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Original Investigation
August 16, 2016

Effect of Abaloparatide vs Placebo on New Vertebral Fractures in Postmenopausal Women With OsteoporosisA Randomized Clinical Trial

Author Affiliations
  • 1Colorado Center for Bone Research, Lakewood
  • 2Radius Health, Waltham, Massachusetts
  • 3Nordic Bioscience, Copenhagen, Denmark
  • 4Center for Health & Medical Research, Hong Kong, People’s Republic of China
  • 5Center for Clinical and Basic Research, Rio de Janeiro, Brazil
  • 6Center for Clinical and Basic Research, Vejle, Denmark
  • 7Centro Paulista de Investigação Clinica; São Paulo, Brazil
  • 8Clinical Research Center, Helen Hayes Hospital, West Haverstraw, New York
JAMA. 2016;316(7):722-733. doi:10.1001/jama.2016.11136
Abstract

Importance  Additional therapies are needed for prevention of osteoporotic fractures. Abaloparatide is a selective activator of the parathyroid hormone type 1 receptor.

Objective  To determine the efficacy and safety of abaloparatide, 80 μg, vs placebo for prevention of new vertebral fracture in postmenopausal women at risk of osteoporotic fracture.

Design, Setting, and Participants  The Abaloparatide Comparator Trial In Vertebral Endpoints (ACTIVE) was a phase 3, double-blind, RCT (March 2011-October 2014) at 28 sites in 10 countries. Postmenopausal women with bone mineral density (BMD) T score ≤−2.5 and >−5.0 at the lumbar spine or femoral neck and radiological evidence ≥2 mild or ≥1 moderate lumbar or thoracic vertebral fracture or history of low-trauma nonvertebral fracture within the past 5 years were eligible. Postmenopausal women (>65 y) with fracture criteria and a T score ≤−2.0 and >−5.0 or without fracture criteria and a T score ≤−3.0 and >−5.0 could enroll.

Interventions  Blinded, daily subcutaneous injections of placebo (n = 821); abaloparatide, 80 μg (n = 824); or open-label teriparatide, 20 μg (n = 818) for 18 months.

Main Outcomes and Measures  Primary end point was percentage of participants with new vertebral fracture in the abaloparatide vs placebo groups. Sample size was set to detect a 4% difference (57% risk reduction) between treatment groups. Secondary end points included change in BMD at total hip, femoral neck, and lumbar spine in abaloparatide-treated vs placebo participants and time to first incident nonvertebral fracture. Hypercalcemia was a prespecified safety end point in abaloparatide-treated vs teriparatide participants.

Results  Among 2463 women (mean age, 69 years [range, 49-86]), 1901 completed the study. New morphometric vertebral fractures occurred in 0.58% (n = 4) of the abaloparatide group, 4.22% (n = 30) of the placebo group (risk difference [RD] vs placebo, −3.64 [95% CI, −5.42 to −2.10]; relative risk, 0.14 [95% CI, 0.05-0.39]; P < .001), and 0.84% (n = 6) of the teriparatide group. The Kaplan-Meier estimated event rate for nonvertebral fracture was 2.7% for abaloparatide, 4.7% for placebo (RD, −2.01 [95% CI, −4.02 to −0.00]; hazard ratio [HR], 0.57 [95% CI, 0.32-1.00]; P = .049), and 3.3% for teriparatide. BMD increases were greater with abaloparatide than with placebo (all P < .001). Incidence of hypercalcemia was lower with abaloparatide (3.4%) than with teriparatide (6.4%) with an RD of −2.96 (95% CI, −5.12 to −0.87; P = .006).

Conclusions and Relevance  Among postmenopausal women with osteoporosis, the use of subcutaneous abaloparatide, compared with placebo, reduced the risk of new vertebral and nonvertebral fractures over 18 months. Further research is needed to understand the clinical importance of RD, the risks and benefits of abaloparatide treatment, and the efficacy of abaloparatide vs other osteoporosis treatments.

Trial Registration  clinicaltrials.gov Identifier: NCT01343004

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