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Original Investigation |

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

Paul D. Miller, MD1; Gary Hattersley, PhD2; Bente Juel Riis, MD3; Gregory C. Williams, PhD2; Edith Lau, MD4; Luis Augusto Russo, MD, PhD5; Peter Alexandersen, MD6; Cristiano A. F. Zerbini, MD7; Ming-yi Hu, PhD2; Alan G. Harris, MD2; Lorraine A. Fitzpatrick, MD2; Felicia Cosman, MD8; Claus Christiansen, MD3 ; for the ACTIVE Study Investigators
[+] 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.
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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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Figure 1.
Patient Flow Through Phases of a Randomized Trial of Abaloparatide vs Placebo for New Vertebral Fracture Prevention Among Postmenopausal Women With Osteoporosis

aTwo women experienced events that resulted in hospitalization and were therefore categorized as having serious adverse events (1, fracture of the left femoral neck; 1, head of the humerus fracture); however, these events occurred prior to and, in fact, prevented randomization. They were not associated with study treatment.

bCategory includes patients lost to follow-up for the following reasons: did not return, refused to perform procedures, no longer wished to participate, administrative reasons, unknown reasons, and breast cancer (1 patient).

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Figure 2.
Change From Baseline in Bone Mineral Density

Mean percent changes in bone mineral density at the total hip, femoral neck, and lumbar spine were evaluated using dual-energy x-ray absorptiometry based on the intent-to-treat population. Values shown are mean percent change from baseline using a mixed-effect repeated-measures model. Improvements in bone mineral density associated with abaloparatide were significantly greater than with placebo at all 3 sites and at all time points (P < .001). Improvements with teriparatide were significantly greater than with placebo at all 3 sites at all time points (P < .001). Improvements with abaloparatide were significantly greater than those with teriparatide at the total hip and femoral neck at all time points (P < .001) and at lumbar spine at 6 and 12 months (P < .001). Error bars indicate 95% CIs.

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Figure 3.
Time to Event of Nonvertebral, Clinical, and Major Osteoporotic Fractures

A, Kaplan-Meier curves indicate time to the first nonvertebral fracture—a prespecified secondary end point. Nonvertebral fractures were defined as fractures excluding those of the spine, sternum, patella, toes, fingers, skull, and face and those with high trauma. For abaloparatide vs placebo, the hazard ratio (HR) was 0.57 (95% CI, 0.32-1.00; P = .049) and for teriparatide vs placebo, the HR was 0.72 (95% CI, 0.42-1.22; P = .22).

B, Curves indicate time to the first clinical fracture—a prespecified exploratory end point. Clinical fractures were defined as all fractures that would cause a patient to seek medical care, regardless of the level of trauma, including clinical spine. For abaloparatide vs placebo, the HR was 0.57 (95% CI, 0.35-0.91; P = .02) and for teriparatide vs placebo, the HR was 0.71 (95% CI, 0.46-1.09; P = .11).

C, Curves indicate time to the first major osteoporotic fracture—a prespecified exploratory end point. Major osteoporotic fractures were defined as fractures of the wrist, upper arm, hip, and clinical spine. For abaloparatide vs placebo, the HR was 0.30 (95% CI, 0.15-0.61; P < .001) and for teriparatide vs placebo, the HR was 0.67 (95% CI, 0.39-1.14; P = .14).The median durations in days of follow-up for all 3 fracture categories were 568 (interquartile range [IQR], 557-572) for placebo, 568 (IQR, 477-572) for abaloparatide, and 567 (IQR, 558-571) for teriparatide.

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Figure 4.
Median Change From Baseline in Serum Bone Metabolism Markers Over Time by Treatment Group

Error bars indicate median interquartile ranges. Levels indicate change from baseline for a bone turnover marker population subset (n = 184 placebo, n = 189 abaloparatide, and n = 227 teriparatide participants).

A, All comparisons for serum procollagen type I N-terminal propeptide (s-PINP) of abaloparatide vs placebo and of teriparatide vs placebo, P < .001. For abaloparatide vs teriparatide at 1 month, P = .13; at month 3, P = .02; at months 6, 12, and 18, P < .001.

B, Comparisons for serum carboxy-terminal cross-linking telopeptide of type I collagen (s-CTX) of abaloparatide vs placebo at 1 month, P = .40; at 3, 6, and 12 months, P < .001; at 18 months, P = .27. For teriparatide vs placebo, P < .01 at all time points. For abaloparatide vs teriparatide, P < .001 at all time points except for at 1 month, P = .04.

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