Reassessment of Fracture Risk in Women After 3 Years of Treatment With Zoledronic Acid: When is it Reasonable to Discontinue Treatment?

CONTEXT: Data are needed to guide therapeutic decisions about stopping bisphosphonates after an initial treatment period. OBJECTIVE: To define significant predictors of fracture and quantify fracture incidence in risk factor-defined subgroups of women who discontinue zoledronic acid (ZOL) after 3 years of treatment. To determine if continuing ZOL reduces fracture risk in subgroups. DESIGN: This study is based on data from the 3 year extension of HORIZON. SETTING: Subjects were in the ZOL arm of the Multicenter HORIZON trial. PARTICIPANTS: One thousand two hundred thirty three women who previously received 3 ZOL treatments during the Core trial. INTERVENTION: Randomization to three additional annual ZOL (Z6, n = 616) or placebo infusions (Z3P3, n = 617). MAIN OUTCOMES: The risk of morphometric vertebral fractures (MorphVertFx) and clinical nonvertebral fractures (NVF). RESULTS: The incidence of MorphVertFx in Z3P3 was predicted by femoral neck (FN) t-score ≤-2.5 OR 3.3 (1.4, 8.0), p = .008, total hip (TH) t-score ≤-2.5 OR 4.0 (1.8, 9.0), p = .0007, and incident MorphVertFx during Core OR 4.75 (1.4, 16.8), p < .015. Incidence of NVF was predicted by TH t-score for 1 decline, HR 1.7 (1.2, 2.6), p = .008, incident NVF during Core HR 2.5 (1.2, 5.3), p = .014, and prevalent vertebral fracture HR 3.0 (1.4, 6.3), p = .005. For MorphVertFx, there were no significant treatment subgroup interactions; absolute fracture reductions with continued ZOL were greatest in high-risk subgroups. For NVF, there were no significant treatment reductions overall or in subgroups and no significant interactions. CONCLUSIONS: After 3 years of ZOL, in women who have a TH t-score above -2.5, no recent incident fracture and no more than one risk factor (almost 55% of the population), risk for subsequent fracture (over three additional years) is low if treatment is discontinued (for MorphVertFx, average risk 3.2% and for NVF, average risk 5.8%). In these patients, discontinuation for up to 3 years is reasonable.