Abstract
Biphosphonate (BPN) are widely used in clinics to treat meta- static cancer and osteoporosis thus representing a problem not only for patients but also for workers involved in their prepara- tion and administration. A similar exposure occurred years ago in match-making workers undergoing bone alterations similar to those consequent to BPN exposure. Osteonecrosis of the jaw (ONJ) is a main adverse effect related to BPN administration, which is performed in millions of patients worldwide for osteopo- rosis and cancer therapy, thus representing an emerging problem in public health. In susceptible patients, BPN induce severe, pro- gressive, and irreversible degeneration of facial bones, resulting in avascular ONJ often triggered by dental surgery. BPN induced ONJ occurs in subjects depending on lifestyle factors of both environmental and endogenous origins. Exogenous risk factors include cigarette smoke, alcohol consumption, bacterial infec- tions, and cyclosporine therapy. Endogenous risk factors include systemic diseases such as diabetes or hypertension and adverse polymorphisms of genes involved in metabolism (CYPs, MTHFR), thrombosis (Factor V, Prothrombin), and detoxification (MDR). Available molecular findings provide evidence that ONJ is related to risk-factors associated with environmental mutagenesis and gene-environment interactions. This issues may be useful to iden- tify susceptible subjects by molecular analyses in order to prevent ONJ occurrence.References
Shane E, Goldring S, Christakos S, et al. Osteonecrosis of the jaw: more research needed. J. J. Bone Miner Res. 2006;21:1503–1505.
Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg. 2003;61:1115–1117.
Baldi D, Izzotti A, Bonica P, et al. Degenerative periodontal diseases and oral osteonecrosis: the role of gene-environment interactions. Mutat Res. 2009;667:118–131.
Fehm T, Beck V, Banys M, et al. Biphosphonate-induced osteonecrosis of the jaw (ONJ): incidence and risk factors in patients with breast cancer and gynecological malignancies. Gynecologic Oncol. 2009;112:605–609.
Wilder L, Jaeggi KA, Glatt M, et al. Higly potent geminal bisphosphonates. From pamidronate disodium to zolendronic acid. J Med Chem. 2002;45:3721–3738.
Oizumi T, Yamaguchi K, Funayama H, et al. Necrotic actions of nitrogen-containing biphosphonates and their inhibition by chlodronate, a non-nitrogen-containing biphosphonate in mice: potential for utilization of clodronate as a combination drug with a nitrogen-containing biphosphonate. Basic Clinical Pharmacol Toxicol. 2009;104:384–392.
Shmeeda H, Amitay Y, Tzemach D, et al. Liposome encapsulation of zoledronic acid results in major changes in tissue distribution and increase in toxicity. J Control Release. 2013;167:265–275.
Gao J, Liu J, Qiu Y, et al. Multi-target-directed design, syntheses, and characterization of fluorescent bisphosphonate derivatives asmultifunctional enzyme inhibitors in mevalonate pathway. Biochim Biophys Acta. 2013;1830:3635–3642.
Black DM, Schwartz AV, Ensrud KE. Effects of continuing or stopping aledronate after 5 years of treatment: the fracture intervention trial long term extension – a randomized trial. J Am M Ass. 2006;296:2927–2938.
Berenson JR, Rosen LS, Howell A, et al. Zolendronic acid reduces skeletal-related events in patients with osteolytic metastases. Cancer. Cancer;91:1191–1200.
Sharma D, Ivanovski S, Slevin M, et al. Bisphosphonate-related osteonecrosis of jaw (BRONJ): diagnostic criteria and possible pathogenic mechanisms of an unexpected anti-angiogenic side effect. Vascular Cell. 2013;5:1–1.
Mönkkönen H, Ottewell PD, Kuokkanen J, et al. Zoledronic acid-induced IPP/ApppI production in vivo. Life Sci. 2007;81:1066–1070.
Roelofs AJ, Thompson K, Gordon S, et al. Molecular mechanisms of action of bisphosphonates: current status. Clin Cancer Res. 2006;12:62225–62305.
Mcleod NMH, Davies BJB, Brennan PA. Biphosphonates osteonecrosis of the jaws; an increasing problem for the dental pratictioner. British Dental J. 2007;203:641–644.
Lane NE. Epidemiology ethiology and diagnosis of osteoporosis. Am J Obstet Gynecol. 2006;194:S3–S11.
Leon A. Assael. Oral Bisphosphonates as a Cause of a Bisphosphonates- Related Osteonecrosis of the Jaws: Clinical Findings, Assessment of Risks, and Preventive Strategies. J Oral Maxillofac Surg. 2009;67:35–43.
Durie BG, Katz M, Crowley J. Osteonecrosis of the jaw and biphosphonates. N Engl J Med. 2005;353:99–102.
Rosen LS, Gordon D, Kaminski M, et al. Zoledronic acid versus pamidronate in the treatment of skeletalmetastases in patients with breast cancer or osteolytic lesions of multiplemyeloma: a phase III, double-blind, comparative trial. Cancer J. 2001;7:377–387.
Wessel JH, Dodson TB, Zavras AI. Zoledronate smoking and obesity are strong risk factors for osteonecrosis of the jaw: a case–control study. J Oral Maxillofac Surg. 2008;66:625–631.
Dodson TB. Intravenous biphosphonate therapy and biphosphonate- related osteonecrosis of the jaws. J Oral maxillofac Surg. 2009;67:44–52.
Dimitrakopoulos I, Magopoulos C, Karakasis D. Bisphosphonate- induced avascular osteonecrosis of the jaws: a clinical report of 11 cases. Int J Oral Maxillofac Surg. 2006;35:588–593.
Cartson V, Zhu S, Zavras A. Biphosphonates use and the risk of adverse jaw outcomes: a medical claims study of 714,217 people. J Am Dent Ass. 2008;139:23–30.
Ezra A, Golomb G. Adminitsration routes and delivery systems of biphosphonates for the treatment of bone resorption. Adv Drug Deliv Rev. 2000;42:175–195.
Woo SB, Hellstein JW, Kalmar JR. Narrative (corrected) review: biphosphonates and osteonecrosis of the jaws. Ann Intern Med. 2006;144:753–761.
Sedghizadeh PP, Stanley K, Caligiuri M, et al. Oral biphosphonate use and the prevalence of osteonecrosis of the jaw: an institutional inquiry. J Am Dent Assoc. 2009;140:61–66.
Hugoson A, Koch G, Göthberg C, et al. Oral health of individuals aged 3-80 years in Jönköping, Sweden during 30 years (1973–2003). I. Review of findings on dental care habits and knowledge of oral health. Swed. Dent J. 2005;29:125–138.
Silverman SL, Landesberg R. Osteonecrosis of the jaw and the role of biphosphonates: a critical review. Am J Med. 2009;122:S33–S45.
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.
Edwards B, Gounder M, McKoy JM, et al. Pharmacovigilance and reporting oversight in US FDA fast-track process: biphosphonates and osteonecrosis of the jaw. Lancet Oncol. 2008;9:1666–1672.
Wood J, Bonjean K, Ruerz S, et al. Novel antiangiogenic effects of the bisphosphonatecompound zoledronic acid. J Pharmacol Exp Ther. 2002;302:1055–1061.
Badros A, Weikel D, Salama A, et al. Osteonecrosis of the jaw in multiple myeloma patients: clinical features and risk factors. J Clin Oncol. 2006;24:945–952.
Hwang D, Wang HL. Medical contraindications to implant therapy: part I: absolute contraindications. Implant Dent. 2006;15:353–360.
Ruggiero SL, Mehrota B, Rosenberg TJ, et al. Osteonecrosis of the jaws associated with the use of biphosphonates: a review of 63 cases. J Oral maxillofac Surg. 2004;62:527–534.
Pool BL, Berger M, Schlehofer JR, et al. In vivo and in vitro investigations on biological effects of aromaticbis-(2-chloroethyl) amino-bisphosphonic acids, new agents proposed for chemotherapy of bone tumors: cytostatic activity in rat osteosarcoma; toxicity and genotoxicity in liver and bone marrow; mutagenicity in S. typhimurium. Invest New Drugs. 1988;6:67–78.
Polovich M. Safe handling of hazardous drugs. Online J Issues Nurs. 2004;9(3):6–6. 30.
ASHP guidelines on handling hazardous drugs Developed through the ASHP Council on Professional Affairs and approved by the ASHP Board of Directors on January 12, 2006.
Fukuda A, Hikita A, Wakeyama H, et al. Regulation of osteoclast apoptosis and motility by small GTPase binding protein Rac1. J Bone Miner Res. 2005;20:2245–2253.
Wang Y, Lebowitz D, Sun C, et al. Identifying the Relative Contributions of Rac1 and Rac2 to Osteoclastogenesis. J Bone Miner Res. 2008;23:260–270.
Plotkin LI, Lezcano V, Thostenson J, et al. Connexin 43 is required for the anti-apoptotic effect of bisphosphonates on osteocytes and osteoblasts in vivo. J. Bone Miner Res. 2008;23:1712–1721.
King AE, Umland EM. Osteonecrosis of the jaw in patients receiving intravenous or oral biphosphonates. Pharmacother. 2008;28:667–677.
Elder GJ. From marrow oedema to osteonecrosis: common paths in the development of post-transplant bone pain. Nephrology. 2006;11:560–567.
Borel JF. Comparative study of in vitro and in vivo drug effects on cell mediated cytotoxicity. Immunology. 1976;31:631–641.
Tiu J, Li H, Rassekh C, et al. Molecular basis of posttransplant squamous cell carcinoma: the potential role of cyclosporine A in carcinogenesis. Laryngoscope. 2006;116:762–769.
Meller AT, Rumjanek VM, Sansone C, et al. Oral mucosa alterations induced by cyclosporin in mice: morphological features. J Periodontal Res. 2002;37:412–415.
Christodoulou C, Pervena A, Klouvas G, et al. Combination of biphosphonates and antiangiogenetic factors induces osteonecrosis of the jaw more frequently than biphosphonates alone. Oncology. 2009;76:209–211.
Assouline-Dayan Y, Chang C, Greenspan A, et al. Pathogenesis and natural history of osteonecrosis. Semin Arthritis Rheum. 2002;32:94–124.
Izzotti A, Cartiglia C, Longobardi M, et al. Alterations of gene expression in skin and lung of mice exposed to light and cigarette smoke. FASEB J. 2004;18:1559–1561.
Bagan JV, Jiménez Y, Gómez D, et al. Collagen telopeptide (serum CTX) and its relationship with the size and number of lesions in osteonecrosis of the jaws in cancer patients on intravenous bisphosphonates. Oral Oncol. 2008;4:1088–1089.
Koka S, Clarke BL, Amin S, et al. Oral biphosphonate therapy and osteonecrosis of the jaw: what to tell the concerned patient. Int J Prosthodont. 2007;20:115–122.
Rayman S, Almas K, Dincer E. Biphosphonate-related jaw necrosis: a team approach management and prevention. Int J Dent Hygiene. 2009;7:90–95.
Sarasquete M, García-Sanz R, Marín L, et al. Bisphosphonaterelated osteonecrosis of the jaw is associated with polymorphisms of the cytochrome P450 CYP2C8 in multiple myeloma: a genome-wide single nucleotide polymorphism analysis. Blood. 2008:709–712.
Ingelman-Sundberg M, Sim SC, Gomez A, et al. Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol Ther. 2007;116:496–526.
Björkman A, Burtscher IM, Svensson PJ, et al. Factor V Leiden and the prothrombin 20210A gene mutation and osteonecrosis of the knee. Arch Orthop Trauma Surg. 2005;125:51–55.
Chang JD, Hur M, Lee SS, et al. Genetic background of nontraumatic osteonecrosis of the femoral head in the Korean population. Clin Orthop Relat Res. 2008;466:1041–1046.
Kohler HP, Grant P J. Plasminogen-activator inhibitor type 1 and coronary artery disease. N Engl J Med. 2000;342:1792–1801.
Asano T, Takahashi KA, Fujioka M, et al. ABCB1 C3435T and G2677T/A polymorphism decreased the risk for steroid-induced osteonecrosis of the femoral head after kidney transplantation. Pharmacogenetics. 2003;13:675–682.
Goldwaser BR, Chuang SK, Kaban LB, et al. Risk factor assessment for the development of osteoradionecrosis. J Oral Maxillofac Surg. 2007;65:2311–2316.
Cury PR, Joly JC, Freitas N, et al. Effect of tumor necrosis factor- alpha gene polymorphism on peri-implant bone loss following prosthetic reconstruction. Implant Dent Mar. 2007;16:80–88.
Shapira L, Stabholz A, Rieckmann P, et al. Genetic polymorphism of the tumor necrosis factor (TNF)-alpha promoter region in families with localized early-onset periodontitis. J Periodontal Res. 2001;36:183–186.
American Dental Association Council on Scientific Affairs , author. Dental management of patients receiving oral biphosphonates therapy. J Amer Dent Ass. 2006;137:1144–1150.
Lin JT, Lane JM. Biphosphonates. J AM Acad Orthop Surg. 2003;11:1–4.
Zarychanski R, Elphee E, Walton P, et al. Osteonecrosis of the jaw associated with pamidronate therapy. Am J Emathol. 2006;81:73–75.
Wooltorton E. Patients receiving intravenous biphosphonates should avoid invasive dental procedures. CMAJ. 2005;172:1684–1684.
Migliorati CA, Castiglia J, Epstein J, et al. Managing the care of patients with biphosphonate-associated osteonecrosis: an American Academy of Oral Medicine position paper. J Am Dent As. 2005;136:1658–1668.
Flora S, Scarfì S, Izzotti A, et al. Induction by 7,12-dimethylbenz(a)anthracene of molecular and biochemical alterations in stem-derived human mammary epithelial cells, and protection by N-acetylcysteine. Int J Oncology. 2006;29:521–529.
Flora S, Izzotti A, D'Agostini F, et al. Mechanisms of N-acetylcysteine in the prevention of DNA damage and cancer,with special reference tosmoking related end-points. Carcinogenesis. 2001;22:999–1013.