bone is exposed with associated pain and soft tissue infection. In stage 3, the patient is affected by the pathologic fractures, oral and extra-oral fistulae.

According to previous publications.16,35,36 and American Association of Oral and Maxillofacial Surgeons’ guidelines, we treated patients in Stage 1 (five patients; 26,3%) and Stage 2 (nine patients; 47.4%), with small sequestra, using pharmacologic and conservative protocols. In Stage 3 (five patients; 26.3%), when the large suppurative necrotic area did not heal, the conservative treatment led to poor results so a more invasive surgical treatment should be indicated (Table 1).37

Table 1Treatment of patients with osteonecrosis of the jaw

Under a therapeutic point of view the clinician should be paid attention to the perimaxillary soft tissue study, and to their vascularization since a periostium and mucosa highly vascularized are the only possibility to try to cover the necrotic area after the removal of the sequestrum.

Oxygen therapy with a hyperbaric chamber is useful to prepare the patient to the surgical treatment and platelet-rich plasma to improve soft tissue attachment (Figure 9).3842

Figure 9Use of platelet-rich plasma in the surgical treatment of the lesion in patient treated with Zometa® for 12 months (59 years old, female, breast cancer).


In conclusion, BRON-J shows a complex clinical picture of unclear pathogenesis, even though it seems clearly related to intravenous biphosphonate administration. Numerous retrospective studies confirmed that pharmacologic and surgical therapies are not able to cure this complication, whose consequences are extremely invalidating for the patient. For this reason, several scientific societies underlined the importance of a risk staging for preventing the development of the disease in oncologic patients treated with intravenous biphosphonates as an adjuvant intervention.4,12,23,24

In the most severe cases the treatment should guarantee: pain relief, control of the infection, prevention of the necrotic area spreading, and of the development of new contiguous lesions. When pharmacologic treatments with antibiotics and local antiseptics are not able to control the development of BRON-J’s complications, the clinicians should perform radical surgical treatments, such as the resection of the bone involved followed by reconstructive surgery with vascularized bone grafts.16 Today, prevention is mandatory in patients who have to be treated with biphosphonates43 and in those that are under treatment for a long period of time.

A multidisciplinary team composed by oncologists, pathologists, bone metabolism specialists, dentists, oral surgeons, and maxillofacial surgeons must cooperate to carefully evaluate the patients’ clinical conditions, general and local risk factors, radiological and biohumoral exams, are useful in the prevention and in the staging of the disease.



The authors report no conflicts of interest in this work.


1. Marx R. Pamidronate (Aredia) and zoledonate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg. 2003;61:1115–1117. [PubMed]

2. Ruggiero SL, Mehrota B. Osteonecrosis of the jaws associated with the use of bisphophonates; a review of 63 cases. J Oral Maxillofac Surg. 2004;62:527–534. [PubMed]

3. Marx RE, Sawatari Y, Fortin M, Broumand V. Bisphosphonates-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention and treatment. J Oral Maxillofac Surg. 2005;63:1567–1575. [PubMed]

4. Migliorati CA, Casiglia J, Epstein J, Jacobsen PL, Siegel MA, Woo SB. Managing the care of patients with bisphosphonate-associated osteonecrosis: an American Academy of Oral Medicine position paper. J Am Dent Assoc. 2005;136:1658–1668. Erratum in: J Am Dent Assoc. 2006;137:26. [PubMed]

5. Badros A, Weichel D. Osteonecrosis of the jaw in multiple myeloma patients: clinical features and risk factors. J Clin Oncol. 2006;24:945–952. [PubMed]

6. Dimopoulos MA, Kastritis E. Osteonecrosis of the jaw in patient with multiple myeloma treated with bisphosphonates: evidence of increased risk after treatment with zoledronic acid. Haematologica. 2006;91:968–971. [PubMed]

7. Tosi P, Zamagni E. Osteonecrosis of the jaw in newly diagnosed multiple myeloma patient treated with zoledronic acid and thalidomide-dexamethasone. Blood. 2006;108:3951–3952. [PubMed]

8. Major PP, Cook RJ. Multiple event analysis of zoledronic acid trials in patients with cancer metastases to bone. Proc Am Soc Clin Oncol. 2003;22:762.

9. Rosen LS, Gordon DH. Zoledronic acid is superior to pamidronate for the treatment of bone metastases in breast carcinoma patients with at least one ostelytic lesion. Cancer. 2004;100:36–43. [PubMed]

10. Berenson JR, Hillner BE, Kyle RA, et al. American Society of Clinical Oncology Bisphosphonates Expert Panel. American Society of Clinical Oncology clinical practice guidelines: the role of bisphosphonates in multiple myeloma. J Clin Oncol. 2002;20:3719–3736. [PubMed]

11. Body JJ. Breast cancer: bisphosphonates therapy for metastatic bone disease. Clin Cancer Res. 2006;12(20 Suppl):6258–6263.

12. American Association of Oral and Maxillofacial Surgeons Position paper on bisphosphonate-related osteonecrosis of the jaws, approved by the Board of Trustees September 25, 2006 [cited on 2008 Dec 6]Available from http://www.aaoms.org/docs/position_papers/osteonecrosis.pdf.

13. Durie BGM, Katz M, editors. Osteonecrosis of the jaws and bisphosphonates N Engl J Med 2005. 35399–102.discussion 99–102. [PubMed]

14. Hillner BE, Ingle JN. ASCO 2003 update on the role of Bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol. 2003;21:40–42.

15. Bilezikian JP. Osteonecrosis of the jaw. Do Bisphosphonates pose a risk? N Engl J Med. 2006;355:2278–2281. [PubMed]

16. Ruggiero SL, Fantasia J, Carlson E. Bisphosphonate-related osteonecrosis of the jaw: background and guidelines for diagnosis, staging and management. Oral Surg Oral Med Oral Path Oral Rad Endod. 2006;102:433–441.

17. Conte PF, Guarnieri V. Safety of intravenous and oral bisphosphonates and compliance with dosing regimens. Oncologist. 2004;9(Suppl 4):28–37. [PubMed]

18. Peterson LJ, Ellis E. Contemporary oral and maxillofacial surgery. New York: Mosby; 1998. pp. 418–432.

19. Viale PH, Lin A. Exposed bone in oral cavities. J Clin Oncol Nurs. 2005;9:355–357.

20. Ficarra G, Beninati F, Rubino I, et al. Osteonecrosis of the jaws in periodontal patients with a history of bisphosphonates treatment. J Clin Periodontol. 2005;32:1125–1128.

21. Chiandussi S, Biasiotto M, Dore F, Cavalli F, Cova MA, Di Leonarda R. Clinical and diagnostic imaging of bisphosphonate-associated osteonecrosis of the jaws. Dentomaxillofac Radiol. 2006;35:236–243. [PubMed]

22. Hermans R, Fossion E, Ioannides C, Van de Bogaert W, Ghekiere J, Baert AL. CT findings in osteoradionecrosis of the mandibule. Skeletal Radiol. 1996;25:31–36. [PubMed]

23. Woo SB, Hellstein JW, Kalmar JR. Narrative [corrected] review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med. 2006;144:753–761. [PubMed]

24. Resza AA, Rodan GA. Nitrogen-containing bisphosphonates mechanism of action. Mini Rev Med Chem. 2004;4:711–719. [PubMed]

25. Green JR. Bisphosphonates preclinical review. Oncologist. 2004;9(Suppl 4):3–13. [PubMed]

26. Nase JB, Suzuki JB. Osteonecrosis of the jaw and oral bisphosphonate treatment. J Am Dent Assoc. 2006;137:1115–1119. [PubMed]

27. Vescovi P, Merigo E, Melet M, Manfredi M. Bisphosphonate-associated osteonecrosis (BON) of the jaws: a possibile treatment? J Oral Maxillofac Surg. 2006;64:1460–1462. [PubMed]

28. Tonelli P, Duvina M, Brancato L, Viviani C. Osteonecrosis of the jaw: A dramatic complication in patients with history of bisphosphonates treatment and bone disease. Study of 19 cases. Monaco: Poster Session in International Symposium, Osteology; May 10–12, 2007.

29. Borgioli A, Tonelli P, Brandi ML, Giombetti A, Duvina M, Spinelli G, Brancato L. Osteonecrosi dei mascellari da bifosfonati. L’Esperienza Fiorentina: Aspetti clinici e terapeuticiAlessandria: Abstract Presentation in Workshop: BRONJ, present and future, gennaio 20, 2007.

30. Durie BG. Osteonecrosis of the jaw and bisphosphonates. N Engl J Med. 2005;353:99–102. [PubMed]

31. Migliorati CA, Schubert MM, Peterson DE, Seneda LM. Bisphosphonate-associated osteonecrosis of mandibular bone. Cancer. 2005;104(1):83–93. [PubMed]

32. Jimenez-Soriano Y, Bagan JV. Bisphosphonates as a new cause of drug-induced jaw osteonecrosis: an update. Med Oral Patol Oral Cir Bucal. 2005;10(Suppl 2):88–91. [PubMed]

33. Robinson NA. Bisphosphonates a word of caution. Ann Acad Med Singapore. 2004;33:48–49. [PubMed]

34. Novartis Pharmaceuticals CorporationAppendix 11: Expert panel recommendation for the prevention, diagnosis and treatment of osteonecrosis of the jaw. Oncologic Drugs Advisory Committee (ODAC), Meeting March 4, 2005 [cited 2008 Dec 6]. Available from: http://www.fda.gov/OHRMS/DOCKETS/AC/05/briefing/2005-4095B2_02_12-Novartis-Zometa-App-11.pdf.

35. Mehrotra B, Ruggiero S. Bisphosphonates complications including osteonecrosis of the jaw. Hematology Am Soc Hematolol Educ Program. 2006;3:356–360.

36. Ruggiero SL, Gralow J, Marx RE, Hoff AO, Schubert MM, Huryn JM. Practical guidelines for the prevention, diagnosis and treatment of osteonecrosis of the jaw in patients with cancer. J Clin Oncol Prac. 2006;2:7–14.

37. Zavras AL, Zhu S. Bisphosphonates are associated with increased risk for jaw surgery in medical claims data: is it osteonecrosis? J Oral Maxillofac Surg. 2006;64:917–923. [PubMed]

38. Martins M, Saraceni G, Koga DH, Feber O, Olivetra dos Santos M, Zardetto C. Treatment of avascular osteonecrosis of the mandibule in cancer patients with a history of bisphosphonate therapy by combining bone resection and autologous platelet-rich plasma: report of 3 cases. J Oral Maxillofac Surg. 2007;65:349–355. [PubMed]

39. Shimura K, Shimazaki C, Taniguchi K, et al. Hyperbaric oxygen in addition to antibiotic therapy is effective for bisphosphonate-induced osteonecrosis of the jaw in a patient with multiple myeloma. Int J Hematol. 2006;84:343–345. [PubMed]

40. Tonelli P, Brancato L, Paggetti B, Duvina M, Borgioli A. La terapia iperbarica nel trattamento dell’osteomielite dei mascellari. Rome: Sessione Poster Collegio dei Docenti in Odontoiatria Roma; 2004.

41. Giombetti A, Borgioli A, Brancato L, Spinelli G. L’Osteomielite farmacologica dei mascellari. Montecatini Terme: Poster Presentation, Congresso Nazionale della Società Italiana di Chirurgia Orale (SICO): la Pianificazione del trattamento in Chirurgia Orale; Ottobre 7–8, 2005.

42. Borgioli A, Duvina M, Brancato L, Duvina G, Tonelli P. Bad and good bisphosphonates in implantology: Clinical report. Rome: Sessione Poster Collegio dei Docenti in Odontoiatria Roma; 2007.

43. Mavrokokki T, Cheng A, Stein B, Goss A. Nature and frequency of bisphosphonate-associated osteonecrosis of the jaws in Australia. J Oral Maxillofac Surg. 2007;65:415–423. [PubMed]

Lasers Med Sci. 2009 Nov;24(6):849-56. Epub 2009 Mar 11.

Osteonecrosis of the jaws caused by biphosphonates: evaluation of a new therapeutic approach using the Er:YAG laser.

Angiero F, Sannino C, Borloni R, Crippa R, Benedicenti S, Romanos GE.

Pathological Anatomy, University of Milan-Bicocca, Ospedale S Gerardo Monza, Milan, Italy. f.angiero@teos.it

A series of 49 patients diagnosed with osteonecrosis and all treated with latest-generation bisphosphonates was reviewed retrospectively to evaluate the use of erbium-doped: yttrium, aluminum, and garnet laser (Er:YAG) in terms of clinical outcome, and examine current trends from the clinical-therapeutic standpoint. Pathology reports on specimens submitted over the previous 7 years from either the mandible or the maxilla were reviewed; 49 patients were identified as having osteonecrosis of the jaws. For each of these cases, the medical history and profile were evaluated; 19 were treated with conservative therapy, 20 with radical surgery, and 10 with Er:YAG laser (2,940 nm). Of the 20 patients treated surgically (bone baquette, curettage, sequestrectomy of the necrotic bone), some required re-treatment, which resulted in bone fracturing. None of the patients were treated successfully. The 19 cases treated conservatively produced an improvement in symptoms, but not remission of the lesions. Of the ten patients treated with Er:YAG laser, six achieved total remission of signs and symptoms, four an improvement, and re-treatment was required in one case. Our present approach is to recommend intensive prophylactic care before the administration of bisphosphonates, and great caution is advised even in simple maneuvers like curettage, because this may exacerbate the avascular process. The use of Er:YAG laser appears to be promising (within the limits of our experience). It can be concluded that at 1 year of laser surgery, the treatment led to significant improvements in clinical parameters, and may represent a valid alternative, although studies on a larger scale are needed.

Lasers Surg Med. 2009 Jan;41(1):26-30.

A preliminary report about treatment of biphosphonate related osteonecrosis of the jaw with Er:YAG laser ablation.

Stübinger S, Dissmann JP, Pinho NC, Saldamli B, Seitz O, Sader R.

Hightech Research Center of Cranio-Maxillofacial Surgery, University of Basel, Basel, Switzerland. sstuebinger@uhbs.ch

BACKGROUND AND OBJECTIVES: This preliminary report describes a new laser-assisted treatment option for the emerging complication of bisphosphonate related osteonecrosis (BON) of the jaw.

MATERIALS AND METHODS: In eight tumour patients (three women, five men) ten bony lesions in the maxilla and mandible in the course of intravenous bisphosphonate therapy were treated with a variable square pulsed (VSP) Er:YAG laser. For the treatment, the Er:YAG laser was applied with a pulse energy of 1,000 mJ, a pulse duration of 300 microseconds, and a frequency of 12 Hz (energy density 157 J/cm(2)). The spot size was 0.9 mm and the handpiece was kept at a distance of about 10 mm from the bone surface. The diseased bone was ablated exclusively with the Er:YAG laser by subsequently sweeping the bone surface in a well directed scanning mode.

RESULTS: The surgical procedure and postoperative wound healing were without any complications and a complete soft tissue recovering was achieved within 4 weeks. During follow-up examinations over 12 months soft tissue conditions were stable. The pulsed laser ablation caused a characteristic microstructured and craggy bone surface without a condensation or a smear layer on the laser rims.

CONCLUSION: The bone ablation technique using a VSP Er:YAG laser yielded promising clinical results without impairment of wound healing. A further analyse of the chemical, physical and pharmacological aspects of laser assisted treatment of BON lesions is necessary to get a safe and reliable treatment protocol for bisphosphonate-related osteonecrosis of the jaw.

Rev Belge Med Dent. 2009;64(2):87-95.

Surgical treatment of maxillary osteonecrosis dur to biphosphonates using an Er:YAG (2940 nm) laser.  Discussion of 17 clinical cases.

[Article in French]

Vescovi P, Merigo E, Manfredi M, Meleti M, Fornaini C, Bonanini M, Rocca EP, De Moor RJ, Nammour S.

Department of ENT/Dental/Ophthalmological and Cervico-Facial Sciences, Università degli Studi di Parma, Via Gramsci 14, 43100 Parma, Italy.paolo.vescovi@unipr.it.

Reports of cases of ONJ are significantly increased during the last five years as a iatrogenic complication of therapy with bisphosphonates (BPT). The aim of this work is to present the advantages of surgery using Er:YAG laser for treatment of ONJ. Er:YAG laser can gradually reach the healthy bone without causing any heating damage of tissues. This device results very versatile and gives the possibility of choose among different surgical techniques depending by the case (e.g.: vaporization or ostectomy). Moreover, different studies have demonstrated the presence of both bactericidal and biomodulating effect on bone and surrounding tissues, with biostimulation of microcirculation and neoangiogenesis. Seventeen sites of ONJ, classified according to the staging system developed by Ruggiero and observed in 12 patients with multiple myeloma (9 patients), bone metastases (2 patients) and osteoporosis (1 patient), were treated with Er:YAG laser (Fidelis Plus, Fotona-Slovenia). Laser device was used in non-contact or near-contact way (VSP, 300 m3 30 Hz, Fluence 60 J/cm2) on 17 sites (4 Stage I and 13 Stage II) on 3 different types of surgery: sequestrectomy + debridement, sequestrectomy + corticotomy and vaporization. For an average follow-up of 9 months (SD +/- 6 months), complete healing of ONJ (Stage 0) was obtained for 13 sites (76.5%) and resolution of symptoms was obtained (Stage 1) for 3 sites (17.5%). For one site at Stage II (6%), recovery was obtained but this result was not maintained over 3 months. Positive results were independent by the anatomical area (mandible or maxilla), primary disease (osteoporosis, multiple myelomas or metastasis) and discontinuation of BPT before surgery. Er:YAG laser (2940 nm), in our experience, represents a valid therapeutic option for ONJ-BP related, especially in early stages of the disease.

Photomed Laser Surg. 2008 Feb;26(1):37-46

Nd:YAG laser biostimulation in the treatment of biphosphonate-associated osteonecrosis of the jaw: clinical experience in 28 cases.

Vescovi P, Merigo E, Manfredi M, Meleti M, Fornaini C, Bonanini M, Rocca JP, Nammour S.

Unit of Oral Pathology and Medicine, Section of Dentistry, Department of ENT/Dental/Ophthalmological and Cervico-Facial Sciences, University of Parma, Parma, Italy. paolo.vescovi@unipr.it.

OBJECTIVE: To research an efficient treatment for the management of bisphosphonate-associated osteonecrosis.

BACKGROUND DATA: Necrosis of the jawbone has recently been described in association with systemic bisphosphonate therapy with drugs including zoledronic acid, pamidronate, and alendronate. The extent and clinical characteristics of bisphosphonate-associated osteonecrosis (BON) of the jaw are extremely variable, and range from the presence of fistulae in the oral mucosa or orofacial tissues, to large exposed areas of necrotic bone within the oral cavity. Clinical signs and symptoms commonly reported include pain, swelling, the presence of pus, loose teeth, ill-fitting dentures, and paresthesias of the inferior alveolar nerve when the necrosis affects the mandible. Fractures have also been reported. The treatment of BON of the jaw is still controversial since no therapy has proven to be efficacious as shown by the literature on the subject.

MATERIALS AND METHODS: In this study we report results achieved with 28 patients affected by BON of the jaw, who received treatment with the Nd:YAG laser alone or in combination with conventional medical or surgical treatment. Clinical variables such as severity of symptoms, presence of pus, and closure of mucosal flaps before and after therapy were evaluated to establish the effectiveness of laser irradiation. The 28 patients with BON were subdivided into four groups: eight patients were treated with medical therapy only (antibiotics with or without antimycotics and/or antiseptic rinses), six patients were treated with medical and surgical therapy (necrotic bone removal and bone curettage), six patients were treated with medical therapy associated with laser biostimulation, and eight patients were treated with medical therapy associated with both surgical therapy and laser biostimulation.

RESULTS: Of the 14 patients who underwent laser biostimulation, nine reported complete clinical success (no pain, symptoms of infection, or exposed bone or draining fistulas), and three improved their symptomatology only, with a follow-up of between 4 and 7 mo.

CONCLUSIONS: While the results reported in this study are not conclusive, they indicate that laser therapy has potential to improve management of BON.

Acta Biomed. 2006 Aug;77(2):109-17.

Bone necrosis of the jaws associated with biphosphonate treatment: a report of twenty-nine cases.

Merigo E, Manfredi M, Meleti M, Guidotti R, Ripasarti A, Zanzucchi E, D’Aleo P, Corradi D, Corcione L, Sesenna E, Ferrari S, Poli T, Bonaninil M, Vescovi P.

Unit of Oral Pathology and Medicine, Section of Odontostomatology, Department of ENT/Dental/Ophthalmological and Cervico-Facial Sciences, University of Parma, Parma, Italy. elisabetta.merigo@unipr.it

Bone necrosis of the jaws is often related to head and neck radiotherapy, to surgical procedures at maxillary or mandibular level but also to various local and systemic factors such as haematological diseases, haemoglobinopathies and systemic lupus eritematosus; its pathogenesis maybe associated with defects of vascularization. Bisphosphonate are synthetic analogues of pyrophosphate used for the treatment of hypercalcemia in patients with malignancies and bone metastasis and for the treatment of many other disorders such as metabolic bone diseases, Paget’s disease, and osteoporosis; their pharmacological activity is related to the inhibition of the osteoclastic function which leads to resorption and reduction of bone vascularization. Since the end of 2003 Bisphosphonate-associated Osteonecrosis (BON) has become an increasing problem and the test of that is the increase of the relative published case report and case series. Here we report 29 cases of bone necrosis of the jaws in patients treated with pamidronate (Aredia), zoledronate (Zometa) and alendronate: 15 underwent surgical procedures and 14 occurred spontaneously. Among these patients (21 females, 8 males; mean age between 45 and 83 years); 14 were treated for bone metastasis, 12 for multiple myeloma and 3 for osteoporosis. Bone necrosis involved only maxilla in 7 patients, only mandible in 20 patients and both in 2 patients. Six patients had multiple osteonecrotic lesions, 3 contemporary lesions and 3 non contemporary. In these patients we performed 3 kinds of therapy, associated or not: medical therapy (with antibiotic drugs, antimycotics and antiseptic mouthwashes), surgical therapy with curettage or sequestrectomy and Nd:YAG laser biostimulation.