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Antibody Builds Bone, Slows Its Loss in Women
  By Nancy Walsh, Staff Writer, MedPage Today
Published: October 15, 2012

Action Points

· Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

· Note that this study suggests that an antibody targeting the Wnt signaling pathway and its osteocyte-regulating molecule sclerostin increases bone formation while decreasing bone resorption.

MINNEAPOLIS -- An antibody targeting the Wnt signaling pathway and its osteocyte-regulating molecule sclerostin increases bone formation while decreasing bone resorption, offering a possible new approach to the treatment of osteoporosis, a researcher reported here.

One year of treatment with the antibody romosozumab (formerly AMG 785) led to an 11.3% absolute increase in bone mineral density (BMD) in postmenopausal women with low BMD, according to Michael R. McClung, MD, of the Oregon Osteoporosis Center in Portland.

That compared with BMD increases of only 7% with teriparatide (Forteo), 4% with alendronate (Fosamax), and no change with placebo (P<0.001), McClung told attendees at the annual meeting of the American Society for Bone and Mineral Research

"The discovery of sclerostin as an osteocyte-mediated stimulator of osteoblast function and bone formation opened the door for considering the inhibition of this protein and regulator as a target for osteoporosis treatment," McClung said.

In preclinical and phase I studies, the administration of antibodies neutralizing sclerostin resulted in stimulation of bone formation and interfered with resorption of bone through effects on the Wnt pathway, he said.

To further explore the therapeutic potential of this antibody, the researchers conducted an international phase II study that enrolled 419 women whose lumbar spine, total hip, or femoral neck T-score was between -2 and -3.5.

Participants were randomized to receive romosozumab in dosages of 70 mg, 140 mg, or 210 mg each month, 140 or 210 mg every 3 months, or placebo.

In addition, there were open-label comparator groups receiving 70 mg alendronate weekly or 20 μg teriparatide daily.

Mean age of the participating women was 67.

Baseline mean T-scores at the femoral neck, lumbar spine, and total hip were -1.9, -2.3, and -1.5, respectively.

The 11.3% decrease in BMD at the lumbar spine seen after 12 months was for the 210 mg per month group; that group was used for the remainder of the analyses.

Total hip increase in BMD with romosozumab was 4.1% at 12 months, which was approximately double that seen with alendronate and teriparatide (P<0.0001).

Changes also were seen in biomarkers of bone metabolism. As expected, decreases in both serum type 1 procollagen N terminal (P1NP) and serum collagen type 1 cross-linked C telopeptide (CTX) were seen with alendronate and increases in both markers with teriparatide.

A different pattern was seen with romosozumab, McClung noted, with increases seen for serum P1NP, favoring bone formation, and decreases in serum CTX, suggesting a slowing of bone resorption, after 1 week of treatment.

After 1 month in the romosozumab-treated patients, increases up to 100% were seen in P1NP, which then decreased to baseline after 6 months despite continuation of therapy.

For CTX, the changes with romosozumab were as expected, showing a substantial decrease of about 50% within the first week.

"Over 12 months, there was a persistence of inhibition of this marker of bone resorption," McClung observed.

Adverse events were similar in the treatment groups, with the most common being pharyngitis and back or extremity pain.

Serious adverse events were seen in 9.8% of the romosozumab groups and in 14% of the placebo group.

The only treatment-related adverse events that occurred more commonly in the romosozumab groups were injection site reactions, but these were mild and did not lead to treatment discontinuation.

Binding antibodies to sclerostin were observed in 20% of patients on at least one occasion, and neutralizing antibodies developed in 3%, but no effect of the antibodies was seen clinically.

The study was funded by Amgen and UCB. All investigators were supported by or were employees of the companies.

McClung also has received support from other companies including Lilly, Merck, and Novartis.

Primary source: American Society for Bone and Mineral Research Source reference: McClung M, et al "Inhibition of sclerostin with AMG 785 in postmenopausal women with low bone mineral density: phase 2 trial results" ASBMR 2012; Abstract 1025.

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