Risk factors for bisphosphonate-associated osteonecrosis of the jaw in the prospective randomized trial of adjuvant bisphosphonates for early-stage breast cancer (SWOG 0307)

Abstract

Purpose: Bisphosphonates reduce bone metastases in postmenopausal women with early-stage breast cancer but carry the risk of bisphosphonate-related osteonecrosis of the jaw (BRONJ). We describe risk factors for BRONJ and compare BRONJ provoked by infection or trauma with spontaneous lesions, which carry a better prognosis.

Methods: SWOG 0307 randomized women with stage I-III breast cancer to receive zoledronic acid (ZA), clodronate (CL), or ibandronate (IB) for 3 years, implemented BRONJ prevention guidelines, and collected information about dental health and development of BRONJ. All statistical tests were two-sided.

Results: Of 6018 women, 48 developed BRONJ. Infection was present in 21 (43.8%). Median time to BRONJ was 2.1 years for ZA, 2.0 years for IB, and 3.4 years for clodronate (p = 0.04). BRONJ was associated with bisphosphonate type (28/2231 (1.26%) for ZA, 8/2235 (0.36%) for CL, 12/1552 (0.77%) for IB), dental calculus (OR 2.03), gingivitis (OR 2.11), moderate/severe periodontal disease (OR 2.87), and periodontitis > 4 mm (OR 2.20) (p < 0.05). Of 57 lesions, BRONJ occurred spontaneously in 20 (35.1%) and was provoked by dental extraction in 20 (35.1%), periodontal disease in 14 (24.6%), denture trauma in 6 (10.5%), and dental surgery in 2 (3.5%). Spontaneous BRONJ occurred more frequently at the mylohyoid ridge. There were no differences in dental disease, infection, or bisphosphonate type between spontaneous and provoked BRONJ.

Conclusion: ZA and worse dental health were associated with increased incidence of BRONJ, with a trend toward additive risk when combined. BRONJ incidence was lower than in similar studies, with prevention strategies likely linked to this.

Clinical trial number: NCT00127205 REGISTRATION DATE: July 2005.

Keywords: Bisphosphonate; Breast cancer; Clinical trials; Osteonecrosis of the jaw.

Conflict of interest statement

Conflict of interest: Dr. Ingle reports grants from U.S. National Cancer Institute, during the conduct of the study. Dr. Falkson reports grants from Seattle Genetics, grants from Pfizer, other from Biotheranostics, other from Agendia, grants from Genentech/Roche, other from ExactSciences/OncotypeDx, outside the submitted work. Dr. Barlow reports grants from the National Cancer Institute, during the conduct of the study. Dr. Hortobagyi reports grants and personal fees from Novartis, outside the submitted work. Dr. Gralow reports other from Roche/Genentech, other from Novartis, other from Radius, other from Astra Zeneca, other from Pfizer, other from Puma, other from Immunomedics, other from Seattle Genetics, other from Sandoz/Hexal AG, outside the submitted work. All other authors declare no conflicts of interest.

Figures

Figure 1:

ONJ onset among patients with ONJ (months)