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

Data are needed to guide therapeutic decisions about stopping bisphosphonates after an initial treatment period. 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. This study is based on data from the 3 year extension of HORIZON. Subjects were in the ZOL arm of the Multicenter HORIZON trial. One thousand two hundred thirty three women who previously received 3 ZOL treatments during the Core trial. Randomization to three additional annual ZOL (Z6, n = 616) or placebo infusions (Z3P3, n = 617). The risk of morphometric vertebral fractures (MorphVertFx) and clinical nonvertebral fractures (NVF). 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. 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.