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Drugs under study may build bone
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Most osteoporosis medications are antiresorptive — they prevent or decrease bone loss, but are not anabolic or bone-forming. A humanized monoclonal antibody, romosozumab, appears promising for reversing osteoporosis. This drug targets a glycoprotein termed sclerostin. Secreted by osteocytes, sclerostin interferes with osteoblast proliferation, thus resulting in decreased bone formation.
Recent romosozumab data
A phase 2 study by McClung and colleagues enrolled 419 participants and assigned 367 of them to one of five subcutaneous doses of romosozumab (Amgen/UCB Pharma) every 3 months or to an open-label comparator of 70-mg oral alendronate weekly or 20-mcg teriparatide (Forteo, Eli Lilly) subcutaneously each day. The remaining 52 individuals were randomly assigned placebo injections once a month or every 3 months.
Study participants were postmenopausal women aged 55 to 85 years who had low bone mineral density, defined as a T-score between –3.5 and –2 at the lumbar spine, total hip or femoral neck.
Edward C. Chao
At 12 months, all dose levels of romosozumab were associated with significant increases from baseline in BMD at the lumbar spine. The greatest increase was associated with the 210-mg monthly dose; the mean increase was 11.3% at the lumbar spine, 3.7% at the femoral neck and 4.1% at the total hip. The increases with alendronate and teriparatide were 4.1% and 7.1%, respectively; a decrease of 0.1% occurred with placebo.
BMD at the total hip and lumbar spine also was significantly greater in all romosozumab groups compared with the pooled placebo group (P<.006) at month 6.
Circulating markers of bone formation — serum type 1 procollagen (P1NP), bone-specific alkaline phosphatase (BSAP), and osteocalcin — rapidly increased with romosozumab but were transient. These levels returned to baseline values or lower between months 2 and 9, although romosozumab was administered without interruption. A decrease in a circulating marker of bone resorption, B-CTX (collagen type 1 cross-linked C-telopeptide), was maintained during the 12-month dosing period. Why this effect was short-lived is unknown.
Possible combination
The rapid and significant increases in lumbar spine and total hip BMD seen in the romosozumab group in the first year were sustained through a second year. The greatest gains were observed in the 210-mg once-monthly group, with increases in BMD of 15.7% in lumbar spine and 6% in total hip. These results were reported September at the annual meeting of the American Society for Bone and Mineral Research.
In participants who were changed to denosumab (Prolia, Xgeva; Amgen) for the third year of the trial, BMD continued to increase at a rate similar to that of year 2 with romosozumab. BMD returned to pretreatment levels in those who were switched to placebo. Participants on denosumab further showed a rapid stimulation of P1NP and decreased CTX.
Questions remain
Antiresorptive agents and the anabolic agent teriparatide have their shortcomings. For instance, teriparatide carries a black-box warning on osteosarcoma in rats, and is injected subcutaneously. None of the currently available therapeutic agents for osteoporosis has shown romosozumab’s combination of both enhanced bone building and diminished bone resorption.
Questions certainly remain: In the romosozumab phase 2 study, BMD increased markedly in all sites except the distal one-third of the radius. Why this region showed no change in BMD is unclear. While we await further data from two phase 3 trials, the study results for romosozumab alone and its use with deonsumab appear promising.
For more information:
- McClung MR. Abstract 1152. Presented at: American Society for Bone and Mineral Research 2014 Annual Meeting; Sept. 14, 2014; Houston.
- McClung MR. N Engl J Med. 2014;370:412-420.
Disclosures:
- Edward C. Chao, DO, is Associate Professor of Clinical Medicine at the University of California, San Diego, and Staff Physician at VA Medical Center, San Diego. He reports no relevant financial relationships.