Romosozumab, a monoclonal antibody that targets the osteoblast inhibitor sclerostin, increased bone mineral density and bone formation while decreasing bone resorption in a phase II clinical trial in 419 postmenopausal women with low bone mass, according to a report published online Jan. 13 in the New England Journal of Medicine.
"The consequence of these divergent effects on bone formation and bone resorption ... is a strongly positive balance in bone turnover, accounting for the rapid and large increases in bone mineral density that we observed," said Dr. Michael R. McClung of the Oregon Osteoporosis Center, Portland, and his associates.
Dr. Michael R. McClung
After 1 year of periodic subcutaneous injections of romosozumab, BMD at the lumbar spine was significantly greater than it was with placebo injections, regardless of the dose frequency or dose level of the active drug. Total hip and femoral neck BMD also were significantly greater with romosozumab.
These improvements in BMD also were significantly greater than those obtained with two comparator drugs used open-label in this trial, alendronate and teriparatide, Dr. McClung and his colleagues noted.
Sclerostin is a glycoprotein secreted by osteocytes that is known to be a key regulator of bone formation, capable of impeding osteoblast proliferation and function. Expression of the gene that encodes sclerostin is confined to skeletal tissue, which suggests that a drug that targets sclerostin should have minimal effects on other tissues.
Patients who have a genetic deficiency of sclerostin have greater than average bone mass, with corresponding bone strength and resistance to fractures. And, in animal models of estrogen deficiency, treatment with antisclerostin antibodies restored bone mass and bone strength to higher than normal levels.
In a previous phase I study, single injections of the humanized monoclonal antisclerostin antibody increased BMD, stimulated bone formation, and decreased bone resorption. Dr. McClung and his associates now report the results of their phase II study assessing the efficacy and safety of a variety of doses of romosozumab in postmenopausal women aged 55-85 years who had low bone mass.
The study participants were treated and followed at 28 medical centers in Europe, five dosing regimens of romosozumab (70 mg, 140 mg, or 210 mg injected once monthly; or 140 mg or 210 mg injected once every 3 months); or to 70 mg oral alendronate weekly; or to 20 mcg teriparatide injected daily; or to placebo injections that mirrored the dosing schedules of romosozumab.
A total of 383 women (91%) completed the 1-year study; 86% were white, and the mean T scores were –2.29 at the lumbar spine, –1.53 at the total hip, and –1.93 at the femoral neck.
The primary endpoint was change in BMD at the lumbar spine at 1 year. Participants in the pooled romosozumab groups showed a significant increase in this measure, compared with those pooled in the placebo groups, regardless of dose frequency or dose level.
Similarly, each of the romosozumab groups showed a significant increase in this measure when compared with the pooled placebo groups. Women who received romosozumab also showed significantly greater increases in BMD at the total hip and the femoral neck, but not at the wrist.
The greatest improvements were noted among women who received the highest monthly dose of romosozumab (210 mg), who showed a mean increase of 11.3% at the lumbar spine, 4.1% at the total hip, and 3.7% at the femoral neck at 1 year, the investigators said (N. Engl. J. Med. 2014 [doi:10.1056/NEJMoa1305224]).
The improvements in BMD with romosozumab also were significantly greater than those with alendronate and teriparatide.
The onset of action for romosozumab was swift. "The increase in BMD at the lumbar spine and proximal femur was rapid and substantial with romosozumab by 3 months, and by 6 months, the increase was greater with the 210-mg monthly dose of romosozumab than with either active comparator," Dr. McClung and his associates said.
The increase in BMD was accompanied by a significant decrease in bone resorption. This dual action differs markedly from the effects of bisphosphonates and other agents, which reduce both bone formation and bone resorption, they noted.
Overall, romosozumab’s effects on bone formation were strong but transitory, diminishing after 6 months even though the participants continued taking the drug. In contrast, romosozumab’s effects on bone resorption were more moderate but more sustained, continuing throughout the study period.
The study population was too small to allow adequate assessment of the drug’s safety, the investigators noted.
The overall incidence of adverse events and of serious adverse events was similar among all the study groups, except that mild injection-site reactions were more common with romosozumab. No serious adverse events were considered to be related to any of the treatments, and none of the study subjects showed any notable changes in vital signs, laboratory values, or ECG factors.