Abaloparatide Fracture Reductions Sustained in Osteoporosis

Nancy A Melville

September 12, 2017

DENVER — Substantial reductions in fracture risk in postmenopausal women with osteoporosis seen after 18 months of treatment with the new osteoanabolic drug abaloparatide (Tymlos, Radius Health) are sustained for up to 2 years after switching to maintenance with the bisphosphonate alendronate, according to final results from the Abaloparatide Comparator Trial in Vertebral Endpoints Extension ACTIVExtend) trial.

"The results show that 18 months of abaloparatide followed by consolidation therapy with 24 months of alendronate resulted in rapid and sustained fracture risk reduction throughout the skeleton," said first author Henry G Bone, MD, director of the Michigan Bone and Mineral Clinic, in Detroit.

With its approval from the US Food and Drug Administration (FDA) in April, abaloparatide became the first osteoanabolic drug to enter the US market in almost 15 years, with an indication for treatment of postmenopausal women with osteoporosis who are at high risk for fracture due to a prior osteoporotic fracture or multiple risk factors for fracture or who do not respond to or cannot tolerate other available osteoporosis therapy.

The approval was based on the results of the original ACTIVE trial and an interim analysis of the ACTIVExtend trial at 6 months, published in February in Mayo Clinic Proceedings.

The final results from the full 2-year extension, presented here at the American Society of Bone and Mineral Research (ASBMR) 2017 Annual Meeting, further support those findings.

In commenting on the study, Harry K Genant, MD, professor emeritus at the University of California, San Francisco, agreed that the findings suggest an important role for abaloparatide in osteoporosis treatment.

"This new treatment, abaloparatide, is very exciting and important as a potent anabolic to rapidly reduce fracture risk over a relatively short duration of drug exposure," he told Medscape Medical News.

Effect of Abaloparatide "Carried Forward"

The multinational, randomized, double-blind ACTIVE trial involved 2463 postmenopausal women between the ages of 49 and 86 with osteoporosis.

The women were randomized to either placebo (n = 821) or abaloparatide, in a once-daily subcutaneous dose of 80 μg (n = 824) for 18 months. A third group was treated with once-daily subcutaneous teriparatide 20 μg (n = 818); however, results from that group were not included in the study's primary end point.

The findings of this trial showed a highly significant 86% relative reduction in the risk of a vertebral fracture in the abaloparatide group, compared with placebo (< .001).

For safety reasons, anabolic drugs are typically administered for only 18 to 24 months and patients then need to be transitioned to drugs such as antiresorptive agents to maintain the benefits.

To further evaluate abaloparatide's effects in that type of maintenance setting, the ACTIVExtend trial, which began a month after the original 18 months, involved patients in both groups who were switched to treatments of alendronate 70 mg weekly for 2 years, including 581 in the original placebo group and 558 in the original abaloparatide group.

Over the course of the combined trials — 43 months — five of 544 evaluable women (0.9%) in the abaloparatide group had at least one new vertebral fracture compared with 32 of 568 (5.6%) in the placebo group, representing an 84% relative risk reduction (P < .001).

In terms of nonvertebral fractures, the abaloparatide group had a 39% risk reduction in the ACTIVExtend results, with 27 fractures (5%) compared with 45 (8%) in the placebo group (= .03).

 And greater reductions in fractures with abaloparatide in the full ACTIVE intention-to-treat analysis were seen in all fracture types, including nonvertebral (= .03), major osteoporotic (= .001), clinical (= .04) and hip fractures (= .02).

There were no significant differences in adverse events among both arms.

"The striking finding was that a progressive benefit was seen even when the patients from the previous abaloparatide and placebo groups were both maintained on alendronate," Dr Bone told Medscape Medical News.

"So, it looks like there is an effect that can really be carried forward with this type of regimen."

He noted that alendronate was used in the study because it is a known benchmark for bisphosphonates, but other drugs in that class would likely show similar results.

"I think any of the bisphosphonates would have produced a benefit," Dr Bone said.

"For example, zoledronic acid infusion probably would have worked in a similar manner."

Dr Genant agreed that these results are notable: "The maintenance of substantial fracture reduction during the extended 18 months for the abaloparatide/alendronate group relative to the placebo/alendronate group was very impressive and supports the long-term benefit of the initial abaloparatide treatment."

However, "The principal caveat is the overall small numbers of fractures observed in the extension period," he concluded.

And there was some criticism when the 6-month results of ACTIVExtend were reported in February.

Benjamin Leder, MD, associate professor of medicine, Harvard Medical School, Boston, Massachusetts, and chair of the professional practice committee of the American Society of Bone Mineral Research (ASBMR), said the results didn't really show anything new; they simply replicated the findings of ACTIVE. He questioned the study design, in which women at high risk of fracture at baseline were assigned to placebo — something he doesn't think would ethically be likely to happen if the trial were starting now, and he criticized the fact that patients in the arm comparing abaloparatide with teriparatide in the original ACTIVE study were not included in the extension study.

The study was funded by Radius Health. Dr Bone is a consultant for Amgen. Dr Genant is a cofounder and senior consultant for Synarc.

American Society for Bone and Mineral Research. September 10, 2017, Denver, Colorado. Abstract 1074.

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