The goal of the MEDEX-OP trial was to compare the efficacy of a known effective high-intensity resistance and impact training (HiRIT) with a low-intensity exercise control (Buff Bones® [BB]), alone or in combination with antiresorptive bone medication, on indices of fracture risk (bone mass, body composition, muscle strength, functional performance), compliance, and safety. Primary study outcomes were 8-month change in lumbar spine (LS) and total hip (TH) bone mineral density (BMD). Healthy postmenopausal women with low bone mass (T-score ≤ −1.0) on or off stable doses (≥12 months) of antiresorptive medication were recruited. A total of 115 women (aged 63.6 ± 0.7 years; body mass index [BMI] 25.5 kg/m2; femoral neck [FN] T-score −1.8 ± 0.1) were randomly allocated to 8-month, twice-weekly, 40-minute HiRIT (5 sets of 5 repetitions, >80% to 85% 1 repetition maximum) or BB (low-intensity, Pilates-based training), stratified by medication intake, resulting in four groups: HiRIT (n = 42), BB (n = 44), HiRIT-med (n = 15), BB-med (n = 14). HiRIT improved LS BMD (1.9 ± 0.3% versus 0.1 ± 0.4%, p < 0.001) and stature (0.2 ± 0.1 cm versus −0.0 ± 0.1 cm, p = 0.004) more than BB. Both programs improved functional performance, but HiRIT effects were larger for leg and back muscle strength and the five times sit-to-stand test (p < 0.05). There was a positive relationship between maximum weight lifted and changes in LS BMD and muscle strength in the HiRIT groups. Exploratory analyses suggest antiresorptive medication may enhance exercise efficacy at the proximal femur and lumbar spine. Exercise compliance was good (82.4 ± 1.3%) and both programs were well tolerated (7 adverse events: HiRIT 4; BB 3). HiRIT improved indices of fracture risk significantly more than Buff Bones®. More trials combining bone medication and bone-targeted exercise are needed. © 2021 American Society for Bone and Mineral Research (ASBMR).