Risk factors for bisphosphonate-associated osteonecrosis of the jaw in the prospective randomized trial of adjuvant bisp

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ORIGINAL ARTICLE

Risk factors for bisphosphonate-associated osteonecrosis of the jaw in the prospective randomized trial of adjuvant bisphosphonates for early-stage breast cancer (SWOG 0307) Darya A. Kizub 1 & Jieling Miao 2 & Mark M. Schubert 3,4 & Alexander H. G. Paterson 5 & Mark Clemons 6 & Elizabeth C. Dees 7 & James N. Ingle 8 & Carla I. Falkson 9 & William E. Barlow 2 & Gabriel N. Hortobagyi 10 & Julie R. Gralow 11 Received: 5 June 2020 / Accepted: 4 September 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020

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 Clinical trials . Breast cancer . Bisphosphonate . Osteonecrosis of the jaw

Introduction Bisphosphonates reduce the risk of bone metastases in a lowestrogen environment [1] and are recommended as adjuvant * Darya A. Kizub [email protected] 1

The Everett Clinic, Everett, WA, USA

2

SWOG Statistical Center, Seattle, WA, USA

3

Fred Hutchinson Cancer Research Center, Seattle, WA, USA

4

University of Washington School of Dentistry, Seattle, WA, USA

5

Tom Baker Cancer Center, Calgary, Alberta, Canada

therapy in post-menopausal women with early-stage breast cancer [2–4]. Bisphosphonates inhibit the ability of osteoclasts to resorb bone, decreasing local metabolic activity and making for a less hospitable environment for metastasized 6