CHICAGO – Postmenopausal women on denosumab for 8 years straight showed a continued near-linear 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 fractures 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 drug. In addition, 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," the endocrinologist 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.

Levels of the bone turnover markers serum C-terminal telopeptide of type 1 collagen and procollagen type 1 N-terminal propeptide quickly dropped upon initiation of denosumab and have remained low through 8 years.

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."

"I don’t know the reason why, but there are several hypotheses worth considering," he continued. "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’s a possible parathyroid hormone effect that may play a role here: There is a larger and longer-lasting increase in parathyroid hormone with denosumab as compared with bisphosphonates. And finally, there’s animal data in monkeys showing ongoing bone modeling taking place with denosumab; it’s possible that may also play a role."

Denosumab is a fully human monoclonal antibody directed against the receptor activator of nuclear factor-kappa B (RANK) ligand.

The FREEDOM study is supported by Amgen. Dr. Lewiecki reported serving as a consultant to that company as well as to AgNovos Healthcare, Lilly, Merck, and Radius Health.

bjancin@frontlinemedcom.com

Denosumab's benefits persist through 8 years