Bisphosphonate-associated osteonecrosis of the jaw
|Bisphosphonate-associated osteonecrosis of the jaw|
|Synonyms||BON of the jaw, bisphosphonate-related osteonecrosis of the jaw (BRONJ), bisphosphonate-induced osteonecrosis of the jaw (BIONJ)|
|Classification and external resources|
Bisphosphonate-associated osteonecrosis of the jaw (BON, BONJ) is osteonecrosis of the jaw in a person with a history of bisphosphonate use who undergoes subsequent dental surgery. It may lead to surgical complication in the form of impaired wound healing following oral and maxillofacial surgery, periodontal surgery, or endodontic therapy.
An association between history of bisphosphonate use and osteonecrosis of the jaw after later surgery was detected for several years before the exact nature of the relationship (cause, pathogenesis) could begin to be understood, and it is still not entirely clear, although it has been nicknamed "bis-phossy jaw" based on its similarity with phossy jaw. There is no known prevention for bisphosphonate-associated osteonecrosis of the jaw. Avoiding the use of bisphosphonates is not a viable prevention on a general-population basis because the drugs have more benefit throughout the population (preventing osteoporotic fractures and treating bone cancers) than harm (BONJ).
Osteonecrosis, or localized death of bone tissue, of the jaws is a rare potential complication in cancer patients receiving treatments including radiation, chemotherapy, or in patients with tumors or infectious embolic events. In 2003, reports surfaced of the increased risk of osteonecrosis in patients receiving these therapies concomitant with intravenous bisphosphonate. Matrix metalloproteinase 2 may be a candidate gene for bisphosphonate-associated osteonecrosis of the jaws, since it is the only gene known to be associated with both bone abnormalities and atrial fibrillation, another side effect of bisphosphonates.
In response to the growing base of literature on this association, the United States Food and Drug Administration issued a broad drug class warning of this complication for all bisphosphonates in 2005.
Signs and symptoms
Lesions and areas of necrotic bone may remain asymptomatic for weeks, months, or even years, and most commonly become symptomatic with inflammation of surrounding tissues. Clinical signs and symptoms associated with but not limited to BONJ include the following:
- Jaw pain and neuropathy
- Loose teeth 
- Mucosal swelling 
- Suppuration 
- Soft tissue ulceration  persisting for more than 8 weeks
- Trismus 
- Non-healing extraction sockets 
- Paraesthesia or numbness in the jaw 
- Bad breath
- Exposed necrotic jaw bone 
Although the methods of action are not yet completely understood, it is hypothesized that bisphosphonate-associated osteonecrosis of the jaw is related to a defect in jaw bone healing and remodelling. The inhibition of osteoclast differentiation and function, precipitated by bisphosphonate therapy, leads to decreased bone resorption and remodelling. Evidence also suggests bisphosphonates induce apoptosis of osteoclasts, resulting in resorption of bones. Another suggested factor is the inhibition of angiogenesis due to bisphosphonates but its effect remains uncertain. Several studies have proposed that bisphosphonates cause excessive reduction of bone turnover, resulting in a higher risk of bone necrosis when repair is needed.
Because bisphosphonates are preferentially deposited in bone with high turnover rates, it is possible that the levels of bisphosphonate within the jaw are selectively elevated. To date, there have been no reported cases of bisphosphonate-associated complications within bones outside the craniofacial skeleton.
- the patient possesses an area of exposed bone in the jaw persisting for more than 8 weeks,
- the patient must present with no history of radiation therapy to the head and neck
- the patient must be taking or have taken bisphosphonate medication.
According to the updated 2009 BRONJ Position Paper published by the American Association of Oral and Maxillofacial Surgeons, both the potency of and the length of exposure to bisphosphonates are linked to the risk of developing bisphosphonate-associated osteonecrosis of the jaw.
Cases of BRONJ have also been associated with the use of the following two intravenous and three oral bisphosphonates, respectively: Zometa (zoledronic acid) and Aredia (pamidronate) & Fosamax (alendronate), Actonel (risedronate) and Boniva (ibandronate).
The overwhelming majority of BRONJ diagnoses, however, were associated with intravenous administration of bisphosphonates (94%). Only the remaining 6% of cases arose in patients taking bisphosphonates orally.
Although the total United States prescriptions for oral bisphosphonates exceeded 30 million in 2006, less than 10% of BON cases were associated with patients taking oral bisphosphonate drugs. Studies have estimated that BRONJ occurs in roughly 20% of patients taking intravenous zoledronic acid for cancer therapy and in between 0-0.04% of patients taking orally administered bisphosphonates.
Owing to prolonged embedding of bisphosphonate drugs in the bone tissues, the risk for BRONJ is high even after stopping the administration of the medication for several years.
Treatment usually involves antimicrobial mouth washes and oral antibiotics to help the immune system fight the attendant infection, and it also often involves local resection of the necrotic bone lesion. Many patients with BRONJ have successful outcomes after treatment, meaning that the local osteonecrosis is stopped, the infection is cleared, and the mucosa heals and once again covers the bone.
The treatment the person receives depends on the severity of osteonecrosis of the jaws.
Dentoalveolar surgery is a significant risk factor for development of BRONJ. Prevention including the maintenance of good oral hygiene, comprehensive dental examination and dental treatment including extraction of teeth of poor prognosis and dentoalveolar surgery should completed prior to commencing any medication which is likely to cause osteonecrosis (ONJ). Patients with removable prostheses should be examined for areas of mucosal irritation. Procedures which are likely to cause direct osseous trauma, e.g. tooth extraction, dental implants, complex restoration, deep root planning, should be avoided in preference of other dental treatments. Some[who?] have advocated “drug holiday’s”, but this remains controversial.
Patients should be educated regarding the warning signs and symptoms of ORN and the importance of maintaining good oral health throughout the treatment period.
Indicated in patients who have evidence of exposed bone but no evidence of infection. It may not necessarily eliminate all the lesions, but it may provide patients with a long term relief. This approach involves a combination of antiseptic mouthwashes and analgesics and the use of teriparatide. However, note that the teriparatide treatment should not be used in cancer patients, or patients with a history of skeletal radiation or active bone metastases. Splints may be used to protect sites of exposed necrotic bone.
Indicated for patients with exposed bone with symptoms of infection. This treatment modality may also be utilised for patients with other co-morbidities which precludes invasive surgical methods. This approach requires antimicrobial mouthwashes, systemic antibiotics and antifungal medication and analgesics.
Surgical intervention is indicated in patients with symptomatic exposed bone with fistula formation and one or more of the following: exposed and necrotic bone extending beyond the alveolar bone resulting in pathological fracture; extra-oral fistula; oral antral communication or osteolysis extending from the inferior border of the mandible or the sinus floor. Surgical management involves necrotic bone resection, removal of loose sequestra of necrotic bone and reconstructive surgery. The objective of surgical management is to eliminate areas of exposed bone to prevent the risk of further inflammation and infection. The amount of surgical debridement required remains controversial.
- Osteonecrosis of the jaw, see section on Bisphosphonates
- Phossy jaw
- C-terminal telopeptide, commonly known as CTX, a serum biomarker for bone turnover rate and a tool used to evaluate patient risk for complications due to BRONJ
- Osteoradionecrosis, a term for osteonecrosis caused by radiotherapy
- Nase JB, Suzuki JB (August 2006). "Osteonecrosis of the jaw and oral bisphosphonate treatment". J Am Dent Assoc. 137 (8): 1115–9; quiz 1169–70. PMID 16873327. doi:10.14219/jada.archive.2006.0350.
- Abu-Id, Mario; et al. (2008). "'Bis-phossy jaws' – High and low risk factors for bisphosphonate-induced osteonecrosis of the jaw". Journal of Cranio-Maxillofacial Surgery. 36 (2): 95–103. doi:10.1016/j.jcms.2007.06.008.
- Osteoporosis medications and your dental health pamphlet #W418, American Dental Association/National Osteoporosis Foundation, 2008
- Marx RE (September 2003). "Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic". J. Oral Maxillofac. Surg. 61 (9): 1115–7. PMID 12966493. doi:10.1016/S0278-2391(03)00720-1.
- Migliorati CA (November 2003). "Bisphosphanates and oral cavity avascular bone necrosis". J. Clin. Oncol. 21 (22): 4253–4. PMID 14615459. doi:10.1200/JCO.2003.99.132.
- Appendix 11: Expert Panel Recommendation for the Prevention, Diagnosis and Treatment of Osteonecrosis of the Jaw
- Lehrer S, Montazem A, Ramanathan L, et al. (January 2009). "Bisphosphonate-induced osteonecrosis of the jaws, bone markers, and a hypothesized candidate gene". J. Oral Maxillofac. Surg. 67 (1): 159–61. PMID 19070762. doi:10.1016/j.joms.2008.09.015.
- Ruggiero SL (March 2008). "Bisphosphonate-related Osteonecrosis of the Jaws". Compendium of Continuing Education in Dentistry. 29 (2): 97–105.
- Allen, Matthew R.; Ruggiero, Salvatore L. (2009-07-01). "Higher bone matrix density exists in only a subset of patients with bisphosphonate-related osteonecrosis of the jaw". Journal of Oral and Maxillofacial Surgery. 67 (7): 1373–1377. ISSN 1531-5053. PMID 19531405. doi:10.1016/j.joms.2009.03.048.
- Khan, Aliya A.; Morrison, Archie; Hanley, David A.; Felsenberg, Dieter; McCauley, Laurie K.; O'Ryan, Felice; Reid, Ian R.; Ruggiero, Salvatore L.; Taguchi, Akira (2015-01-01). "Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus". Journal of Bone and Mineral Research. 30 (1): 3–23. ISSN 1523-4681. PMID 25414052. doi:10.1002/jbmr.2405.
- Zadik Y, Benoliel R, Fleissig Y, Casap N (February 2012). "Painful trigeminal neuropathy induced by oral bisphosphonate-related osteonecrosis of the jaw: a new etiology for the numb-chin syndrome". Quintessence Int. 43 (2): 97–104. PMID 22257870.
- Sharma, Dileep; Ivanovski, Saso; Slevin, Mark; Hamlet, Stephen; Pop, Tudor S.; Brinzaniuc, Klara; Petcu, Eugen B.; Miroiu, Rodica I. (2013-01-01). "Bisphosphonate-related osteonecrosis of jaw (BRONJ): diagnostic criteria and possible pathogenic mechanisms of an unexpected anti-angiogenic side effect". Vascular Cell. 5 (1): 1. ISSN 2045-824X. PMC . PMID 23316704. doi:10.1186/2045-824X-5-1.
- Goodell, Dr. Gary G. (Fall 2012). "Endodontics: Colleagues for Excellence" (PDF). American Association of Endodontists. 211 E. Chicago Ave., Suite 1100 Chicago, IL 60611-2691: American Association of Endodontists.
- Otto, Sven; Hafner, Sigurd; Grötz, Knut A. (2009-03-01). "The role of inferior alveolar nerve involvement in bisphosphonate-related osteonecrosis of the jaw". Journal of Oral and Maxillofacial Surgery. 67 (3): 589–592. ISSN 1531-5053. PMID 19231785. doi:10.1016/j.joms.2008.09.028.
- Baron, Roland; Ferrari, Serge; Russell, R. Graham G. (2011-04-01). "Denosumab and bisphosphonates: different mechanisms of action and effects". Bone. 48 (4): 677–692. ISSN 1873-2763. PMID 21145999. doi:10.1016/j.bone.2010.11.020.
- Russell, R. G. G.; Watts, N. B.; Ebetino, F. H.; Rogers, M. J. (2008-06-01). "Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy". Osteoporosis international: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 19 (6): 733–759. ISSN 0937-941X. PMID 18214569. doi:10.1007/s00198-007-0540-8.
- Lindsay R, Cosman F. Osteoporosis. In: Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL, eds. Harrison’s principles of internal medicine. New York:McGraw-Hill, 2001:2226-37.
- Wood, J; Bonjean, K; Ruetz, S; Bellahcene, A; Devy, L; Foidart, JM; Castronovo, V; Green, JR (2002). "Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid". J Pharmacol Exp Ther. 302: 1055–61. doi:10.1124/jpet.102.035295.
- Vincenzi, B; Santini, D; Dicuonzo, G; Battistoni, F; Gavasci, M; La Cesa, A; Grilli, C; Virzi, V; Gasparro, S; Rocci, L; Tonini, G (2005). "Zoledronic acid-related angiogenesis modifications and survival in advanced breast cancer patients". J Interferon Cytokine Res. 25: 144–51. doi:10.1089/jir.2005.25.144.
- Santini, D; Vincenzi, B; Dicuonzo, G; Avvisati, G; Massacesi, C; Battistoni, F; Gavasci, M; Rocci, L; Tirindelli, MC; Altomare, V; Tocchini, M; Bonsignori, M; Tonini, G (2003). "Zoledronic acid induces significant and long-lasting modifications of circulating angiogenic factors in cancer patients". Clin Cancer Res. 9: 2893–7.
- Chapurlat, Roland D; Arlot, Monique; Burt-Pichat, Brigitte; Chavassieux, Pascale; Roux, Jean Paul; Portero-Muzy, Nathalie; Delmas, Pierre D (2007-10-01). "Microcrack Frequency and Bone Remodeling in Postmenopausal Osteoporotic Women on Long-Term Bisphosphonates: A Bone Biopsy Study". Journal of Bone and Mineral Research. 22 (10): 1502–1509. ISSN 1523-4681. doi:10.1359/jbmr.070609.
- Stepan, Jan J.; Burr, David B.; Pavo, Imre; Sipos, Adrien; Michalska, Dana; Li, Jiliang; Fahrleitner-Pammer, Astrid; Petto, Helmut; Westmore, Michael (2007-09-01). "Low bone mineral density is associated with bone microdamage accumulation in postmenopausal women with osteoporosis". Bone. 41 (3): 378–385. ISSN 8756-3282. PMID 17597017. doi:10.1016/j.bone.2007.04.198.
- Woo, Sook-Bin; Hellstein, John W.; Kalmar, John R. (2006-05-16). "Narrative [corrected] review: bisphosphonates and osteonecrosis of the jaws". Annals of Internal Medicine. 144 (10): 753–761. ISSN 1539-3704. PMID 16702591. doi:10.7326/0003-4819-144-10-200605160-00009.
- Medical News Today AAOMS Updates BRONJ Position Paper, January 23, 2009
- American Dental Association Osteonecrosis of the Jaw
- Grbic JT, Landesberg R, Lin SQ, et al. (January 2008). "Incidence of osteonecrosis of the jaw in women with postmenopausal osteoporosis in the health outcomes and reduced incidence with zoledronic acid once yearly pivotal fracture trial". J Am Dent Assoc. 139 (1): 32–40. PMID 18167382. doi:10.14219/jada.archive.2008.0017.
- Cartsos VM, Zhu S, Zavras AI (January 2008). "Bisphosphonate use and the risk of adverse jaw outcomes: a medical claims study of 714,217 people". J Am Dent Assoc. 139 (1): 23–30. PMID 18167381. doi:10.14219/jada.archive.2008.0016.[permanent dead link]
- Zadik Y, Abu-Tair J, Yarom N, Zaharia B, Elad S (September 2012). "The importance of a thorough medical and pharmacological history before dental implant placement.". Aust Dent J. 57 (3): 388–392. PMID 22924366. doi:10.1111/j.1834-7819.2012.01717.x.
- Aliya A Khan; Archie Morrison; David A Hanley; Dieter Felsenberg; Laurie K McCauley; Felice O’Ryan; Ian R Reid; Salvatore L Ruggiero; Akira Taguchi; Sotirios Tetradis; Nelson B Watts; Maria Luisa Brandi; Edmund Peters; Teresa Guise; Richard Eastell; Angela M Cheung; Suzanne N Morin; Basel Masri; Cyrus Cooper; Sarah L Morgan; Barbara Obermayer-Pietsch; Bente L Langdahl; Rana Al Dabagh; K. Shawn Davison; David L Kendler; George K Sándor; Robert G Josse; Mohit Bhandari; Mohamed El Rabbany; Dominique D Pierroz; Riad Sulimani; Deborah P Saunders; Jacques P Brown & Juliet Compston (April 2014). "Diagnosis and Management of Osteonecrosis of the Jaw: A Systematic Review and International Consensus". JBMR. 30: 3–23. PMID 25414052. doi:10.1002/jbmr.2405.
- Svejda, B.; Muschitz, Ch; Gruber, R.; Brandtner, Ch; Svejda, Ch; Gasser, R. W.; Santler, G.; Dimai, H. P. (1946). "[Position paper on medication-related osteonecrosis of the jaw (MRONJ)]". Wiener Medizinische Wochenschrift. 166 (1-2): 68–74. ISSN 1563-258X. PMID 26847441. doi:10.1007/s10354-016-0437-2.
- R. Fliefel; M. Tro¨ltzsch; J. Kühnisch; M. Ehrenfeld; S. Otto (May 2015). "Treatment strategies and outcomes of bisphosphonaterelated osteonecrosis of the jaw (BRONJ) with characterization of patients: a systematic review". International Journal of Oral and Maxillofacial Surgery. 44: 568–85. PMID 25726090. doi:10.1016/j.ijom.2015.01.026.
- Blus, Cornelio (23 August 2013). "Use of Ultrasonic Bone Surgery (Piezosurgery) to Surgically Treat Bisphosphonate-Related Osteonecrosis of the Jaws (BRONJ). A Case Series Report with at Least 1 Year of Follow-Up". The Open Dentistry Journal. 7 (1): 94–101. PMC . PMID 24044030. doi:10.2174/1874210601307010094.