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Denosumab's benefits persist through 8 years.


CHICAGO -- Postmenopausal women on denosumab for 8 years straight showed a continued nearlinear increase in bone mineral density at the lumbar spine as well as persistent reduction of bone turnover markers and a sustained low incidence of new vertebral and nonvertebral firactures in the ongoing FREEDOM open-label extension study.

Moreover, no new safety signals have emerged during 5 years of additional denosumab (Prolia) on top of an initial 3 years occurring in the pivotal, phase III, randomized, double-blind, placebo-controlled FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months) trial. Importantly, the overall risk of adverse events has not increased over time, and rates of malignancies, serious infections, eczema, hypocalcemia, and other adverse events in denosumab-treated patients remain comparable to rates seen in placebo-treated controls in the earlier double-blind phase, Dr. E. Michael Lewiecki reported at the joint meeting of the International Congress of Endocrinology and the Endocrine Society.

"The benefit/risk profile for denosumab remains favorable," declared Dr. Lewiecki, director of the New Mexico Clinical Research and Osteoporosis Center, Albuquerque.

The FREEDOM open-label extension is designed to assess the efficacy and safety of up to 10 years of denosumab therapy. Dr. Lewiecki presented the latest update, based on 8 years of treatment, or 5 years for patients in the original placebo arm who later elected to crossover to denosumab upon completing the 3-year double-blind phase. His report included 2,243 women on denosumab at 60 mg by subcutaneous injection every 6 months continuously for 8 years and another 2,207 on the drug for 5 years.

Five cases of osteonecrosis of the jaw have occurred in the long-term therapy group, as well as three cases among those who crossed over to the drue. There has been one atypical femoral fracture during 8 consecutive years on denosumab and one case in the crossover group.

Impressively, lumbar spine bone mineral density (BMD) has increased by 18.4% over baseline with 8 years of denosumab and by 13.7% with 5 years of active therapy. "The near-linear slope of increase is unchanged over the course of the study. A similar slope is seen in the crossover group," he observed.

Total hip BMD increased by 8.3% with 8 years of denosumab and 4.9% with 5 years of therapy.

In the pivotal phase III FREEDOM trial, 3 years of denosumab reduced the risk of vertebral fractures by 68% compared to placebo, hip fractures by 40%, and nonvertebral fractures by 20% (N. Engl. J. Med. 2009;361:756-65).

The yearly incidence of new vertebral fractures was 0.7%-1.1% in denosumab-treated patients during years 1-3 and 1.1%-1.3% annually in open-label years 4-8. The annual incidence of new nonvertebral fractures in the denosumab group was 2.1%-2.6% in the first 3 years of double-blind therapy and has trended lower since then: 1.5% in year 4, 1.2% in year 5, 1.8% in year 6, 1.6% in year 7, and 0.7% in year 8.

"There's a suggestion of a further reduction in the risk of nonvertebral fractures out to the 8-year time point. It'll be fascinating to look at the data for years 9 and 10 to see if that's just a statistical aberrance or that very low risk of nonvertebral fractures persists," Dr. Lewiecki commented.

Asked about the mechanism underlying the continued linear increase in lumbar spine BMD seen through 8 years of denosumab, in sharp contrast to the bisphosphonates, where BMD plateaus, Dr. Lewiecki confessed that "Many of us are scratching our heads about this and trying to come up with an explanation.

"One is that the effects on cortical bone appear to be different with denosumab than with bisphosphonates. We see a reduction in cortical porosity and a larger improvement in bone mineral density at cortical skeletal sites. Secondly, there is a larger and longer-lasting increase in parathyroid hormone with denosumab as compared with bisphosphonates," he said.


Key clinical point: An ongoing major study provides reassurance regarding the long-term safety and effectiveness of denosumab for postmenopausal osteoporosis.

Major finding: Eight years of denosumab was associated with sustained low fracture rates, steadily increasing bone mineral density, persistent reduction of bone turnover, and no increase in adverse events over time.

Data source: The FREEDOM trial open-label extension includes 4,450 women on denosumab for either 5 or 8 years and counting.

Disclosures: The study was sponsored by Amgen. The presenter serves as a consultant to the company.
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Title Annotation:GYNECOLOGY
Author:Jancin, Bruce
Publication:OB GYN News
Date:Aug 1, 2014
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