Twice yearly injections of denosumab (previously known as AMG 162) significantly increased bone mineral density (BMD) in the total hip, lumbar spine, distal 1/3 radius, and total body of postmenopausal women compared with placebo, according to a phase II trial published in the February 23, 2006, issue of the New England Journal of Medicine.¹

Denosumab is a fully human monoclonal antibody that targets nuclear factor-kB (RANK) ligand (RANKL), a protein that acts as the primary mediator of osteoclast activity. It is currently being investigated in the treatment of osteoporosis, treatment-induced bone loss, bone metastases, multiple myeloma and rheumatoid arthritis.

In the study, 412 postmenopausal women with low BMD were randomly assigned to one of four treatment groups and received either denosumab every 3 months (6, 14, or 30 mg), denosumab every 6 months (14, 60, 100, or 210 mg), open-label oral alendronate once weekly (70 mg), or placebo. The primary endpoint was the percentage change from baseline in bone mineral density at the lumbar spine at 12 months. Changes in bone turnover were assessed by measurement of serum and urine telopeptides and bone-specific alkaline phosphatase.

The study demonstrated that subcutaneous injections of denosumab every 3 or 6 months significantly increased BMD at the lumbar spine from 3.0% to 6.7% after 12 months, as compared with a decrease of 0.8% in the placebo-treated patients (P <.001). In addition, at 12 months, BMD at the total hip increased from 1.9% to 3.6% in women who were administered denosumab as compared with a decrease of 0.6% in the placebo group (P <.001). Across all doses and dosing intervals, distal 1/3 radius BMD increased from 0.4% to 1.3% at 12 months as compared with a decrease of 2.0% in those taking placebo (P <.001). Total body BMD also increased from 0.6% to 2.8% in participants taking denosumab (except for those who received 14 mg every 6 months) as compared with a decrease of 0.2% in the placebo group (P <.01).

Moreover, as compared to those receiving placebo (P <.001), subjects who received denosumab showed decreased levels of C-telopeptide as early as 3 days after dosing, and the duration of the decrease was dose-dependent. Finally, after a 1-month delay, levels of bone-specific alkaline phosphatase were shown to be significantly lower in subjects receiving denosumab compared to placebo (P <.001).

The incidence of adverse events was similar among the denosumab, placebo, and alendronate groups, with the exception of dyspepsia, which occurred in 7% of placebo patients, 6% to 15% of denosumab patients, and 26% of open-label alendronate patients. The most common adverse events among all groups included upper respiratory infection, arthralgia, nasopharyngitis, back pain, and headache. Two subjects receiving denosumab at a dose of 100 mg every 6 months developed denosumab-binding antibodies, but they were not neutralizing on the basis of results from a bioassay.

Advantages of denosumab

"Since denosumab is given by injection every 6 months, ‘adherence' does not depend upon patients taking the tablets—or taking them correctly," explains lead study author Michael McClung, MD, director of the Oregon Osteoporosis Center in Portland, Oregon. "Most patients begun on current osteoporosis medications stop before 6 months," he says.
 
The new agent may have other advantages over the currently available bisphosphonates, including the very rapid onset of action, the different tolerability profile, and the unique and elegant mechanism of action, Dr. McClung tells CIAOMed. "These are preliminary findings documenting that a RANKL inhibitor has measurable effects and attractive attributes for the treatment of osteoporosis and perhaps other bone diseases," he says. "The study helped select a dose (60 mg every 6 months) to study further in the phase III trials that are now underway, [and] these studies will determine exactly how effective denosumab is, so stay tuned."

New osteoporosis drug needed

The new agent "looks very potent with a single dose," adds Kerry Siminoski, MD, associate professor of radiology and medicine and an endocrinologist at the University of Alberta in Edmonton, Canada.

One of its advantages may be convenience. "It makes life a lot simpler, and we also have people in whom current drugs don't work or who can't take them, so we need a new agent that works entirely differently to treat that population," he says. "It may be expensive, but worthwhile in [these patients]."

In an editorial accompanying the new study,² Michael P. Whyte, MD, Director of the Center for Metabolic Bone Disease and Molecular Research at Shriner's Hospitals for Children in St. Louis, Missouri, writes that long-acting doses of denosumab should enhance the pharmaceutical arsenal for the treatment of osteoporosis by improving convenience and compliance for some patients. However, he notes, "this issue is also being addressed by the availability of increasingly potent antiresorptive bisphosphonates. Alendronate, risedronate, and ibandronate were marketed with administration schedules that increasingly simplified oral therapy from once daily to weekly to monthly. Another advanced-generation bisphosphonate, zoledronic acid, is being tested in the form of a brief intravenous infusion administered yearly."

Some concerns exist with denosumab

"Denosumab could globally disrupt the signaling pathway that involves RANKL, osteoprotegerin, RANK, and nuclear factor-B. RANK is expressed on cells other than osteoclast precursors, including dendritic cells and T and B cells," Dr. Whyte explains. "RANKL not only regulates osteoclastogenesis but also functions within the immune system."

Moreover, Dr. Whyte notes, the effects of denosumab could differ from those of the bisphosphonates, the selective estrogen-receptor modulator raloxifene, and salmon calcitonin. "Accordingly, larger and longer clinical trials of denosumab for the prevention of osteoporotic fracture must search for these potential complications," he says.

References

1. McClung MR, Lewiecki EM, Cohen SB, et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med. 2006;354:821-831.
2. Whyte MP. The long and short of bone therapy. N Engl J Med. 2006;354:860-863.