Waseem Mehmood Nizamani, Ameet Kumar Jesrani, Mujtaba Khan, Kalthoum Tlili, Nadar Al Khuraish, Sara Waqar



Bisphosphonates which are used in bone diseases like osteoporosis, multiple myeloma and metastatic bone diseases can lead to the most lethal complication of osteonecrosis of the jaw which particularly involves the mandible. (Aragon-Ching et al., 2009). The pathophysiology of BRONJ is not clear. However, it is considered that it is due to the defect in osteoblast and osteoclast activity as a result of which bone remodeling and wound healing is affected. It is also believed that dental procedures can lead to the BRONJ (Ikebe, 2013). Because bone cells are highly networked, the importance of multicellular interactions during the onset of these risk factors cannot be overstated. As such, this perspective addresses current research on the effects of BPs, mechanical load and inflammation on bone remodeling and on development of BRONJ. Our investigation has led us to conclude that improved in vitro systems capable of adequately recapitulating multicellular communication and incorporating effects of osteocyte mechanosensing on bone resorption and formation are needed to elucidate the mechanism(s) by which BRONJ ensues.


Keywords: Bisphosphonates, Osteonecrosis, Jaw


Full Text:




Migliorati C.A., Saunders D., Conlon M.S., Ingstad H.K., Vaagen P., Palazzolo M.J., Herlofson B.B. Assessing the association between bisphosphonate exposure and delayed mucosal healing after tooth extraction. J. Am. Dent. Assoc. 2013;144(4):406–414.

Saia G., Blandamura S., Bettini G., Tronchet A., Totola A., Bedogni G., Ferronato G., Nocini P.F., Bedogni A. Occurrence of bisphosphonate-related osteonecrosis of the jaw after surgical tooth extraction. J. Oral Maxillofac. Surg. 2010;68:797–804.

Ruggiero S.L., Dodson T.B., Fantasia J., Goodday R., Aghaloo T., Mehrotra B., O'Ryan F. American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw – 2014 update. J. Oral Maxillofac. Surg. 2014;72:1938–1956.

Qaisi M., Hargett J., Loeb M., Brown J., Caloss R. Denosumab related osteonecrosis of the jaw with spontaneous necrosis of the soft palate: report of a life threatening case. Case Rep. Dent. 2016;2016:5070187.

Viviano M., Rossi M., Cocca S. A rare case of osteonecrosis of the jaw related to imatinib. J. Korean Assoc. Oral Maxillofac. Surg. 2017; 43(2):120–124.

Feller L., Wood N.H., Khammissa R.A.G., Lemmer J., Raubenheimer E.J. The nature of fibrous dysplasia. Head Face Med. 2009;5

Zara S., De Colli M., di Giacomo V., Zizzari V.L., Di Nisio C., Di Tore U., Salini V., Gallorini M., Tetè S., Cataldi A. Zoledronic acid at subtoxic dose extends osteoblastic stage span of primary human osteoblasts. Clin Oral Investig. 2015;19:601–611.

Manzano-Moreno F.J., Ramos-Torrecillas J., De Luna-Bertos E., Ruiz C., García-Martínez O. High doses of bisphosphonates reduce osteoblast-like cell proliferation by arresting the cell cycle and inducing apoptosis. J. Craniomaxillofac. Surg. 2015;43:396–401.

Heymann D. Bisphosphonates and bone diseases: past, present and future. Curr. Pharm. Des. 2010;16(27):2948–2949.

Landesberg R., Woo V., Cremers S., Cozin M., Marolt D., Vunjak-Novakovic G., Kousteni S., Raghavan S. Potential pathophysiological mechanisms in osteonecrosis of the jaw. Ann. N. Y. Acad. Sci. 2011;1218:62–79.

Ikebe T. Pathophysiology of BRONJ: drug-related osteoclastic disease of the jaw. Oral Sci. Int. 2013;10:1–8.

Otto S., Schreyer C., Hafner S., Mast G., Ehrenfeld M., Stürzenbaum S., Pautke C. Bisphosphonate-related osteonecrosis of the jaws – characteristics, risk factors, clinical features, localization and impact on oncological treatment. J. Craniomaxillofac. Surg. 2012;40:303–309.

Abu-Id M.H., Warnke P.H., Gottschalk J., Springer I., Wiltfang J., Acil Y., Russo P.A.J., Kreusch T. “Bis-phossy jaws” – high and low risk factors for bisphosphonate-induced osteonecrosis of the jaw. J. Craniomaxillofac. Surg. 2008;36:95–103.

Aragon-Ching J.B., Ning Y., Chen C.C., Latham L., Guadagnini J., Gulley J.L., Arlen P.M., Wright J.J., Parnes H., Figg W.D., Dahut W.L. Higher incidence of osteonecrosis of the jaw (ONJ) in patients with metastatic castration resistant prostate cancer treated with anti-angiogenic agents. Cancer Investig. 2009;27(2):221–226.

Epari D.R., Duda G.N., Thompson M.S. Mechanobiology of bone healing and regeneration: in vivo models. Proc. Inst. Mech. Eng. H. 2010;224(12):1543–1553.

Huang C., Ogawa R. Mechanotransduction in bone repair and regeneration. FASEB J. 2010;24(10):3625–3632.

Duncan R.L., Turner C.H. Mechanotransduction and the functional response of bone to mechanical strain. Calcif. Tissue Int. 1995;57:344–358.

Turner C.H., Pavalko F.M. Mechanotransduction and functional response of the skeleton to physical stress: the mechanisms and mechanics of bone adaptation. J. Orthop. Sci. 1998;3:346–355.

Fliefel R., Tröltzsch M., Kühnisch J., Ehrenfeld M., Otto S. Treatment strategies and outcomes of bisphosphonate-related osteonecrosis of the jaw (BRONJ) with characterization of patients: a systematic review. Int. J. Oral Maxillofac. Surg. 2015;44(5):568–585.

Lee SH, Chan RC, Chang SS, Tan YL, Chang KH, Lee MC, et al. Use of bisphosphonates and the risk of osteonecrosis among cancer patients: a systemic review and meta-analysis of the observational studies. Support Care Cancer. 2014;22:553–560.

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 Pathol Oral Radiol Endod. 2006;102:433–441.

Lehrer S, Montazem A, Ramanathan L, Pessin-Minsley M, Pfail J, Stock RG, et al. Normal serum bone markers in bisphosphonate-induced osteonecrosis of the jaws. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2008;106:389–391.

Ficarra G, Beninati F. Bisphosphonate-related osteonecrosis of the jaws: an update on clinical, pathological and management aspects. Head Neck Pathol. 2007;1:132–140.

Ortega C, Montemurro F, Faggiuolo R, Vormola R, Nanni D, Goia F, et al. Osteonecrosis of the jaw in prostate cancer patients with bone metastases treated with zoledronate: a retrospective analysis. Acta Oncol. 2007;46:664–668.

Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg. 2003;61:1115–1117.

Magopoulos C, Karakinaris G, Telioudis Z, Vahtsevanos K, Dimitrakopoulos I, Antoniadis K, et al. Osteonecrosis of the jaws due to bisphosphonate use. A review of 60 cases and treatment proposals. Am J Otolaryngol. 2007;28:158–163.

Kos M, Kuebler JF, Luczak K, Engelke W. Bisphosphonate-related osteonecrosis of the jaws: a review of 34 cases and evaluation of risk. J Craniomaxillofac Surg. 2010;38:255–259.

Campisi G, Di Fede O, Musciotto A, Lo Casto A, Lo Muzio L, Fulfaro F, et al. Bisphosphonate-related osteonecrosis of the jaw (BRONJ): run dental management designs and issues in diagnosis. Ann Oncol. 2007;18(Suppl 6):vi168–vi172.

Morag Y, Morag-Hezroni M, Jamadar DA, Ward BB, Jacobson JA, Zwetchkenbaum SR, et al. Bisphosphonate-related osteonecrosis of the jaw: a pictorial review. Radiographics. 2009;29:1971–1984.


  • There are currently no refbacks.

© Copyright PJR 2008-