Abaloparatide (ABL), a synthetic PTHrP(134) analogue (75% homology with PTHrP), has high affinity for the RG subtype of the PTH1R and low affinity for the R0 conformation, resulting in a greater stimulus to bone formation vs resorption. In animals, ABL increases bone formation markers with minimal resorption marker increase, increases bone mass, improves microarchitecture and bone strength. In the Phase 3 Abaloparatide Comparator Trial in Vertebral Endpoints study (ACTIVE), 2463 postmenopausal women with osteoporosis (age 4986, mean 69 years), were randomized to blinded daily subcutaneous ABL vs placebo or open label teriparatide (TPTD). At 18 months, spine BMD increased similarly with ABL and TPTD, however, in the Total Hip and Femoral Neck, BMD increments were faster and significantly larger with ABL. New vertebral fracture incidence (the primary endpoint) was 4.2% with placebo, 0.6% with ABL and 0.8% with TPTD (risk reductions: 86% for ABL and 80% for TPTD; both P<0.001). Time to first nonvertebral fracture revealed early separation between ABL and both placebo and TPTD. Over 18 months, nonvertebral fractures occurred in 4.7% of placebo, 2.7% of ABL and 3.3% of TPTD (risk reductions 43% with ABL, P=0.049, and 28% with TPTD, P=0.22). Participants from ABL and Placebo who completed ACTIVE (n=1139) were enrolled in an extension where all participants received alendronate (Aln) for 24 months. At the end of the 43-months, with Pbo/Aln, the new vertebral fracture rate was 5.6%, vs 0.9% with ABL/Aln (84% risk reduction; P<0.001). At 43 months, there was a sustained 39% risk reduction for nonvertebral fractures with ABL/Aln vs Pbo/Aln (P<0.05). Although all women received alendronate for 2 years of the 3.5-year trial, those who originally received ABL had significantly fewer fractures, suggesting persistent benefit. ABL represents a potent therapy for patients at high risk for fracture.