Scintigraphic evaluation of mandibular bone turnover in patients with solid tumors receiving zoledronic acid q Tim Van den Wyngaert a,b, * , Manon T. Huizing a , Eric Fossion c , Jan B. Vermorken a a Department of Medical Oncology, Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium b Department of Nuclear Medicine, Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium c Department of Oral and Maxillo-Facial Surgery, ZNA Middelheim, Lindendreef 1, 2020 Wilrijk, Belgium article info Article history: Received 11 December 2009 Received in revised form 3 January 2010 Accepted 4 January 2010 Available online 6 February 2010 Keywords: Zoledronic acid Bisphosphonate ONJ Mandible Bone turnover Scintigraphy summary Bisphosphonates (BP) have been associated with the occurrence of osteonecrosis of the jaw (ONJ), possi- bly by causing an excessive bone turnover inhibition. However, little in vivo evidence exists to support this theory. The 99m Tc-medronate scintigrams of patients with skeletal metastases and BP use (n = 40) were indi- vidually matched with cancer patients without BP exposure (n = 40) and controls with neither malig- nancy nor BP use (n = 40). Patients with established ONJ or intense focal abnormalities in the studied regions were excluded. Mandibular (MBT) bone turnover was quantified relative to the femur by defining regions-of-interest with correction for background activity. The patients with BP exposure (34 female, 6 male) had a median age of 63 years (range 25–81) and received a median number of 11 zoledronic acid administrations (range 1–44). Most patients suffered from breast cancer (n = 30). The mean ratio of the MBT in cancer patients with BP use over non-users was 0.88 (95% CI 0.80–0.96; p = 0.003), and 0.83 (95% CI 0.73–0.94; p = 0.001) when BP using oncological patients were compared with controls without malignancy or BP use. The ratio of MBT’s between BP naive patients was 0.95 (95% CI 0.83–1.07; p = 0.8). No dose–response effect between the number of BP administrations and MBT could be demonstrated (r = 0.02; p = 0.9). These findings suggest that, relative to the femur, BP exert a stronger effect on mandibular bone turn- over, which strengthens the hypothesis that the inhibition of bone turnover may be important in the pathophysiology of ONJ. Ó 2010 Elsevier Ltd. All rights reserved. Introduction Bisphosphonate therapy has recently received a lot of attention in oncology, oral medicine and clinical dentistry due to their asso- ciation with the occurrence of osteonecrosis of the jaw (ONJ), in particular after dental trauma. 1,2 By consensus, ONJ has been de- fined as the persistence of exposed bone in the oral cavity, despite an adequate treatment for 8 weeks, without local evidence of malignancy and no prior radiotherapy to the affected region. 3 Although the underlying pathophysiology is not well under- stood, the powerful inhibition of bone resorption by bisphospho- nates and the subsequent reduction in remodeling capacity is believed to leave the jaw unable to adapt to external stresses. A re- cent report on the accumulation of microfractures in bone samples from patients with ONJ appears to corroborate this assumption. 4 Further evidence comes from the clinical observation that ONJ also occurred in two large phase III trials with denosumab, a monoclo- nal antibody against the receptor activator of nuclear factor-jB ligand (RANKL) and reversible inhibitor of osteoclast-mediated bone resorption. 5,6 The particular vulnerability of the jaws is theorized to stem from, amongst others, a higher dependence on active bone turnover compared to other parts of the skeleton, making it more vulnerable to antiresorptive therapy. 4,7,8 In support of this theory, animal research has shown that bone turnover in skeletally mature dogs is approximately 3- to 10-fold greater in the alveolar process of the mandible compared with other skeletal sites with high cortical bone content, such as the femur and tibia. 9,10 Moreover, a higher mandibular bone formation rate has been demonstrated compared with the maxilla. 11 Although these 1368-8375/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.oraloncology.2010.01.001 q Statement on originality: The results of this study were presented at the annual meeting of the American Society of Clinical Oncology (ASCO) 2009. This manuscript or the data contained within are not under consideration for publication by another journal. * Corresponding author. Address: Department of Medical Oncology, Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium. Mobile: +32 473 542124; fax: +32 3 8253308. E-mail addresses: tim.van.den.wyngaert@skynet.be (T. Van den Wyngaert), manon.huizing@uza.be (M.T. Huizing), eric.fossion@zna.be (E. Fossion), jan.b.ver- morken@uza.be (J.B. Vermorken). Oral Oncology 46 (2010) 214–218 Contents lists available at ScienceDirect Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology