It is unclear whether the antifracture efficacy of bisphosphonates depends on pretreatment bone turnover. We analyzed the risedronate phase III clinical programs using the urinary excretion of deoxypyridinoline (uDPD) as an index of pretreatment bone resorption rates. Risedronate reduced incident vertebral fractures in women with postmenopausal osteoporosis independent from pretreatment bone resorption. BACKGROUND Earlier studies on postmenopausal osteoporosis have suggested that the therapeutic efficacy of antiresorptive therapies might be influenced by pretreatment bone turnover. Because all of these studies have used bone mineral density (BMD) as the primary endpoint, it remains unclear whether this association holds true for incident fractures. METHODS This study aims to answer this question in a post hoc analysis of a subset of the risedronate phase III clinical programs, using the urinary excretion of deoxypyridinoline (uDPD) as an index of pretreatment bone resorption (PBR). A total of 1593 women with postmenopausal osteoporosis that had baseline uDPD values and paired spinal radiographs available were pooled, in similar proportions, from the risedronate multinational and North American VERT, and from the risedronate HIP trials. Patients from treatment and placebo groups were stratified by the uDPD premenopausal normative median. The four resulting groups were balanced for age, years since menopause, body mass index, baseline femoral neck BMD, and number of prevalent fractures, but baseline lumbar spine BMD was significantly higher in patients with low PBR rates. RESULTS In all groups, the proportion of patients with new vertebral fractures was higher in patients with baseline uDPD levels above the normative median. The incidence of vertebral fracture was significantly lower in groups assigned to risedronate compared with placebo. This effect was independent of PBR: in patients with high PBR, the relative risk (RR) of vertebral fracture after 1 year of risedronate was 0.28 (p = 0.03 compared with controls, absolute risk reduction 7.1%). In patients with low PBR, the RR of fracture after 1 year was 0.33 (p < 0.001, absolute risk reduction 4%). After 3 years, the RR of fracture was 0.52 (p = 0.042, absolute risk reduction 8.3%) in patients with high PBR, and 0.54 (p = 0.002, absolute risk reduction 7.1%) in patients with low PBR. Results were similar after adjusting for age, baseline lumbar spine BMD, and prevalent fractures. The number needed to treat to avoid one vertebral fracture at 12 months was 15 in the group of patients with high PBR and 25 in patients with low PBR. Risedronate significantly increased lumbar spine BMD. During the first year of treatment, women with high PBR gained lumbar spine BMD at a faster rate than patients with low PBR. Treatment-by-PBR status interactions were not significantly different over time. CONCLUSIONS The efficacy of risedronate to reduce incident vertebral fractures in women with postmenopausal osteoporosis is largely independent of pretreatment bone resorption rates.