Abstract
To estimate the cumulative randomized evidence for the overall incidence of bisphosphonates induced jaw osteonecrosis in adjuvant treatment of breast cancer. Systematic review and meta-analysis of randomized clinical trials. Trials were located through PubMed, ISI, Cochrane Library, and major cancer scientific meetings searches. We identified 15 studies reporting data on osteonecrosis of the jaw. A total of 10,694 randomized women were included, of whom 5,312 received bisphosphonates and 5,382 received either placebo or no treatment. Osteonecrosis of the jaw was a rare event, occurring in 13 (0.24%) of the 5,312 patients receiving bisphosphonates, and in one of the 5,382 patients in the control group. All the 13 events of osteonecrosis of the jaw reported among bisphosphonates arms occur in patients undergoing treatment with zoledronic acid (13/3,987, 0.33%). No events of osteonecrosis of the jaw were reported among patients randomized to receive clodronate (n = 669), pamidronate (n = 460), risedronate (n = 171), and ibandronate (n = 25); however, these samples were too small to be able to rule out the condition. Treatment with zoledronic acid was significantly associated to the occurrence of osteonecrosis of the jaw (OR = 3.23, 95% CI = 1.7–8) compared with no use. No significant between-study heterogeneity was observed. Despite use of zoledronic acid is associated to a higher number of events compared with no use, the osteonecrosis of the jaw during the adjuvant treatment of breast cancer is a rare event. At current dosage, adjuvant use of bisphosphonates in breast cancer treatment is safe.
Similar content being viewed by others
References
Pfeilschifter J, Diel IJ (2000) Osteoporosis due to cancer treatment: pathogenesis and management. J Clin Oncol 18:1570–1593
Shapiro CL, Manola J, Leboff M (2001) Ovarian failure after adjuvant chemotherapy is associated with rapid bone loss in women with early-stage breast cancer. J Clin Oncol 19:3306–3311
Eastell R, Hannon RA, Cuzick J et al (2006) Effect of an aromatase inhibitor on bmd and bone turnover markers: 2-year results of the Anastrozole, Tamoxifen, Alone or in Combination (ATAC) trial (18233230). J Bone Miner Res 21:1215–1223
Mincey BA, Duh MS, Thomas SK et al (2006) Risk of cancer treatment-associated bone loss and fractures among women with breast cancer receiving aromatase inhibitors. Clin Breast Cancer 7:127–132
Cummings SR, Browner WS, Bauer D et al (1998) Endogenous hormones and the risk of hip and vertebral fractures among older women. Study of Osteoporotic Fractures Research Group. N Engl J Med 339:733–738
Hoff AO, Gagel RF (2005) Osteoporosis in breast and prostate cancer survivors. Oncology (Williston Park) 19:651–658
Brufsky A, Bosserman L, Caradonna R, Haley B, Jones M, Moore H, Dong M, Warsi G, Lacerna L, Perez E (2007) The effect of zoledronic acid on aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole: the Z-FAST study 36-month follow-up. Breast Cancer Res Treat 106(Suppl. 1):S8 (Abstract 27)
De Boer R, Eidtmann H, Lluch A et al (2007) The ZO-FAST trial: zoledronic acid effectively inhibits aromatase inhibitor associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole: 24 month BMD results. Breast Cancer Res Treat 106(Suppl. 1):S36 (Abstract 501)
Greenspan SL, Brufsky A, Lembersky BC, Bhattacharya R, Vujevich KT, Perera S, Sereika SM, Vogel VG (2008) Risedronate prevents bone loss in breast cancer survivors: a 2-year, randomized, double-blind, placebo-controlled clinical trial. J Clin Oncol 26:2644–2652
Lester JE, Dodwell D, Purohit OP, Gutcher SA, Ellis SP, Thorpe R, Horsman JM, Brown JE, Hannon RA, Coleman RE (2008) Prevention of anastrazole-induced bone loss with monthly oral ibandronate during adjuvant aromatase inhibitor therapy for breast cancer. Clin Cancer Res 14:6336–6342
Daubine F, Le Gall C, Gasser J et al (2007) Antitumor effects of clinical dosing regimens of bisphosphonates in experimental breast cancer bone metastasis. J Natl Cancer Inst 99:322–330
van der Pluijm G, Vloedgraven H, van Beek E et al (1996) Bisphosphonates inhibit the adhesion of breast cancer cells to bone matrices in vitro. J Clin Invest 98:698–705
Boissier S, Ferreras M, Peyruchaud O et al (2000) Bisphosphonates inhibit breast and prostate carcinoma cell invasion, an early event in the formation of bone metastases. Cancer Res 60:2949–2954
Senaratne SG, Pirianov G, Mansi JL et al (2000) Bisphosphonates induce apoptosis in human breast cancer cell lines. Br J Cancer 82:1459–1468
Fromigue O, Kheddoumi N, Body JJ (2003) Bisphosphonates antagonise bone growth factors’ effects on human breast cancer cells survival. Br J Cancer 89:178–184
Fournier P, Boissier S, Filleur S et al (2002) Bisphosphonates inhibit angiogenesis in vitro and testosterone-stimulated vascular regrowth in the ventral prostate in castrated rats. Cancer Res 62:6538–6544
Gnant M, Mlineritsch B, Schippinger W, Luschin-Ebengreuth G, Postlberger S, Menzel C, Jakesz R, Seifert M, Hubalek M, Bjelic-Radicic V, Samonigg H, Tausch C, Eidtmann H, Steger G, Kwasny W, Dubsky P, Fridrik M, Fitzal F, Stierer M, Rucklinger E, Greil R (2009) Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med 360:679–691
Bamias A, Kastritis E, Bamia C, Moulopoulos LA, Melakopoulos I, Bozas G et al (2005) Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol 23(34):8580–8587
Sweeting MJ, Sutton AJ, Lambert PC (2004) What to add to nothing? Use and avoidance of continuity corrections in meta-analysis of sparse data. Stat Med 23:1351–1375
Egger M, Smith GD, Altman DG (2001) Systematic reviews in health care: meta-analysis in context. BMJ, London
Petitti DB (2000) Meta-analysis, decision analysis, and cost-effectiveness analysis: methods for quantitative synthesis in medicine. Oxford University Press, New York
Mincey BA, Dentchev T, Sloan JA, Hines SL, Perez EA, Johnson DB, Schaefer PL, Liu H, Kahanic SP, Loprinzi CL (2008) N03CC—a randomized, controlled, open-label trial of upfront vs. delayed zoledronic acid for prevention of bone loss in postmenopausal (PM) women with primary breast cancer (PBC) starting letrozole after tamoxifen. J Clin Oncol 26 (May 20 Suppl) [abstract 564]
Van Poznak C, Hannon R, Clack G, Campone M, Mackey JR, Apffelstaedt J, Eastell R (2008) Managing cancer treatment-induced bone loss: 24-month results from the Study of Anastrozole with the Bisphosphonate RisedronatE (SABRE). Presented at San Antonio Breast Cancer Symposium (Abstract 1137)
Schenk N, Lombart A, Frassoladti A et al (2007) The E-ZO-FAST trial: zoledronic acid (ZA) eff ectively inhibits aromatase inhibitor associated bone loss (AIBL) in postmenopausal women (PMW) with early breast cancer (EBC) receiving adjuvant letrozole (Let). Eur J Cancer 5(Suppl. 5):186–187 (Abstract 2008)
Shapiro CL, Halabi S, Gibson G, Weckstein DJ, Kirshner J, Sikov WM, Winer EP, Hudis CA, Isaacs C, Wecstein D, Schilsky RL, Paskett E (2008) Effect of zoledronic acid (ZA) on bone mineral density (BMD) in premenopausal women who developed ovarian failure (OF) due to adjuvant chemotherapy (AdC): first results of GALGB trial 79809. J Clin Oncol 26(May 20 Suppl) (abstract 512)
Hershman DL, McMahon DJ, Crew KD, Cremers S, Irani D, Cucchiara G, Brafman L, Shane E (2008) Zoledronic acid prevents bone loss in premenopausal women undergoing adjuvant chemotherapy for early-stage breast cancer. J Clin Oncol 26:4739–4745
Hines SL, Mincey BA, Sloan JA, Thomas SP, Chottiner E.G., Loprinzi CL, Atherton PJ, Carlson MD, Salim M, Perez EA (2008) N02C1: A phase III randomized, placebo-controlled, double-blind trial of risedronate for prevention of bone loss in premenopausal women undergoing adjuvant chemotherapy for breast cancer (BC). J Clin Oncol 26 (May 20 Suppl) [abstract 525]
Tevaarwerk A, Stewart JA, Love R, Binkley NC, Black S, Eickhoff J, Mulkerin DL (2007) Randomized trial to assess bone mineral density (BMD) effects of zoledronic acid (ZA) in postmenopausal women with breast cancer. J Clin Oncol 25 (Jun 20 18S) (Abstract 19558)
Saarto T, Vehmanen L, Virkkunen P, Blomqvist C (2004) Ten-year follow-up of a randomized controlled trial of adjuvant clodronate treatment in node-positive breast cancer patients. Acta Oncol 43:650–656
Kristensen B, Ejlertsen B, Mouridsen HT, Jensen MB, Andersen J, Bjerregaard B, Cold S, Edlund P, Ewertz M, Kamby C, Lindman H, Nordenskjöld B, Bergh J (2008) Bisphosphonate treatment in primary breast cancer: results from a randomised comparison of oral pamidronate versus no pamidronate in patients with primary breast cancer. Acta Oncol 47(4):740–746
Powles T, Paterson S, McCloskey E, Schein P, Scheffler B, Tidy A, Ashley S, Smith I, Ottestad L, Kanis J (2006) Reduction in bone relapse and improved survival with oral clodronate for adjuvant treatment of operable breast cancer. Breast Cancer Res 8:R13
Coleman R, Thorpe H, Cameron D et al. (2006) Zoledronic acid is well tolerated and can be safely administered with adjuvant chemotherapy—first safety data from the AZURE trial (BIG01/04) [poster] Presented at: 29th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, 14–17 December 2006 (Abstr 2080)
Delmas PD, Balena R, Confravreux E, Hardouin C, Hardy P, Bremond A (1997) Bisphosphonate risedronate prevents bone loss in women with artificial menopause due to chemotherapy of breast cancer: a double-blind, placebo-controlled study. J Clin Oncol 15:955–962
Fuleihan Gel-H, Salamoun M, Mourad YA, Chehal A, Salem Z, Mahfoud Z, Shamseddine A (2005) Pamidronate in the prevention of chemotherapy-induced bone loss in premenopausal women with breast cancer: a randomized controlled trial. J Clin Endocrinol Metab 90:3209–3214
Vehmanen L, Saarto T, Risteli J, Risteli L, Blomqvist C, Elomaa I (2004) Short-term intermittent intravenous clodronate in the prevention of bone loss related to chemotherapy-induced ovarian failure. Breast Cancer Res Treat 87:181–188
Bryce CJ, Prior JC, Sill K, et al. (2002) Does short-term, intravenous, low dose clodronate, administered with adjuvant chemotherapy for premenopausal breast cancer reduce bone loss in the first year in patients? Proc Am Soc Clin Oncol 21 (Abstr. 270)
Diel IJ, Jaschke A, Solomayer EF, Gollan C, Bastert G, Sohn C, Schuetz F (2008) Adjuvant oral clodronate improves the overall survival of primary breast cancer patients with micrometastases to the bone marrow: a long-term follow-up. Ann Oncol 19:2007–2011
Rosen LS, Gordon D, Antonio BS, Kaminski M (2001) Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. Cancer J 7:377
Author contributions
Antonis Valachis, Davide Mauri and Nikolaos P. Polyzos, Ilias P. Polyzos participated in the design of the study; Antonis Valachis and Davide Mauri participated in data extraction;
Lorenzo L. Pesce performed the statistical analyses; Lorenzo Pesce, Davide Mauri, Konstantinos Kamposioras, and Nikolaos P. Polyzos interpreted the results.
Davide Mauri, Antonis Valachis, and Ilias P. Polyzos wrote the manuscript.
Nikolaos P. Polyzos and Konstantinos Kamposioras review and commented final manuscript.
Conflict of interest statement
There is no conflict of interest.
Role of funding source
The study was completely auto-financed and no financial support was derived from the industry.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Mauri, D., Valachis, A., Polyzos, I.P. et al. Osteonecrosis of the jaw and use of bisphosphonates in adjuvant breast cancer treatment: a metanalysis. Breast Cancer Res Treat 116, 433–439 (2009). https://doi.org/10.1007/s10549-009-0432-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10549-009-0432-z